Citations

Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, disabling, genetic disorder characterized by progressive heterotopic ossification (HO). FOP care pathways are complex, and there are many underrepresented patients globally. Objectives: This scoping review aimed to identify global FOP case reports and investigate real-world management practices. Evidence sources, eligibility criteria, and charting methods: International/local databases and congress proceedings were searched. Publications reporting patient-level data for ⩾1 patient with an FOP primary diagnosis, published January 2000–January 2024, were eligible. Publication details, patient demographics, disease presentation, and care pathway were extracted. Data were charted through categorization of themes and frequency analyses. Results: Of 6064 publications screened, 369 were eligible, reporting on 541 patients with FOP. Most publications (82.4% (304/369)) reported an individual case; the remaining reported 2–25 cases. Cases were from 57 countries, most commonly in the Asia/Pacific region (47.0% (254/541)). Most patients had reportedly seen a single specialist (64.8% (59/91)), and care from multidisciplinary teams was reported for only 5.5% (5/91). HO (84.7% (458/541)) and great toe malformations (66.7% (361/541)) were the most commonly reported signs, though mobility limitations (46.2% (96/208)) and growths/lesions (38.5% (80/208)) were most common before diagnosis. The predominant drug classes reported for FOP treatment were corticosteroids (52.6% (102/194)) and nonsteroidal anti-inflammatory drugs (39.7% (77/194)). Surgeries were reported in 35.1% (190/541) of patients. Where specified, the most common surgery types were malformation correction/bone resection (43.6% (78/179)) and biopsies (34.1% (61/179)). Conclusion: This scoping review synthesized valuable real-world insights from case reports of FOP, potentially supporting outreach initiatives in underserved regions and facilitating shared learnings on diagnosis and treatment. Although the inherent selection bias of case studies toward atypical cases limits definitive conclusions, some global trends in the clinical management practices were revealed.

Key Points The kidney microvasculature was quantified reliably in human autosomal dominant polycystic kidney disease early on, using super-resolution ultrasound localization microscopy. Microvascular parameters correlated with structural and functional indices, constituting promising biomarkers to evaluate noncystic parenchyma. Microvascular parameters may serve to assess disease severity and monitor progression from the early stages of the disease. Background In vitro studies in individuals with autosomal dominant polycystic kidney disease (ADPKD) have shown extensive intrarenal microvascular remodeling. However, analyses have been limited to the time of kidney failure because of the invasive nature of current methodologies to assess the intrarenal microvasculature. We hypothesized that super-resolution ultrasound microvascular imaging, known as ultrasound localization microscopy, enabled by high-framerate ultrasound imaging and microbubble localization and tracking postprocessing techniques, would safely, reliably, and reproducibly assess the intrarenal microvasculature in individuals with ADPKD at an early stage of the disease. Methods We prospectively enrolled young (<40 years of age), well-characterized, early-stage (eGFR >90 ml/min per 1.73 m 2 ) individuals with ADPKD, and sex–age 1:1 matched controls ( n =17 each) and assessed the intrarenal microvasculature using ultrasound localization microscopy. We determined the intersonographer reliability, intraobserver repeatability, and interobserver reproducibility of microvascular parameters in both groups, and the day-to-day variability in the control group. Microvascular parameters were correlated with structural (total kidney volume) and functional (eGFR) markers in individuals with ADPKD. Results Ultrasound localization microscopy provided a super-resolved map of the intrarenal microvasculature in ADPKD and matched controls. Intrarenal microvascular parameters ( e.g ., vessel density) were quantified in a safe, reliable (intraclass correlation coefficients, 0.96; 95% confidence interval, 0.91 to 0.98), reproducible (intraclass correlation coefficient, 0.96; 95% confidence interval, 0.93 to 0.98), and repeatable (coefficient of variations, 3.6%) manner. In control individuals, the day-to-day variability of most parameters was low, with coefficient of variation ranging from 1.8% to 10.7%. Microvascular parameters differed in individuals with ADPKD compared with controls, despite preserved eGFR. Interestingly, cortical vessel density and its derived perfusion correlated directly with eGFR, whereas tortuosity indices presented an inverse correlation. Conclusions Ultrasound localization microscopy provided a safe and reliable in vivo assessment of the human intrarenal microvasculature.

