Plants of the USA: recordings on native North American useful species by Alexander von Humboldt.

BACKGROUND: The German naturalist Alexander von Humboldt conducted an expedition through the American continent, alongside Aimé Bonpland, from 1799 to 1804. Before finally returning to Europe, they decided to take a side trip to the USA between May 20 and July 7, 1804. Humboldt's most detailed account of his time in the USA consists of a manuscript entitled "Plantae des États-Unis" (1804), containing information on useful plants and timber of the country. The aim of this paper is to retrieve, for the first time, ethnobotanical information regarding North American plants and their uses inside this Humboldt's manuscript as well as to highlight the erasure and invisibilization of North American Indigenous knowledge within historical documents and bibliography, mainly during the nineteenth century. METHODS: "Plantae des États-Unis" (digitized version and its transcription) was carefully analyzed, and information on plant species mentioned in the manuscript (including botanical and vernacular names, traditional uses, and general observations) was retrieved. Traditional uses were correlated with ethnobotanical data from the Native American Ethnobotany Database and encyclopedic literature on North American plants from the nineteenth and early twentieth centuries, as well as recent pharmacological studies searched in scientific papers. RESULTS: In the manuscript are mentioned 28 species distributed in 15 botanical families, with Fagaceae (9 Quercus species) being the most representative. All species are USA natives, except for one undetermined species (only the genus was mentioned, Corylus). Four species were directly mentioned as medicinal (Toxicodendron radicans, Liriodendron tulipifera, Actaea racemosa, and Gillenia stipulata), while other four were described as tanning agents (astringent) (Cornus florida, Diospyros virginiana, Quercus rubra, and Quercus velutina). Two species were described as bitter (Xanthorhiza simplicissima and A. racemosa). Nine Quercus species were described, but five were reported as the most useful oaks for cultivation in Europe (Quercus bicolor, Quercus castanea, Quercus virginiana, Quercus michauxii, and Quercus alba); three of them were used for ship construction (Q. virginiana, Q. michauxii, and Q. alba), two as astringent (Q. rubra and Q. stellata), and one had wood of poor quality (Quercus phellos). One species was described as a yellow dye (Hydrastis canadensis), and the other was mentioned as toxic (Aesculus pavia). Ten species did not have any useful applications listed. CONCLUSIONS: Although "Plantae des États-Unis" is a brief collection of annotations, these data reveal a historical scenario of outstanding plants with social and economic interest in the USA at the beginning of the nineteenth century. The data highlight a clear process of suppression of the traditional knowledge of Native North American Indigenous peoples in past historical records and literature, due to the lack of acknowledgment by white European settlers and American-born explorers. This ethnobotanical inventory may help us understand the relationship between plants and Native North American Indigenous peoples, as well as European naturalists and settlers, and USA-born people in the past, and reflect on the importance of Indigenous traditional knowledge, bioeconomy, sustainable management, and conservation of biodiversity in the present and future.

Access for ALL in ALS: A large-scale, inclusive, collaborative consortium to unlock the molecular and genetic mechanisms of amyotrophic lateral sclerosis.

Recent progress in therapeutics for amyotrophic lateral sclerosis (ALS) has spurred development and imbued the field of ALS with hope for more breakthroughs, yet substantial scientific gaps persist. This unmet need remains a stark reminder that innovative paradigms are needed to invigorate ALS research. To move toward more informative, targeted, and personalized drug development, the National Institutes of Health (NIH) established a national ALS clinical research consortium called Access for ALL in ALS (ALL ALS). This new consortium is a multi-institutional effort that aims to organize the ALS clinical research landscape in the United States. ALL ALS is operating in partnership with several stakeholders to operationalize the recommendations of the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS) Public Private Partnership. ALL ALS will provide a large-scale, centralized, and readily accessible infrastructure for the collection and storage of a wide range of data from people living with ALS (symptomatic cohort) or who may be at risk of developing ALS (asymptomatic ALS gene carriers). Importantly, ALL ALS is designed to encourage community engagement, equity, and inclusion. The consortium is prioritizing the enrollment of geographically, ethnoculturally, and socioeconomically diverse participants. Collected data include longitudinal clinical data and biofluids, genomic, and digital biomarkers that will be harmonized and linked to the central Accelerating Medicines Partnership for ALS (AMP ALS) portal for sharing with the research community. The aim of ALL ALS is to deliver a comprehensive, inclusive, open-science dataset to help researchers answer important scientific questions of clinical relevance in ALS.

