Pakistan journal of pharmaceutical sciencesLinhua Zhu, Yongfang Yue, Lili Cao
BACKGROUND: Intrauterine adhesion (IUA) is a common complication of endometrial injury. Bone marrow mesenchymal stem cells (BMSCs) have been implicated in endometrial repair, but strategies to enhance their therapeutic efficacy remain to be optimized. The C-X-C chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis plays a pivotal role in BMSC homing. OBJECTIVE: This study aimed to test the hypothesis that ATI-2341, a functionally selective allosteric regulator of CXCR4, enhances the therapeutic efficacy of BMSCs in a rat IUA model. METHODS: After establishing the endometrial injury model, rat BMSCs were extracted and treated with ATI-2341 TFA (100 ng/mL). IUA model rats were randomly divided into model control group, BMSCs group, BMSCs+ATI-2341 TFA group, BMSCs+PBS group and Positive control group (n=10 each). Endometrial thickness was assessed by hematoxylin and eosin (HE) staining; cell proliferation by the methyl thiazolyl tetrazolium (MTT) assay; matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) protein expression by Western blot; and cytokeratin and vimentin expression by immunohistochemistry. RESULTS: ATI-2341 TFA-pre-treated BMSCs significantly increased endometrial thickness compared to untreated BMSCs (P < 0.05) or estrogen (P < 0.05). ATI-2341 TFA enhanced BMSC proliferation at 48 h (P < 0.05) and 72 h (P < 0.05). BMSCs exposed to ATI-2341 TFA or estrogen exhibited strong cytokeratin positivity and vimentin negativity. MMP-9 was downregulated (P < 0.05) and TIMP-1 upregulated (P < 0.05) in the ATI-2341 TFA group relative to controls. CONCLUSION: ATI-2341 TFA promotes acquisition of epithelial-like immunophenotype in BMSCs within the injured endometrial microenvironment and is associated with improved endometrial morphology in IUA rats. These findings provide preliminary evidence for the functional modulation of BMSCs by CXCR4-targeted therapy in endometrial repair.
The authors have informed the Pakistan Journal of Pharmaceutical Sciences (PJPS) of an error in Figure 5 of the published article. During the editorial revision process, an incorrect version of Figure 5 was inadvertently included in the final published version. The authors have confirmed that the extreme-right panel (panel D) should be removed and that the remaining panels constitute the corrected Figure 5. Accordingly, Figure 5 is corrected by removing panel D. No other part of the figure is modified. The caption of Figure 5 remains unchanged, and no other figures or content of the article require modification. This corrigendum records the correction to the published version of the article. The correction is limited to the removal of panel D from Figure 5.
Sociology of health & illnessEliza Brown, Stefan Timmermans
Notions of good or bad luck sit uncomfortably in contemporary medical practice defined by efforts to control life through biomedical knowledge and skilled expertise. Yet, talk about luck is common in healthcare to explain medical courses of action. Framing medical results as fortunate or unfortunate bridges the gap between predicted probabilities and variation in individual cases without undermining scientific neutrality. Luck mediates between the rational ideal of biomedical determinism that does not easily account for variable health outcomes and the magical invocation of faith or fate that denotes a moral judgement. Drawing from ethnographic studies of heart transplantation and fertility medicine, we find that luck is employed as an anticipatory frame to guide decision-making in medicine and as a retroactive frame to justify unlikely outcomes. Invoking luck primes patients for the possibility of a favourable outcome and inserts a positive bias in medical care. The analysis underlines how luck frames in healthcare can shift attention away from structural reasons for disparate outcomes, attempt to absolve healthcare providers of blame from medical errors and promote continuing treatment. These findings indicate that focusing on when healthcare providers and patients invoke luck reveals the scope and limits of medical power and control.
BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation and joint destruction. Bone marrow mesenchymal stem cells (BMSCs) have shown therapeutic potential in RA, but the underlying mechanisms remain poorly understood. OBJECTIVES: To investigate the effects of BMSCs on human RA fibroblast-like synovial MH7A cells and complete Freund's adjuvant (CFA)-induced arthritis in rats and to explore the involvement of the JAK/STAT and TLR-4/NF-κB signaling pathways. METHODS: BMSCs were isolated and co-cultured with MH7A cells. CFA-induced arthritis rat models were established. MH7A cell viability, inflammatory cytokine levels, paw withdrawal thermal latency (PWTL), gait parameters and the expression of JAK/STAT and TLR-4/NF-κB pathway-related genes and proteins were assessed. RESULTS: In-vitro, BMSC co-culture significantly inhibited MH7A cell viability and reduced TNF-α, IL-6 and IL-8 levels. BMSC treatment also downregulated the expression of JAK2, p-JAK2, STAT3, p-STAT3, TLR4, P65 and p-P65 in MH7A cells. In-vivo, BMSC administration improved PWTL and gait parameters, reduced serum inflammatory cytokine levels and suppressed the expression of JAK/STAT and TLR-4/NF-κB pathway components in synovial tissues of CFA-induced arthritic rats. CONCLUSION: BMSCs alleviate RA by inhibiting inflammatory responses in vitro and in vivo and the underlying mechanism may involve blockade of the JAK/STAT and TLR-4/NF-κB signaling pathways.
Liver international : official journal of the International Association for the Study of the LiverSubin Heo, Do Kyung Yoon, Soyeon Shin, Dami Youn, Youngeun Yoo, In Hye Song, Hyo Jeong Kang, Young-In Yoon, Kyunggon Kim, Seung Soo Lee, Sung Won Chung, Jonggi…
BACKGROUND AND AIMS: Porto-sinusoidal vascular disorder (PSVD) is a rare liver condition characterized by specific histological features primarily affecting the hepatic sinusoidal and periportal vasculature, in the absence of cirrhosis. This study aimed to identify prognostic factors and regulatory pathways associated with PSVD by integrating transcriptomic and clinical data. METHODS: A total of 114 PSVD patients were included, with 74 followed longitudinally for liver-related events. RNA sequencing was performed on 21 liver samples and compared to six histologically normal livers. Associations between clinical parameters, such as liver-to-spleen volume ratio (LSVR) and fibrosis stage, with liver-related events were assessed. Transcriptomic analyses, including co-expression and cell deconvolution, were conducted based on these parameters. RESULTS: Among the 114 patients, 32 (28.1%) underwent liver transplantation at diagnosis. LSVR strongly correlated with fibrosis stage, which was significantly associated with liver transplantation (per 1-stage increase: adjusted OR, 14.88; 95% CI: 3.72-59.58). Over a mean follow-up of 6.7 years in the longitudinal cohort, 12 patients (16.2%) experienced liver-related events. LSVR was identified as a significant prognostic marker, with an optimal cut-off value of 1.33 for predicting liver-related events. Transcriptomic analysis based on LSVR and fibrosis stage revealed distinct gene expression patterns and cellular changes in PSVD, including shifts in liver sinusoidal endothelial cell (LSEC) distribution, an increased hepatic stellate cell population, and upregulation of IL-6 signalling, without changes in immune cell composition as the disease progresses. CONCLUSIONS: This study identified LSVR as a novel prognostic marker in PSVD and suggests that IL-6 trans-signalling-induced endotheliopathy in LSECs may play a role in the proinflammatory and fibrotic changes associated with disease progression.
Liver international : official journal of the International Association for the Study of the LiverEva Maria Schleicher, Christian Labenz, Frank Erhard Uschner, Julian Pohl, Moritz Passenberg, Michael Praktiknjo, Marcus Maximilian Mücke, Henrik Karbannek, Ni…
BACKGROUND AND AIMS: Volume expansion with albumin is recommended to establish a diagnosis of hepatorenal syndrome-acute kidney injury (HRS-AKI). The optimal duration of albumin administration is debated and requires balancing the risk of overtreatment with the need for timely diagnosis and treatment. Therefore, this study aimed to compare the impact of different albumin treatment durations on terlipressin response and the prognosis of patients with HRS-AKI treated with terlipressin and albumin. METHODS: This multicenter, retrospective secondary analysis included patients with suspected HRS-AKI who were treated with terlipressin and albumin at 12 German centers. One hundred forty five patients were available for further analysis. The cohort was dichotomized into patients treated with albumin for < 24 h and for 24-60 h before initiation of terlipressin. Patients were followed for treatment response to terlipressin, need for haemodialysis (HD), survival, or liver transplantation (LT). RESULTS: Median MELD score of the cohort was 25 [IQR 21; 31]. During follow-up, 59 patients (40.7%) achieved a complete response to treatment with terlipressin, and 96 patients (66.2%) died or received an LT. Response rates to terlipressin therapy did not differ between albumin treatment groups (< 24 h vs. 24-60 h). In multivariable competing risk models, treatment duration of albumin was not associated with any response to terlipressin, considering death and LT as competing events. Of note, albumin treatment duration did not affect HD-/LT-free survival. CONCLUSION: Extending albumin treatment beyond 24 h had no impact on treatment response to terlipressin and albumin or HD-/LT-free survival in patients with HRS-AKI. CLINICAL TRIAL NUMBER: NCT06161766.