Abstract Background: Advantages of covalent Bruton Tyrosine Kinase inhibitor (cBTKi) treatment (tx), as compared to BCL2 inhibitor (BCL2i) containing regimens, include ease of initial administration without a requirement for frequent laboratory monitoring, even in patients (pts) with bulky disease. However, limitations of cBTKi monotherapy include acquired resistance, cumulative toxicity and the financial burden associated with continuous administration. CLL pts treated on the E1912 study who discontinued (dc) ibrutinib for reasons other than progression of disease (PD) had a median progression free survival (PFS) of ~2.7 years from ibrutinib dc, suggesting that a time-limited cBTKi strategy may be feasible for some pts(Shanafelt et al. Blood Advances 2025). We hypothesized that acalabrutinib (acala) and obinutuzumab (O) could be administered as a time-limited initial tx for CLL with duration guided by minimal residual disease (MRD). Methods: This is an ongoing phase II, multicenter, investigator-initiated study of acala and O for previously untx pts with CLL/small lymphocytic lymphoma (SLL) requiring tx per iwCLL 2018 criteria (NCT04722172). Pts with TP53 aberrancy are excluded. Pts receive acala 100 mg twice daily and O during 28-day cycles (C) 2-7. Undetectable MRD is defined with a 10-4 sensitivity in the peripheral blood (PB) by ClonoSeq next generation sequencing (uMRD4). Pts undergo MRD testing at C13; if uMRD4 at C13 with a complete response (CR) or partial response (PR), pts dc acala and enter tx free observation (TFO). If detectable MRD4 (dMRD4) at C13, pts continue acala until uMRD4, with repeat MRD testing occurring at C16, 19, 22 and 25. All pts dc acala after a maximum of 26C and enter TFO, even if dMRD4. If pts have PD meeting iwCLL criteria for tx during TFO, re-tx consists of acala + 6 cycles of O. Pts are followed for 13C of re-tx. Primary endpoint is 36-month PFS. Results: 55 pts initiated tx. Baseline characteristics include: median age 67, 64% male, 47% LN ≥ 5 cm, 73% IGHV unmutated. Best overall response rate (ORR) was 95% (CR: 4, PR: 48, SD: 0, PD: 1, unknown: 2). Best uMRD4 rate at any time during the study was 49% (n=27 pts, intention-to-treat, IIT). 5 pts dc tx prior to C13 MRD testing (2 pt decision, 2 AE, 1 due to PD after ~4C). At C13, 22 pts (40% of IIT) were uMRD4; 21 entered TFO after 13C and 1 pt had 19C tx prior to TFO. 28 pts had dMRD4 (51% ITT) at C13. Between C13 and 26, 2 pts became uMRD4 and entered TFO, 1 pt died (COVID-19), and 2 pts stopped acala for tx of other cancers. 21 pts completed 26C acala per protocol prior to entering TFO; 2 additional pts had PD at C25 and EOT. Median tx duration was 19C. In univariate analyses, age, del11q, del13q, IGHV mutational status and baseline LN ≥ 5 cm were not predictive of uMRD4 at C13. At a median follow-up of 38 months, the median PFS for the overall cohort is 42 months (95% confidence interval (CI): 37, not reached), with an estimated 36-month PFS of 69% (95% CI: 57%, 84%). At data cutoff, of 46 pts entering TFO, 29 pts remained in TFO without PD, 7 pts had PD during TFO but had not met iwCLL criteria for re-tx, and 10 pts had PD requiring tx (5 pts re-tx pe protocol, 5 came off study for non-protocol tx approach). The overall median TFO period (measured from acala dc to PD) was 25 months (95% CI: 21 – not reached, n=46 pts). 5 pts have initiated re-tx with acala + O (1 pt best response PR and uMRD4; 4 ongoing tx). Median time to re-tx was 18 months (range 6-34, n=5 pts). Conclusions: This study is proof-of-concept that cBTKi may be administered as a time-limited tx without the addition of a BCL2i. While the initial PFS is shorter than historical studies examining continuous cBTKi, of patients entering TFO after 1-2 years of acala, the median duration of TFO until PD is 25 months, and longer follow-up will provide re-tx outcomes. Potential advantages to MRD-guided, time-limited cBTKi tx include time off tx for pts, limiting acquired resistance, the ability to re-challenge with cBTKi at progression, and reserving BCL2i for third-line or later tx.