Growth, survival and events in patients with aortic arch pathology.

OBJECTIVES: This study describes aortic growth, survival and events in patients with aortic arch pathology. METHODS: Patients with an index diameter ≥4.5 cm or other pathology of the native aortic arch, were followed with longitudinal computed tomography and clinical data collected retrospectively. Aortic growth was estimated using a linear mixed model. Survival and event rates were estimated using Kaplan-Meier methods. Cox analysis assessed clinical and radiological predictors with outcomes (death, local or remote aortic events (acute aortic syndromes or intervention)). Results. 186 patients underwent 683 CT scans during 638 of patient years. The estimated annual growth was 0.28 (mm/year). 47 (25%) patients had an event and a 66% five-year event-free survival. 29 patients died, of whom 11 suffered an aortic death. 19 events were local and 25 events were remote, mostly primary events were interventions. In Cox analysis, increasing descending aortic diameter was an independent predictor of all cause of death (hazard ratio [HR], 2.16), aortic death (HR 4.81), and local event (HR 1.71). Conclusions. In patients with aortic arch pathology, growth, and aortic events should be expected. Increasing descending aortic diameter could presage an added risk, but other variables appear needed to identify patients at risk, select them for intervention or surveillance.

Epidemiology and natural history of chronic Hepatitis B in the Canadian province of Alberta from 2012 to 2021: A population-based study.

INTRODUCTION AND OBJECTIVES: There are limited recent data on the burden of chronic hepatitis B (CHB) in the North American general population. We aimed to identify the CHB burden from a Canadian population-based perspective. PATIENTS AND METHODS: Using a retrospective cohort design, we searched Alberta Analytics administrative databases including the Provincial Laboratory database, to describe CHB epidemiology and natural history in Alberta, Canada between fiscal years 2012-2020. We analyzed incidence and prevalence trends using a Poisson regression model and conducted Kaplan-Meier analyses to examine the incident cohort's survival. RESULTS: The age/sex-adjusted incidence of CHB between 2015-2020 was 27.1/100,000 person/years (29.6/100,000 in males and 24.5/100,000 in females) and was highest among individuals aged 45-64 years. Despite a decrease in annual incidence of CHB from 36.4 to 13.4/100,000 between 2015-2020, prevalence increased from 98.9 to 210.3/100,000 in the same period. Of 6,860 incident cases, 2.1% died, and 0.2% underwent liver transplantation during a median follow-up of 3.6 years (interquartile range 2.0-4.9 years). CHB patients had significantly lower survival rates compared to age/sex-matched Canadians, with a standardized mortality ratio of 3.9 (95% confidence interval [CI] 3.3-4.6). Male sex (hazard ratio [HR] 1.7; 95% CI 1.2-2.5), older age at diagnosis (HR, 1.08; 95% CI 1.07-1.09) independently predicted mortality. CONCLUSIONS: CHB incidence decreased in Alberta, which is consistent with nationwide trends. Males and individuals aged 45-64 had higher CHB incidence and prevalence. CHB patients' lower survival rates emphasize the need to address barriers to guideline recommended HBV care linkage.

Clearance of anal and penile HPV 6, 11, 16, and 18 DNA and antibodies among adolescent men who have sex with men (HYPER): An observational cohort study.