Nursing in critical careFranziska Wefer, Lars Krüger, Stella Calo, Ralph Möhler, Martin Nikolaus Dichter, Andrea Mühring, Jan Gummert, Sascha Köpke
BACKGROUND: Hospitalised patients with advanced chronic heart failure (CHF) waiting for transplantation may experience increased thirst due to their critical illness and therapy-related requirements. The perspective of patients and nurses is important for developing a nurse-based counselling intervention to reduce thirst. AIMS: To identify patients' and nurses' experiences and perceptions of thirst, as well as their information needs and preferences on information dissemination. STUDY DESIGN: This convergent mixed methods study used semi-structured interviews with patients, focus groups and a survey with nurses in Germany. We analysed the qualitative data using content analysis and the quantitative data descriptively. We compared the results of both methodological approaches and summarized the data as meta-inferences. RESULTS & FINDINGS: We conducted 10 interviews with patients on intensive care units, intermediate care units and general wards during their waiting time for transplantation, two focus groups with, respectively, five nurses and a survey with 59 nurses caring for these patients. Analyses resulted in five common categories: experiences of thirst, factors that influence thirst, assessment of thirst, dealing with thirst and information about thirst. Patients' experiences with thirst differ markedly, ranging from mild to severe thirst, and they use various strategies to deal with thirst. Nurses consider thirst relevant for patients and nursing care. Strategies used in practice for assessment of thirst are very heterogeneous. In the survey, less than half of the nurses claimed to regularly assess patients' thirst. Nurses and patients wish to receive individual information and counselling. CONCLUSIONS: Thirst in hospitalised patients with advanced CHF waiting for transplantation can be severe and is experienced differently. Standardised procedures for assessing and managing thirst on the ward seem essential to address patients' needs and preferences. RELEVANCE TO CLINICAL PRACTICE: Patients and nurses express a need for professional counselling on managing thirst in clinical practice.
BMJ case reportsMaria Laura Passaro, Matteo Airaldi, Tobi Somerville, Laura Atkinson, Alfredo Borgia, Stephen B Kaye
A woman in her 60s who was a soft contact lens wearer presented with rapidly progressive microbial keratitis unresponsive to intensive empirical therapy. Despite extensive investigations - including conventional cultures, impression cytology, in vivo imaging, and repeated targeted PCR from corneal and aqueous samples - the aetiology remained unclear, with all tests persistently negative. Progressive inflammation, enlarging hypopyon, stromal melt and rising intraocular pressure necessitated anterior chamber (AC) washout followed by therapeutic penetrating keratoplasty with extracapsular cataract extraction. Histopathology and PCR from the excised button were again non-diagnostic. When new epithelial breakdown and an AC mass raised concern for ongoing recrudescence of the infection, a loose corneal suture was removed and analysed: broad-range ITS2 rRNA sequencing detected fungal DNA consistent with Fusarium, providing the first microbiological clue after weeks of negative investigations although not corroborated by other tests and guiding targeted antifungal therapy. This case underscores the limitations of standard microbiology and targeted PCR in deep, pre-treated keratitis and highlights the value of broad-range Internal Transcribed Spacer sequencing as a critical complementary diagnostic tool when conventional methods repeatedly fail.
Journal of molecular neuroscience : MNTiefeng Li, Shuyu Lyu, Xinyu Yao, Ting Xia, Zuojun Geng, Defeng Liu, Huiling Yi, Jiecong Zhang, Ao Zhang, Qi Wang, Lanxiang Liu
Cerebral ischemic stroke (CIS) leads to high mortality and disability due to cerebrovascular obstruction. Current therapeutic approaches such as thrombolysis have limitations, and many patients suffer from long-term functional impairments, so new treatment strategies are urgently needed. Both low-intensity pulsed ultrasound (LIPUS) and mesenchymal stem cell-derived exosomes (MSC-EXOs) have demonstrated some therapeutic potential for CIS, but their efficacy is less pronounced when used alone. Therefore, this study aims to evaluate whether the combination of MSC-EXOs and LIPUS exerts an additive effect in the treatment of cerebral ischemic stroke. Adult rats subjected to middle cerebral artery occlusion (MCAO) were randomly assigned to sham, MCAO, MSC-EXO, LIPUS, or combination groups. Outcomes were assessed using the modified Neurological Severity Score (mNSS), corner and Y-maze tests, histological staining (HE and immunofluorescence), transmission electron microscopy (TEM), and quantitative real-time polymerase chain reaction (q-PCR). The combination group showed notable improvements in neurological function, with the highest proportion of cluster of differentiation 31 (CD31)/alpha-smooth muscle actin (α-SMA)/doublecortin (DCX)-positive immunofluorescence area, up-regulation of circular RNA SCMH-1(circSCMH-1), and the best restoration of synaptic ultrastructure. Compared with MSC-EXOs or LIPUS alone, the combined treatment appeared to have an additive effect, supporting neurovascular regeneration and functional recovery after cerebral ischemic stroke.
Journal of hematopathologyGökhan Burul, Çagla Karaoglan, Erdem Bektaş, Cemal Bes, Leylagül Kaynar, İstemi Serin, Şeniz Öngören
BACKGROUND: VEXAS syndrome is a somatic autoinflammatory disorder caused by UBA1 mutations in hematopoietic progenitor cells, typically affecting older men and characterized by systemic inflammation and hematologic abnormalities. Early-onset cases are extremely rare. CASE PRESENTATION: We report a 25-year-old male patient presenting with recurrent fever, weight loss, arthralgia, and inflammation mimicking orbital cellulitis. Imaging demonstrated orbital soft tissue inflammation. Laboratory investigations revealed macrocytic anemia, leukopenia, thrombocytopenia, and elevated inflammatory markers; FDG-PET/CT showed splenomegaly and hypermetabolic lymphadenopathy. Bone marrow examination revealed hypercellularity, multilineage morphological abnormalities, and vacuolated blasts. Following exclusion of infectious and classical autoinflammatory diseases, the somatic UBA1 c.121A > G (p.Met41Val) mutation confirmed VEXAS syndrome. The patient initially responded to corticosteroids but subsequently developed refractory disease and progressive pancytopenia despite tocilizumab therapy. He underwent allogeneic hematopoietic stem cell transplantation from a 10/10 HLA-matched sibling donor using a myeloablative conditioning regimen. At 3 months post-transplantation, 99% donor chimerism and hematologic remission were achieved. CONCLUSION: VEXAS syndrome should be considered in young adults presenting with unexplained systemic inflammation and cytopenias, even with atypical manifestations such as orbital cellulitis. Early genetic evaluation is crucial for diagnosis, and allogeneic stem cell transplantation may provide effective disease control in refractory cases.
Annals of transplantationChan Woo Cho, Namkee Oh, Jinsoo Rhu, Kyeong Sik Kim, Do Hyeon Lee, Hyoung Joo Kim, Gyu-Seong Choi
BACKGROUND Pure laparoscopic donor major hepatectomy (PLDMH) offers important advantages for donors but has largely been restricted to expert surgeons. Evidence on fellowship-trained surgeons (FTSs) performing PLDMH after structured training is limited. This study evaluated donor safety and operative efficiency of FTSs using propensity score matching (PSM) and cumulative sum (CUSUM) analysis. MATERIAL AND METHODS We retrospectively reviewed 517 consecutive PLDMHs from 3 centers, including 1 expert surgeon (n = 462) and 3 FTSs (n = 55). FTSs underwent a structured, phase-task-based training program; 2 received short-term on-site proctorship for initial cases. To reduce baseline differences, we applied 1: 3 propensity score matching (PSM) between FTS and expert cases. Donor and recipient characteristics were balanced. Learning curves were assessed using risk-adjusted CUSUM for major donor complications and residual CUSUM for operative time. RESULTS After PSM, 55 FTS cases were matched to 165 expert cases. Major donor complications were comparable (5.5% vs 4.2%, P=0.714) and no case required conversion to open surgery. Donor operative time was longer in the FTS group (338±102 vs 220±44 minutes, P<0.001). Recipient biliary leakage was more frequent in the FTS group (18.2% vs 8.5%, P=0.046), whereas other outcomes were similar after matching. Risk-adjusted CUSUM demonstrated stabilization of donor safety within 8 to 10 cases per FTS, while operative efficiency stabilized after 6 to 15 cases. CONCLUSIONS FTSs demonstrated acceptable donor safety outcomes under structured training conditions, with operative performance showing a trend toward improvement after approximately 10 to 15 cases.
