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Our aim was to assess the visual outcomes of patients with Leber hereditary optic neuropathy (LHON) harboring the m.11778G>A MT-ND4 mutation who had no treatment (natural history) or received idebenone or lenadogene nolparvovec. Efficacy outcomes included clinically relevant recovery (CRR) from nadir and final best-corrected visual acuity (BCVA). For the natural history and idebenone groups, we performed a systematic review of the literature and available clinical/regulatory reports. For the lenadogene nolparvovec group, all data from phase 3 studies were included. The overall effect and its 95 % confidence interval (CI) were estimated using a random effects model. For each meta-analysis, patients had a mean age of approximately 30 years at vision loss and were mostly (≥78 %) men. The CRR from nadir [95 % CI] at eye level was 17 % [7 %; 30 %] (n=316 eyes), 31 % [24 %; 40 %] (n=313) and 59 % [54 %; 64 %] (n=348) in untreated, idebenone-treated and lenadogene nolparvovec-treated patients, respectively. This gradient of efficacy was also observed with CRR at the patient level and final BCVA. There was a gradient of efficacy in all assessed visual outcomes, more marked for CRR than for final BCVA, with lenadogene nolparvovec gene therapy superior to idebenone treatment, and both superior to the natural history of the disease. • LHON caused by the MT-ND4 mutation can severely impact visual acuity in both eyes. • Three meta-analyses of visual outcomes were conducted in patients with MT-ND4 LHON. • Natural course of the disease, idebenone and lenadogene nolparvovec were compared. • Lenadogene nolparvovec was superior to idebenone, and both superior to the natural history. • Lenadogene nolparvovec is a promising new therapeutic option for MT-ND4 LHON. [ABSTRACT FROM AUTHOR]

Deep neck infection with abscess (DNI) may cause dysphagia as a late complication. This study aimed to determine the rate of DNI related dysphagia (DNIRD) and the effectiveness of rehabilitation and surgery for DNIRD. As a multicenter retrospective study, we conducted a nationwide survey by sending questionnaires to specialist training institutions certified by the Japan Broncho-esophagological Society (JBES). The questionnaire was sent to 227 facilities. This survey targeted patients with DNI aged 20 years or older who were hospitalized after April 1, 2011 and discharged by March 31, 2021. Of the 1058 cases of DNI included in this study, DNIRD was observed in 161 of 1058 patients (15.2 %). Of the 1058 cases of DNI, 139 cases showed descending necrotizing mediastinitis (DNM) (13.1 %), and DNIRD was observed in 64 of the DNM cases (46 %). DNIRD cases tended to be older (71 ± 13.5 vs. 64 ± 17.7 years old, p < 0.001), have a higher tracheostomy rate (91.3 % vs. 43.7 %, p < 0.0001), and have a longer hospital stay (51 ± 34.7 vs. 17 ± 15.4 days, p < 0.0001) than non-DNIRD cases. There were 125 cases in which only rehabilitation was performed, 8 cases in which surgery was performed to improve swallowing function, and 28 cases in which the natural course was observed. The improvement rates of DNIRD in the natural history group, rehabilitation group, and surgery group were 78.6 %, 91.8 %, and 100 %, respectively, and the rehabilitation group tended to improve more than the natural course group (p = 0.08). This nationwide survey revealed that 15.2 % of patients with DNI resulted in DNIRD and that 46 % of descending necrotizing mediastinitis patients developed DNIRD. Rehabilitation for DNIRD is generally useful, and that additional surgical treatment can improve outcomes for DNIRD patients where rehabilitation alone is not effective. [ABSTRACT FROM AUTHOR]

This study aimed to explore the natural history of distal tibial deformity in varus ankle osteoarthritis and to identify risk factors for its progression. This retrospective longitudinal observational study included 97 ankles with moderate to severe varus ankle osteoarthritis, monitored for > 2 years. Radiographic assessments were conducted on weightbearing plain radiographs at the initial and final visit. Significant tibial anterior surface angle reduction (p = 0.008), talus center medial migration (p = 0.038), and tibial lateral surface angle increase (p = 0.034) occurred. Multiple logistic analysis revealed an association between progression and coronal talar tilt angle at the first visit (odds ratio 1.17, p = 0.015) The progression of radiographic distal tibial deformity in varus ankle osteoarthritis was clarified, identifying the coronal talar tilt angle as a risk factor. Level IV, retrospective longitudinal observation study [ABSTRACT FROM AUTHOR]

To determine the natural history of menstrual pain without pelvic pathology, the role of progesterone in its pathophysiology, and associated risk factors in a longitudinal study of early postmenarchal girls in North Carolina. Participants contributed daily urine samples for up to 3.5 years to measure pregnanediol-3-glucuronide (PdG) (mean 589 urines/participant), completed menstrual diaries, and reported menstrual pain using the Menstrual Symptom Questionnaire (MSQ) biannually. MSQ scores were log-transformed and generalized estimating equations assessed associations with gynecologic age, cycle peak PdG, presumed ovulation, physical activity, anxiety, and depression. Models were adjusted for age at menarche, baseline body mass index, race/ethnicity, parental education and employment, and gynecologic age. Forty-three girls, aged 12.6 ± 1.1 years (mean ± SD) at enrollment with a gynecologic age 0.3 ± 0.2 years, participated. Total MSQ scores were higher for every 1-year increase in gynecologic age (MSQ score ratio: 1.12; 95% CI: 1.08, 1.17; P <.0001). Overall MSQ (ratio: 1.04; 95% CI: 1.02, 1.06; P =.0002) and abdominal pain-specific (ratio: 1.04; 95% CI: 1.01, 10.7; P =.004) scores were higher for every 1000 ng/mg creatinine increase in peak PdG in the preceding cycle. Overall MSQ scores were higher (ratio 1.26; 95% CI: 1.11, 1.44; P =.0005) if the preceding cycle was presumed ovulatory. Menstrual pain was not associated with physical activity, anxiety, or depression. In early postmenarchal girls, gynecologic age and PdG were associated with menstrual pain, suggesting a pathophysiologic role for progesterone and other unknown factors in the development of menstrual pain. [ABSTRACT FROM AUTHOR]

The natural history of rotator cuff tears often involves progressive pain development, tear enlargement, and advancing muscle fatty degeneration. Both surgery and conservative management have proven to be effective treatments. Our study purpose was to compare the short- to mid-term effects of rotator cuff repair on shoulder function, progression of tear size, and muscle degeneration compared to controls with asymptomatic tears that developed pain and were managed nonoperatively. This comparative study consists of 2 separate longitudinal study arms. The control group consisted of asymptomatic degenerative cuff tears followed until pain development and then managed nonoperatively with continued surveillance. The surgical group consisted of subjects with degenerative tears that failed nonoperative treatment and underwent surgical intervention with a minimum of 2 years follow-up. Outcomes included visual analog scale pain, American Shoulder and Elbow Surgeons, active range of motion, strength, and ultrasonography. There were 83 controls and 65 surgical shoulders. The surgical group was younger at enrollment (58.9 ± 5.3 yr vs. 61.2 ± 7.8 yr, P =.04). The median follow-up for control subjects after pain development was 5.1 years (interquartile range [IQR] 3.6) and the median postoperative follow-up for the surgical group was 3.0 years (IQR 0.2). Baseline tear widths (median 14 mm, IQR 9 vs. 13 mm, IQR 8; P =.45) and tear lengths (median 14 mm, IQR 13 vs. median 11 mm, IQR 8; P =.06) were similar between the surgical group and controls. There were no differences in the baseline prevalence of fatty degeneration of the supraspinatus or infraspinatus muscles between groups (P =.43 and P =.58, respectively). At final follow-up, the surgical group demonstrated significantly lower visual analog scale pain (0 [IQR 2] vs. 3.5 [IQR 4], P =.0002), higher composite American Shoulder and Elbow Surgeons (95 [IQR 13] vs. 65.8 [IQR 32], P =.0002), and activities of daily living scores (29 [IQR 4] vs. 22 [IQR 8], P =.0002), greater abduction strength (69.6 N [standard deviation {SD} 29] vs. 35.9 N [SD 29], P =.0002), greater active forward elevation (155° [SD 8] vs. 142° [SD 28], P =.002), greater active external rotation in abduction (mean 98.5°, SD 12 vs. mean 78.2°, SD 20; P =.0002) compared to controls. Additionally, the prevalence of fatty muscle degeneration was lower in the surgical group for the supraspinatus and infraspinatus (25% vs. 41%, P =.05; 17% vs. 34%, P =.03; respectively). This prospective longitudinal study comparing a surgical cohort undergoing rotator cuff repair with a control group treated nonoperatively supports the notion that surgical intervention has the potential to alter the early natural history of degenerative rotator cuff disease. Patients in the surgical group demonstrated clinically relevant differences in pain and functional outcomes. Surgical intervention was protective against progressive muscle degeneration compared to nonoperative treatment. [ABSTRACT FROM AUTHOR]