Background: Clearance of human papillomavirus (HPV) among adolescent men who have sex with men (MSM) is not well studied. This study aimed to evaluate the clearance of HPV DNA and antibodies among adolescent MSM. Methods: In our cohort study, we enrolled adolescent MSM in Melbourne between October 2010 and September 2013. At baseline, 3, 6, and 12 months, anal and penile swabs for HPV DNA and serum for HPV antibodies against genotypes 6, 11, 16, and 18, were collected. Definite clearance was defined as HPV DNA (same site) /antibodies for the same genotype undetected following a positive HPV DNA /antibodies test at baseline or month 3. Possible clearance was defined as HPV DNA (same site) /antibodies for the same genotype undetected at month 12 following a positive HPV DNA/antibodies test at month 6. Overall clearance was defined as either definite or possible clearance. The agreement between HPV DNA clearance and antibodies clearance was calculated. Results: A total of 183 MSM were included (median age: 19 years, interquartile [IQR]: 18 to 20). At the anus, overall clearance rate was 21.6 (95 % confidence interval[CI]: 7.9 to 47.0), 44.8 (19.3 to 88.3), 51.9 (20.9 to 106.9) and 33.7 (7.0 to 98.5) per 1000 person months (PM) for HPV 6, 11, 16 and 18. At the penis, overall clearance rate was 64.5 (13.3 to 188.5), 71.3 (14.7 to 208.2), 96.5 (31.3 to 225.3) and 333.3 (8.4 to 1857.2) per 1000 PM for HPV 6, 11, 16 and 18. For antibodies, overall clearance rate was 22.2 (9.6 to 43.7), 18.8 (3.9 to 55.0), 10.8 (0.3 to 60.1) and 19.0 (2.3 to 68.8) per 1000 PM. Agreement between anal/penile HPV DNA clearance and antibodies clearance was low: kappa = -0.18 (95 % CI: -0.28 to 0.08)/-0.13 (-0.24 to -0.02), 0.04 (-0.29 to 0.36)/0.22 (-0.32 to 0.76), -0.10 (-0.27 to 0.08)/-0.14 (-0.37 to 0.10) and -0.14 (-0.28 to 0.01)/-0.14 (-0.33 to 0.06) for HPV 6, 11, 16 and 18, respectively. Conclusion: Clearance rates of HPV DNA were low and varied by genotypes and anatomical sites among adolescent MSM. Antibodies against HPV were stable during the study period.

The impact of genotype on age at loss of ambulation in individuals with Duchenne muscular dystrophy treated with corticosteroids: A single-center study of 555 patients.

INTRODUCTION/AIMS: Studies have demonstrated that certain genotypes in Duchenne muscular dystrophy (DMD) have milder or more severe phenotypes. These studies included individuals treated and not treated with corticosteroids and multiple sites with potentially varying standards of care. We aimed to assess genotype-phenotype correlations for age at loss of ambulation (LoA) in a large cohort of individuals with DMD treated with corticosteroids at one center. METHODS: In this retrospective review of medical records, encounters were included for individuals diagnosed with DMD if prescribed corticosteroids, defined as daily deflazacort or prednisone or high-dose weekend prednisone, for 12 consecutive months. Encounters were excluded if the participants were taking disease-modifying therapy. Data were analyzed using survival analysis for LoA and Fisher's exact tests to assess the percentage of late ambulatory (>14 years old) individuals for selected genotypes. RESULTS: Overall, 3948 encounters from 555 individuals were included. Survival analysis showed later age at LoA for exon 44 skip amenable (p = .004), deletion exons 3-7 (p < .001) and duplication exon 2 (p = .043) cohorts and earlier age at LoA for the exon 51 skip amenable cohort (p < .001) when compared with the rest of the cohort. Individuals with deletions of exons 3-7 had significantly more late ambulatory individuals than other cohorts (75%), while those with exon 51 skip amenable deletions had significantly fewer (11.9%) compared with other cohorts. DISCUSSION: This confirms previous observations of genotype-phenotype correlations in DMD and enhances information for trial design and clinical management.

Metastatic disease and major adverse cardiovascular events preceding diagnosis are the main determinants of disease-specific survival of pheochromocytoma/paraganglioma: long-term follow-up of 303 patients.

