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BACKGROUND: Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype. OBJECTIVE: A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials. METHODS: A cohort of 83 patients with Becker muscular dystrophy (5-75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes. RESULTS: Deletion mutations of dystrophin exons 45-47 or 45-48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter. CONCLUSIONS: There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset.

The Storms and Precipitation Across the continental Divide Experiment (SPADE) addressed key questions related to water availability and processes associated with water partitioning over a major continental divide using special [...]

On September 25 and 26, 2021, the Alzheimer's Association hosted the first meeting focused on people with early-onset Alzheimer's disease (EOAD)-sometimes referred to as younger onset Alzheimer's disease (AD). Though a diagnosis of AD can be devastating at any age, those with a younger onset-defined as symptoms developing prior to 65 years of age-face unique challenges. EOAD occurs when people are in the prime of their lives, often with multiple responsibilities including careers, community activities, and raising children and caring for older family members. These challenges warrant special consideration and study, yet people with EOAD are often excluded from AD research because of their atypical age of onset. To help fill this gap, we designed and launched the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) to enroll and follow 500 people with EOAD from > 15 sites in the United States, which the National Institute on Aging funded in 2018. The September 2021 meeting was designed to inform people with EOAD and their family members and caregivers about the latest research on the biology of EOAD, treatments in the pipeline, practical considerations about legal and financial arrangements for families, and the support networks available to them. More than 217 registrants attended.

Natural history museums are vital repositories of specimens, samples and data that inform about the natural world; this Formal Comment revisits a Perspective that advocated for the adoption of compassionate collection practices, querying whether it will ever be possible to completely do away with whole animal specimen collection.

Largely due to the small number of individuals in captivity, birds of prey remain an understudied, but promising, group for animal cognition research. Variations on the classic string-pulling task have been applied across species to evaluate abilities such as associative learning, means-end understanding, and insight problem solving. Previous research has examined only a few species of raptor on the task such as the Harris’s hawk, great grey owl, and turkey vulture. Here, we explored how 1-3 individuals from each of seven raptor species (turkey vulture, Cathartes aura; barn owl, Tyto alba; western screech owl, Megascops kennicottii; eastern screech owl, Megascops asio; red-tailed hawk, Buteo jamaicensis; Swainson’s hawk, Buteo swainsoni; and Harris’s hawk, Parabuteo unicinctus) responded to a standardized vertical apparatus. Our goal was to replicate, diversify, and extend the literature by documenting how these different species approached the same problem. Two strings were tied around a perch, one of which was baited. Birds underwent multiple 60-min trials. At least one bird from four of the seven species retrieved the food reward. Three individuals retrieved the food consistently across trials, including the first recorded solving by a western screech owl. Birds displayed diverse apparatus-directed behaviors and solving methods which supported our predictions regarding sociality and predation method. We frame our findings as a roadmap for future researchers studying physical problem-solving by raptors.

Abstract Background Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if energy intake is not controlled. Diazoxide choline extended-release (DCCR) tablets have previously been evaluated for their effects on hyperphagia and other behavioral complications of people with PWS in a Phase 3 placebo-controlled study of participants with PWS, age 4 and older with hyperphagia (C601) and in an open label extension study, C602. Methods To better understand the longer-term impact of DCCR, a cohort from PATH for PWS, a natural history study that enrolled participants with PWS age 5 and older, who met the C601 age, weight and baseline hyperphagia inclusion criteria and had 2 hyperphagia assessments ≥ 6 months apart, were compared to the C601/C602 cohort. Hyperphagia was measured using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT, range 0–36). The primary analysis used observed values with no explicit imputation of missing data. A sensitivity analysis was conducted in which all missing HQ-CT assessments in the C601/C602 cohort were assigned the highest possible value (36), representing the worst-case scenario. Other behavioral changes were assessed using the Prader-Willi Syndrome Profile questionnaire (PWSP). Results Relative to the PATH for PWS natural history study cohort, the DCCR-treated C601/C602 cohort showed significant improvements in HQ-CT score at 26 weeks (LSmean [SE] -8.3 [0.75] vs. -2.5 [0.43], p

Abstract Background Migraine is a highly prevalent neurological disease with a substantial societal burden due to lost productivity. From a societal perspective, we assessed the cost-effectiveness of eptinezumab for the preventive treatment of migraine. Methods An individual patient simulation of discrete competing events was developed to evaluate eptinezumab cost-effectiveness compared to best supportive care for adults in the United Kingdom with ≥ 4 migraine days per month and prior failure of ≥ 3 preventive migraine treatments. Individuals with sampled baseline characteristics were created to represent this population, which comprised dedicated episodic and chronic migraine subpopulations. Clinical efficacy, utility, and work productivity inputs were based on results from the DELIVER randomised controlled trial (NCT04418765). Timing of natural history events and treatment holidays—informed by the literature—were simulated to unmask any natural improvement of the disease unrelated to treatment. The primary outcomes were monthly migraine days, migraine-associated costs, quality-adjusted life years (QALYs), incremental cost-effectiveness ratio, and net monetary benefit, each evaluated over a 5-year time horizon from 2020. Secondary analyses explored a lifetime horizon and an alternative treatment stopping rule. Results Treatment with eptinezumab resulted in an average of 0.231 QALYs gained at a saving of £4,894 over 5 years, making eptinezumab dominant over best supportive care (i.e., better health outcomes and less costly). This result was confirmed by the probabilistic analysis and all alternative assumption scenarios under the same societal perspective. Univariate testing of inputs showed net monetary benefit was most sensitive to the number of days of productivity loss, and monthly salary. Conclusions This economic evaluation shows that from a societal perspective, eptinezumab is a cost-effective treatment in patients with ≥ 4 migraine days per month and for whom ≥ 3 other preventive migraine treatments have failed. Trial registration N/A. Graphical Abstract

Abstract Background Metachromatic leukodystrophy (MLD; OMIM 250100 and 249900) is a rare lysosomal storage disease caused by deficient arylsulfatase A activity, leading to accumulation of sulfatides in the nervous system. This systematic literature review aimed to explore the effect of MLD on the lives of patients. Methods The Ovid platform was used to search Embase, MEDLINE, and the Cochrane Library for articles related to the natural history, clinical outcomes, and burden of illness of MLD; congress and hand searches were performed using ‘metachromatic leukodystrophy’ as a keyword. Of the 531 publications identified, 120 were included for data extraction following screening. A subset of findings from studies relating to MLD natural history and burden of illness (n = 108) are presented here. Results The mean age at symptom onset was generally 16–18 months for late-infantile MLD and 6–10 years for juvenile MLD. Age at diagnosis and time to diagnosis varied widely. Typically, patients with late-infantile MLD presented predominantly with motor symptoms and developmental delay; patients with juvenile MLD presented with motor, cognitive, and behavioral symptoms; and patients with adult MLD presented with cognitive symptoms and psychiatric and mood disorders. Patients with late-infantile MLD had more rapid decline of motor function over time and lower survival than patients with juvenile MLD. Commonly reported comorbidities/complications included ataxia, epilepsy, gallbladder abnormalities, incontinence, neuropathy, and seizures. Conclusions Epidemiology of MLD by geographic regions, quantitative cognitive data, data on the differences between early- and late-juvenile MLD, and humanistic or economic outcomes were limited. Further studies on clinical, humanistic (i.e., quality of life), and economic outcomes are needed to help inform healthcare decisions for patients with MLD.