Despite research advances and progress in health care, schizophrenia remains a debilitating and costly disease. Onset occurs typically during youth and can lead to a relapsing and ultimately chronic course with persistent symptoms and functional impairment if not promptly and properly treated. Consequently, over time, schizophrenia causes substantial distress and disability for patients, their families and accrues to a collective burden to society. Recent research has revealed much about the pathophysiology that underlies the progressive nature of schizophrenia. Additionally, treatment strategies for disease management have been developed that have the potential to not just control psychotic symptoms but limit the cumulative morbidity of the illness. Given the evidence for their effectiveness and feasibility for their application, it is perplexing that this model of care has not yet become the standard of care and widely implemented to reduce the burden of illness on patients and society. This begs the question of whether the failure of implementation of a potentially disease-modifying strategy is due to the lack of evidence of efficacy (or belief in it) and readiness for implementation, or whether it's the lack of motivation and political will to support their utilization. To address this question, we reviewed and summarized the literature describing the natural history, pathophysiology and therapeutic strategies that can alleviate symptoms, prevent relapse, and potentially modify the course of schizophrenia. We conclude that, while we await further advances in mental health care from research, we must fully appreciate and take advantage of the effectiveness of existing treatments and overcome the attitudinal, policy, and infrastructural barriers to providing optimal mental health care capable of providing a disease-modifying treatment to patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Thoracic dorsal arachnoid webs are intradural membranes that may cause obstruction of cerebrospinal fluid flow and spinal cord compression. Although well recognized, they are rare and there is a paucity of long-term data on their natural history and prognosis. We reviewed radiographic features, surgical indications, and pathologic specimens of patients diagnosed with focal thoracic dorsal arachnoid webs. A radiology database and surgical case logs were queried for thoracic arachnoid webs at a single hospital system for a 10-year period. A retrospective chart review was performed on identified cases. We identified 127 patients with dorsal thoracic arachnoid webs. Arachnoid webs were radiographically classified into 3 morphologic types: type 1 (54%) causing spinal cord deformity only, type 2 (32%) producing cord deformity with myelomalacia, and type 3 (14%) with cord deformity, myelomalacia, and syringomyelia. These arachnoid webs were commonly centered at the upper thoracic T4 segmental level. Forty-one cases (32%) required surgery, generally for thoracic myelopathy with gait instability (46%) and lower extremity numbness and pain (39%). In patients who underwent surgery, 79% experienced symptomatic improvement and 21% remained stable, after an average of 21 months follow-up evaluation. Surgical pathology revealed fibrous connective tissue (100%) with calcifications (26%) or inflammation (7%). Most patients in a large series of patients with dorsal arachnoid webs did not undergo surgical intervention, but those with myelomalacia and syrinx experienced radiographic and clinical deterioration without surgery. Surgery to treat symptomatic arachnoid webs results in significant clinical improvement with low surgical morbidity. [ABSTRACT FROM AUTHOR]

Current knowledge of the natural history of patients with porto-sinusoidal vascular disorder (PSVD) is derived from small studies. The aim of the present study was to determine the natural history of PSVD and prognostic factors in a large multicenter cohort of patients. We performed a retrospective study on patients with PSVD and signs of portal hypertension (PH) prospectively registered in 27 centers. A total of 587 patients were included, median age of 47 years and 38% were women. Four-hundred and one patients had an associated condition, which was graded as severe in 157. Median follow-up was 68 months. At diagnosis, 64% of patients were asymptomatic while 36% had a PH-related complication: PH-related bleeding in 112 patients, ascites in 117, and hepatic encephalopathy in 11. In those not presenting with bleeding, the incidence of first bleeding was 15% at 5 years, with a 5-year rebleeding rate of 18%. The 5-year cumulative incidence of new or worsening ascites was 18% and of developing portal vein thrombosis was 16%. Fifty (8.5%) patients received a liver transplantation and 109 (19%) died, including 55 non-liver-related deaths. Transplant-free survival was 97% and 83% at 1 and 5 years, respectively. Variables independently associated with transplant-free survival were age, ascites, serum bilirubin, albumin and creatinine levels at diagnosis and severe associated conditions. This allowed for the creation of a nomogram that accurately predicted prognosis. The prognosis of PSVD is strongly determined by the severity of the associated underlying conditions and parameters of liver and renal function. Porto-sinusoidal vascular liver disorder (PSVD) is a rare entity that usually affects young people, frequently causes severe complications of portal hypertension, and may reduce life expectancy. To date, there is scarce information regarding its clinical manifestations, natural history and prognostic factors. The present study, including the largest number of patients with PSVD reported so far, shows that overall, when managed at centers of expertise, the prognosis of patients with PSVD is good, with LT-free survival rates of 83% and 72% at 5 and 10 years, respectively. Presence and severity of an underlying associated condition, presence of ascites, age and bilirubin, albumin and creatinine levels were associated with poor prognosis. These results are important to know for hepatologists. A final model combining these parameters enabled development of a nomogram that predicts prognosis with good discrimination and calibration capacity and can be easily applied in clinical practice. [Display omitted] • PSVD is a rare entity that causes portal hypertension. • PSVD must be suspected in patients with portal hypertension and lower liver stiffness and HVPG values than expected in cirrhosis. • Presence and severity of an associated condition, ascites, age, bilirubin, albumin and creatinine are associated with poor prognosis. [ABSTRACT FROM AUTHOR]

To assess the age and MECP2 variants of recently identified males and set the stage for further study of clinical features in males. Genetic information on the specific MECP2 variant was acquired from the coordinator (K.F.) of the Parent Group for Males. Data were collected indicating whether these variants were de novo or transmitted from the mother and whether males who appeared to meet the diagnostic criteria for Rett syndrome had mosaicism for the MECP2 variant. Fifty-nine males were identified through the parent group. Their ages ranged from 2 to 28 years, with the median age being 7.0 years and the mean age being 10.8 years. Of these variants, 46 (78.0%) were de novo , nine (15.3%) were maternally inherited, and for four (6.8%) inheritance was not known. Eleven (18.6%) were mosaic, 10 with somatic mosaicism and one with Klinefelter syndrome (47XXY). Together with males reported previously from the US Natural History Study, the total group represents 85 males, of whom 27 are deceased. These data on males with MECP2 variants are important to caregivers, physicians, and researchers to begin to characterize their historical and clinical features, improve diagnostic recognition and overall care, and accelerate access to therapeutic studies including gene replacement strategies. Equal access to such therapies for males is critical. [ABSTRACT FROM AUTHOR]

Developmental and epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS) is a rare neurodevelopmental spectrum of disorders marked by regression associated with spike-and-wave activation in sleep. As roughly 10% have a related genetic underpinning, we sought to describe narrative clinical histories of four patients at a single academic medical center with monogenic variants associated with DEE-SWAS. In sharing this case series, we aim to build on recent work investigating genetic DEE-SWAS. Findings from this case series not only aid in accurate diagnosis and prognosis for our patients but also may provide potential targets for future therapeutic interventions. This natural history case series also highlights the difficulty in differentiating genetic phenotype from the effects of DEE-SWAS. [ABSTRACT FROM AUTHOR]

• Characterization of colored engraving inks. • Multispectral imaging. • SEM/EDS analysis. This study was carried out on a collection of coloured gravures, which are bound in one book volume entitled "Histoire Naturelle des Perroquets". This book belongs to the Benaki's Collection of the Hellenic Parliament Library, Athens, Greece. Each page has a coloured print, depicting a different bird species. In most cases, the prints present oxidation s caused by the additives used in paper and printing inks manufacture, i.e. fillers, sizing agents, binders, solvents, and other chemical compounds. By employing microscopic imaging, multispectral imaging, and Scanning Electron Microscopy/Energy Dispersive X-ray spectroscopy (SEM/EDS) analysis significant information on the materials used, engraving techniques, as well as the preservation state of the printings studied can be obtained. The combination of the proposed methods yields successful results in identifying the materials used in the colour inks, as well as the paper support of the printings. [ABSTRACT FROM AUTHOR]