Purpose: The natural history in unselected cohorts of patients with pheochromocytoma/ paraganglioma (PPGL) followed for a period >10 years remains limited. We aimed to describe baseline characteristics and outcome of a large cohort and to identify predictors of shorter survival. Methods: This retrospective single-center study included 303 patients with newly diagnosed PPGL from 1968 to December 31, 2023, in 199 prospectively supplemented since July 2020. Mean follow-up was 11.4 (range 0.3-50) years, germline genetic analyses were available in 92.1%. The main outcome measures were overall (OAS), disease-specific (DSS), recurrence-free (RFS) survival and predictors of shorter survival evaluated in patients with metastases at first diagnosis (n=12), metastatic (n=24) and nonmetastatic (n=33) recurrences and without evidence of PPGL after first surgery (n=234). Results: Age at study begin was 49.4 ± 16.3 years. There were 72 (23.8%) deaths, 15 (5.0%), 29 (9.6%) and 28 (9.2%) due to PPGL, cardiovascular disease (CVD) and malignant or other diseases, respectively. Median OAS, DSS1 (tumor-related) and DSS2 (DSS1 and death caused by CVD) were 4.8, 5.9 and 5.2 years (patients with metastases at first diagnosis), 21.2, 21.2 and 19.9 years, and 38.0, undefined and 38.0 years (patients with metastatic and with nonmetastatic recurrences, respectively). Major adverse cardiovascular events (MACE) preceded the first diagnosis in 15% (n=44). Shorter DSS2 correlated with older age (P ≤ 0.001), male sex (P ≤ 0.02), MACE (P ≤ 0.01) and primary metastases (P<0.0001, also for DSS1). Conclusion: The clinical course of unselected patients with PPGL is rather benign. Survival rates remain high for decades, unless there are MACE before diagnosis or metastatic disease.

Puberty changes the natural history of idiopathic scoliosis: three prediction models for future radiographic curve severity from 1563 consecutive patients.

PURPOSE: Understanding idiopathic scoliosis (IS) natural history during growth is essential for shared decision-making between patients and physicians. We developed a retrospective model with the largest available sample in the literature and we aimed to investigate if using three peri-pubertal growth periods provides better prediction than a unique model. METHODS: Secondary analysis of a previous study on IS natural history data from radiographs before and at the first consult. Three groups: BEFORE (age 6-10), AT (age 11-Risser 2) and AFTER (from Risser 3) the pubertal growth spurt. Available predictors: Cobb angle, curve type, sex, observation time, and Risser score. We used linear mixed-effects models to predict future Cobb angles in each group. We internally validated prediction accuracy with over 100 patients per group (3 to 5-fold cross-validation). RESULTS: We included 1563 participants (275 BEFORE, 316 AFTER, 782 females and 190 males AT). Curves increased over time mostly in AT, importantly in BEFORE, but also in AFTER. All models performed better than the general one. In BEFORE, 74.2% of the predictions were within ± 5o, 71.8% in AFTER, 68.2% in AT females, and 60.4% in males. The predictors (baseline curve, observation time also squared and cubic, and Risser score) were similar in all the models, with sex influencing only AFTER. CONCLUSION: IS curve severities increase differently during growth with puberty stages. Model accuracy increases when tailored by growth spurt periods. Our models may help patients and clinicians share decisions, identify the risk of progression and inform treatment planning.

PDE6A-Associated Retinitis Pigmentosa, Clinical Characteristics, Genetics and Natural History.

PURPOSE: To analyze the genetics, clinical characteristics, and natural history of PDE6A-associated retinitis pigmentosa. DESIGN: Retrospective, longitudinal, observational cohort study. PARTICIPANTS: Patients with molecularly confirmed PDE6A-associated retinal dystrophy in a single tertiary referral center. METHODS: Review of medical records and retinal imaging, including fundus autofluorescence (FAF) imaging and spectral-domain optical coherence tomography (SD-OCT). Genetic results were reviewed, and the detected variants were assessed. RESULTS: Sixteen patients (32 eyes) were identified and evaluated longitudinally. Genetic analysis identified 14 variants in the PDE6A gene, including 8 novel variants. The mean age (±SD, range) was 34.8 years (± 17.4, 12 - 76) at baseline, with a mean follow-up time of 4.8 years. Best-corrected visual acuity (BCVA) was 0.45 ± 0.45 LogMAR (range 0.0 - 1.6) at baseline and 0.65 ± 0.7 LogMAR (range 0.0 - 2.3) at the last visit. BCVA was similar among eyes in 88% of patients. A hyperautofluorescent ring was observed on FAF in 50% and 44% of the eyes at baseline and follow up visit respectively, with a mean area of 9.7 ± 4.5mm2 at baseline and mean of 8.6 ± 4.8 mm2 at the follow-up visit. Mean horizontal ellipsoid zone width (EZW) at baseline was 1765 ± 1093 µm, which decreased to 1580 ± 1077 µm at follow up. Eighteen eyes exhibited cystoid macular oedema at baseline (56%), and 17 eyes (53%) at follow-up. There were statistically significant changes during the follow-up period in terms of BCVA, hyperautoflouroscent ring area and the EZW. CONCLUSIONS: This study highlights the natural history of PDE6A-retinopathy. The majority of the patients in this cohort had mild BCVA loss, and slowly progressive disease, based on FAF and OCT measurements.