Beekeeping is an activity with positive effects for biodiversity and food security; furthermore, it is compatible with the conservation objectives of protected areas. Likewise, previous studies show that the participation of women in beekeeping projects gives them access to paid work and triggers the possibility of their empowerment. The aim of the article is to explore the process of women's empowerment as one of the social results that derives from the meliponic farmers and beekeepers' projects implemented in the protected area of the Usumacinta Canyon, Mexico. For this research project, visits were made to the places of honey production in the Usumacinta Canyon, notes were collected from participant observation and unstructured interviews were taken at the site. The findings indicate that the participation of women in these projects has given them access to material resources, such as earning income from their work, and they exhibited other dimensions of the empowerment process, in particular agency--the ability to define and achieve their goals. Keywords: Women's empowerment, Beekeeping, Usumacinta Canyon, Mexican women, Participant observation, Women's agency, Protected areas., Introduction Protected areas constitute a strategy in the conservation of biodiversity, the number and extension of which was promoted after the 1992 UN Conference on Environment and Development, mainly in [...]

As it enters the Gulf of Mexico, the shape-shifting stream of tropical water known as the Loop Current passes between the Yucatan Peninsula to the west and Cuba to the [...]

The age and growth of northern quahogs Mercenaria mercenariu (=hard clam) from inner Tokyo Bay, central Japan, were investigated by observing the annuli in their hinge teeth. The ages in the shallow and deep areas are 2-9+ and 1-13+, respectively. Significant differences in growth between clams found in the shallow and deep areas were detected. The growth coefficient and shell length of clams of a particular age in the shallow area were greater than those in the deep areas. Northern quahogs in both shallow and deep areas were confirmed to spawn around summer. A larger gonadosomatic index and a higher proportion of spawning individuals were found in shallow areas. These results indicate that shallow habitats provide enhanced conditions for somatic development in northern quahogs in this region. KEY WORDS: Mercenariu mercenaria, growth function, shell sectioning, INTRODUCTION The northern quahog (=hard clam Mercenaria mercenaria inhabits shallow water from the intertidal zones to approximately 10m depth (Walker & Tenore 1984, Walker & Sweeney-Reeves 2000). The native distribution [...]

Pregnant women with chronic hepatitis B (CHB) are a priority population for hepatitis B care. Identification of HBV status prior to pregnancy would facilitate timely maternal interventions and perinatal care. In our study, we aimed to study the epidemiology of CHB among women of childbearing age (WoCBA, 18–49 years) in Alberta, Canada. We retrospectively analysed Alberta Analytics databases to study CHB epidemiology, natural history and care linkage among WoCBA in Alberta, between April 2012 and March 2021. A Poisson regression was conducted to estimate incidence of newly identified CHB cases and prevalence trends, whereas predictors of care linkage were determined using logistic regression. Age/sex‐adjusted incidence of newly identified CHB among WoCBA between 2015 and 2020 was 36.2/100,000 person/years, highest among individuals aged 30–39 years. Incidence of newly identified CHB decreased from 52.6 to 18.2/100,000 between 2015 and 2020, but prevalence increased from 131.7 to 248.6/100,000 in the same period. Newly identified CHB incident cases (n = 2124) had lower survival rates than age/sex‐matched Canadians, with a standardized mortality ratio of 5.7 (95% CI 2.6–11.0). Increasing age (years) at diagnosis (HR, 1.2; 95% CI 1.1–1.3) was independently associated with mortality. Comorbid hepatocellular carcinoma, anti‐HBV treatment and year of diagnosis were not significantly associated with mortality. Of the 1927 women with 2436 hepatitis B surface antigen‐positive pregnancies from 2012 to 2020, only 27.6% had recommended HBV assessment during pregnancy. Of those women meeting criteria for antiviral therapy to prevent mother‐to‐child transmission (MTCT), only 66.4% received treatment. Suboptimal management during pregnancy and overall lower survival rates highlight the need to address care linkage barriers in women of childbearing age living with CHB. [ABSTRACT FROM AUTHOR]

LAMA2‐related dystrophies (LAMA2‐RD) constitute a rare neuromuscular disorder with a broad spectrum of phenotypic severity. Our understanding of the genotype–phenotype correlations in this condition remains incomplete, and reliable clinical data for clinical trial readiness is limited. In this retrospective study, we reviewed the genetic data and medical records of 114 LAMA2‐RD patients enrolled at seven research centers in Brazil. We identified 58 different pathogenic variants, including 21 novel ones. Six variants were more prevalent and were present in 81.5% of the patients. Notably, the c.1255del, c.2049_2050del, c.3976 C>T, c.5234+1G>A, and c.4739dup variants were found in patients unable to walk and without cortical malformation. In contrast, the c.2461A>C variant was present in patients who could walk unassisted. Among ambulatory patients, missense variants were more prevalent (p < 0.0001). Although no specific hotspot regions existed in the LAMA2, 51% of point mutations were in the LN domain, and 88% of the missense variants were found within this domain. Functional analysis was performed in one intronic variant (c.4960‐17C>A) and revealed an out‐of‐frame transcript, indicating that the variant creates a cryptic splicing site (AG). Our study has shed light on crucial phenotype–genotype correlations and provided valuable insights, particularly regarding the Latin American population. [ABSTRACT FROM AUTHOR]

Background: Onasemnogene abeparvovec has been approved for the treatment of spinal muscular atrophy 5q type 1 in several countries, which calls for an independent assessment of the evidence regarding efficacy and safety. Objective: Conduct a meta-analysis to assess the efficacy and safety of onasemnogene abeparvovec in patients diagnosed with SMA type 1, based on the available evidence. Methods: This article results from searches conducted on databases up to November 2022. Outcomes of interest were global survival and event-free survival, improvement in motor function and treatment-related adverse events. Risk of bias assessment and certainty of evidence were performed for each outcome. Proportional meta-analysis models were performed when applicable. Results: Four reports of three open-label, non-comparative clinical trials covering 67 patients were included. Meta-analyses of data available in a 12-month follow-up estimate a global survival of 97.56% (95%CI: 92.55 to 99.86, I2 = 0%, n = 67), an event-free survival of 96.5% (95%CI: 90.76 to 99.54, I2 = 32%, n = 66) and a CHOP-INTEND score ≥ 40 points proportion of 87.28% (95%CI: 69.81 to 97.83, I2 = 69%, n = 67). Proportion of 52.64% (95%CI: 27.11 to 77.45, I2 = 78%, n = 67) of treatment-related adverse events was estimated. Conclusion: The results indicate a potential change in the natural history of type 1 SMA, but the methodological limitations of the studies make the real extent of the technology's long-term benefits uncertain. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusion To report clinical and genetic characteristics of familial exudative vitreoretinopathy (FEVR) in the Finnish population.Detailed clinical and genetic data of 35 individuals with heterozygous pathogenic variants in FZD4 were gathered and analysed.Thirty‐two individuals with FZD4 c.313A>G variant and three individuals with FZD4 c.40_49del were included in the study. The clinical phenotype was variable even among family members with the same FZD4 variant. Only 34% (N = 12/35) of variant‐positive individuals had been clinically diagnosed with FEVR. The median age of the onset of symptoms was 2.3 years, ranging between 0 to 25 years. Median visual acuity was 0.1 logMAR (0.8 Snellen decimal), ranging between light perception and −0.1 logMAR (1.25 Snellen decimal). Most (N = 33/35, 94%) were classified as not visually impaired. Despite unilateral visual loss present in some, they did not meet the criteria of visual impairment according to the WHO classification. Two study patients (N = 2/35, 6%) had severe visual impairment. The most common FEVR stage in study patient's eyes (N = 28/70 eyes, 40%) was FEVR stage 1, that is, avascular periphery or abnormal vascularisation. Most of FZD4‐variant‐positive study patient's eyes (N = 31/50 eyes, 62%) were myopic. Two individuals presented with persistent hyperplastic primary vitreous expanding the phenotypic spectrum of FEVR. Shared haplotypes extending approximately 0.9 Mb around the recurrent FZD4 c.313A>G variant were identified.Most study patients were unaffected or had mild clinical manifestations by FEVR. Myopia seemed to be overly common in FZD4‐variant‐positive individuals. [ABSTRACT FROM AUTHOR]

TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype–phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The natural history of rectal intussusception (RI) is poorly understood. We hypothesized that decline in pelvic floor integrity and function leads to increasing RI grades. METHODS: Retrospective analysis of a registry of patients with defecatory disorders with high-resolution anorectal manometry and magnetic resonance defecography was performed. Association of risk factors on increasing RI grades was assessed using logistic regression. RESULTS: Analysis included a total of 238 women: 90 had noRI, 43 Oxford 1--2, 49 Oxford 3, and 56Oxford 4--5. Age (P 5 0.017), vaginal delivery (P 5 0.008), and prior pelvic surgery (P 5 0.032) were associated with increased Oxford grades. Obstructive defecation symptoms and dyssynergic defecation were observed at relatively high rates across groups. Increased RI grades were associated with less anal relaxation at simulated defecation yet, higher rates of normal balloon expulsion (P < 0.05), linked to diminished anal sphincter. Indeed, increased RI grades were associated with worsening fecal incontinence severity, attributed to higher rates of anal hypotension. Levator ani laxity, defined by increased levator hiatus length and its excessive descent at straining,was associated with increasing RI grades, independent of age, history of vaginal delivery, and pelvic surgeries and could independently predict increased RI grades. Concurrent anterior and posterior compartments, and visceral prolapse were associated with higher Oxford grades. DISCUSSION: Our data suggest that decline in pelvic floor integrity with abnormal levator ani laxity is associated with increased RI grades, a process that is independent of age, history of vaginal deliveries, and/or pelvic surgeries, and perhaps related to dyssynergic defecation. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The natural history of autoimmune gastritis (AIG) has been poorly described. In this study, we report the long-term natural history and clinical clustering of the full spectrum of AIG, from the potential to the complicated stage. METHODS: Prospective single-center study conducted in a tertiary referral center. Patients with AIG at any stage (0 5 potential; 1 5 early; 2 5 florid; 3 5 severe; and 4 5 complicated) were enrolled (January 2000--December 2022). The histopathological evolution, the clinical presentation, and the correlates of evolution of potential AIG were assessed. RESULTS: Four hundred ninety-eight patients with AIG (meanage 56.7615.2 years, F:M ratio 2.5:1) were included, of whom93 experienced potential AIG. Themaximum disease durationwas 27 years (median 18, interquartile range 14--23), while the overall median follow-up was 52 months (interquartile range 12--95). Age was significantly lower in stage 0 compared with that in the other stages. Accidental histologic evidence and hematologic findings were the most commonclusters of diagnosis. Theover all median rate of progression was 7.29 per 100 persons/yr (95% confidence interval [CI] 6.19--8.59), while the stage-specific rates of progression were 10.85 (stage 0; 95% CI 7.75--15.18), 14.83 (stages 1--2; 95% CI 11.89--18.49), and 2.68 (stage 3; 95% CI 1.88--3.84). Newly onset neoplastic complications at follow-up occurred in 41/483 patients (8.5%; 23 neuroendocrine tumors and 18 epithelial dysplasia). No cases of adenocarcinoma were noticed. Male sex was associated with a greater likelihood of evolving from potential AIG to overt AIG. DISCUSSION: AIG is a progressive disorder, with a virtually absent risk of gastric adenocarcinoma. Patients with potential AIG should be monitored because they carry a high risk of evolving into overt AIG. [ABSTRACT FROM AUTHOR]

Summary: Recursive partitioning of healthy consortia led to the development of the Clonal Hematopoiesis Risk Score (CHRS) for clonal haematopoiesis (CH); however, in the practical setting, most cases of CH are diagnosed after patients present with cytopenias or related symptoms. To address this real‐world population, we characterize the clinical trajectories of 94 patients with CH and distinguish CH harbouring canonical DNMT3A/TET2/ASXL1 mutations alone ('sole DTA') versus all other groups ('non‐sole DTA'). TET2, rather than DNMT3A, was the most prevalent mutation in the real‐world setting. Sole DTA patients did not progress to myeloid neoplasm (MN) in the absence of acquisition of other mutations. Contrastingly, 14 (20.1%) of 67 non‐sole DTA patients progressed to MN. CHRS assessment showed a higher frequency of high‐risk CH in non‐sole DTA (vs. sole DTA) patients and in progressors (vs. non‐progressors). RUNX1 mutation conferred the strongest risk for progression to MN (odds ratio [OR] 10.27, 95% CI 2.00–52.69, p = 0.0053). The mean variant allele frequency across all genes was higher in progressors than in non‐progressors (36.9% ± 4.62% vs. 24.1% ± 1.67%, p = 0.0064). This analysis in the post‐CHRS era underscores the natural history of CH, providing insight into patterns of progression to MN. [ABSTRACT FROM AUTHOR]

The article explores a specific type of paroxysmal nocturnal haemoglobinuria (PNH) known as ahemolytic PNH or white cell PNH. Unlike typical PNH, this subtype does not exhibit signs of hemolysis but is characterized by bone marrow failure and thrombophilia. The document suggests that this subtype may be caused by a PIGA mutation in a committed progenitor cell rather than a stem cell. The authors recommend considering screening for ahemolytic PNH in cases of thromboembolic events and bone marrow failure without hemolysis. [Extracted from the article]

Background: The natural history of spinal muscular atrophy (SMA) is well understood, with progressive muscle weakness resulting in declines in function. The development of contractures is common and negatively impacts function. Clinically, joint hypermobility (JH) is observed but is poorly described, and its relationship with function is unknown. Methods: Lower-limb ROM (range of motion) assessments of extension and flexion at the hip, knee, and ankle were performed. ROMs exceeding the published norms were included in the analysis. The functional assessments performed included the six-minute walk test (6 MWT) and the Hammersmith Functional Motor Scale—Expanded (HFMSE). Results: Of the 143 participants, 86% (n = 123) had at least one ROM measure that was hypermobile, and 22% (n = 32) had three or more. The HFMSE scores were inversely correlated with hip extension JH (r = −0.60, p = 0.21; n = 6) and positively correlated with knee flexion JH (r = 0.24, p = 0.02, n = 89). There was a moderate, inverse relationship between the 6 MWT distance and ankle plantar flexion JH (r = −0.73, p = 0.002; n = 15). Conclusions: JH was identified in nearly all participants in at least one joint in this study. Hip extension, knee flexion and ankle plantar flexion JH was associated with function. A further understanding of the trajectory of lower-limb joint ROM is needed to improve future rehabilitation strategies. [ABSTRACT FROM AUTHOR]