To describe long-term lower urinary tract outcomes and incontinence management after AUS erosion, including risk factors associated with each outcome. We retrospectively reviewed our prospectively maintained AUS database for men undergoing device explantation for urethral erosion from January 1, 1986 to October 10, 2023. Outcomes included development of urethral stricture and management of post-explant incontinence (eg, pads/clamp, catheter, salvage AUS, supravesical diversion). Risk factors were tested for association with stricture formation and repeat AUS erosion using logistic regression. Around 1943 unique patients underwent AUS implantation during the study period, and 217 (11%) had a device explantation for urethral erosion. Of these, 194 had complete records available and were included for analysis. Median follow-up from implantation was 7.5 years (IQR 2.7-13.7) and median time to erosion was 2 yrs (IQR 0-6). Ninety-six patients (49%) underwent salvage AUS placement. Of those, 38/96 (40%) were explanted for subsequent erosion. On multivariable analysis, no factors were significantly associated with risk of salvage AUS erosion. On multivariable model, pelvic radiation (OR 2.7; 95% CI 1.0-7.4) and urethral reapproximation during explant for erosion (OR 4.2; 95% CI 1.5-11.2) were significantly associated with increased risk of urethral stricture (P <.05). At the time of last follow-up, 69/194 (36%) patients had a functioning salvage AUS, including both initial and subsequent salvage implants. Following AUS erosion, radiation history and urethral reapproximation at explantation were risk factors for development of urethral stricture. Salvage AUS replacement can be performed, but has a higher rate of repeat urethral erosion. [ABSTRACT FROM AUTHOR]

The role of stereotactic radiosurgery (SRS) in the management of grade 2 and 3 meningiomas is not well elucidated. Unfortunately, local recurrence rates are high, and guidelines for management of recurrent disease are lacking. To address this knowledge gap, we conducted STORM (Salvage Stereotactic Radiosurgery for Recurrent WHO Grade 2 and 3 Meningiomas), a multicenter retrospective cohort study of patients treated with primary SRS for recurrent grade 2 and 3 meningiomas. Data on patients with recurrent grade 2 and 3 meningioma treated with SRS at first recurrence were retrospectively collected from 8 academic centers in the United States. Patients with multiple lesions at the time of initial diagnosis or more than 2 lesions at the time of first recurrence were excluded from this analysis. Patient demographics and treatment parameters were extracted at time of diagnosis, first recurrence, and second recurrence. Oncologic outcomes, including progression-free survival (PFS) and overall survival, as well as toxicity outcomes, were reported at the patient level. From 2000 to 2022, 108 patients were identified (94% grade 2, 6.0% grade 3). A total of 106 patients (98%) had upfront surgical resection (60% gross-total resection) with 18% receiving adjuvant radiation therapy (RT). Median time to first progression was 2.5 years (IQR, 1.34-4.30). At first recurrence, patients were treated with single or fractionated SRS to a median marginal dose of 16 Gy to a maximum of 2 lesions (87% received single-fraction SRS). The median follow-up time after SRS was 2.6 years. The 1-, 2-, and 3-year PFS was 90%, 75%, and 57%, respectively, after treatment with SRS. The 1-, 2-, and 3-year overall survival was 97%, 94%, and 92%, respectively. In the multivariable analysis, grade 3 disease (HR, 6.80; 95% CI, 1.61-28.6), male gender (HR, 3.48; 95% CI, 1.47-8.26), and receipt of prior RT (HR, 2.69; 95% CI, 1.23-5.86) were associated with worse PFS. SRS dose and tumor volume were not correlated with progression. Treatment was well tolerated, with a 3.0% incidence of grade 2+ radiation necrosis. This is the largest multicenter study to evaluate salvage SRS in recurrent grade 2 and 3 meningiomas. In this select cohort of patients with primarily grade 2 meningioma with a potentially more favorable natural history of delayed, localized first recurrence amenable to salvage SRS, local control rates and toxicity profiles were favorable, warranting further prospective validation. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy is a progressive and fatal X-linked neuromuscular disease. Emergent disease-modifying therapy (DMT) in nonsense Duchenne muscular dystrophy (nmDMD) has brought new perspectives to slow down functional decline in this fatal disease. To investigate if there are differences in natural history between nmDMD and other genotypes, we described a retrospective cohort analysis of 25 nonsense mutation DMD (nmDMD) boys without disease-modifying therapy, aged between 1 and 22 years, over the last 15 years (2007–2022) in a single neuromuscular center in Rio de Janeiro and use published data on DMD natural history for comparison. Regarding prognostic factors, there were remarkable and statistically significant early loss of ambulation (at 9.1y ±2.1) and shortening of life expectancy (17.6y ±2.1) in our nmDMD group. Late acquisition of neurodevelopmental milestones and annual rates of decline in respiratory, cardiac, and timed motor function tests are the same between nmDMD patients with standard care and other DMD genotypes as described in the literature. Our data indicates the similarity of natural history and disease progression among DMD boys with nmDMD mutations compared to different mutations. • The natural history of nmDMD boys on the standard of care only seems similar to those of boys with other DMD genotypes. • Nonsense DMD patients had an interestingly higher percentage of intellectual disability (80 %). • The annual function decline in motor and respiratory tests is strongly predicted by FVC (r = 0.82, p < 0.001), and 10MRT (r = 0.87, p < 0.001). [ABSTRACT FROM AUTHOR]

This study aims to comprehend the natural history of adolescent idiopathic scoliosis (AIS) patients and determine risk factors for facet joint bridging in adolescent-onset adult idiopathic scoliosis with thoracolumbar/lumbar (TL/L) curves. We included 50 patients with residual AIS with TL/L curves (3 males, 47 females; age 41.5 ± 17.3 years, TL/L Cobb angle 59.4 ± 11.8°). They were >20 years old and diagnosed with AIS during their adolescence. Radiographic parameters were measured, and facet joint bridging was defined from axial computed tomography images. The sagittal vertical axis (SVA) significantly increased with age (r = 0.71, P < 0.01). Coronal Cobb angle of the TL/L curve, L4 tilt, C7 translation, lumbar lordosis (LL), pelvic incidence-LL, pelvic tilt, and thoracolumbar kyphosis were also correlated to age (P < 0.05). There were significant differences in age, SVA, pelvic incidence-LL, vertebral bridging, facet tropism, and apical vertebral rotation (AVR) between the facet joint bridging group (n = 10) and the non-facet joint bridging group (n = 40). In the multivariate logistic regression analysis, SVA, vertebral bridging, and AVR emerged as notable risk determinants for facet joint bridging. The threshold for facet joint bridging based on SVA was 2.1 cm (area under the curve: 0.801; sensitivity = 90%; specificity = 65%). This research revealed that large SVA, the presence of vertebral bridging, and large AVR are associated with facet joint bridging in adolescent-onset adult idiopathic scoliosis patients with TL/L curves. The cutoff value for facet joint bridging based on SVA was 2.1 cm. [ABSTRACT FROM AUTHOR]