BMJ openRebeka Jenkins, Gillian Hardman, Karen Booth, John Dark, Andrew Fisher, Catherine Exley
OBJECTIVES: This study explores decision-making in organ transplantation. The number of patients waiting for a solid organ transplant continues to rise despite efforts to increase the available pool of donor organs. This has focused attention on maximising the number of organs offered that are subsequently transplanted, a process termed organ utilisation. There is a paucity of work exploring how clinicians decide to decline or accept offers of donor organs. This study aims to better understand the factors that influence organ utilisation decision-making in cardiac and thoracic transplantation through qualitative methods. DESIGN: Semi-structured qualitative interviews undertaken online over a 5-month period. Data collection and analysis occurred simultaneously. Transcripts were inductively analysed to generate themes. SETTING: Clinicians representing all six adult UK cardiothoracic transplant centres. PARTICIPANTS: Consultant cardiothoracic transplantation surgeons (n=9) and cardiothoracic transplant coordinators (n=10). RESULTS: 19 interviews were undertaken. The following themes pertinent to utilisation decision-making were identified: anticipation of outcomes; data; motivation; out-of-hours; micro-culture and experiential learning. CONCLUSIONS: This study is the first to explore the process of organ utilisation decision-making from a clinician's perspective through interviews. This documents an important and nuanced understanding of the interrelated factors involved in utilisation decision-making in practice. By providing evidence for the human inconsistencies in utilisation decision-making, this work may inform a more considered approach to strategies to improve utilisation rates.
European journal of trauma and emergency surgery : official publication of the European Trauma SocietyMustafa Yıldız, Muhammed Köroğlu, Mustafa Ertuğrul Karabaş, İpek Balıkçı Çiçek, Thomas Stevenson, Ahmet Harma
OBJECTIVE: Segmental bone transport offers biological reconstruction and limb preservation for extensive lower-extremity long-bone defects, but treatment often involves prolonged external fixation, planned stages, and unplanned reoperations. We evaluated reconstructive and functional outcomes and examined the association between cumulative operative burden and final patient-reported function. METHODS: This retrospective single-centre study screened 44 patients treated between January 2012 and March 2023. Thirty-six patients, representing 37 reconstructed long bones, had complete final outcome ascertainment. ASAMI bone outcome was reported per reconstructed bone (n = 37); limb preservation and all functional and multivariable analyses were patient-level (n = 36). Outcomes included limb preservation, ASAMI bone and functional results, the Lower Extremity Functional Scale (LEFS), the Karlström-Olerud score, healing indices, treatment-related events, and the cumulative number of formal operations. Multivariable linear regression, bootstrap resampling, sensitivity analyses, and exploratory receiver operating characteristic analysis were performed. RESULTS: Mean defect length was 10.32 ± 4.67 cm and the mean defect-to-bone length ratio was 26.3% ± 12.4%. Patients underwent a mean of 8.08 ± 4.21 operations (median, 7; range, 3-18). Mean follow-up after external-fixator removal was 5.69 ± 3.62 years. Limb preservation was achieved in 35 of 36 patients (97.2%). Combined excellent/good ASAMI bone and functional outcomes were 75.7% and 77.8%, respectively. Pin-site infection occurred in 17 patients and accounted for 32 fixation-element events; premature consolidation occurred in 11 patients and accounted for 18 episodes. After adjustment for age, defect length, and consolidation index, each additional operation was associated with a 1.94-point lower LEFS (β=-1.94, 95% CI - 3.12 to - 0.76; p=.002). Excluding the patient who underwent below-knee amputation and had an LEFS of 0 did not materially alter this association (n = 35; β=-1.86, 95% CI - 2.85 to - 0.86; p<.001). Older age was also independently associated with lower LEFS (β=-0.46 points/year; p=.006). Follow-up duration was not associated with LEFS and did not alter the principal association. Exploratory ROC analysis for LEFS < 40 yielded an AUC of 0.846 (bootstrap 95% CI 0.689-0.968); the internally derived ≥ 11-operation threshold was regarded as hypothesis-generating. CONCLUSION: Segmental bone transport achieved high limb preservation and largely favourable ASAMI outcomes despite a substantial treatment burden. A greater cumulative number of operations was associated with lower final LEFS. Operation count should be interpreted as a summary marker of case complexity and the treatment course, not as evidence that repeated surgery alone caused poorer function.
BMJ case reportsLasse Schopmeyer, Maaike Biewenga, Menno van der Voort, Michael van Herwerden
A male in his 20s with no medical history was found with generalised seizures and profound hypoglycaemia after consuming improperly stored, reheated rice.Initial laboratory tests showed acute liver failure with hyperammonaemia, acute kidney injury and lactic acidosis, which rapidly progressed to multi-organ failure requiring urgent liver transplantation evaluation.With maximal supportive therapy, including glucose, ammonia and glutamine scavengers, renal replacement therapy, haemodynamic and respiratory support, he gradually improved, avoiding transplantation and achieving full neurological recovery. Toxicological analysis of the rice and serum revealed high concentrations of cereulide, a toxin produced by Bacillus cereus This case illustrates that cereulide intoxication can be associated with potentially fatal multi-organ failure, particularly after ingestion of improperly stored starchy foods.Early recognition through targeted dietary history, focused laboratory evaluation and prompt supportive therapy are essential. Increasing awareness among healthcare professionals and safe food storage practices are key preventive measures.
Gynecological endocrinology : the official journal of the International Society of Gynecological EndocrinologyXiangyan Ruan, Juan Du, Muqing Gu, Fengyu Jin, Jing Jin, Yanglu Li, Jiaojiao Cheng, Yanqiu Li, Weimin Kong, Qi Zhang, Zecheng Wang, Mingzhen Zhang, Anming Liu,…
OBJECTIVE: This article reports on the world's first live birth after ovarian tissue cryopreservation and transplantation (OTCT) in a patient with colon cancer. METHODS: A 29-year-old unmarried nulliparous patient underwent ovarian tissue cryopreservation before chemotherapy. After chemotherapy-induced premature ovarian insufficiency, she received the first transplantation of six thawed ovarian cortex strips. Despite normal ovarian function being maintained for over 2 years, she requested and underwent a second transplantation with another six strips to maximize her chances of pregnancy. RESULTS: After the first transplantation, she resumed spontaneous menstruation with restored ovarian function, which was remained functional for 28 months until the second transplantation. Following the second transplantation, she conceived spontaneously without assisted reproductive technology two months after grafting. Routine prenatal examinations showed normal fetal development without abnormalities. She delivered a healthy baby girl weighing 2785 g with Apgar scores of 8/9 at 1 and 5 min. CONCLUSIONS: This case demonstrates the feasibility and safety of OTCT for fertility and ovarian function preservation in patients with colon cancer.
Orphanet journal of rare diseasesLucia Laugwitz, Pascal Martin, Nils Janzen, Sebastian Hegert, Thomas Neiße, Madeleine Wacker, Jan Kern, Nadja Kaiser, Christiane Kehrer, Annina-Clarissa Jaeger…
BACKGROUND: Metachromatic leukodystrophy (MLD) is a rapidly progressive leukodystrophy that leads to severe disability and early death if untreated. Autologous hematopoietic stem and progenitor cell gene therapy (HSPC-GT, atidarsagene autotemcel, arsa-cel) for early onset subtypes and allogenic hematopoietic stem cell transplantation (HSCT) for late onset disease substantially alters disease progression for early onset disease when administered before symptom onset, creating a strong rationale for newborn screening (NBS). At the same time, NBS technique for MLD in dried blood spots has recently been demonstrated to be robust and highly accurate. The aim was to give real-world results from the world's first NBS pilots for clinical management and treatment of identified children. METHODS: Between September 2021 and July 2025, 359,282 newborns underwent NBS for MLD in two different laboratories in Germany and Austria using a three-tier algorithm integrating sulfatide quantification, arylsulfatase A (ARSA) activity measurement, and ARSA sequencing. Screen-positive infants underwent a predefined care pathway including standardized confirmatory diagnostics, genotype-based and biochemical prediction of disease onset, clinical assessment and management guiding early treatment and surveillance at the qualified treatment center (QTC) in Tübingen. RESULTS: Nine newborns screened positive and all were confirmed to have MLD (detection rate approximately 1 per 40,000). Based on genotype and leukocyte ARSA enzyme activity, disease onset prediction was possible in all of them. Seven infants were classified as having pre-symptomatic early-onset MLD and were referred for HSPC-GT. All treated infants showed preserved neurological function up to 30 months after treatment (median 18.5 months). Two infants predicted to develop late-onset MLD entered structured surveillance for treatment with HSCT and have remained clinically asymptomatic for CNS signs of disease. No false-positive or known false-negative results were observed. CONCLUSION: These results from our pilot programs demonstrate that NBS enables reliable early identification of MLD and support streamlined care pathways leading to timely intervention. Importantly, this study provides real-world evidence illustrating that NBS for MLD can enable timely, pre-symptomatic treatment and structured surveillance within standard national healthcare systems. These findings further substantiate the value of NBS for MLD at a critical moment as several countries consider national implementation of MLD screening.