Abstract Description RNA- and DNA-binding proteins are crucial for regulating gene expression by affecting DNA accessibility, transcription, and repair, as well as RNA splicing, transport, and stability. Dysfunction, mislocalization, aggregation, and liquid-liquid phase separation of these proteins are common in neurodegenerative and neuroinflammatory diseases. TDP43 mislocalization is notably implicated in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In 97% of ALS cases, the loss of nuclear TDP43 and the formation of cytoplasmic aggregates (TDP43 proteinopathy) in motor neurons are observed. This loss or mislocalization of TDP43 disrupts nucleic acid sequestration and may activate cytosolic DNA and RNA sensors such as RIG1 and cGas-STING pathways, leading to the expression of interferon-stimulated genes (ISGs). Evidence suggests that the ubiquitin-like protein ISG15 contributes to neuron loss. Using primary murine cortical neurons, human IPSC-derived motor neurons, and mixed neural cultures, we report the impact of TDP43 knockdown and mislocalization on neuronal interferon signaling and ISG15 expression. We also use ISG15-deficient neurons to measure ISG15-dependent impacts on neuron viability. Our findings show ISG15-dependent effects on cGas-STING signaling, astrogliosis, and neuron loss in an AAV-C9orf72 mouse model of ALS using global and conditional ISG15 KO mice. Funding Sources Supported by Dominium Foundation Career Development Award (Clarkson). Topic Categories Neuroimmunology (NEUR)

ABSTRACT Cues such as fast‐food advertisements associated with food can provoke food cravings which may lead to unhealthy overeating. To effectively control such cravings, we need to better understand the factors that reduce food cue reactivity and reveal corresponding ‘anti‐craving’ brain mechanisms. We previously reported that access to environmental enrichment (EE), that provides cognitive and physical stimulation in mice, reduced cue‐evoked sucrose seeking and prelimbic cortex (PL) neuronal reactivity. To date, the phenotype of PL neurons that undergo EE‐induced adaptations has not been fully elucidated. Therefore, we used brain slice electrophysiology to investigate how EE modulated intrinsic excitability in the general population of PL interneurons and pyramidal cells. Additionally, we used retrograde tracing and the neuronal activity marker ‘Fos’ to investigate how EE modulated cue‐evoked recruitment of pyramidal cells projecting to the paraventricular nucleus of the thalamus (PVT) and nucleus accumbens core (NAc). Before the cue‐evoked sucrose seeking test, EE increased the general, baseline excitability of inhibitory interneurons, but not pyramidal cells. During cue‐evoked sucrose seeking, EE selectively suppressed recruitment of corticothalamic (PL → PVT), but not corticoaccumbens (PL → NAc), projections. Collectively, these findings advance our understanding of EE's ‘anti–food‐seeking’ actions by demonstrating both cell type‐specific increases in local inhibitory tone and circuit‐specific modulation of PL output pathways.

OBJECTIVE The implementation of robotics and spinal anesthesia (SA) in spine surgery is rapidly expanding, offering significant benefits for an increasingly complex and aging patient population with degenerative spinal disease. Here, the authors present the largest cohort to date evaluating the combined use of these two techniques in minimally invasive (MIS) transforaminal lumbar interbody fusion (TLIF). METHODS The authors retrospectively analyzed surgical outcomes of a series of patients who underwent robot-assisted (RA)–MIS TLIF under SA and general anesthesia (GA) at their institution from 2018 to 2024. Primary outcomes included operative times and postoperative pain intensity. Secondary outcomes included estimated blood loss, intraoperative complications, postoperative functional status, length of stay (LOS), and discharge status. To address potential confounders, a 1:1 propensity score–matching and regression analysis was implemented. Statistical analyses were conducted using Python. RESULTS A total of 209 patients underwent RA-MIS TLIF, with 31 (14.83%) receiving SA and 178 (85.17%) GA. After propensity score matching, the SA cohort demonstrated significantly shorter median total operating room (OR) time, total procedure time, time from entering the OR to skin incision, and time from closure to leaving the OR (all p < 0.01). Additionally, postoperative pain scores were significantly lower (p < 0.01), and LOS was significantly shorter (p < 0.01) in the SA cohort. Regression analysis, adjusting for potential confounders, further supported these findings. CONCLUSIONS RA-MIS TLIF fusion under SA is a safe and effective approach that significantly reduces operative time, postoperative pain, and hospital LOS in patients undergoing surgery for degenerative lumbar spine disease.