The clinical significance of change in liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) in patients with non-alcoholic fatty liver disease (NAFLD) is not well-understood. We prospectively defined rates of progression to and regression from LSM-defined compensated advanced chronic liver disease (cACLD) and their associations with liver-related events (LREs). Participants in the NASH Clinical Research Network-led NAFLD Database 2 and 3 studies were included. Progression to cACLD was defined as reaching LSM ≥10 kPa in participants with LSM <10 kPa on initial VCTE; regression from cACLD was defined as reaching LSM <10 kPa in participants with baseline LSM ≥10 kPa. LREs were defined as liver-related death, liver transplant, hepatocellular carcinoma, MELD >15, development of varices, or hepatic decompensation. Univariate and multivariable interval-censored Cox regression analyses were used to compare the cumulative LRE probability by LSM progression and regression status. In 1,403 participants, 89 LREs developed over a mean follow-up of 4.4 years, with an annual incidence rate for LREs of 1.5 (95% CI 1.2-1.8). In participants at risk, progression to LSM ≥10 or ≥15 kPa occurred in 29% and 17%, respectively, whereas regression to LSM <10 or <15 kPa occurred in 44% and 49%, respectively. Progressors to cACLD (≥10 kPa) experienced a higher cumulative LRE rate vs. non-progressors (16% vs. 4%, adjusted hazard ratio 4.0; 95% (1.8-8.9); p < 0.01). Regressors from cACLD (to LSM <10 kPa) experienced a lower LRE rate than non-regressors (7% vs. 32%, adjusted hazard ratio 0.25; 95% CI 0.10-0.61; p < 0.01). Change in LSM over time is independently and bi-directionally associated with risk of LRE and is a non-invasive surrogate for clinical outcomes in patients with NAFLD. The prognostic value of change in LSM in patients with NAFLD is not well understood. In this large prospective study of patients with NAFLD and serial vibration-controlled transient elastography exams, baseline and dynamic changes in LSM were associated with the risk of developing liver-related events. LSM is a useful non-invasive surrogate of clinical outcomes in patients with NAFLD. [Display omitted] • The clinical significance of changes in LSM over time in NAFLD is not well-studied. • Of 1,403 prospectively followed patients with NAFLD, 89 developed liver-related events over 4.4 years. • Of those at risk, 29% progressed to LSM ≥10 kPa, and 44% regressed from LSM >10 kPa. • Progressors had a four-fold increase whereas regressors had a 75% decrease in risk of liver-related events. • Changes in LSM over time are a useful surrogate for clinical outcomes in NAFLD. [ABSTRACT FROM AUTHOR]

• Highlights the variability in myotonia over time, showing its complexity as a responsive endpoint in clinical trials due to its interaction with hand-grip strength. • Revealed a complex pattern in activities of daily living, with a general decline but notable variability. • MRC grading system might not be suitable for detecting small but meaningful changes in disease progression within a clinical trial. • Hand-grip strength is capable of reflecting overall muscle function and can be suitable for detecting meaningful changes in disease progression. Myotonic dystrophy type 1 (DM1) is a heterogeneous neuromuscular disorder characterized by progressive muscle weakness and myotonia. This study investigates the progression of muscular strength and function over a four-year period. Patients with DM1 were examined at baseline and four years later. The following metrics were assessed over time: muscle strength (Medical Research Council-sumscore), hand-grip strength (Martin-Vigorimeter), hand-grip relaxation time (myotonia), and limitations in activities of daily living and (DM1ActivC questionnaire). A total of 648 patients entered the registry. Recruitment and follow-up is ongoing. In our manuscript, we focus on, 187 patients who were followed for 4 years. A significant decline in MRC sum score was observed, with distal muscles showing more deterioration. Hand-grip strength decreased significantly, with notable differences between sex and phenotype classified by disease onset. Surprisingly, an improvement of myotonia was observed. Follow-up analysis revealed a significant interaction between myotonia and grip-strength over time. Thus, the improvement in myotonia is likely explained by decreased in grip strength. Finally, there was a significant reduction in DM1ActivC score, indicating decreased activity and social participation. This study demonstrated variability in disease progression depending on sex, phenotype and disease status. This research demonstrates a nuanced pattern of disease progression, highlighting the need to combine different outcome measures to fully understand the complexity of DM1. [ABSTRACT FROM AUTHOR]

Organismal diversification can be modeled as the gain of new cell types. Just as the variation that arises during embryonic development can drive the emergence of new adult forms, so, too, can intracellular variation serve as a driver of cell type biodiversity. Examining phenomena, such as heterochrony, homeosis, and plasticity, in individual cells encourages the development of testable, mechanistic hypotheses regarding the emergence of new cell types. Application of new sequencing technologies to organisms from across the tree of life provides increased resolution for evaluating hypotheses about the relationship between genotype and phenotype at the individual cell level. The development of new tools for manipulating genomes frees us from the limited phenotypes that evolution has produced, allowing us to generate new cell phenotypes and explore the boundaries of cellular novelty. Organisms are complex assemblages of cells, cells that produce light, shoot harpoons, and secrete glue. Therefore, identifying the mechanisms that generate novelty at the level of the individual cell is essential for understanding how multicellular life evolves. For decades, the field of evolutionary developmental biology (Evo-Devo) has been developing a framework for connecting genetic variation that arises during embryonic development to the emergence of diverse adult forms. With increasing access to new single cell 'omics technologies and an array of techniques for manipulating gene expression, we can now extend these inquiries inward to the level of the individual cell. In this opinion, I argue that applying an Evo-Devo framework to single cells makes it possible to explore the natural history of cells, where this was once only possible at the organismal level. [ABSTRACT FROM AUTHOR]

The genus Mixcoatlus is composed of three species: Mixcoatlus barbouri , M. browni , and M. melanurus , of which the venom composition of M. melanurus , the most common species of the three, has only recently been described. However, very little is known about the natural history of M. barbouri and M. browni , and the venom composition of these two species has remained thus far unexplored. In this study we characterize the proteomic profiles and the main biochemical and toxic activities of these two venoms. Proteomic data obtained by shotgun analysis of whole venom identified 12 protein families for M. barbouri , and 13 for M. browni. The latter venom was further characterized by using a quantitative 'venomics' protocol, which revealed that it is mainly composed of 51.1 % phospholipases A 2 (PLA 2), 25.5 % snake venom serine proteases (SVSP), 4.6 % l -amino oxidases (LAO), and 3.6 % snake venom metalloproteases (SVMP), with lower percentages other six protein families. Both venoms contained homologs of the basic and acidic subunits of crotoxin. However, due to limitations in M. barbouri venom availability, we could only characterize the crotoxin-like protein of M. browni venom, which we have named Mixcoatlutoxin. It exhibited a lethal potency in mice like that described for classical rattlesnake crotoxins. These findings expand knowledge on the distribution of crotoxin-like heterodimeric proteins in viper snake species. Further investigation of the bioactivities of the venom of M. barbouri , on the other hand, remains necessary. [Display omitted] • The first proteomic characterization of Mixcoatlus browni and M. barbouri venoms is reported. • A new Crotoxin-like protein in the venom of Mixcoatlus browni is characterized. • Mixcoatlus barbouri venom contains homologs of acidic and basic subunits of Crotoxin. • The Antivipmyn antivenom can neutralize the lethality of M. browni. [ABSTRACT FROM AUTHOR]

Glioma resection is associated with prolonged survival, but neuro-oncological trials have frequently refrained from quantifying the extent of resection. The Response Assessment in Neuro-Oncology (RANO) resect group is an international, multidisciplinary group that aims to standardise research practice by delineating the oncological role of surgery in diffuse adult-type gliomas as defined per WHO 2021 classification. Favourable survival effects of more extensive resection unfold over months to decades depending on the molecular tumour profile. In tumours with a more aggressive natural history, supramaximal resection might correlate with additional survival benefit. Weighing the expected survival benefits of resection as dictated by molecular tumour profiles against clinical factors, including the introduction of neurological deficits, we propose an algorithm to estimate the oncological effects of surgery for newly diagnosed gliomas. The algorithm serves to select patients who might benefit most from extensive resection and to emphasise the relevance of quantifying the extent of resection in clinical trials. [ABSTRACT FROM AUTHOR]

