Estimated Prevalence and Incidence of Amyotrophic Lateral Sclerosis and SOD1 and C9orf72 Genetic Variants.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare neurological disorder characterized by progressive deterioration of motor neurons. Assessment of the size/geographic distribution of the ALS population, including ALS with genetic origin, is needed to understand the burden of the disease and the need for clinical intervention and therapy. OBJECTIVES: The main objective of this study was to estimate the number of prevalent and incident ALS cases overall and superoxide dismutase 1 (SOD1) and chromosome 9 open reading frame 72 (C9orf72) ALS in 22 countries across Europe (Belgium, France, Germany, Ireland, Italy, Netherlands, Norway, Russia, Spain, Sweden, and UK), North America (USA and Canada), Latin America (Argentina, Brazil, Colombia, Mexico, and Uruguay), and Asia (China, Japan, South Korea, and Taiwan). METHODS: A comprehensive literature search was conducted to identify population-based studies reporting ALS prevalence and/or incidence rates. Pooled prevalence and incidence rates were obtained using a meta-analysis approach at the country and regional geographic level. A country-level pooled estimate was used when ≥2 studies were available per country and geographic regional pooled estimates were used otherwise. The proportion of cases with a SOD1 or C9orf72 mutation among sporadic (sALS) and familial (fALS) cases were obtained from a previous systematic review and meta-analysis. RESULTS: Pooled prevalence rates (per 100,000 persons) and incidence rates (per 100,000 person-years) were 6.22 and 2.31 for Europe, 5.20 and 2.35 for North America, 3.41 and 1.25 for Latin America, 3.01 and 0.93 for Asian countries excluding Japan, and 7.96 and 1.76 for Japan, respectively. Significant heterogeneity in reported incidence and prevalence was observed within and between countries/geographic regions. The estimated number of 2020 ALS cases across the 22 countries is 121,028 prevalent and 41,128 incident cases. The total estimated number of prevalent SOD1 cases is 2,876 cases, of which, 1,342 (47%) were fALS and 1,534 (53%) were sALS, and the number of incident SOD1 cases is 946 (434 [46%] fALS and 512 [54%] sALS). The total estimated number of prevalent C9orf72 cases is 4,545 (1,198 [26%] fALS, 3,347 [74%] sALS), and the number of incident C9orf72 cases is 1,706 (450 [26%] fALS and 1,256 [74%] sALS). DISCUSSION: The estimated number of patients with SOD1 and C9orf72 ALS suggests that although the proportions of SOD1 and C9orf72 are higher among those with fALS, the majority of SOD1 and C9orf72 ALS cases may be found among those with sALS (about 53 and 74%, respectively). These results suggest that classification of fALS based on reported family history does not capture the full picture of ALS of genetic origin.

Clinical and genetic predictors of atypical hemolytic uremic syndrome phenotype and outcome.

Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, life-threatening disease. The Global aHUS Registry collects real-world data on the natural history of the disease. Here we characterize end-stage renal disease (ESRD)-free survival, the rate of thrombotic microangiopathy, organ involvement and the genetic background of 851 patients in the registry, prior to eculizumab treatment. A sex-specific difference was apparent according to age at initial disease onset as the ratio of males to females was 1.3:1 for childhood presentation and 1:2 for adult presentation. Complement Factor I and Membrane Cofactor Protein mutations were more common in patients with initial presentation as adults and children, respectively. Initial presentation in childhood significantly predicted ESRD risk (adjusted hazard ratio 0.55 [95% confidence interval 0.41-0.73], whereas sex, race, family history of aHUS, and time from initial presentation to diagnosis, did not. Patients with a Complement Factor H mutation had reduced ESRD-free survival, whereas Membrane Cofactor Protein mutation was associated with longer ESRD-free survival. Additionally extrarenal organ manifestations occur in 19%-38% of patients within six months of initial disease presentation (dependent on organ). Thus, our real-world results provide novel insights regarding phenotypic variables and genotypes on the clinical manifestation and progression of aHUS.

Association of moderate to severe lower urinary tract symptoms with incident type 2 diabetes and heart disease.