Characterization of therapeutic antibody efficacy against multiple SARS-CoV-2 variants in the hamster model.

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and onset of the coronavirus disease-19 (COVID-19) pandemic led to an immediate need for therapeutic treatment options. Therapeutic antibodies were developed to fill a gap when traditional antivirals were not available. In late 2020, the United States Government undertook an effort to compare candidate therapeutic antibodies in virus neutralization assays and in the hamster model of SARS-CoV-2 infection. With the emergence of SARS-CoV-2 variants, the effort expanded to evaluate the efficacy of nearly 50 products against major variants. A subset of products was further evaluated for therapeutic efficacy in hamsters. Here we report results of the hamster studies, including pathogenicity with multiple variants, neutralization capacity of products, and efficacy testing of products against Delta and Omicron variants. These studies demonstrate the loss of efficacy of early products with variant emergence and support the use of the hamster model for evaluating therapeutics.

Persistence of Lugol-unstaining is Associated With an Increased Risk of Progression to Malignancy in the Esophagus.

BACKGROUND & AIMS: The aim of this study was to investigate the persistence of Lugol-unstained lesions (LULs) in the esophagus detected by chromoendoscopy and explore their association with progression to malignancy. METHODS: We enrolled 647 participants from a population-based screening trial who had biopsied LULs at the baseline chromoendoscopy and underwent a chromoendoscopy reexamination after a median of 4.39 years. Cases of persistent LUL were defined as those in whom a visible LUL was observed during reexamination at the documented location (±2 cm) where a LUL was detected at baseline chromoendoscopy. Logistic regression was applied to explore risk factors for the persistence of LULs. The primary outcome was clinical-stage esophageal squamous cell carcinoma identified over 6.78 years of follow-up, and the secondary outcome was re-examination-detected severe dysplasia and above lesions. The cumulative incidence was calculated to assess the progression risk associated with the persistence of LULs. RESULTS: The proportion of participants with persistent LULs was 81.92%. Dysplasia (adjusted odds ratio [OR], 6.16; 95% confidence interval [CI], 2.70-17.80), large LULs (adjusted OR, 1.90; 95% CI, 1.18-3.15), and irregularly shaped LULs (adjusted OR, 1.63; 95% CI, 1.03-2.56) at baseline were associated with an increased risk of LUL persistence. Eleven clinical-stage esophageal squamous cell carcinoma cases and 31 severe dysplasia and above lesions detected during reexamination were identified, all of which originated from patients with persistent LULs (Pclinical-stage ESCC = .136; Preexamination-detected SDA = .015). CONCLUSION: The persistence of LULs is associated with progression to malignancy in the esophagus, even in individuals without dysplastic lesions. Based on this, a more efficient post-screening surveillance strategy could be established.

Does surgical intervention alter the natural history of degenerative rotator cuff tears? Comparative analysis from a prospective longitudinal study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Long-Term Socioeconomic and Neurologic Outcome for Individuals with Childhood-Onset Multiple Sclerosis.