Background: Decades following the introduction of vincristine as treatment for haematological malignancies, vincristine-induced peripheral neuropathy (VIPN) remains a pervasive, untreatable side-effect. However there remains a gap in understanding the characteristics of VIPN in adults. This study presents a comprehensive phenotyping of VIPN. Methods: Adult patients (n = 57; age = 59.8 ± 14.6) were assessed cross-sectionally following completion of vincristine (months post treatment = 16.3 ± 15.6, cumulative dose = 7.6 ± 4.4), with a subset of 20 patients assessed prospectively during treatment. Patient reported measures (EORTC-QLQ-CIPN20, R-ODS) were used to profile symptoms and disability. Neurological assessment was undertaken using the Total Neuropathy Score and nerve conduction studies. Sensory threshold and fine motor tasks were also undertaken. Comparisons of data between timepoints were calculated using paired-sample t tests or Wilcoxon matched-pairs signed-rank test. Comparisons between outcome measures were calculated with independent sample t tests or Mann–Whitney U tests for non-parametric data. Results: The majority of patients developed VIPN by mid-treatment (77.8%, 7.0 ± 3.3 weeks post baseline) with the prevalence remaining stable by end-of-treatment (75%, 8.1 ± 1.7 weeks post mid-treatment). By 3 months post-completion, 50% of patients still reported VIPN although there were significant improvements on neurological grading and functional assessment (P < 0.05). VIPN presented with sensorimotor involvement in upper and lower limbs and was associated with decreased sensory and motor nerve amplitudes, reduced fine-motor function and increased disability. Conclusion: VIPN in adults presents as a sensorimotor, upper- and lower-limb neuropathy that significantly impacts disability and function. Neuropathy recovery occurs in a proportion of patients; however, VIPN symptoms may persist and continue to affect long-term quality of life. [ABSTRACT FROM AUTHOR]

While global patterns of bee diversity have been modelled, our understanding of fine‐scale regional patterns is more limited, particularly for under‐sampled regions such as Africa. South Africa is among the exceptions on the African continent; its bee fauna (ca. 1253 species) has been well collected and documented, including mass digitising of its natural history collections. It is a region with high floral diversity, high habitat heterogeneity and variable rainfall seasonality.Here, we combine a South African bee species distributional database (877 bee species) with a geospatial modelling approach to determine fine‐scale (~11 × 11 km grid cell resolution) hotspots of bee species richness, endemism and range‐restricted species.Our analyses, based on the probabilities of occurrence surfaces for each species across 108,803 two‐minute grid cells, reveal three bee hotspots of richness: Winter rainfall, Aseasonal rainfall and Early‐to‐late summer rainfall. These hotspots contain large numbers of endemic and geographically restricted taxa. Hotspots with particularly high bee diversity include the Fynbos, Succulent Karoo and Desert biomes; the latter showing 6–20 times more species per unit area than other biomes. Our results conform with global species‐area patterns: areas of higher‐than‐expected bee density are largely concentrated in Mediterranean and arid habitats.This study further enhances our knowledge in identifying regional and global hotspots of richness and endemism for a keystone group of insects and enabling these to be accounted for when setting conservation priorities. [ABSTRACT FROM AUTHOR]

Objectives: Many congenital hydronephroses spontaneously resolve. This study evaluated a long‐term follow‐up of more than 4 years of patients with congenital hydronephrosis at a single center. Methods: In total, 215 patients (286 kidneys) with congenital hydronephrosis were included. Hydronephrosis outcomes (resolution, improvement, and persistence) and time‐to‐outcome were evaluated. Results: Fourteen patients underwent early surgical intervention until the age of 2 years. A total of 189 congenital hydronephrosis cases (66%) showed resolution at a median of 16 months (interquartile range: 7–21 months) and 169 (80%) of 210 kidneys with grade I to II hydronephrosis showed resolution at a median of 14 months (interquartile range: 6–23 months). Of 76 kidneys with grade III to IV hydronephrosis, 24 (32%) showed resolution at a median of 29 months (interquartile range: 24–41 months), and 56 (74%) showed improvement to grade II or less at a median of 12 months (interquartile range: 5–23 months). Of the 76 kidneys with grade III to IV hydronephrosis, five required delayed pyeloplasty at a median of 66 months (interquartile range: 42–89 months). One patient was asymptomatic, with a marked worsening of hydronephrosis and decreased renal function 6 years after the resolution of hydronephrosis. Conclusions: None of the patients with grade I to II hydronephrosis required surgical treatment, and a shorter follow‐up may be sufficient. Grade III to IV severe hydronephrosis should be considered for a longer and more careful follow‐up, given the possibility of asymptomatic exacerbation of hydronephrosis. [ABSTRACT FROM AUTHOR]

Regulatory marketing authorisation is not enough to ensure patient access to new medicinal products. Health Technology Assessment bodies may require data on effectiveness, relative effectiveness, and cost-effectiveness. Healthcare systems may require data on clinical utility, savings, and budget impact. Furthermore, the exact requirements of these bodies vary country by country and sometimes even region to region, resulting in a patchwork of different data requirements to achieve effective, reimbursed patient access to new therapies. In addition, clinicians require data to make informed clinical management decisions. This requirement is of key importance in rare diseases where there is often limited data and clinical experience at the time of regulatory approval. This paper describes an innovative initiative that is called Project SATURN: Systematic Accumulation of Treatment practices and Utilization, Real world evidence, and Natural history data for the rare disease Osteogenesis Imperfecta. The objective of this project is to generate a common core dataset by utilising existing data sources to meet the needs of the various stakeholders and avoiding fragmentation through multiple approaches (e.g., a series of individual national requests/approaches, and unconnected with the regulators' potential requirements). It is expected that such an approach will reduce the time for patient access to life-changing medications. Whilst Project SATURN applies to Osteogenesis Imperfecta, it is anticipated that the principles could also be applied to other rare diseases and reduce the time for patient access to new medications. [ABSTRACT FROM AUTHOR]

Newborn screening for 5qSMA offers the potential for early, ideally pre-symptomatic, therapeutic intervention. However, limited data exist on the outcomes of individuals with 4 copies of SMN2, and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of SMN2 from the SMArtCARE registry in Germany, Austria and Switzerland. Inclusion criteria required comprehensive baseline data and diagnosis outside of newborn screening. Only data prior to initiation of disease-modifying treatment were included. The median age at disease onset was 3.0 years, with a mean of 6.4 years. Significantly, 55% of patients experienced symptoms before the age of 36 months. 3% never learned to sit unaided, a further 13% never gained the ability to walk independently and 33% of ambulatory patients lost this ability during the course of the disease. 43% developed scoliosis, 6.3% required non-invasive ventilation and 1.1% required tube feeding. In conclusion, our study, in line with previous observations, highlights the substantial phenotypic heterogeneity in SMA. Importantly, this study provides novel insights: the median age of disease onset in patients with 4 SMN2 copies typically occurs before school age, and in half of the patients even before the age of three years. These findings support a proactive approach, particularly early treatment initiation, in this subset of SMA patients diagnosed pre-symptomatically. However, it is important to recognize that the register will not include asymptomatic individuals. [ABSTRACT FROM AUTHOR]