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in CancerMotahareh Tahmasebi, Romina Kaveh-Ahangaran, Maryam Barkhordar, Mazda Rad-Malekshahi, Mohammad Vaezi, Leyla Sharifi Aliabadi, Mobina Sadat Zarabadi, Bita Shahr…
PURPOSE: Oral mucositis (OM) is a frequent and clinically important toxicity of conditioning therapy for hematopoietic cell transplantation (HCT). This trial evaluated whether prophylactic N-acetylcysteine (NAC) mouthwash reduces the incidence and severity of OM in HCT recipients. METHODS: In this single-center, double-blind, randomized, placebo-controlled trial, adults undergoing autologous or allogeneic HCT were assigned 1:1 to NAC mouthwash (600 mg every 6 h; 2400 mg/day) or matching placebo from the first day of conditioning until day +14 after transplantation or neutrophil engraftment, whichever occurred first. OM was assessed daily using the World Health Organization (WHO) Oral Toxicity Scale. The primary outcomes were the incidence of any OM and severe OM (WHO grades 3-4). Safety and exploratory predictors of OM were also evaluated. RESULTS: A total of 106 patients were randomized (NAC, n = 54; placebo, n = 52) and included in the intention-to-treat efficacy analysis. Any-grade OM occurred in 33/54 patients (61.1%) receiving NAC and 38/52 patients (73.1%) receiving placebo (P = 0.190). Severe OM was significantly less frequent with NAC than with placebo (3/54 [5.6%] vs. 13/52 [25.0%]; P = 0.006), and the overall distribution of WHO grades favored NAC (P = 0.046). NAC was well tolerated; gastrointestinal adverse events were mild and infrequent. In multivariable analysis, allogeneic HCT, myeloablative conditioning, suboptimal adherence, and placebo assignment were associated with higher odds of OM. CONCLUSION: NAC mouthwash did not significantly reduce the overall incidence of OM but significantly reduced severe OM in adults undergoing HCT. Given its low cost, availability, and favorable tolerability, NAC mouthwash may be a practical supportive-care strategy for reducing clinically consequential mucosal toxicity. Multicenter trials with standardized formulations and patient-reported outcomes are warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT07325383 (registered on November 16, 2025); Iranian Registry of Clinical Trials (IRCT20140818018842N42).
To classify the severity of bone flap resorption (BFR) following autologous cranioplasty under bone tissue bank storage conditions and to identify potential risk factors by analyzing clinical cases exhibiting postoperative bone resorption. A retrospective analysis was conducted on clinical data from 61 patients who developed bone flap resorption after autologous cranioplasty performed with bone flaps stored under bone tissue bank conditions. Based on the Oulu Resorption Scale, patients were categorized into four groups: no bone flap resorption (NBFR), mild BFR (MBFR), intermediate BFR (IBFR), and severe BFR (SBFR). Clinical characteristics were compared across these groups. Variables showing statistical significance (p < 0.05) in univariate analyses were subsequently entered into a multivariate ordinal logistic regression model to evaluate their association with the development and severity of BFR. All 61 patients completed follow-up, with a median follow-up duration of 378.0 days (interquartile range: 178.5-605.5 days). By the end of follow-up, 16 patients (26.2%) had developed BFR, including 9 cases (14.8%) of MBFR, 4 cases (6.6%) of IBFR, and 3 cases (4.9%) of SBFR. Univariate analysis revealed that smoking Pre- decompressive craniectomy (Pre-DC), traumatic brain injury (TBI), number of bone flaps ≥ 2, cranial defect area > 92.11 cm², and bone flaps located in the frontotemporoparietal region were significantly associated with an increased risk of BFR (all p < 0.05). Multivariate ordinal logistic regression analysis identified smoking Pre-DC, TBI, and cranial defect area > 92.11 cm² as independent risk factors for BFR, whereas having fewer than two bone flaps served as a protective factor against resorption (all p < 0.05). Autologous cranioplasty using bone flaps preserved under bone tissue bank conditions is associated with a low complication rate. With careful patient selection, it remains an admissible reconstructive option following decompressive craniectomy.
Population aging has led to a substantial increase in the prevalence of neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and stroke. As current therapeutic strategies are largely limited to symptomatic management, the identification of disease-modifying treatments remains a major unmet clinical need. Mesenchymal stem cells (MSCs) and MSCs-derived microRNAs (miRNAs) have emerged as promising therapeutic candidates for these conditions. A systematic literature search was conducted in the PubMed and Scopus databases in accordance with the PRISMA guidelines. The aim was to synthesize the available evidence regarding the effects of MSCs-derived miRNAs on cellular processes, including apoptosis, proliferation, inflammation, oxidative stress, and motor function in experimental models of PD, AD, and stroke. Risk of bias was assessed using the SYRCLE Risk of Bias tool for animal intervention studies and the modified OHAT Risk of Bias Rating Tool (mOHAT). A total of 37 preclinical studies were included in the review: 9 focused on PD, 10 on AD, and 18 on stroke. The synthesized evidence indicates that specific MSCs-derived miRNAs, particularly miR-133b, miR-146a, miR-17-92, and miR-223, exert significant neuroprotective effects. These miRNAs actively modulate gene expression, attenuate neuroinflammation and apoptosis, and reduce the accumulation of disease-specific pathological markers, including α-synuclein and amyloid-β (Aβ). Furthermore, targeted delivery of these miRNAs was associated with improved motor and cognitive outcomes across the evaluated animal models. MSCs-derived miRNAs demonstrate considerable therapeutic potential for the treatment of neurodegenerative diseases and stroke through the modulation of multiple pathological pathways. However, as the current evidence is derived exclusively from in vitro and animal studies, future research should focus on the development of safe, standardized, and reproducible protocols to facilitate the translation of these findings into human clinical trials. The review was registered in the Open Science Framework (OSF): https://osf.io/cxt9b .
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in CancerA M G A Laheij, J E Raber-Durlacher, B Hasséus, M C Huysmans, S J M van Leeuwen, K Garming Legert, J E Johansson, S Isom, D M Kline, M D Hazenberg, F R Rozema,…
PURPOSE: The percentage of cases with fever of unknown origin after hematopoietic cell transplantation (HCT) is high. An often overlooked clinical infection in HCT recipients may be chronic inflammation from the oral cavity. Therefore, the aim of the present study was to assess fever in the pre-engraftment phase after HCT and to examine the relationship between oral foci of infection before and in the first weeks after HCT and fever. METHODS: Adult patients, scheduled for autologous or allogeneic HCT, were included in this prospective, observational multicenter cohort study. Oral health was determined pre-HCT. Following HCT conditioning, fever was registered daily; and oral mucositis and other oral side effects were registered three times weekly. RESULTS: Data from 186 patients were available. The mean age was 53.0 years (± 12.9), and 55.4% were male. The most common malignancies were multiple myeloma, acute myeloid leukemia, and lymphoma. In total, 69.4% of the patients developed fever and 43.1% had an oral ulcerative lesion. After correction for age, site, conditioning regimen, diarrhea, vomiting, and duration of leukopenia, oral ulceration size remained significantly associated with fever, especially when fever was defined as ≥ 38.5°C. Pre-HCT chronic dental and oral conditions showed no association with post-HCT fever. CONCLUSION: Fever was common during the pre-engraftment phase after HCT and significantly associated with the extent of oral ulcerations. In contrast, pre-HCT dental and oral conditions showed no association with post-HCT fever, highlighting the specific role of mucosal injury in febrile episodes.