Background Outcome selection in regional anesthesia and acute pain research is inconsistent, often lacking patient-centered priorities and validated instruments. We aimed to prioritize key outcomes and propose suitable measurement tools to improve the quality, consistency, and relevance of regional anesthesia research. Methods We conducted a multiround Delphi process, including two electronic voting rounds, a multiday in-person meeting, and a patient panel. Experts and patients evaluated existing and proposed outcomes for importance, validity, and relevance. Outcomes reaching ≥70% agreement were prioritized, and appropriate measurement instruments were identified. Results Thirty-two experts and three patients participated. Across three Delphi rounds, 10 outcomes were prioritized for future regional anesthesia research: seven efficacy outcomes (pain scores; opioid consumption; Brief Pain Inventory; functional outcomes; cognitive function; length of stay; block duration); two multidimensional outcomes (quality of recovery and development of a regional anesthesia-specific quality-of-recovery instrument); one safety outcome (chronic postsurgical pain). Patients prioritized cognitive recovery, function, chronic pain, and pain scores. Conclusions This consensus-based, patient-centered framework defines the core priorities for future regional anesthesia and acute pain research. Future work should focus on developing and validating a regional anesthesia-specific quality-of-recovery instrument, refining multidimensional measures such as functional recovery, cognitive outcomes, and the Brief Pain Inventory, and standardizing the reporting of chronic pain and opioid-related outcomes. Adoption of these priorities will enhance methodological consistency, comparability, and patient relevance in future clinical trials.

Treatment-induced ovarian function loss is a significant concern for many young patients with breast cancer. Accurately predicting this risk is crucial for counselling young patients and informing their fertility-related decision-making. However, current risk prediction models for treatment-related ovarian function loss have limitations. To provide a broader representation of patient cohorts and improve feature selection, we combined retrospective data from six datasets within the FoRECAsT (Infertility after Cancer Predictor) databank, including 2679 pre-menopausal women diagnosed with breast cancer. This combined dataset presented notable missingness, prompting us to employ cross imputation using the k-nearest neighbours (KNN) machine learning (ML) algorithm. Employing Lasso regression, we developed an ML model to forecast the risk of treatment-related amenorrhea as a surrogate marker of ovarian function loss at 12 months after starting chemotherapy. Our model identified 20 variables significantly associated with risk of developing amenorrhea. Internal validation resulted in an area under the receiver operating characteristic curve (AUC) of 0.820 (95% CI: 0.817–0.823), while external validation with another dataset demonstrated an AUC of 0.743 (95% CI: 0.666–0.818). A cutoff of 0.20 was chosen to achieve higher sensitivity in validation, as false negatives—patients incorrectly classified as likely to regain menses—could miss timely opportunities for fertility preservation if desired. At this threshold, internal validation yielded sensitivity and precision rates of 91.3% and 61.7%, respectively, while external validation showed 92.9% and 60.0%. Leveraging ML methodologies, we not only devised a model for personalised risk prediction of amenorrhea, demonstrating substantial enhancements over existing models but also showcased a robust framework for maximally harnessing available data sources.

Abstract Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome‐wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co‐development with hepatitis C virus‐negative (HCV‐negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV‐negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale heritability of each trait at 0.02 to ensure reliable inferences with adequate study power. Next, we observed significant positive genetic correlations between HCV‐negative HCC and blood‐based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between HCV‐negative HCC and diseases associated with metabolic dysfunction‐associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Taken together, our results help to identify polygenic and pleiotropic signals related to different phenotypic traits associated with HCC and support further exploration of the predictive power of blood‐based biomarkers identified in this study for inferring HCC development among HCV‐negative individuals.