INTORDUCTION: Most studies on the progression of childhood-onset multiple sclerosis (MS) involve relatively short follow-up periods, focusing primarily on neurological outcomes and disability progression. The influence of these and other factors on the health-related quality of life is not known. To gain a comprehensive understanding of early-onset MS, it is crucial to evaluate the effects of treatment and the disease on quality of life. METHOD: This pilot project aimed to evaluate the feasibility of using an online survey tool for long-term follow-up data collection from patients with childhood-onset MS. An anonymized, monocentric, prospective survey was conducted on a convenience cohort of patients treated at a certified centre for neuromuscular diseases in childhood between 2007 and 2019. RESULTS: A total of 27 patients completed the survey. There were no mandatory items, therefore some patients chose not to answer all the questions in the questionnaire. Patients exhibited promising educational achievements, low neurological disease burden, and high resilience. However, anxiety, depression, and pain significantly impacted their perceived health status. CONCLUSION: This single-centre study has yielded new insights into childhood-onset MS. To enable more accurate comparisons across different centres and countries, it is essential to establish a minimum data set and questionnaire subset for patients with paediatric-onset MS transitioning into adulthood.

[The value of revascularisation of atherosclerotic lesions of the innominate artery at the asymptomatic stage of the disease]. / Znachenie revaskulyarizatsii pri ateroskleroticheskikh porazheniyakh brakhiotsefal'nogo stvola na asimptomnoi stadii zabolevaniya.

OBJECTIVE: To analyze the natural course of asymptomatic atherosclerotic lesions of the innominate artery and to study the long-term results of surgical interventions performed at the asymptomatic stage and to compare them with similar results at the symptomatic stage of the disease. MATERIAL AND METHODS: The analysis of the natural course of the disease was performed in 74 asymptomatic patients who were divided into 3 groups depending on the initial degree of severity of the stenosis of the innominate artery: insignificant stenoses (less than 50%), moderate stenoses (50-69%) and haemodynamically significant lesions (70% and more). The analysis of the long-term results of surgical treatment was performed in 62 patients, in 29 of whom intrathoracic reconstructions were performed at the asymptomatic stage of the disease, in 33 - at the symptomatic stage. RESULTS: Cumulative freedom from stroke by the 10th year of follow-up was significantly higher in patients with insignificant stenoses and amounted to 100% in the groups of moderate stenoses and hemodynamically significant lesions - 25% and 0, respectively (log-rank p=0.000). Neurological fatality in patients with hemodynamically significant (initial or developed) lesions was 26.3%, while in patients with hemodynamically insignificant lesions it was 0 (log-rank p=0.004), which is confirmed by cumulative indices (log-rank p=0.008). Asymptomatic innominate artery reconstructions were associated with a lower incidence of stroke: the long-term incidence of stroke in such patients was 3.4%, while in initially symptomatic patients it was 18.2% (p=0.038). Initial degree II or IV cerebrovascular insufficiency was a predictor of stroke in the long-term period (OR=1.71; p=0.000). The cumulative freedom from stroke in asymptomatic patients by the 20th year of follow-up was 95% compared with 74% in symptomatic patients (log-rank p=0.032). CONCLUSION: Surgical interventions in asymptomatic hemodynamically significant lesions of the innominate artery should be performed to prevent primary cerebral circulatory disorders.

Evaluation of natural history communication and shared decision making for self-limiting conditions: Analysis of UK primary care consultations.

OBJECTIVE: To analyse communication about the natural course of self-limiting illnesses, as part of shared decision-making (SDM), in general practice consultations. METHODS: Natural history communication and SDM (using Observing Patient Involvement in Decision-Making (OPTION-12) and Assessing Communication about Evidence and Patient Preferences (ACEPP) items) were rated by two raters using transcripts from the UK 'One in a Million' database. RESULTS: Of 55 eligible consultations, a 'wait and see' option was mentioned in 27 consultations (49 %), using varying terminology, with a general recovery timeframe provided in 21. Mean OPTION-12 score (of 100) was 25.2 (SD=7.4), indicating a low level of SDM. Mean ACEPP score (out of 5) was 1.2 (SD=0.5), indicating minimal communication about the options' benefits and harms. Recovery likelihood was quantified in only two consultations, while harms were quantified in none. CONCLUSION: Communication about the natural history of self-limiting illnesses was generally limited. The 'wait and see' approach, along with its benefits and harms, was typically not explicitly presented as an option for patients to consider. PRACTICE IMPLICATIONS: Improving clinicians' awareness of the importance of and skills for communicating the natural history of self-limiting illnesses, as part of SDM, may facilitate informed decision-making in managing these conditions.