MedicineYoung-Keun Lee, Ji Woong Ho, Jin Young Kim
Pediatric scaphoid nonunion is uncommon. Immobilization is initially attempted; however, it causes delays in both intervention and healing. Therefore, surgical intervention has gained broader acceptance and has been implemented in recent years. Among these, arthroscopic management has emerged as a contemporary technique. This study evaluated the clinical outcomes of pediatric scaphoid nonunion treated with arthroscopic-assisted bone grafting and Kirschner (K) wire fixation. Six pediatric patients with scaphoid nonunion treated with arthroscopic bone grafting and K-wire fixation between November 2009 and August 2021 were retrospectively reviewed. All included patients were male. Fracture locations included three distal thirds, two mid-thirds, and one proximal third. The mean time from injury to intervention was 7.83 months. Three patients underwent autogenous iliac bone grafting, and 3 received bone substitute grafts. The mean follow-up duration was 40.67 months. Bone union was evaluated using serial plain radiographs and computed tomography. Functional outcomes were assessed by comparing range of motion (ROM), grip strength, modified Mayo wrist score, quick disabilities of the arm, shoulder, and hand (DASH) score, and visual analog scale (VAS) before surgery and at the latest follow-up. Radiological assessment was performed by comparing the scapholunate (SL) and radiolunate (RL) angles preoperatively and at the last follow-up. Complete union was achieved in all patients. The mean time to radiological union was 9.83 weeks. Functional measures, including grip strength (% of normal side, 67→92), ROM (% of normal side, 77→94), average VAS score (4.17→0.83), quick DASH score (40.15→7.58), and modified Mayo wrist score (53.33→80.00), demonstrated significant improvement. Radiological analysis also demonstrated a significant improvement in the SL angle (59.83→50.92). Arthroscopic-assisted bone grafting with percutaneous K-wire fixation is an effective treatment modality for pediatric scaphoid nonunions. In addition, bone substitute grafts may serve as viable alternatives to autogenous bone grafts in pediatrics.
RATIONALE: Myelosuppression after autologous stem cell transplantation (ASCT) exposes patients with multiple myeloma to substantial infection and bleeding risks and may be accompanied by marked psychological distress during protective isolation. Although supportive care is central to posttransplant recovery, reports describing how narrative nursing can be integrated into routine transplantation care remain limited. PATIENT CONCERNS: A 46-year-old married man with multiple myeloma was admitted 7 months after ASCT because of fever for half a day and erosive oral-labial mucosal lesions. He presented with febrile neutropenia, oral mucositis, severe pancytopenia, anxiety, hopelessness, and concern about his family role as the main financial provider. DIAGNOSES: The patient was diagnosed with multiple myeloma after ASCT complicated by prolonged myelosuppression, febrile neutropenia, oral mucositis, and severe pancytopenia. Delayed hematopoietic reconstitution and infection, including possible fungal infection, were considered during the clinical course. INTERVENTIONS: The patient received protective isolation in a laminar airflow room, empiric broad-spectrum antimicrobial therapy, granulocyte colony-stimulating factor, hemostatic prophylaxis, blood component support, meticulous oral and skin-mucosal care, nutrition and hydration support, and dynamic monitoring. A supplemental infusion of autologous hematopoietic stem cells was administered on hospital day 2. Individualized narrative nursing was provided through repeated one-to-one conversations, emotional validation, misconception correction, achievable daily goal setting, family communication, and discharge planning. OUTCOMES: During the 16-day hospitalization, fever and mucositis resolved, leukocyte and neutrophil counts gradually recovered, inflammatory markers declined, and no new infection or major bleeding occurred. The patient reported reduced fear, improved sleep, and greater willingness to participate in care and follow-up. LESSONS: This case suggests that structured narrative nursing can be feasibly embedded in routine ASCT supportive care during prolonged myelosuppression and may support emotional adjustment, treatment engagement, and family-centered coping.
Tacrolimus is a key immunosuppressant with a narrow therapeutic range in kidney transplantation. Early fluctuations in trough concentrations may influence graft stability, yet the clinical significance of early intrapatient variability remains uncertain. This study aimed to evaluate whether tacrolimus variability during the first posttransplant month is associated with renal function at 12 months. This single-center retrospective cohort study included adult kidney transplant recipients receiving tacrolimus-based immunosuppression between January 2017 and December 2021. Tacrolimus variability was quantified as the absolute difference (Δ, ng/mL) between maximum and minimum trough concentrations during the first 30 days, classified as high (Δ > 8 ng/mL) or low (Δ ≤ 8 ng/mL). Renal function was assessed using eGFR at 1, 3, 6, and 12 months. Statistical analyses applied appropriate parametric and nonparametric tests with a significance level of P < .05. High variability was associated with more frequent subtherapeutic and supratherapeutic trough concentrations and transient reductions in early graft performance. However, 12-month eGFR was not significantly different between variability groups. In multivariable models, recipient age, donor age, and biopsy-proven graft dysfunction were consistently associated with lower eGFR across follow-up. Male donor sex showed a positive association with eGFR only at 6 months, whereas early tacrolimus variability was not independently associated with eGFR at any time point.
Archives of orthopaedic and trauma surgeryKadri Ozer
INTRODUCTION: Complex dorsal finger soft tissue defects remain a challenging reconstructive problem, particularly when associated with exposure of bone and extensor apparataus. Advances in the anatomical understanding of the dorsal cutaneous vascular system of the digits have allowed adipofascial flaps in this region to evolve from random-pattern to axial-pattern designs, improving vascular reliability. However, a structured and comprehensive approach for managing these combined defects has not been clearly defined in the literature. This study aims to present a holistic loco-regional strategy that optimizes the reconstructive ladder while minimizing donor-site morbidity and technical complexity. MATERIALS AND METHODS: This clinical series includes seven fingers with complex soft tissue defects involving the dorsal aspect of the middle and distal phalanges. All cases were managed using an ipsilateral loco-regional protocol consisting of three components: (1) an extended axial adipofascial turnover flap for soft tissue coverage, (2) tendon reconstruction using juncturae tendinum harvested from the fourth intermetacarpal space, and (3) full-thickness skin grafting from the wrist. Patients were followed for a minimum of six months. Functional outcomes were evaluated by range of motion and complication rates. RESULTS: Complete flap survival was achieved in all cases. All fingers demonstrated satisfactory functional outcomes with acceptable flexion and extension ranges of motion at follow-up. No major complications, including infection, osteomyelitis, or significant donor-site morbidity, were observed. CONCLUSIONS: The perforator-based axial adipofascial turnover flap combined with juncturae tendinum grafting provides reliable single-stage reconstruction of complex dorsal finger defects without the need for microsurgical anastomosis. This structured loco-regional approach enables immediate reconstruction without the need for microsurgical equipment or advanced microvascular expertise, offering a practical and reproducible alternative within the reconstructive ladder. LEVEL OF EVIDENCE: IV.
Liver international : official journal of the International Association for the Study of the LiverFuquan Liu, Kan Zhang, Yu Zhang, Quanwei He, Mingming Meng, Xuemei Ma, Bing Zhu, Yifan Wu, Linjing An, Yifan Lv, Fuhuang Lin, Ke Zhang, Bowen Liu, Xiujuan Chan…
BACKGROUND/AIMS: International guidelines recommend initiating transjugular intrahepatic portosystemic shunt (TIPS) placement with an 8-mm stent. However, there is an evident lack of randomized controlled trials evaluating TIPS diameters < 8 mm in cirrhotic patients with a relatively small liver. The aim of this study was to determine whether 7 mm-covered TIPS, compared with 8-mm stents, could achieve comparable shunt function with a lower incidence of hepatic encephalopathy (HE). METHODS: In this multicenter randomized controlled trial, patients with cirrhosis and relatively small liver were randomized 1:1 to receive TIPS with a 7-mm (n = 92) or 8-mm (n = 92) covered stent to prevent variceal rebleeding. The primary endpoint was the incidence of overt HE after randomization. All-cause rebleeding, orthotopic liver transplantation (OLT)-free survival and a composite of these outcomes, were designated as secondary endpoints. RESULTS: Among the 184 enrolled patients, the predominant etiologies of liver cirrhosis were hepatitis B virus infection (56.0%) and alcohol-related liver disease (20.7%). Over a median follow-up of 26.5 months, overt HE occurred in 19 patients (20.7%) in the 7-mm group and 33 patients (35.9%) in the 8-mm group. The 2-year cumulative incidence of overt HE was significantly lower in the 7-mm group than in the 8-mm group (21.4% vs. 37.2%, p = 0.02). Stent diameter, post-TIPS portosystemic pressure gradient, pre-covert HE and MELD-Na score were identified as independent risk factors for overt HE. The rates of shunt dysfunction were statistically similar between groups (8.7% vs. 8.7%, p = 1.0), as were 2-year rebleeding rates (10.9% vs. 9.8%, p = 0.81) and OLT-free survival rates (91.3% vs. 88.0%, p = 0.82). CONCLUSIONS: A 7-mm covered TIPS demonstrated comparable shunt function to an 8-mm covered stents, with a significantly lower risk of overt HE. These findings support consideration of 7-mm TIPS stents for preventing variceal rebleeding in cirrhotic patients with a small liver who are undergoing TIPS. TRAIL REGISTRATION: ClinicalTrials.gov, NCT02541825.