• The paper provides a revision of the existing protocols for videofluoroscopy and discussion on which one should be used in routine clinical practice and in research settings. • The interprofessional routine assessments of bulbar function, with a review of the recent clinical tools specifically developed for SMA and on the assessments performed by speech and language therapists/pathologists in the new SMA phenotypes is provided. • As the new therapies have changed the natural history particular attention should be paid to rehabilitation for bulbar dysfunction. Progressive bulbar involvement is frequent in spinal muscular atrophy, with prevalence and severity of deficits associated with type. The report provides an overview of the presentations made at the workshop grouped into 4 sessions: the first section was dedicated to videofluoroscopy with a revision of the existing protocols and discussion on which one should be used in routine clinical practice and in research settings. The second session was dedicated to interprofessional routine assessments of bulbar function, with a review of the recent clinical tools specifically developed for SMA. The third section was focused on the assessments performed by speech and language therapists/pathologists in the new SMA phenotypes. The last section focused on how the new therapies have changed the approach in rehabilitation for bulbar dysfunction. Finally, we present the consensus that was achieved on these aspects and possible action points from these. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To describe the natural history of diabetes in Indians. RESEARCH DESIGN AND METHODS: Data are from participants older than 20 years in the Centre for Cardiometabolic Risk Reduction in South Asia longitudinal study. Glycemic states were defined per American Diabetes Association criteria. Markov models were used to estimate annual transition probabilities and sojourn time through states. RESULTS: Among 2,714 diabetes-free participants, 641 had isolated impaired fasting glucose (iIFG), and 341 had impaired glucose tolerance (IGT). The annual transition to diabetes for those with IGT was 13.9% (95% CI 12.0, 15.9) versus 8.6% (7.3, 9.8) for iIFG. In the normoglycemia ↔ iIFG → diabetes model, mean sojourn time in normoglycemia was 40.3 (34.6, 48.2) years, and sojourn time in iIFG was 9.7 (8.4, 11.4) years. For the normoglycemia ↔ IGT → diabetes model, mean sojourn time in normoglycemia was 34.5 (29.5, 40.8) years, and sojourn time in IGT was 6.1 (5.3, 7.1) years. CONCLUSIONS: Individuals reside in normoglycemia for 35–40 years; however, progression from prediabetes to diabetes is rapid. [ABSTRACT FROM AUTHOR]

The 2023 Marburg virus disease outbreaks in Equatorial Guinea and Tanzania highlighted the importance of better understanding this lethal pathogen. We did a systematic review (PROSPERO CRD42023393345) of peer-reviewed articles reporting historical outbreaks, modelling studies, and epidemiological parameters focused on Marburg virus disease. We searched PubMed and Web of Science from database inception to March 31, 2023. Two reviewers evaluated all titles and abstracts with consensus-based decision making. To ensure agreement, 13 (31%) of 42 studies were double-extracted and a custom-designed quality assessment questionnaire was used for risk of bias assessment. We present detailed information on 478 reported cases and 385 deaths from Marburg virus disease. Analysis of historical outbreaks and seroprevalence estimates suggests the possibility of undetected Marburg virus disease outbreaks, asymptomatic transmission, or cross-reactivity with other pathogens, or a combination of these. Only one study presented a mathematical model of Marburg virus transmission. We estimate an unadjusted, pooled total random effect case fatality ratio of 61·9% (95% CI 38·8–80·6; I2=93%). We identify epidemiological parameters relating to transmission and natural history, for which there are few estimates. This systematic review and the accompanying database provide a comprehensive overview of Marburg virus disease epidemiology and identify key knowledge gaps, contributing crucial information for mathematical models to support future Marburg virus disease epidemic responses. [ABSTRACT FROM AUTHOR]

Autonomous sensors provide opportunities to observe organisms across spatial and temporal scales that humans cannot directly observe. By processing large data streams from autonomous sensors with deep learning methods, researchers can make novel and important natural history discoveries. In this study, we combine automated acoustic monitoring with deep learning models to observe breeding-associated activity in the endangered Sierra Nevada yellow-legged frog (Rana sierrae), a behavior that current surveys do not measure. By deploying inexpensive hydrophones and developing a deep learning model to recognize breeding-associated vocalizations, we discover three undocumented R. sierrae vocalization types and find an unexpected temporal pattern of nocturnal breeding-associated vocal activity. This study exemplifies how the combination of autonomous sensor data and deep learning can shed new light on species' natural history, especially during times or in locations where human observation is limited or impossible. [ABSTRACT FROM AUTHOR]

Objective: Rathke cleft cysts (RCCs) are benign, epithelial-lined sellar lesions that arise from remnants of the craniopharyngeal duct. Due to their rarity in the pediatric population, data are limited regarding the natural history and optimal management of growing or symptomatic RCCs. We present our institutional experience with the surgical management of RCCs. Methods: We performed a retrospective study of consecutive RCC patients ≤ 18 years old treated surgically at our institution between 2006 and 2022. Results: Overall, 567 patients with a diagnosis of pituitary mass or cyst were identified. Of these, 31 had a histopathological diagnosis of RCC, 58% female and 42% male. The mean age was 13.2 ± 4.2 years. Presenting symptoms included headache (58%), visual changes (32%), and endocrinopathies or growth delay (26%); 13% were identified incidentally and subsequently demonstrated growth on serial imaging. Six percent presented with symptomatic intralesional hemorrhage. Surgical approach was transsphenoidal for 90% of patients and orbitozygomatic for 10%. Preoperative headaches resolved in 61% of patients and preoperative visual deficits improvement in 55% after surgery. New pituitary axis deficits were seen in 9.7% of patients. Only two complications occurred from a first-time surgery: one cerebrospinal fluid leak requiring lumbar drain placement, and one case of epistaxis requiring cauterization. No patients experienced new visual or neurological deficits. Patients were followed postoperatively with serial imaging at a mean follow-up was 62.9 ± 58.4 months. Recurrence requiring reoperation occurred in 32% of patients. Five-year progression-free survival was 47.9%. Except for one patient with multiple neurological deficits from a concurrent tectal glioma, all patients had a modified Rankin Scale score of 0 or 1 (good outcome) at last follow-up. Conclusion: Due to their secretory epithelium, pediatric RCCs may demonstrate rapid growth and can cause symptoms due to local mass effect. Surgical management of symptomatic or growing pediatric RCCs via cyst fenestration or partial resection of the cyst wall can be performed safely, with good neurologic outcomes. There is a nontrivial risk of endocrinologic injury, and long-term follow up is needed due to high recurrence rates. [ABSTRACT FROM AUTHOR]