Coronary microvascular dysfunction (CMD) is a prevalent condition among patients with cardiovascular risk factors, leading to a reduced quality of life and an increased risk of major adverse cardiovascular events. Novel invasive techniques have emerged to more accurately diagnose CMD. However, CMD's natural history remains poorly understood due to limited data. To address this knowledge gap, the Coronary Microvascular Disease Registry (CMDR) was established with the primary aim of standardizing comprehensive coronary functional testing and understanding of CMD. CMDR is a prospective, multicenter registry enrolling an unlimited number of consecutive subjects who undergo comprehensive invasive hemodynamic assessment of the entire coronary arterial vasculature. Patients undergoing acetylcholine provocation test for coronary vasospasm will also be included. Follow-up assessments will be conducted at 30 days and annually for up to 5 years. The primary endpoint is Canadian Cardiovascular Society angina grade over time. Secondary endpoints, including all-cause mortality, cardiovascular death, acute myocardial infarction, stroke, hospitalizations, medication changes, and subsequent coronary interventions, will be analyzed to establish long-term safety and clinical outcomes in patients undergoing invasive CMD assessment. CMDR aims to characterize the clinical and physiologic profile of patients undergoing comprehensive invasive coronary functional testing, simultaneously providing crucial longitudinal information on the natural history and outcomes of these patients. This will shed light on CMD's course and clinical implications, which, in turn, holds the potential to significantly improve diagnostic and treatment strategies for CMD patients, ultimately leading to the enhancement of their overall prognosis and quality of life. clinicaltrials.gov , NCT05960474 • CMD leads to reduced quality of life and increased risk of MACE. • CMD's natural history remains poorly understood due to limited data. • Coronary Microvascular Disease Registry aims to standardize CMD understanding. • CMDR will characterize CMD patients' clinical and physiologic profiles. • This holds the potential to improve diagnosis and treatment of CMD patients. [ABSTRACT FROM AUTHOR]

ZC4H2 -associated rare disorder (ZARD) is caused by pathogenic variations in the ZC4H2 gene on the X chromosome. This gene codes for a zinc finger protein involved in neural development. ZARD is characterized by highly variable symptoms, potentially influenced by the sex of the individual. The ZC4H2 -Associated Rare Disorder Natural History Study is a prospective natural history study conducted among individuals with ZARD that consists of standardized interviews, developmental assessments, and neurological examinations conducted every six months for two years. In this article, we present data from baseline visits with 40 participants, the largest ZARD cohort studied thus far, focusing on genotype-phenotype correlations and sex differences. Fisher exact, maximum likelihood χ 2, and Mann-Whitney tests were utilized. Males tended to have maternally inherited ZC4H2 pathogenic variations, whereas females tended to have de novo variations (P < 0.001). Female participants were more likely to have contractures at birth (P < 0.01), arthrogryposis multiplex congenita (P < 0.001), spasticity on examination (P < 0.1), and lower limb muscle atrophy (P < 0.05). Male participants were more likely to have seizures (P < 0.1), intermittent pain (P < 0.01), severe vision impairment (P < 0.05), dysphagia for solids (P < 0.01), and generalized muscle atrophy (P < 0.05). Our study suggests there is significant overlap in severity and range of symptoms between males and females, although several symptoms are more common in one sex than the other. Further analysis is needed to better understand how pathogenic variation type affects phenotype. [ABSTRACT FROM AUTHOR]

We report on a subfossil carpometacarpus of an extinct species of lapwing, Vanellus madagascariensis , restricted to Madagascar and inferred to be less than 3,000 years old. Lapwings, comprising 24 species in the New and Old World, are not recorded in the modern Malagasy avifauna. Members of this genus are often well-adapted to human induced habitat modifications. Material of this species has been recovered from three subfossil sites, each site with a single element, in the southwest of the island, including two humeri and a carpometacarpus. The carpal spur of V. madagascariensis was notably more developed than any living species of lapwing. It is presumed that these formidable armaments were employed to defend territories and hinder predation on nest contents and young. Large-scale desiccation in southwestern Madagascar starting about 3,000 years ago would have had a direct impact on local freshwater aquatic environments, in turn diminishing local habitat for this species, and ultimately leading to its extinction. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the epidemiology of post-coronavirus disease 2019 (COVID-19) conditions (PCCs) beyond 3 years and identify factors associated with their persistence longer than 2 years. Cross-sectional questionnaire-based survey. We surveyed patients who had recovered from COVID-19 and visited our institution from February 2020 to November 2021. Demographic and clinical data and information on the presence and duration of PCCs were obtained. We identified factors associated with the persistence of PCCs longer than 2 years using multivariate linear regression analyses. Among 935 patients surveyed, 407 completed the survey. Among them, 360 patients had mild disease in the acute phase. The proportions of participants with at least one symptom at 1, 2, and 3 years after symptom onset or COVID-19 diagnosis were 33.2%, 29.8%, and 5.7%, respectively. The numbers of participants with and without any residual symptoms 2 years after the onset of COVID-19 were 87 and 193, respectively. After multivariate adjustment, persistence of PCCs longer than 2 years was associated with lower body mass index, presence of any underlying medical conditions, and number of symptoms lasting for more than 1 month ≥ 5. The prevalence of PCCs decreased 2 years after symptom onset or COVID-19 diagnosis. We also identified factors associated with PCC persistence longer than 2 years, which could help primary care physicians and patients with PCCs predict the duration of PCCs and better understand their natural history, thus reducing patients' anxiety about their duration. [ABSTRACT FROM AUTHOR]

Isolated tumefactive demyelinating lesions (≥2 cm) may be difficult to distinguish from contrast-enhancing brain tumors, central nervous system infections, and (rarely) tissue dysgenesis, which may all occur with increased signal on T2-weighted images. Establishing an accurate diagnosis is essential for management, and we delineate our single-center experience. We performed a retrospective review of medical records, imaging, and biopsy specimens for patients under 18 years presenting with isolated tumefactive demyelination over a 10-year period. Ten children (eight female) met inclusion criteria, with a median age of 14.1 years. Lesions were most likely to involve the thalamus (six of 10), brainstem (five of 10), basal ganglia (four of 10), or corpus callosum (four of 10). Eighty percent had perilesional edema at presentation, and 60% had midline shift. Biopsies demonstrated demyelination with perivascular lymphocytic infiltration and axonal damage ranging from mild to severe. All patients were initially treated with high-dose corticosteroids, and eight of 10 required additional medical therapies such as intravenous immunoglobulin, plasmapheresis, cyclophosphamide, or rituximab. Increased intracranial pressure was managed aggressively with two of 10 patients requiring decompressive craniectomies. Clinical outcomes varied. Solitary tumefactive demyelinating lesions are rare, and aggressive management of inflammation and increased intracranial pressure is essential. Biopsy is helpful to evaluate for other diagnoses on the differential and maximize therapies. Treatment beyond initial therapy with corticosteroids is often required. Isolated tumefactive demyelinating lesions are uncommon; multicenter natural history studies are needed to better delineate differential diagnoses and optimal therapies. [ABSTRACT FROM AUTHOR]

To analyze the genetic findings, clinical spectrum, and natural history of Best vitelliform macular dystrophy (BVMD) in a cohort of 222 children and adults. Single-center retrospective, consecutive, observational study. Patients with a clinical diagnosis of BVMD from pedigrees with a likely disease-causing monoallelic sequence variant in the BEST1 gene. Data were extracted from electronic and physical case notes. Electrophysiologic assessment and molecular genetic testing were analyzed. Molecular genetic test findings and clinical findings including best-corrected visual acuity (BCVA), choroidal neovascularization (CNV) rates, and electrophysiologic parameters. Two hundred twenty-two patients from 141 families were identified harboring 69 BEST1 variants. Mean age at presentation was 26.8 years (range, 1.3–84.8 years) and most patients (61.5%) demonstrated deterioration of central vision. Major funduscopic findings included 128 eyes (30.6%) with yellow vitelliform lesions, 78 eyes (18.7%) with atrophic changes, 49 eyes (11.7%) with fibrotic changes, 48 eyes (11.5%) with mild pigmentary changes, and 43 eyes (10.3%) showing a vitelliruptive appearance. Mean BCVA was 0.37 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, 20/47) for the right eye and 0.33 logMAR (Snellen equivalent, 20/43) for the left eye at presentation, with a mean annual loss rate of 0.013 logMAR and 0.009 logMAR, respectively, over a mean follow-up of 9.7 years. Thirty-seven patients (17.3%) received a diagnosis of CNV over a mean follow-up of 8.0 years. Eyes with CNV that received treatment with an anti–vascular endothelial growth factor (VEGF) agent showed better mean BCVA compared with eyes that were not treated with an anti-VEGF agent (0.28 logMAR [Snellen equivalent, 20/38] vs. 0.62 logMAR [Snellen equivalent, 20/83]). Most eyes exhibited a hyperopic refractive error (78.7%), and 13 patients (6.1%) received a diagnosis of amblyopia. Among the 3 most common variants, p.(Ala243Val) was associated with a later age of onset, better age-adjusted BCVA, and less advanced Gass stages compared with p.(Arg218Cys) and p.(Arg218His). BVMD shows a wide spectrum of phenotypic variability. The disease is very slowly progressive, and the observed phenotype–genotype correlations allow for more accurate prognostication and counselling. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Extracranial vertebral artery aneurysms are extremely rare and are usually associated with trauma or dissection. Primary extracranial vertebral artery aneurysms are far less common. They may be of mycotic origin or associated with systemic diseases (e.g., neurofibromatosis). The presentation and natural history remain idiopathic, and operative management can be often difficult. Angiography remains the criterion standard in diagnosis and characterization of these lesions. We hereby present a case of a primary aneurysm of the extracranial portion of the vertebral artery and its surgical management, which implied an initial endovascular approach followed by a 2-step surgery to resect the aneurysm and stabilize the spine. [ABSTRACT FROM AUTHOR]