PharmacotherapyLaura Cotiguala, Anne Przybylski, Lance Linberger, Marissa Brokhof, Nicole Kenyon, Cara Joyce, Michelle Dierker, Katie Ferguson, Megan A Rech, Christine Trotte…
UNLABELLED: The use of apixaban prior to kidney transplantation is on the rise. However, optimal perioperative management remains uncertain, particularly regarding the need for preoperative reversal with four-factor prothrombin complex concentrate (4F-PCC). Prior reports suggest clinically relevant bleeding without reversal, but potential thrombotic consequences of prophylactic 4F-PCC warrant caution. We hypothesized that withholding preoperative 4F-PCC in patients taking apixaban before kidney transplantation would not increase early postoperative surgical-bed bleeding. METHODS: This retrospective, two-center study included adult kidney transplant recipients (KTRs) from January 2019 to September 2025 who had taken apixaban within 48 h before surgery. Patients were stratified by receipt versus nonreceipt of preoperative 4F-PCC. The primary endpoint was surgical-bed bleeding within 3 days of transplant. A one-sided noninferiority test (margin of 15%) was used for the primary endpoint. RESULTS: Fifty KTRs were included, and 14 (28%) received preoperative 4f-PCC and 36 (72%) did not. The median time since the last known apixaban dose was 21 h (interquartile range [IQR], 16-24 h) before transplant. Surgical-bed bleeding occurred in 7.1% in the preoperative 4F-PCC cohort and in 5.6% of the no preoperative 4F-PCC cohort (differences, 1.6%; upper one-sided confidence interval [CI], 21.5%; p = 0.11), suggesting similar event rates but not confirming noninferiority. No significant differences were observed between groups in transfusion requirements, delayed graft function, kidney function, venous thromboembolism (1 in the reversal group; 0 in the non-reversal group), or reoperation. Two deaths occurred in the reversal group. CONCLUSIONS: Withholding preoperative 4F-PCC in apixaban-treated KTR appears safe, with surgical-bed bleeding rates comparable to those in patients who received preoperative 4F-PCC. Findings support individualized rather than routine preoperative reversal strategies to balance bleeding and thrombotic risks.
HLAAleksandra Gazikalovic, Christina Bade-Döding, Murielle Verboom, Susann Zirzow, Michael Hallensleben, Rainer Blasczyk, Jens Gottlieb, Funmilola Josephine Hauka…
ddcfDNA emerged as a biomarker for post-transplantation management strategies. Lung retransplant recipients represent a particularly vulnerable patient population with an increased risk of allograft injury. The demand for understanding if ddcfDNA levels differ between primary lung transplant recipients and lung retransplant recipients becomes obvious. Eight lung retransplant recipients and 50 primary lung transplant recipients with comparable HLA Class I and Class II mismatch scores were included in this retrospective study. During post-transplant monitoring, ddcfDNA results were evaluated alongside data on patient humoral immune responses pre- and post-transplantation. Antibody profiles of lung retransplant recipients did not differ significantly from those of their primary transplant comparisons. However, significantly higher ddcfDNA levels were observed in the retransplant cohort (median: 1.463%, IQR: 0.810-2.745) compared with primary transplant cohort (median: 0.550%, IQR: 0.338-0.935), U = 100.50, Z = -2.24, p = 0.012, r = 0.29. We identified that lung retransplant recipients exhibit increased allograft injury not solely attributable to humoral responses. Our study highlights that these patients face a higher immunological risk and supports the need for closer clinical follow-up using a resilient biomarker such as ddcfDNA. Incorporating ddcfDNA as a surrogate marker into post-transplant monitoring would provide early and unambiguous insights into allograft rejection, enabling prompt interventions to prevent unfavourable outcomes in this particularly fragile patient group.
Clinical transplantationAlexa Lavergne, Kirti Magudia, Tommi Jarvinen, Alexander Reed, Samantha Morrison, Mustafa R Bashir, Michael Rosenthal, Mohamed Sobhi Jabal, John M Reynolds, Br…
BACKGROUND: Lung transplantation is a complex therapy for end stage lung disease with variable postoperative outcomes. Textbook outcomes, defined by freedom from perioperative morbidity and mortality, have emerged as a comprehensive measure of surgical success. Body mass index (BMI) is commonly used to assess nutritional status but does not distinguish between skeletal muscle and adipose tissue. CT-based body composition analysis can differentiate these tissues and may provide a more precise assessment of physiologic reserve in lung transplantation. METHODS: We performed a retrospective cohort study of 377 adults undergoing single or bilateral lung transplantation at a single academic institution (2019-2023). Preoperative abdominal CT scans were used to quantify skeletal muscle, subcutaneous fat, and visceral fat areas. A composite textbook outcome was defined as freedom from intraoperative complications; postoperative reintervention; readmission, acute rejection, and dialysis within 30 days; 90-day mortality; primary graft dysfunction; ECMO at 72 h; tracheostomy within 7 days; reintubation; and extubation >48 h. Multivariable logistic regression assessed associations between body composition metrics and lung transplant outcomes after adjusting for potential confounders. RESULTS: Among 377 recipients, 108 (28.6%) achieved textbook outcome. Increased skeletal muscle area was associated with increased odds of achieving textbook outcome (OR per 50cm2: 1.808 [1.061-3.119]) and decreased odds of 1-year mortality (OR per 50cm2: 0.423 [0.195-0.890]). Subcutaneous fat area, visceral fat area, and BMI were not significantly associated with outcomes. CONCLUSION: CT-based skeletal muscle was associated with textbook outcome and 1-year mortality, whereas BMI was not. CT-based body composition analysis may be a promising tool for lung transplant risk stratification.
Journal of neuroendocrinologyPeter Stålberg, Mairéad G McNamara, Simona Grozinsky-Glasberg, Andreas Pascher, Beata Kos-Kudla, Timm Denecke, Nehara Begum, Wendy Martin, Stephanie Alband, Cl…
Liver transplantation (LT) may offer survival or symptomatic benefit for highly selected patients with advanced, well-differentiated small-intestinal or pancreatic neuroendocrine tumours and unresectable liver-dominant metastases. However, its role remains controversial, as LT is rarely curative, recurrence is common, and benefits must be weighed against perioperative risk, lifelong immunosuppression, alternative therapies, and organ allocation ethics. This ENETS position statement summarises current evidence and expert consensus, reframing LT within a transplant-benefit model rather than fixed eligibility criteria. It outlines biologically informed selection principles and multidisciplinary assessment, as well as addressing the need for standardised characterisation, prospective registries, and long-term outcome data to better define the net clinical benefit of LT in this rare patient population.
Clinical transplantationXuechun Zhao, Bo Yang, Hongmei Jiang, Yuanyuan Zhao, Lai Wei, Zhishui Chen, Dong Chen
BACKGROUND: Accurate differentiation of acute rejection (AR) from other causes of graft dysfunction after liver transplantation remains challenging in real-world clinical practice. Although donor-derived cell-free DNA (dd-cfDNA) has emerged as a promising non-invasive biomarker of graft injury, its specificity may be limited in clinically suspected rejection due to concurrent inflammatory and non-rejection-related graft injuries. Immune activation markers may provide complementary information by reflecting ongoing alloimmune responses. METHODS: In this prospective diagnostic study, we enrolled liver transplant recipients presenting with graft dysfunction and classified them as AR or non-rejection based on biopsy. Plasma dd-cfDNA levels and peripheral immune activation markers, including interleukin-2 receptor (IL-2R) and activated T-cell subsets, were measured. Diagnostic performance was evaluated using receiver operating characteristic analysis and multivariable models. RESULTS: A total of 33 patients were included, comprising 18 with biopsy-proven AR and 15 with non-rejection graft dysfunction. dd-cfDNA levels were significantly higher in AR patients. Selected immune activation markers demonstrated complementary diagnostic characteristics. A simplified combined model integrating dd-cfDNA percentage with activated T-cell subsets achieved improved discrimination compared with individual markers. Decision curve analysis indicated a higher net clinical benefit across a range of threshold probabilities. CONCLUSION: Integration of dd-cfDNA with immune activation markers provides a complementary non-invasive strategy for evaluating acute rejection in liver transplant recipients with clinically suspected graft dysfunction. This approach may improve real-world diagnostic assessment and assist clinical decision-making while reducing unnecessary liver biopsies.