Purpose: Given that syrinx is often considered an indication of surgery in children with Chiari I malformation (CM1), understanding of the natural history of these patients is very challenging. In this study, we investigate the natural history of children with CM1 that have syrinx and/or prominence of the central canal on presentation. Methods: All pediatric Chiari I patients who had syrinx and/or prominence of the central canal who underwent MR imaging of the head and spine from 2007 to 2020 were reviewed. Patients were divided into 3 groups (early surgery, delayed surgery, and conservative management). We focused on those patients who did not initially undergo surgery and had at least 1 year of clinical follow-up. We assessed if there were any radiological features that would correlate with need for delayed surgical intervention. Results: Thirty-seven patients met the inclusion criteria. Twenty-one patients were female and 16 were male. The mean age at presentation was 8.7 (5.8 SD). Fourteen (38%) patients had early surgical intervention, with a mean of 2.5 months after initial presentation, 8 (16%) had delayed surgery due to new or progressive neurological symptoms and 46% of patients did not require intervention during follow-up. The length of tonsillar herniation and the position of the obex were associated with the need of surgery in patients who were initially treated conservatively. Conclusion: In pediatric patients with CM1 with syringomyelia and prominence of the central canal, conservative treatment is initially appropriate when symptoms are absent or mild. Close follow-up of patients with CM1 and dilatation of the central canal who have an obex position below the foramen magnum and greater tonsillar herniation is suggested, as these patients show a trend towards clinical deterioration over time and may require earlier surgical intervention. [ABSTRACT FROM AUTHOR]

Pediatric pial arteriovenous shunts in the brain and spine are challenging to understand because of low incidence, variable presentation, and associations with genetic syndromes. What is known about their natural history comes from reviews of small series. To better understand the natural history and role for intervention, two cases are presented followed by a review of the literature. In the first case, an infant with a prior history of intracranial hemorrhage from a ruptured pial fistula returns for elective embolization for a second pial fistula which was found to be spontaneously thrombosed 2 weeks later. In the second case, a 5-year-old with a vertebro-vertebral fistula, identified on work up for a heart murmur and documented with diagnostic angiography, is brought for elective embolization 6 weeks later where spontaneous thrombosis is identified. In reviewing the literature on pediatric single-hole fistulae of the brain and spine, the authors offer some morphologic considerations for identifying which high-flow fistulae may undergo spontaneous thrombosis to decrease the potentially unnecessary risk associated with interventions in small children. [ABSTRACT FROM AUTHOR]

Aim: Intraspecific genetic variation is key for adaptation and survival in changing environments and is known to be influenced by many factors, including population size, dispersal and life‐history traits. We investigated genetic variation within Neotropical amphibian species to provide insights into how natural history traits, phylogenetic relatedness, climatic and geographic characteristics can explain intraspecific genetic diversity. Location: Neotropics. Taxon: Amphibians. Methods: We assembled data sets using open‐access databases for natural history traits, genetic sequences, phylogenetic trees, climatic and geographic data. For each species, we calculated overall nucleotide diversity (π) and tested for isolation by distance (IBD) and isolation by environment (IBE). We then identified predictors of π, IBD and IBE using random forest (RF) regression or RF classification. We also fitted phylogenetic generalized linear mixed models (PGLMMs) to predict π, IBD and IBE. Results: We compiled 4052 mitochondrial DNA sequences from 256 amphibian species (230 frogs and 26 salamanders), georeferencing 2477 sequences from 176 species that were not linked to occurrence data. RF regressions and PGLMMs were congruent in identifying range size and precipitation (σ) as the most important predictors of π, influencing it positively. RF classification and PGLMMs identified minimum elevation as an important predictor of IBD; most species without IBD tended to occur at higher elevations. Maximum latitude and precipitation (σ) were the best predictors of IBE, and most species without IBE occur at lower latitudes and in areas with more variable precipitation. Main Conclusions: This study identified predictors of genetic variation in Neotropical amphibians using both machine learning and phylogenetic methods. This approach was valuable to determine which predictors were congruent between methods. We found that species with small ranges or living in zones with less variable precipitation tended to have low genetic diversity. We also showed that Western Mesoamerica, Andes and Atlantic Forest biogeographic units harbour high diversity across many species that should be prioritized for protection. These results could play a key role in the development of conservation strategies for Neotropical amphibians. [ABSTRACT FROM AUTHOR]

Diet studies of cracids have highlighted the group's significance as seed dispersers and the impact of their disappearance from natural environments. However, the diet of Penelope jacucaca remains largely unknown, limiting our understanding of its natural history and potential ecosystem services. In this study, we investigated the diet of P. jacucaca in two Caatinga fragments with varying levels of preservation using fecal material analysis. The diet of the species consisted primarily of fruits, flowers, and leaves, comprising a total of 22 food items. The number of seeds found in individual fecal samples exhibited a negative correlation with individual seed masses. The species demonstrated a preference for zoocoric fruits of different sizes from the local vegetation. The diet varied between the sampled areas, suggesting that P. jacucaca exhibits dietary flexibility based on local vegetation. However, it is also possible that fragmentation affects the nutritional value of the species' diet. Due to its large body size, the White-browed guan can ingest a wide variety of fruits, including larger ones, incorporating seeds that are rarely explored by other birds. We propose that plant species with "large" seeds (> 15 mm), such as Ziziphus joazeiro, Brosimum gaudichaudii, and Ximenia americana, would be mainly negatively affected by the absence of P. jacucaca in the studied areas. The decline in the population of this important seed disperser in the region is likely to have negative implications for the viability of many zoocoric plants, thereby posing a threat to the vegetation of the studied fragments. [ABSTRACT FROM AUTHOR]

Mutations in the CLN6 gene cause late infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disease of childhood onset. Clinically, individuals present with progressive motor and cognitive regression, ataxia, and early death. The aim of this study is to establish natural history data of individuals with classic, late-infantile-onset (age less than five years) CLN6 disease. We analyzed the natural history of 25 patients with late-infantile-onset CLN6, utilizing the Hamburg motor-language scale to measure disease progression. The key outcomes were CLN6 disease progression, assessed by rate of decline in motor and language clinical domain summary scores (0 to 6 total points); onset and type of first symptom; onset of first seizure; and time from first symptom to complete loss of function. Median age of total motor and language onset of decline was 42 months (interquartile range 36 to 48). The estimated rate of decline in total score was at a slope of −1.20 (S.D. 0.30) per year, after the start of decline. Complete loss of both motor and language function was found to be, on average, 88.1 months (S.D. 13.5). To our knowledge, this is the largest international study that monitors the longitudinal natural history and progression of CLN6 disease. These data may serve as a template for future interventional trials targeted to slow the progression of this devastating disease. [ABSTRACT FROM AUTHOR]