Cross-sectional survey study of the natural history of LAMA2-related dystrophy.

BACKGROUND: LAMA2-related dystrophies (LAMA2-RD) are a rare group of neuromuscular disorders with a broad spectrum of phenotype severity, ranging from mild to severe. We performed a cross-sectional study of LAMA2-RD through motor function and pulmonary tests to establish the disease's natural history. METHODS: Forty-four individuals with LAMA2-RD were included and evaluated once through functional outcome measures including Motor Function Measure 32 (MFM32), Revised Upper Limb Module (RULM), goniometry, and Forced Vital Capacity (FVC). Fixed Effect Regression Model (ERM) and Kaplan-Meier curve were used for calculating the rate of the disease progression RESULTS: Patients were between 2 and 25 years old (mean 11.4), the most frequent phenotype presentation was non-ambulant (N=36, 81.8%) while eight patients (18,2 %) were ambulant. The non-ambulant group presented a more severe progression of the disease. Non-ambulant patients had a 1.85 % decrease in FVC/year against 1.32 %/year among ambulant patients. In the non-ambulant group, there was a 4.2 % drop/year in the MFM32-D2 domain (p<0.00001), a 2.6 % drop/year in the D3 domain (p<0.0001), and a 2.7 % drop/year in the MFM32 global assessment (p<0.0001). However, the non-ambulant group's evaluation of upper limb function through the RULM scale did not show a statistically significant reduction. In the non-ambulant group, elbow and knee retractions worsened 3.22 degrees/year (p=0.00087) and 1.92 degrees/year, respectively. While in those patients who acquired gait, elbow and knee retractions worsened 2.45 degrees/year (p=0.0003) and 1.73 degrees/year (p=0.01), respectively. CONCLUSION: This study confirmed the progressive nature of LAMA2-RD, both in ambulant and non-ambulant patients. MFM32, FVC, and goniometry were identified as promising outcome measures for natural history studies and clinical trials in LAMA2-RD.

A Multicenter Cross-Sectional Study of the Swiss Cohort of LAMA2-Related Muscular Dystrophy.

Background: LAMA2-related muscular dystrophy (LAMA2-RD) is an autosomal-recessive disorder and one of the most common congenital muscular dystrophies. Due to promising therapies in preclinical development, there is an increasing effort to better define the epidemiology and natural history of this disease. Objective: The present study aimed to describe a well-characterized baseline cohort of patients with LAMA2-RD in Switzerland. Methods: The study used data collected by the Swiss Registry for Neuromuscular Disorders (Swiss-Reg-NMD). Diagnostic findings were derived from genetics, muscle biopsy, creatine kinase-level and electrophysiological testing, as well as from brain MRIs. Further clinical information included motor assessments (CHOP INTEND, MFM20/32), joint contractures, scoliosis, ophthalmoplegia, weight gain, feeding difficulties, respiratory function, cardiac investigations, EEG findings, IQ and schooling. Results: Eighteen patients with LAMA-RD were included in the Swiss-Reg-NMD as of May 2023 (age at inclusion into the registry: median age 8.7 years, range 1 month - 31 years F = 8, M = 10). Fourteen patients presented with the severe form of LAMA2-RD (were never able to walk; CMD), whereas four patients presented with the milder form (present or lost walking capability; LGMD). All patients classified as CMD had symptoms before 12 months of age and 11/14 before the age of six months. 15 carried homozygous or compound heterozygous pathogenic or likely pathogenic variants in LAMA2 and two were homozygous for a variant of unknown significance (one patient unknown). Brain MRI was available for 14 patients, 13 had white matter changes and 11 had additional structural abnormalities, including cobblestone malformations, pontine hypoplasia and an enlarged tegmento-vermial angle not reported before. Conclusion: This study describes the Swiss cohort of patients with LAMA2-RD and gives insights into measuring disease severity and disease progression, which is important for future clinical trials, as well as for a better clinical understanding and management of patients with LAMA2-RD.