This paper investigates conceptions of explanation, teleology, and analogy in the works of Immanuel Kant (1724–1804) and Georges Cuvier (1769–1832). Richards (2000, 2002) and Zammito (2006, 2012, 2018) have argued that Kant's philosophy provided an obstacle for the project of establishing biology as a proper science around 1800. By contrast, Russell (1916), Outram (1986), and Huneman (2006, 2008) have argued, similar to suggestions from Lenoir (1989), that Kant's philosophy influenced the influential naturalist Georges Cuvier. In this article, I wish to expand on and further the work of Russell, Outram, and Huneman by adopting a novel perspective on Cuvier and considering (a) the similar conceptions of proper science and explanation of Kant and Cuvier, and (b) the similar conceptions of the role of teleology and analogy in the works of Kant and Cuvier. The similarities between Kant and Cuvier show, contrary to the interpretation of Richards and Zammito, that some of Kant's philosophical ideas, whether they derived from him or not, were fruitfully applied by some life scientists who wished to transform life sciences into proper sciences around 1800. However, I also show that Cuvier, in contrast to Kant, had a workable strategy for transforming the life sciences into proper sciences, and that he departed from Kant's philosophy of science in crucial respects. • Explains the relevance of Kant's philosophy for the emergence of biology. • Explains Cuvier's conception of proper science and explanation. • Explains Cuvier's regulative conception of teleology and analogy. [ABSTRACT FROM AUTHOR]

Tricuspid regurgitation (TR) is associated with an increased mortality. Previous studies have analyzed predictors of TR progression and the clinical impact of baseline TR. However, there is a lack of evidence regarding the natural history of TR: the pattern of change and clinical impact of progression. The authors sought to evaluate predictors of TR progression and assess the prognostic impact of TR progression. A total of 1,843 patients with at least moderate TR were prospectively followed up with consecutive echocardiographic studies and/or clinical evaluation. All patients with less than a 2-year follow-up were excluded. Clinical and echocardiographic features, hospitalizations for heart failure, and cardiovascular death and interventions were recorded to assess their impact in TR progression. At a median 2.3-year follow-up, 19% of patients experienced progression. Patients with baseline moderate TR presented a rate progression of 4.9%, 10.1%, and 24.8% 1 year, 2 years, and 3 years, respectively. Older age (HR: 1.03), lower body mass index (HR: 0.95), chronic kidney disease (HR: 1.55), worse NYHA functional class (HR: 1.52), and right ventricle dilation (HR: 1.33) were independently associated with TR progression. TR progression was associated with an increase in chamber dilation as well as a decrease in ventriculoarterial coupling and in left ventricle ejection fraction (P < 0.001). TR progression was associated with an increased cardiovascular mortality and hospitalizations for heart failure (P < 0.001). Marked individual variability in TR progression hindered accurate follow-up. In addition, TR progression was a determinant for survival regardless of initial TR severity. [Display omitted] [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]

• 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]

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]

The management of branch-duct type intraductal papillary mucinous neoplasms (BD-IPMN) varies in existing guidelines. This study investigated the optimal surveillance protocol and safe discontinuation of surveillance considering natural history in non-resected IPMN, by systematically reviewing the published literature. This review was guided by PRISMA. Research questions were framed in PICO format "CQ1-1: Is size criteria helpful to determine surveillance period? CQ1-2: How often should surveillance be carried out? CQ1-3: When should surveillance be discontinued? CQ1-4: Is nomogram predicting malignancy useful during surveillance?". PubMed was searched from January–April 2022. The search generated 2373 citations. After screening, 83 articles were included. Among them, 33 studies were identified for CQ1-1, 19 for CQ1-2, 26 for CQ1-3 and 12 for CQ1-4. Cysts <1.5 or 2 cm without worrisome features (WF) were described as more indolent, and most studies advised an initial period of surveillance. The median growth rate of cysts <2 cm ranged from 0.23 to 0.6 mm/year. Patients with cysts <2 cm showing no morphological changes and no WF after 5-years of surveillance have minimal malignancy risk of 0–2%. Two nomograms created with over 1000 patients had AUCs of around 0.8 and appear to be feasible in a real-world practice. For patients with suspected BD-IPMN <2 cm and no other WF, less frequent surveillance is recommended. Surveillance may be discontinued for cysts that remain stable during 5-year surveillance, with consideration of patient condition and life expectancy. With this updated surveillance strategy, patients with non-worrisome BD-IPMN should expect more streamlined management and decreased healthcare utilization. [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]

Il est proposé une délinéation des volumes cibles anatomocliniques de la tumeur primitive dans les cancers du sinus maxillaire et des cavités nasales traités par irradiation postopératoire. Ce concept s'appuie sur la connaissance de la radioanatomie et celle de l'histoire naturelle des cancers. Il repose sur le recalage de la scanographie de planification avec les imageries préopératoires pour la remise en place du volume tumoral macroscopique préopératoire et l'utilisation du concept géométrique complété du concept anatomique pour la délinéation des volumes cibles anatomocliniques de la tumeur primitive. Cet article ne traite pas des indications de radiothérapie externe (ni des traitements systémiques concomitants) mais précise les volumes à traiter si une radiothérapie est retenue. In this article, we propose a consensus delineation of postoperative clinical target volumes for the primary tumour in maxillary sinus and nasal cavity cancers. These guidelines are developed based on radioanatomy and the natural history of those cancers. They require the fusion of the planning CT with preoperative imaging for accurate positioning of the initial GTV and the combined use of the geometric and anatomical concepts for the delineation of clinical target volume for the primary tumour. This article does not discuss the indications of external radiotherapy (nor concurrent systemic treatment) but focuses on target volumes when there is an indication for radiotherapy. [ABSTRACT FROM AUTHOR]

Museum collection records are a source of historic data for species occurrence, but little attention is paid to the associated descriptions of habitat at the sample locations. We propose that artificial intelligence methods have potential to use these descriptions for reconstructing past habitat, to address ecological and evolutionary questions. [ABSTRACT FROM AUTHOR]

A great range and number of journals exist to promote and disseminate local knowledge in the areas of natural history, geology, geography and ecology. Many are still active; others are lost. The journals act as mouthpieces for local societies and are a repository of local knowledge. Some are hard to locate but the websites of local societies provide information on topics covered and the regularity of publication of the journals. The loss of journals seems to be the result of the pressure on academics to publish in international outlets and the growth of highly informative websites. [ABSTRACT FROM AUTHOR]

• Ongoing LAMA2-MD natural history studies from 7 countries were reported. • The importance of developing standardised LAMA2-MD registries was acknowledged. • A clinical workgroup on LAMA2-MD was formed. • Patient organisations and patient representatives from 9 countries participated in the workshop. • LAMA2-MD therapy development demonstrated substantial progress. • Monthly online research meetings for clinicians, researchers and patient organizations. The European Joint Programme on Rare Diseases (EJPRD) funded the workshop "LAMA2-Muscular Dystrophy: Paving the road to therapy", bringing together 40 health-care professionals, researchers, patient-advocacy groups, Early-Career Scientists and other stakeholders from 14 countries. Progress in natural history, pathophysiology, trial readiness, and treatment strategies was discussed together with efforts to increase patient-awareness and strengthen collaborations. Key outcomes were (a) ongoing natural history studies in 7 countries already covered more than 350 patients. The next steps are to include additional countries, harmonise data collection and define a minimal dataset; (b) therapy development was largely complementary. Approaches included LAMA2-replacement and correction, LAMA1-reactivation, mRNA modulation, linker-protein expression, targeting downstream processes and identifying modifiers, using viral vectors, muscle stem cells, iPSC and mouse models and patient lines; (c) LAMA2-Europe will inform patients (-representatives) worldwide on standards of care and scientific progress, and enable sharing experiences. Follow-up monthly online meetings and research repositories have been established to create sustainable collaborations. [ABSTRACT FROM AUTHOR]