Background: Genetic, lifestyle, reproductive, and anthropometric factors are associated with the risk of developing breast cancer. However, it is not yet known whether polygenic risk score (PRS) and absolute risk based on a combination of risk factors are associated with the risk of progression of breast cancer. This study aims to estimate the distribution of sojourn time (pre‐clinical screen‐detectable period) and mammographic sensitivity by absolute breast cancer risk derived from polygenic profile and the other risk factors. Methods: The authors used data from a population‐based case‐control study. Six categories of 10‐year absolute risk based on different combinations of risk factors were derived using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm. Women were classified into low, medium, and high‐risk groups. The authors constructed a continuous‐time multistate model. To calculate the sojourn time, they simulated the trajectories of subjects through the disease states. Results: There was little difference in sojourn time with a large overlap in the 95% confidence interval (CI) between the risk groups across the six risk categories and PRS studied. However, the age of entry into the screen‐detectable state varied by risk category, with the mean age of entry of 53.4 years (95% CI, 52.2–54.1) and 57.0 years (95% CI, 55.1–57.7) in the high‐risk and low‐risk women, respectively. Conclusion: In risk‐stratified breast screening, the age at the start of screening, but not necessarily the frequency of screening, should be tailored to a woman's risk level. The optimal risk‐stratified screening strategy that would improve the benefit‐to‐harm balance and the cost‐effectiveness of the screening programs needs to be studied. The age at which individuals with breast cancer enter a screen‐detectable state, as opposed to the length of time spent in that state, varied by absolute risk group. [ABSTRACT FROM AUTHOR]

Background and purpose: The conceptualization of brain death (BD) was pivotal in the shaping of judicial and medical practices. Nonetheless, media reports of alleged recovery from BD reinforced the criticism that this construct is a self‐fulfilling prophecy (by treatment withdrawal or organ donation). We meta‐analyzed the natural history of BD when somatic support (SS) is maintained. Methods: Publications on BD were eligible if the following were reported: aggregated data on its natural history with SS; and patient‐level data that allowed censoring at the time of treatment withdrawal or organ donation. Endpoints were as follows: rate of somatic expiration after BD with SS; BD misdiagnosis, including "functionally brain‐dead" patients (FBD; i.e. after the pronouncement of brain‐death, ≥1 findings were incongruent with guidelines for its diagnosis, albeit the lethal prognosis was not altered); and length and predictors of somatic survival. Results: Forty‐seven articles were selected (1610 patients, years: 1969–2021). In BD patients with SS, median age was 32.9 years (range = newborn–85 years). Somatic expiration followed BD in 99.9% (95% confidence interval = 89.8–100). Mean somatic survival was 8.0 days (range = 1.6 h–19.5 years). Only age at BD diagnosis was an independent predictor of somatic survival length (coefficient = −11.8, SE = 4, p < 0.01). Nine BD misdiagnoses were detected; eight were FBD, and one newborn fully recovered. No patient ever recovered from chronic BD (≥1 week somatic survival). Conclusions: BD diagnosis is reliable. Diagnostic criteria should be fine‐tuned to avoid the small incidence of misdiagnosis, which nonetheless does not alter the prognosis of FBD patients. Age at BD diagnosis is inversely proportional to somatic survival. [ABSTRACT FROM AUTHOR]

Introduction Material and Methods Results Conclusions There is a gap in knowledge regarding development of endometriosis and adenomyosis lesions visible at transvaginal ultrasound. The objectives were to evaluate if women with symptoms suggestive of endometriosis or adenomyosis but normal ultrasound examination develop endometriosis or adenomyosis lesions visible at ultrasound over time and if alterations of symptoms over time are associated with ultrasound findings at follow‐up.This was a prospective cohort study of 100 symptomatic women with normal initial ultrasound examination during 2014–2017 who underwent follow‐up ultrasound examination in 2022. Symptoms suggestive of endometriosis were assessed using visual analog scale at both examinations and minimal clinically important difference of 10 mm was considered as a significant alteration. An examiner with expertise in advanced ultrasound examination of endometriosis performed transvaginal ultrasound examinations in accordance with the consensus protocol by the International Deep Endometriosis Analysis group.At follow‐up ultrasound examination of 100 women, 13 (13% [95% CI 7.1–21.2]) had visible endometriosis or adenomyosis lesions, 8 (8% [95% CI 3.5–15.2]) had endometriosis lesions, and 6 (6% [95% CI 2.2–12.6]) had adenomyosis. At follow‐up, women with endometriosis or adenomyosis lesions reported lower intensity of dysmenorrhea and chronic pelvic pain compared to women without lesions (48 mm [IQR 16–79] vs. 73 mm [IQR 46–85] and 45 mm [IQR 26–57] vs. 57 mm [IQR 36–75], p = 0.087 and p = 0.026, respectively). None of the women with endometriosis or adenomyosis lesions reported increased intensity of dysmenorrhea at follow‐up, compared to 32/86 women (37%) without lesions (p = 0.008). Increased intensity of chronic pelvic pain tended to be less common in women with lesions compared to those without (3/13 [23%] vs. 35/86 [41%], p = 0.223).Our findings suggest that in symptomatic women, endometriosis and adenomyosis lesions visible at ultrasound may develop over time. However, majority of women remain having normal ultrasound examinations despite symptoms. Exacerbation of dysmenorrhea or chronic pelvic pain during follow‐up was not associated with the development of endometriosis or adenomyosis lesions visible at ultrasound, suggesting that even women with less severe symptoms might benefit from a follow‐up ultrasound when indicated. [ABSTRACT FROM AUTHOR]

Among phytophagous insects, life history often evolves as a strategy to cope with seasonality in host plant availability. Whereas specialization often leads to dormancy, aestivation, or longevity, polyphagous species bridge between periods of host availability by exploiting alternative host plants. The aim of the present work was to characterize the life histories of four species of specialist and generalist uni‐ and multivoltine frugivorous fruit flies – Ceratitis capitata Wiedemann, Anastrepha fraterculus Wiedemann, Rhagoletis blanchardi Aczel, and Rhagoletotrypeta pastranai Aczel (all Diptera: Tephritidae) – inhabiting in sympatry in Las Yungas phytogeographical province in Tucumán (northwestern Argentina). For this purpose, infested host plant fruits were sequentially collected during two consecutive years, and flies recovered from these fruits were subjected to demographic experiments to establish longevity and overwintering mechanisms. The results indicated that life cycles were tightly related to host fruit availability, where multivoltine species sequentially exploit different host plants over the year, whereas univoltine species must undergo pupal dormancy to reach the next host fructification period and may extend the duration of dormancy when climatic conditions are acyclic and unpredictable. The present study may broaden knowledge about diapausing Tephritidae in subtropical regions and may contribute to an increased conceptual basis for the improvement of pest control strategies, such as the sterile insect technique (SIT). [ABSTRACT FROM AUTHOR]

Genomes contain conserved non-coding sequences that perform important biological functions, such as gene regulation. We present a phylogenetic method, PhyloAcc-C, that associates nucleotide substitution rates with changes in a continuous trait of interest. The method takes as input a multiple sequence alignment of conserved elements, continuous trait data observed in extant species, and a background phylogeny and substitution process. Gibbs sampling is used to assign rate categories (background, conserved, accelerated) to lineages and explore whether the assigned rate categories are associated with increases or decreases in the rate of trait evolution. We test our method using simulations and then illustrate its application using mammalian body size and lifespan data previously analyzed with respect to protein coding genes. Like other studies, we find processes such as tumor suppression, telomere maintenance, and p53 regulation to be related to changes in longevity and body size. In addition, we also find that skeletal genes, and developmental processes, such as sprouting angiogenesis, are relevant. Author summary: Biologists hope to use data from diverse species to identify the genetic basis of continuous traits such as lifespan or beak shape. To do so, they need methodologies that relate genotypic and phenotypic evolution, while taking account of the relationship between species. The practice of integrating data from many species in this systematic way is relatively new, and existing approaches to the problem are often ad hoc, focus on protein coding genes, or involve discretizing continuous measurements. We avoid these limitations and develop a statistical model and software package that can be used to rapidly analyze alignments with respect to a continuous trait. Our method is illustrated by describing 136,859 conserved non-coding elements from 61 mammalian species with respect to the trait 'long-lived and large-bodied'. We report on the loci highlighted by our model and describe how our results compare to recent studies taking other methodological approaches. We suggest approaches like ours are an important step towards realizing the potential of data collected from across the animal kingdom, whether the aim is to increase our understanding of natural history or to better understand human biology. [ABSTRACT FROM AUTHOR]