Cell stem cellSijin Luozhong, Angelica Varesi, Bowen Li
Traditional ex vivo hematopoietic stem cell (HSC) gene therapy faces manufacturing challenges. A recent study1 in Nature Biomedical Engineering demonstrates that antibody-engineered lipid nanoparticles achieve efficient and durable in vivo editing of HSCs in humanized mice, offering a promising therapeutic strategy for genetic blood diseases.
Journal of clinical pharmacologyRiley M Randolph, Tyler C Dunlap, Stephany Gonzalez Tineo, Ryan M Kemper, Jing Zhu, Kieran Collins, Yu Fei Wang, Pu Ouyang, Nichole Korpi-Steiner, Eric Weimer,…
Allogeneic hematopoietic cell transplant (allo-HCT) is potentially curative for many hematologic diseases but complicated by acute graft-versus-host disease (aGVHD). While tacrolimus remains the cornerstone of aGVHD prophylaxis, regimens are increasingly including post-transplant cyclophosphamide (PTCy). This single-center study evaluated a previously published tacrolimus population pharmacokinetic (popPK) model developed from allo-HCT recipients administered standard (tacrolimus plus methotrexate) aGVHD prophylaxis for generalizability to PTCy recipients. Adult allo-HCT recipients treated with PTCy for aGVHD prophylaxis were included. Applicability of the established popPK model to the PTCy population was based on an evaluation of simulated to observed concentration ratios, and the distribution was interpreted with respect to a clinical equivalence range (0.8 to 1.25). The model was refit using data from both the standard and PTCy cohorts to describe the PK and support extrapolation to the PTCy population. Individual PK parameters from PTCy recipients were used to simulate steady-state concentrations (Ctrough, ss) using the current institutional weight-based dosing strategy and the proposed model-informed precision dosing (MIPD) algorithm. The proportion of patients predicted to experience a subtherapeutic Ctrough, ss (<5 ng/mL) was compared between dosing strategies. Five hundred and ninety-three tacrolimus Ctrough, ss values from 95 allo-HCT recipients who received PTCy were included. The previous model did not successfully predict tacrolimus Ctrough, ss values among PTCy patients, but highlighted similarities between clearance in PTCy and standard aGVHD prophylaxis patients who received reduced-intensity conditioning. Dosing simulations suggested a decreased proportion of PTCy patients would experience subtherapeutic tacrolimus Ctrough, ss with MIPD (3%) compared to conventional weight-based dosing (23%).
The Australian & New Zealand journal of obstetrics & gynaecologyHarrison Odgers, Rhonda Farrell
BACKGROUND: Endometrial cancer is the most common gynaecological malignancy in Australia. Patients diagnosed in their reproductive window may desire a fertility-sparing approach, opposed to standard surgical care. International guidelines on fertility-sparing management exist; however, these highlight the lack of high-level evidence to support the recommendations. There are no Australian-specific guidelines or registries, leading to uncertainty as to how patients are managed locally. AIM: To survey clinicians in Australia regarding fertility-sparing management of endometrial cancer, to identify areas of consensus and variation, barriers to care and research priorities. MATERIALS AND METHODS: A 47-item online survey was distributed to clinicians who manage patients with endometrial cancer in Australia between November 2024 and January 2025. Responses were analysed descriptively. RESULTS: Of 70 eligible clinicians, 56% responded. There was agreement on appropriate candidate selection for FIGO grade 1 disease with absent/focal myoinvasion, use of hysteroscopy for diagnosis, and preference for levonorgestrel intra-uterine device as initial therapy. Opinions were divided on management of patients with Lynch syndrome or more extensive myoinvasion, the diagnostic utility of endometrial pipelle, and treatment of recurrences. POLE mutation testing and hysteroscopic resection were uncommon practices. Most respondents referred patients to fertility specialists, while other members of the multi-disciplinary team were less frequently utilised. The most frequent research priorities were weight-loss strategies (31%) and molecular profiling (27%). CONCLUSIONS: Clinicians in Australia have common approaches to diagnosis and first-line therapy, but there is variation in patient selection, surveillance and engagement with a multi-disciplinary team. These discrepancies highlight the potential benefits of local guidelines and further research.
Clinical transplantationMarina Colella-Santos, Pedro Henrique Pepato, Henrique Machado de Sousa Proença, Luiz Antonio Ribeiro de Moura, José Medina-Pestana, Renato Demarchi Foresto, L…
BACKGROUND: Kidneys from deceased donors with diabetes mellitus are refused because diabetes is considered a marker of lower organ quality. We evaluated 5-year outcomes according to donor-recipient diabetes status and, secondarily, the prognostic value of pre-implantation histopathological findings among accepted diabetic donor kidneys. METHODS: This retrospective single-center cohort study included adult recipients of deceased-donor kidney transplants performed between 2013 and 2017. Five-year kidney function and death-censored graft survival were compared according to donor diabetes status before and after 1:2 propensity score matching. A secondary exploratory analysis evaluated Banff chronicity parameters in pre-implantation pathology reports. RESULTS: Among 3058 recipients, 244 received kidneys from diabetic donors. These donors were older, more frequently hypertensive, and had higher KDPI than non-diabetic donors. In unadjusted analyses, recipients of diabetic donor kidneys had lower eGFR and death-censored graft survival. After matching, eGFR from years 1 to 5, eGFR slope, and death-censored graft survival no longer differed between groups. Recipient diabetes did not significantly modify the association of donor diabetes with graft survival or longitudinal eGFR, although the D+/R+ subgroup was small (n = 39). Among 164 available pre-implantation biopsy reports, diabetes-related glomerular lesions were uncommon, chronic lesions were predominantly vascular and mild to moderate, and no Banff histological parameter independently predicted eGFR <30 mL/min/1.73 m2 or death-censored graft loss at 5 years. CONCLUSIONS: After balancing baseline donor and recipient characteristics, donor diabetes was not associated with significantly lower 5-year kidney function or death-censored graft survival. In the secondary clinicopathological analysis, no individual Banff chronicity parameter independently predicted 5-year outcomes.
Clinical implant dentistry and related researchMaryam Heidaryzadeh, Mohammad Mohammadi, Nazila Lashkarizadeh, Mahsa Kalantari Khandani
AIM: This study evaluated the efficacy of conventional flap and tunneling techniques for horizontal alveolar ridge augmentation using freeze-dried bone allograft (FDBA) particles combined with injectable platelet-rich fibrin (i-PRF). MATERIALS AND METHODS: Forty-five patients were randomly allocated to one of three groups (n = 15 each): conventional flap (CF), tunneling with membrane (TM), or tunneling without membrane (TnM). Preoperative ridge width was measured via cone beam computed tomography (CBCT). All augmentation procedures incorporated FDBA and i-PRF; an absorbable collagen membrane was applied in the CF and TM groups. Follow-up assessments, including CBCT imaging and histomorphometric analysis, were conducted 6 months postoperatively. For normally distributed data, ANOVA with Tukey's post hoc test and paired samples t-test were applied. Non-normally distributed data were analyzed using Kruskal-Wallis, Mann-Whitney U, and Wilcoxon signed-rank tests. RESULTS: Statistical analysis was performed on 43 patients. All groups demonstrated an increase in ridge width after 6 months. At the 2 mm level, the mean width gain was 1.28 mm (95% CI: 0.17 to 2.40) in the TM group, 2.85 mm (95% CI: 1.80 to 3.89) in the TnM group, and 1.95 mm (95% CI: 1.07 to 2.83) in the CF group. However, statistical analysis revealed no significant intergroup variation (p > 0.05). Histomorphometric assessments similarly demonstrated comparable outcomes across all groups, with no statistically significant differences observed (p > 0.05). CONCLUSION: Within the limitations of this study, the tunneling technique, regardless of membrane use, appears to be a clinically viable alternative to the conventional flap method for horizontal alveolar ridge augmentation. However, further studies with longer follow-up periods are required to substantiate these findings. TRIAL REGISTRATION: irct.behdasht.gov.ir identifier: IRCT 20101204005305N21.