An International Retrospective Early Natural History Study of LAMA2-Related Dystrophies.

Background: LAMA2-related dystrophies (LAMA2-RDs) represent one of the most common forms of congenital muscular dystrophy and have historically been classified into two subtypes: complete or partial deficiency of laminin-211 (merosin). Patients with LAMA2-RD with the typical congenital phenotype manifest severe muscle weakness, delayed motor milestones, joint contractures, failure to thrive, and progressive respiratory insufficiency. Objective: While a comprehensive prospective natural history study has been performed in LAMA2-RD patients over 5 years of age, the early natural history of patients with LAMA2-RD 5 years and younger has not been comprehensively characterized. Methods: We extracted retrospective data for patients with LAMA2-RD ages birth through 5 years via the Congenital Muscle Disease International Registry (CMDIR). We analyzed the data using a phenotypic classification based on maximal motor milestones to divide patients into two phenotypic groups: "Sit" for those patients who attained that ability to remain seated and "Walk" for those patients who attained the ability to walk independently by 3.5 years of age. Results: Sixty patients with LAMA2-RD from 10 countries fulfilled the inclusion criteria. Twenty-four patients had initiated non-invasive ventilation by age 5 years. Hospitalizations during the first years of life were often related to respiratory insufficiency. Feeding/nutritional difficulties and orthopedic issues were commonly reported. Significant elevations of creatine kinase (CK) observed during the neonatal period declined rapidly within the first few months of life. Conclusions: This is the largest international retrospective early natural history study of LAMA2-RD to date, contributing essential data for understanding early clinical findings in LAMA2-RD which, along with the data being collected in international, prospective early natural history studies, will help to establish clinical trial readiness. Our proposed nomenclature of LAMA2-RD1 for patients who attain the ability to sit (remain seated) and LAMA2-RD2 for patients who attain the ability to walk independently is aimed at further improving LAMA2-RD classification.

Comprehensive four-year disease progression assessment of myotonic dystrophy type 1.

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.

Natural history of non-polyglutamine CACNA1A disease in Austria.

BACKGROUND AND OBJECTIVES: Non-polyglutamine CACNA1A variants underlie an extremely variable phenotypic spectrum encompassing developmental delay, hemiplegic migraine, epilepsy, psychiatric symptoms, episodic and chronic cerebellar signs. We provide our experience with the long-term follow-up of CACNA1A patients and their response to interval therapy. METHODS: Patients with genetically confirmed non-polyglutamine CACNA1A disease were prospectively followed at the Center for Rare Movement Disorders of the Medical University of Innsbruck from 2004 to 2024. RESULTS: We recruited 41 subjects with non-polyglutamine CACNA1A disease, of which 38 (93%) familial cases. The mean age at the first examination was 35 ± 22 years. Disease onset was in the childhood/adolescence in 31/41 patients (76%). Developmental delay and episodic symptoms were the first disease manifestation in 9/41 (22%) and 32/41 (78%) patients respectively. Chronic neurological signs encompassed a cerebellar syndrome in 35/41 (85%), which showed almost no progression during the observation period, as well as cognitive deficits in 9/20 (45%, MOCA test score < 26), psychiatric and behavioral symptoms in 11/41(27%). Seizures occurred in two patients concomitant to severe hemiplegic migraine. At the last visit, 27/41 patients (66%) required an interval prophylaxis (including acetazolamide, flunarizine, 4-aminopyridine, topiramate), which was efficacious in reducing the frequency and severity of episodic symptoms in all cases. In one patient in his 70ies with progressively therapy resistant hemiplegic migraine, treatment with the anti-CGRP antibody galcanezumab successfully reduced the frequency of migraine days from 4 to 1/month. CONCLUSIONS: Non-polyglutamine CACNA1A disease show an evolving age-dependent presentation. Interval prophylaxis is effective in reducing the burden of episodic symptoms.