To date, no publicly accessible platform has captured and synthesized all of the layered dimensions of genotypic, phenotypic, and mechanistic information published in the field of inborn errors of immunity (IEIs). Such a platform would represent the extensive and complex landscape of IEIs and could increase the rate of diagnosis in patients with a suspected IEI, which remains unacceptably low. Our aim was to create an expertly curated, patient-centered, multidimensional IEI database that enables aggregation and sophisticated data interrogation and promotes involvement from diverse stakeholders across the community. The database structure was designed following a subject-centered model and written in Structured Query Language (SQL). The web application is written in Hypertext Preprocessor (PHP), Hypertext Markup Language (HTML), Cascading Style Sheets (CSS), and JavaScript. All data stored in the Genetic Immunology Advisor (GenIA) are extracted by manually reviewing published research articles. We completed data collection and curation for 24 pilot genes. Using these data, we have exemplified how GenIA can provide quick access to structured, longitudinal, more thorough, comprehensive, and up-to-date IEI knowledge than do currently existing databases, such as ClinGen, Human Phenotype Ontology (HPO), ClinVar, or Online Mendelian Inheritance in Man (OMIM), with which GenIA intends to dovetail. GenIA strives to accurately capture the extensive genetic, mechanistic, and phenotypic heterogeneity found across IEIs, as well as genetic paradigms and diagnostic pitfalls associated with individual genes and conditions. The IEI community's involvement will help promote GenIA as an enduring resource that supports and improves knowledge sharing, research, diagnosis, and care for patients with genetic immune disease. [ABSTRACT FROM AUTHOR]

Investigations into imaging modalities in the diagnosis of extracranial carotid artery occlusion (CAO) have raised questions about the inter-modality comparability of duplex ultrasound (DUS) and cross-sectional imaging (CSI). This study examines the relationship between DUS and CSI diagnoses of extracranial CAO. This single-institution retrospective analysis studied patients with CAO diagnosed by DUS from 2010 to 2021. Patients were identified in our office-based accredited vascular laboratory database. Imaging and clinical data was obtained via our institutional electronic medical record. Primary outcome was discrepancy between DUS and CSI modalities. Secondary outcomes included incidence of stroke and intervention subsequent to CAO diagnosis. Of our 140-patient cohort, 95 patients (67.9%) had DUS follow-up (mean, 42.7 ± 31.3 months). At index duplex, 68.0% of individuals (n = 51) were asymptomatic. Seventy-five patients (53.6%) had CSI of the carotids after DUS CAO diagnosis; 18 (24%) underwent magnetic resonance imaging and 57 (76%) underwent computed tomography. Indications for CSI included follow-up of DUS findings of carotid stenosis/occlusion (44%), stroke/transient ischemic attack (16%), other symptoms (12%), preoperative evaluation (2.7%), unrelated pathology follow-up (9.3%), and outside institution imaging with unavailable indications (16%). When comparing patients with CSI and those without, there were no differences with regard to symptoms at diagnosis, prior neck interventions, or hypertension. There was a significant difference between cross-sectionally imaged and non-imaged patients in anti-hypertensive medications (72% vs 53.8%; P =.04). Despite initial DUS diagnoses of carotid occlusion, 10 patients (13.3%) ultimately had CSI indicating patent carotids. Four of these 10 patients had stenoses of ∼99% (with 1 string sign), four of 70% to 99%, one of 50% to 69%, and one of less than 50% on CSI. The majority of patients (70%) had CSI within 1 month of the index ultrasound. There were no significant relationships between imaging discrepancies and body mass index, heart failure, upper body edema, carotid artery calcification, and neck hardware. Eight individuals (10.7%) underwent ipsilateral revascularization; 62.5% (n = 5) were carotid endarterectomy procedures, and the remaining three procedures were a transcervical carotid revascularization, subclavian to internal carotid artery bypass, and transfemoral carotid artery stenting. Eight patients (10.7%) underwent contralateral revascularization, with the same distribution of procedures as those ipsilateral to occlusions. Two of the 10 patients with discrepancies underwent carotid endarterectomy, and one underwent carotid stenting. In our experience, duplex diagnosis of CAO is associated with a greater than 10% discordance when compared with CSI. These patients may benefit from closer surveillance as well as confirmatory computed tomography or magnetic resonance angiography. Further work is needed to determine the optimal diagnostic modality for CAO. [ABSTRACT FROM AUTHOR]

Collapse cessation is of utmost importance following a long period of collapse due to osteonecrosis of the femoral head (ONFH). This study investigated the relationship between collapse cessation and the extent of the necrotic regions of ONFH. Overall, 74 patients who had symptomatic ONFH (collapse < 3 mm) at the first visit with a minimum follow-up of 3 years were included in this study. Patients were categorized based on collapse progression or cessation into the progression and stable groups. The extent of the antero-posterior (AP) and medio-lateral necrotic regions between the groups was assessed using sagittal and coronal sections of T1-magnetic resonance imaging. Additionally, the most effective cutoff value was determined from the receiving operating characteristic curve where collapse cessation could be obtained, while the survival rates were determined with collapse progression as the endpoints were evaluated. Overall, 45 and 29 patients were in the progression and stable groups, respectively. The AP and medio-lateral necrotic regions were significantly different (P <.01 and P <.01, respectively) between the progression and stable groups. A cutoff value of 62.1% of the AP necrotic regions was determined from the receiving operating characteristic curve analysis. The 5-year survival rates with collapse progression as the endpoints were 5.4 and 77.8% in the AP necrotic regions of ≥62.1 and <62.1%, respectively (P <.01). Cases with AP necrotic regions of ≤62.1% can be expected to have collapse cessation, which could be a useful index for ONFH treatment strategies. Level IV. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the natural history of internal carotid artery (ICA) stenosis progression. This single-institution retrospective cohort study analyzed patients diagnosed with ICA stenosis of 50% or greater on duplex ultrasound from 2015 to 2022. Subjects were drawn from our institutional Intersocietal Accreditation Commission-accredited noninterventional vascular laboratory database. Primary outcomes were incidences of disease progression, and stroke or revascularization after index study. Progression was defined as an increase in stenosis classification category. Imaging, demographic, and clinical data was obtained from our institutional electronic medical record via a database mining query. Cases were analyzed at the patient and artery levels, with severity corresponding to the greatest degree of ICA stenosis on index and follow-up studies. Of 577 arteries in 467 patients, mean cohort age was 73.5 ± 8.9 years at the time of the index study, and 45.0% (n = 210) were female. Patients were followed with duplex ultrasound for a mean of 42.2 ± 22.7 months. Of 577 arteries, 65.5% (n = 378) at the index imaging study had moderate (50%-69%) stenosis, 23.7% (n = 137) had severe (70%-99%) stenosis, and 10.7% (n = 62) were occluded. These three groups had significant differences in age, hypertension, hyperlipidemia prevalence, and proportion on best medical therapy. Of the 467-patient cohort, 56.5% (n = 264) were on best medical therapy, defined as smoking cessation, treatment with an antiplatelet agent, statin, and antihypertensive and glycemic agents as indicated. Mean time to progression for affected arteries was 28.0 ± 20.5 months. Of those arteries with nonocclusive disease at diagnosis, 21.3% (n = 123) progressed in their level of stenosis. Older age, diabetes, and a history of vasculitis were associated with stenosis progression, whereas antiplatelet agent use trended towards decreased progression rates. Of the 467 patients, 5.6% (n = 26) developed symptoms; of those, 38.5% (n = 10) had ischemic strokes, 26.9% (n = 7) had hemispheric transient ischemic attacks, 11.5% (n = 3) had amaurosis fugax, and 23.1% (n = 6) had other symptoms. A history of head and neck cancer was positively associated with symptom development. Of 577 affected arteries, 16.6% (n = 96) underwent intervention; 81% (n = 78) of interventions were for asymptomatic disease and 19% (n = 18) were for symptomatic disease. No patient-level factors were associated with risk of intervention. A significant number of carotid stenosis patients experience progression of disease. Physicians should consider long-term surveillance on all patients with carotid disease, with increased attention paid to those with risk factors for progression, particularly those with diabetes and a history of vasculitis. [ABSTRACT FROM AUTHOR]