Current hematologic malignancy reportsJoseph F Mort, Alex J Ambinder
PURPOSE OF REVIEW: Recent advancements in our understanding of the molecular underpinnings of acute myeloid leukemia (AML) disease biology have translated into breakthroughs in clinical management. In this review, we summarize the latest data incorporating precision approaches to treatment of FLT3-mutated AML with a focus on augmenting the curative role allogeneic hematopoietic cell transplantation (alloHCT) plays in the current treatment paradigm. RECENT FINDINGS: Incorporation of the next-generation FLT3 inhibitors quizartinib and gilteritinib into upfront therapy, whether in combination with intensive induction chemotherapy or less intensive hypomethylating agent/venetoclax combinations, have led to deeper and more durable remissions and resulted in greater transplant eligibility. AlloHCT candidacy has also expanded due to increased use of alternative donors, made possible with post-transplant cyclophosphamide-containing graft-versus-host disease prophylaxis regimens, and more tolerable reduced intensity conditioning. Additionally, risk stratification in the peri-transplant setting using ultra-sensitive FLT3-ITD measurable residual disease (MRD) assays has refined post-transplant maintenance approaches allowing escalation or de-escalation of therapy guided by each patient's risk of relapse. These advances have resulted in improved clinical outcomes for this historically high-risk disease. AlloHCT remains an integral component of the treatment of FLT3-mutated AML. Novel FLT3 inhibitors used in frontline combination regimens have led to more numerous and deeper remissions, and as post-transplant maintenance they have shown success in preventing the early relapse characteristic of this disease. MRD has emerged as an integral component of FLT3-ITD AML risk stratification and surveillance and is likely to further revolutionize our current treatment approaches.
Journal of clinical apheresisYoo Jin Lee, Sang Hyuk Park, Youjin Kim, Ji-Hun Lim, Hyun-Ki Kim, HeeJung Cha, Jae-Cheol Jo
Efficient and safe mobilization of peripheral blood CD34+ stem cells is essential for successful autologous stem cell transplantation (ASCT) in patients with lymphoid malignancies. However, current mobilization strategies are often limited by suboptimal yield, significant toxicity, or high cost. We conducted a prospective observational study including 59 patients with lymphoma or multiple myeloma undergoing ASCT. Patients received fractionated intermediate-dose etoposide (175 mg/m2 twice on days 1 and 2) followed by granulocyte colony-stimulating factor (G-CSF, 10 μg/kg daily). Mobilization efficacy, safety profile, and subsequent transplantation outcomes were evaluated. Successful mobilization (≥ 2 × 106 CD34+ cells/kg) was achieved in 96.6% of patients within three days of apheresis. The median CD34+ cell yield was 5.35 × 106 CD34+ cells/kg on the first day. Notably, 61.0% and 49.2% of patients collected ≥ 4 × 106 and ≥ 6 × 106 CD34+ cells/kg on the first day, respectively. Despite frequent grade 3-4 cytopenias, clinically significant complications were limited, with febrile neutropenia occurring in 16.9% of patients and no treatment-related mortality (TRM). All patients achieved neutrophil and platelet engraftment. Fractionated intermediate-dose etoposide combined with G-CSF achieved a high mobilization success rate, with most patients requiring a limited number of apheresis sessions and no TRM.
Pediatric transplantationAkosua Dansoa Odei, Haoran Jiang, Natasha Anders, Seth Erasmus Murray Wolf, Chelsea Harris, Rebekah Boyd, Matthew Galen Hartwig, Douglas Marvin Overbey, Joseph…
BACKGROUND: Heart transplantation is definitive therapy for children with end-stage heart failure. Because donor availability is unpredictable, transplantation occurs overnight or on weekends. Although studies report mixed findings on the association between operative timing and outcomes, pediatric data remain limited. We evaluated the impact of operative timing on pediatric heart transplant outcomes. METHODS: We studied pediatric heart transplant recipients (< 18 years) in the United Network for Organ Sharing registry from 2000 to 2018. Transplants were classified by time of day (day: 9 AM-8:59 PM; night: 9 PM-8:59 AM) and day of week (weekday vs. weekend). Primary outcome was survival. Secondary outcomes included graft survival, rejection, retransplantation, and postoperative complications. Survival was analyzed using Kaplan-Meier and log-rank testing. Multivariable Cox regression adjusted for recipient and donor characteristics and pre-transplant support. RESULTS: Among 6125 recipients, 2930 (47.8%) transplants occurred during the day and 3195 (52.2%) at night; 4408 (72.0%) occurred on weekdays and 1717 (28.0%) on weekends. Kaplan-Meier analysis demonstrated no significant survival difference between daytime and nighttime transplants (p = 0.266) or weekday and weekend transplants (p = 0.210). In multivariable Cox regression, operative timing was not associated with mortality (night vs. day: hazard ratio 0.97, 95% confidence interval 0.89-1.06, p = 0.554; weekend versus weekday: hazard ratio 1.04, 95% confidence interval 0.94-1.15, p = 0.445). Acute rejection prior to discharge and treatment for rejection within 1 year was more frequent in daytime transplants without affecting graft survival. CONCLUSIONS: Operative timing was not associated with patient survival, graft survival, or postoperative outcomes after pediatric heart transplantation.
INTRODUCTION: Kidney transplant patients (KTPs) exhibit markedly reduced seroconversion rates following SARS-CoV-2 vaccination due to chronic immunosuppression. Torque Teno virus (TTV) viral load has been proposed as a biomarker of immune competence. OBJECTIVES: To determine the seroconversion rate to SARS-CoV-2 vaccination in KTPs and to develop a predictive model based on TTV viral load. METHODS: A prospective observational cohort study was conducted in adult KTPs with complete SARS-CoV-2 vaccination scheme. Anti-Spike IgG antibodies were quantified. TTV viral load was quantified by qPCR. Logistic regression models were developed using TTV viral load alone and with patients' variables (expanded model). Model performance was assessed using receiver operating characteristic analysis and internal validation. RESULTS: Seroconversion rate was 16.9% after complete vaccination, 21.9% after one booster and 55.5% after two boosters. TTV viral load alone showed modest predictive capacity for seroconversion (AUC = 0.634). The expanded model significantly improved prediction capacity (AUC = 0.814) with a NPV of 90.0%. CONCLUSION: Pre-vaccination TTV viral load alone is insufficient to predict seroconversion to SARS-CoV-2 vaccination in KTPs. The expanded model improved this predictive capacity when combined with clinical and vaccine related variables reflecting the multifactorial nature of immune competence. Integrative predictive approaches may help optimize vaccination strategies in immunocompromised populations.
BACKGROUND: Pre-emptive kidney transplantation is the preferred treatment in patients with end-stage kidney disease (ESKD); however, many patients must unavoidably initiate dialysis prior to transplantation. Prolonged dialysis exposure is associated with increased morbidity and mortality, mandating prompt transition to transplant when possible. Delays in transplant readiness are unfortunately prevalent and are often driven by fragmented communication, limited education, and system-level barriers. OBJECTIVE: To reduce time from dialysis initiation to deceased donor kidney transplant (DDKT) activation among pediatric patients through a single-center quality improvement initiative. METHODS: This quality improvement (QI) project was conducted at a tertiary children's hospital affiliated with a pediatric outpatient dialysis unit. Baseline data from 2023 demonstrated a median dialysis-to-DDKT activation time of 211.5 days. Interventions were implemented in 2024 through three Plan-Do-Study-Act cycles (PDSA): (1) establishment of a multidisciplinary Guidance and Planning clinic for early transplant education; (2) implementation of biweekly transplant-dialysis coordination meetings supported by expanded transplant coordinator staffing; (3) distribution of a bilingual patient education booklet at dialysis initiation. The primary outcome measure was time to DDKT activation. Trends were evaluated using descriptive statistics and a run chart. RESULTS: In 2024, 10 patients initiated dialysis during the intervention phase. Excluding 2 patients who were activated for transplantation prior to outpatient dialysis initiation, the median time from dialysis initiation to DDKT activation decreased by 38%, from 211.5 days in 2023 to 130.5 days in 2024. Sixty percent of patients initiating dialysis in 2024 underwent transplantation within the same calendar year. Process measures demonstrated successful implementation of interventions. CONCLUSIONS: Implementation of a structured quality improvement approach was associated with reduced time to transplant activation in pediatric dialysis patients. Improved communication, education, and transplant coordination may represent modifiable factors that may enhance transplant readiness and outcomes.