Accurately determining the diet of wild animals can be challenging if food items are small, visible only briefly, or rendered visually unidentifiable in the digestive system. In some food caching species, an additional challenge is determining whether consumed diet items have been previously stored or are fresh. The Canada jay (Perisoreus canadensis) is a generalist resident of North American boreal and subalpine forests with anatomical and behavioural adaptations allowing it to make thousands of arboreal food caches in summer and fall that are presumably responsible for its high winter survival and late winter/early spring breeding. We used DNA fecal metabarcoding to obtain novel information on nestling diets and compiled a dataset of 662 published and unpublished direct observations or stomach contents identifications of natural foods consumed by Canada jays throughout the year. We then used detailed natural history information to make informed decisions on whether each item identified to species in the diets of winter adults and nestlings was best characterized as 'likely cached', 'likely fresh' (i.e., was available as a non-cached item when it appeared in a jay's feces or stomach), or 'either possible'. Of the 87 food items consumed by adults in the winter, 39% were classified as 'likely cached' and 6% were deemed to be 'likely fresh'. For nestlings, 29% of 125 food items identified to species were 'likely cached' and 38% were 'likely fresh'. Our results support both the indispensability of cached food for Canada jay winter survival and previous suggestions that cached food is important for late winter/early spring breeding. Our work highlights the value of combining metabarcoding, stomach contents analysis, and direct observations to determine the cached vs. non-cached origins of consumed food items and the identity of food caches, some of which could be especially vulnerable to degradation through climate change. [ABSTRACT FROM AUTHOR]

The natural history of moderate/severe atrial functional mitral regurgitation (AFMR) is unknown. The authors sought to study the incidence of left ventricular (LV) systolic dysfunction (LVSD), progression or regression of ≥mild-moderate AFMR, and impact on mortality. Adults with left atrial (LA) volume index ≥40 mL/m2, ≥mild-moderate AFMR, and follow-up echocardiogram were followed for incident LVSD (ejection fraction <50% and ≥10% lower than baseline), progression of mild-moderate/moderate AFMR to severe, and persistent regression of AFMR to no/trivial. Relation of AFMR progression or regression as time-dependent covariates with all-cause mortality was studied. Incidence of LVSD was compared with patients with no/mild AFMR matched on age, sex, comorbidities and ejection fraction. Patients were followed until mitral intervention, myocardial infarction, or last follow-up. A total of 635 patients (median age 75 years, 51% female, 96% mild-moderate/moderate AFMR, 4% severe AFMR) were included. Over a median 2.2 years (Q1-Q3: 1.0-4.3 years), incidence rates per 100 person-years were 3.2 for LVSD (P = 0.52 vs patients with no/mild AFMR), 1.9 for progression of AFMR, and 3.9 for regression. Female sex and larger LA volume index were independently associated with progression, whereas younger age, male sex, absent atrial fibrillation, and higher LA emptying fraction were independently associated with regression. Neither AFMR progression nor regression was independently associated with mortality. Instead, independent risk factors for mortality included older age, concentric LV geometry, and higher estimated LV filling and pulmonary pressures. In patients with predominantly mild-moderate/moderate AFMR, regression of MR was more common than progression, but neither was associated with mortality. Instead, diastolic function abnormalities were more important. Over a median 2-year follow-up, LVSD risk was not increased. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Migraine is a highly prevalent neurological disease with a substantial societal burden due to lost productivity. From a societal perspective, we assessed the cost-effectiveness of eptinezumab for the preventive treatment of migraine. Methods: An individual patient simulation of discrete competing events was developed to evaluate eptinezumab cost-effectiveness compared to best supportive care for adults in the United Kingdom with ≥ 4 migraine days per month and prior failure of ≥ 3 preventive migraine treatments. Individuals with sampled baseline characteristics were created to represent this population, which comprised dedicated episodic and chronic migraine subpopulations. Clinical efficacy, utility, and work productivity inputs were based on results from the DELIVER randomised controlled trial (NCT04418765). Timing of natural history events and treatment holidays—informed by the literature—were simulated to unmask any natural improvement of the disease unrelated to treatment. The primary outcomes were monthly migraine days, migraine-associated costs, quality-adjusted life years (QALYs), incremental cost-effectiveness ratio, and net monetary benefit, each evaluated over a 5-year time horizon from 2020. Secondary analyses explored a lifetime horizon and an alternative treatment stopping rule. Results: Treatment with eptinezumab resulted in an average of 0.231 QALYs gained at a saving of £4,894 over 5 years, making eptinezumab dominant over best supportive care (i.e., better health outcomes and less costly). This result was confirmed by the probabilistic analysis and all alternative assumption scenarios under the same societal perspective. Univariate testing of inputs showed net monetary benefit was most sensitive to the number of days of productivity loss, and monthly salary. Conclusions: This economic evaluation shows that from a societal perspective, eptinezumab is a cost-effective treatment in patients with ≥ 4 migraine days per month and for whom ≥ 3 other preventive migraine treatments have failed. Trial registration: N/A. [ABSTRACT FROM AUTHOR]

FXTAS is a neurodegenerative disorder occurring in some Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene premutation carriers (PMCs) and is characterized by cerebellar ataxia, tremor, and cognitive deficits that negatively impact balance and gait and increase fall risk. Dual-tasking (DT) cognitive-motor paradigms and challenging balance conditions may have the capacity to reveal markers of FXTAS onset. Our objectives were to determine the impact of dual-tasking and sensory and stance manipulation on balance in FXTAS and potentially detect subtle postural sway deficits in FMR1 PMCs who are asymptomatic for signs of FXTAS on clinical exam. Participants with FXTAS, PMCs without FXTAS, and controls underwent balance testing using an inertial sensor system. Stance, vision, surface stability, and cognitive demand were manipulated in 30 s trials. FXTAS participants had significantly greater total sway area, jerk, and RMS sway than controls under almost all balance conditions but were most impaired in those requiring vestibular control. PMCs without FXTAS had significantly greater RMS sway compared with controls in the feet apart, firm, single task conditions both with eyes open and closed (EC) and the feet together, firm, EC, DT condition. Postural sway deficits in the RMS postural sway variability domain in asymptomatic PMCs might represent prodromal signs of FXTAS. This information may be useful in providing sensitive biomarkers of FXTAS onset and as quantitative balance measures in future interventional trials and longitudinal natural history studies. [ABSTRACT FROM AUTHOR]