Article reviews play a pivotal role in fostering students' critical evaluation and critical thinking skills. News & Views (N&V) articles published in Natur e journals are one prominent example of article reviews and serve as excellent models for students to learn and refine their skills in writing article reviews. However, there is limited research on the rhetorical features of N&V articles, especially in terms of textual organization across different disciplines. To address this gap, three corpora were compiled for the present study, representing the disciplinary groups of natural sciences (NS), social sciences (SS), and technology and engineering (TE). Each corpus was comprised of 30 N&V texts from its respective disciplinary group. Using a self-developed coding framework building on previous research, we coded the move and step of each text in the corpora. The coding data were compared and analyzed to uncover the distinguishing textual features of the three disciplinary groups. The analysis revealed that the variations were predominantly at the step level. N&V articles of NS and SS shared most of the moves and steps, but N&Vs in TE exhibited unique stylistic characteristics. These findings hold significant implications for training and teaching article review writing, particularly in relation to disciplinary contexts. • Five moves were identified across the three disciplinary clusters: NS, SS, and TE. • The three clusters shared the same moves and common communicative goals. • Four out of the five moves of N&Vs across the three clusters are obligatory. • N&Vs in natural sciences and social sciences shared most of the steps. • N&Vs in technology and engineering demonstrated a distinct organization pattern. [ABSTRACT FROM AUTHOR]

Late-onset Stargardt disease is a subtype of Stargardt disease type 1 (STGD1), defined by an age of onset of 45 years or older. We describe the disease characteristics, underlying genetics, and disease progression of late-onset STGD1 and highlight the differences from geographic atrophy. Retrospective cohort study. Seventy-one patients with late-onset STGD1. Medical files were reviewed for clinical data including age at onset, initial symptoms, and best-corrected visual acuity. A quantitative and qualitative assessment of retinal pigment epithelium (RPE) atrophy was performed on fundus autofluorescence images and OCT scans. Age at onset, genotype, visual acuity, atrophy growth rates, and loss of external limiting membrane, ellipsoid zone, and RPE. Median age at onset was 55.0 years (range, 45–82 years). A combination of a mild and severe variant in ATP-binding cassette subfamily A member 4 (ABCA4) was the most common genotype (n = 49 [69.0%]). The most frequent allele, c.5603A→T (p.Asn1868Ile), was present in 43 of 71 patients (60.6%). No combination of 2 severe variants was found. At first presentation, all patients have flecks. Foveal-sparing atrophy was present in 33.3% of eyes, whereas 21.1% had atrophy with foveal involvement. Extrafoveal atrophy was present in 38.9% of eyes, and no atrophy was evident in 6.7% of eyes. Time-to-event curves showed a median duration of 15.4 years (95% confidence interval, 11.1–19.6 years) from onset to foveal involvement. The median visual acuity decline was –0.03 Snellen decimal per year (interquartile range [IQR], –0.07 to 0.00 Snellen decimal; 0.03 logarithm of the minimum angle of resolution). Median atrophy growth was 0.590 mm2/year (IQR, 0.046–1.641 mm2/year) for definitely decreased autofluorescence and 0.650 mm2/year (IQR, 0.299–1.729 mm2/year) for total decreased autofluorescence. Late-onset STGD1 is a subtype of STGD1 with most commonly 1 severe and 1 mild ABCA4 variant. The general patient presents with typical fundus flecks and retinal atrophy in a foveal-sparing pattern with preserved central vision. Misdiagnosis as age-related macular degeneration should be avoided to prevent futile invasive treatments with potential complications. In addition, correct diagnosis lends patients with late-onset STGD1 the opportunity to participate in potentially beneficial therapeutic trials for STGD1. The author(s) have no proprietary or commercial interest in any materials discussed in this article. [ABSTRACT FROM AUTHOR]

• SMA natural history has dramatically changed with newborn screening. • Here we report long term follow up of 46 children with SMA and treated with onasemnogene abeparvovec. • Despite treatment within the first 30 days of life, ∼50 % of babies with 2 copies of SMN2 could do better. 5q spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease caused by absence of the SMN1 gene with three FDA approved genetic therapies which significantly improve outcomes. The AAV9 mediated gene replacement therapy, onasemnogene abeparvovec, has the greatest potential for side effects. Here we report the safety and outcomes from 46 children treated with onasemnogene abeparvovec in the state of Ohio between December 2018 and January 2023. In our cohort, onasemnogene abeparvovec treatment remained safe and no child experienced any significant adverse events, including thrombotic microangiopathy, liver failure or death. All children experienced benefit, although the benefit in those with 2 copies of SMN2 was variable. 79 % of the children treated when symptomatic had a SMN2 modifying therapy added on. With careful screening and post treatment monitoring, onasemnogene abeparvovec is safe and effective for children with SMA in the state of Ohio, but more work needs to be done to ensure optimal outcomes for all children with 2 copies of SMN2. [ABSTRACT FROM AUTHOR]

• Ninety percent of LAMA2-MD and SELENON-RM patients has low bone quality. • Low bone quality leads to fragility fractures in a subset of patients. • There is no change in bone mineral density within one year follow-up. • Adequate intake of vitamin D and calcium are recommended. • We advise standard clinical follow-up of bone mineral density in all patients. Fragility fractures are frequently reported in neuromuscular diseases and negatively influence functional prognosis, quality of life and survival. In LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON(SEPN1)-related congenital myopathy (SELENON-RM) cross-sectional and prospective natural history studies on bone quality and fragility long bone fractures (LBFs) are lacking. We therefore aim to systematically assess bone quality and provide recommendations for clinical care. We performed a one-year prospective natural history study in 21 LAMA2-MD and 10 SELENON-RM patients including a standardized fracture history and bone quality assessment through dual energy Xray absorptiometry scan (DEXA-scan) and/or bone health index (BHI). Ninety percent of the LAMA2-MD and SELENON-RM patients showed low bone quality. Eight (38%) LAMA2-MD and five (50%) SELENON-RM patients had a history of fragility LBFs. During the one-year follow-up period, one LAMA2-MD patient (female, 3 years) experienced a fragility LBF of the right humerus. We found no difference in bone mineral density between baseline and one-year follow-up. Based on general international guidelines for osteoporosis, we advise adequate vitamin D and calcium intake, and standardized clinical follow-up through a DEXA-scan or BHI in all LAMA2-MD and SELENON-RM patients. On indication, patients should be referred to the pediatrics or internal medicine for consideration of additional treatments. [ABSTRACT FROM AUTHOR]

Nerve transfer surgery is sometimes offered to patients with acute flaccid myelitis (AFM). The objectives of this study were to evaluate surgical efficacy, assess which clinical and neurophysiological data are valuable for preoperative planning, and report long-term outcomes. This is a single-center, retrospective case series of patients with AFM who received nerve transfer surgery. All patients had preoperative electromyography and nerve conduction studies (EMG/NCS). Matched control muscles that did not receive nerve transfer surgery were defined in the same cohort. Ten patients meeting inclusion criteria received a total of 23 nerve transfers (19 upper extremity, four lower extremity). The mean age at symptom onset was 3.8 years, surgery was 0.5 to 1.25 years after diagnosis, and mean follow-up was 2.3 years (range 1.3 to 4.5 years). Among muscles with preoperative strength Medical Research Council (MRC) grade 0, muscles receiving nerve transfers performed significantly better than those that did not (MRC grade 2.17 ± 0.42 vs 0 ± 0, respectively, P = 0.0001). Preoperative EMG/NCS predicted worse outcomes in recipient muscles with more abundant acute denervation potentials (P = 0.0098). Donor nerves found to be partially denervated performed equally well as unaffected nerves. Limited data suggested functional improvement accompanying strength recovery. Nerve transfer surgery is an effective strategy to restore strength for patients with AFM with persistent, severe motor deficits. Postoperative outcomes in patients with complete paralysis are better than the natural history of disease. This study demonstrates the utility of preoperative clinical and electrophysiological data in guiding patient selection for nerve transfer surgery. [ABSTRACT FROM AUTHOR]