PURPOSE: Increasing evidence suggests a possible link between lower urinary tract symptoms and chronic illnesses. We determined whether lower urinary tract symptoms are associated with incident type 2 diabetes and heart disease in a population based study. MATERIALS AND METHODS: BACH is a population based epidemiological survey of urological symptoms. A multistage, stratified, cluster sample design was used to obtain a random sample of 4,144 men and women 30 to 79 years old at baseline. Median followup was 4.8 years between baseline (2002 to 2005) and followup (2006 to 2010). Type 2 diabetes and heart disease were assessed by self-report. Lower urinary tract symptoms were assessed by the AUA-SI, and voiding and storage subscores. Logistic regression was used to estimate the OR and 95% CI, and adjust for potential confounders. RESULTS: In participants with a body mass index of 30 kg/m(2) or greater the adjusted ORs for incident heart disease were 1.89 (95% CI 1.05, 3.39) for AUA-SI 8 or greater and 2.32 (95% CI 1.33, 4.05) for a storage score of 4 or greater. In participants with abdominal obesity the adjusted ORs for incident type 2 diabetes were 2.06 (95% CI 1.19, 3.55) for AUA-SI 8 or greater and 1.81 (95% CI 1.04, 3.15) for a storage score of 4 or greater. Lower urinary tract symptoms (AUA-SI 8 or greater) were also predictive of type 2 diabetes in men and women younger than 50 years (adjusted OR 2.37, 95% CI 1.18, 4.80). CONCLUSIONS: Longitudinal results of BACH suggest that lower urinary tract symptoms are a marker of increased risk for type 2 diabetes and heart disease in obese men and women. The increased risk in younger men and women suggests that lower urinary tract symptoms may be an indicator of impending disease.

Association of peripheral microvascular dysfunction and erectile dysfunction.

PURPOSE: Increasing evidence of a link between erectile dysfunction and cardiovascular disease suggests a shared vascular etiology with endothelial dysfunction as a plausible underlying biological mechanism. To our knowledge whether this association is different for large arterial endothelium compared to microvascular endothelium has not yet been established. We investigated the association of erectile dysfunction with macrovascular and microvascular endothelial function. MATERIALS AND METHODS: A sample of 390 men with a mean age of 55.5 years was recruited from the BACH survey, a population based survey of urological symptoms. Erectile dysfunction was assessed using IIEF-5. The percent of brachial artery flow mediated dilatation, a measure of macrovascular function, and hyperemic flow velocity in cm per second, a measure of microvascular function, were assessed by ultrasound. Linear regression was used to assess the association of erectile dysfunction and endothelial function, and adjust for potential confounders. RESULTS: Reactive hyperemia was lower in men with vs without erectile dysfunction (mean ± SE 97.1 ± 2.5 vs 106.0 ± 1.6 cm per second, p = 0.003). However, the difference in flow mediated dilatation between men with vs without erectile dysfunction was statistically nonsignificant (mean 6.6% ± 0.33% vs 7.2% ± 0.24%, p = 0.147). The association of erectile dysfunction with reactive hyperemia was attenuated but it remained statistically significant in men with moderate to severe erectile dysfunction (IIEF-5 less than 12) after adjusting for traditional cardiovascular risk factors (p = 0.038). CONCLUSIONS: These results provide evidence of greater microvascular than macrovascular endothelial dysfunction as a potential contributor to erectile dysfunction and an underlying mechanism linking erectile dysfunction and cardiovascular disease.

Changes in erectile dysfunction over time in relation to Framingham cardiovascular risk in the Boston Area Community Health (BACH) Survey.

INTRODUCTION: Erectile dysfunction (ED) is associated with cardiovascular disease (CVD); however, the association between change in ED status over time and future underlying CVD risk is unclear. AIM: The aim of this study was to investigate the association between change in ED status and Framingham CVD risk, as well change in Framingham risk. METHODS: We studied 965 men free of CVD in the Boston Area Community Health (BACH) Survey, a longitudinal cohort study with three assessments. ED was assessed with the five-item International Index of Erectile Function at BACH I (2002-2005) and BACH II (2007-2010) and classified as no ED/transient ED/persistent ED. CVD risk was assessed with 10-year Framingham CVD risk algorithm at BACH I and BACH III (2010-2012). Linear regression models controlled for baseline age, socio-demographic and lifestyle factors, as well as baseline Framingham risk. Models were also stratified by age (≥/< 50 years). MAIN OUTCOME MEASURES: Framingham CVD risk and change in Framingham CVD risk were the main outcome measures. RESULTS: Transient and persistent ED was significantly associated with increased Framingham risk and change in risk over time in univariate and age-adjusted models. In younger men, persistent ED was associated with a Framingham risk that was 1.58 percentage points higher (95% confidence interval [CI]: 0.11, 3.06) and in older men, a Framingham risk that was 2.54 percentage points higher (95% CI: -1.5, 6.59), compared with those without ED. Change in Framingham risk over time was also associated with transient and persistent ED in men <50 years, but not in older men. CONCLUSIONS: Data suggest that even after taking into account other CVD risk factors, transient and persistent ED is associated with Framingham CVD risk and a greater increase in Framingham risk over time, particularly in younger men. Findings further support clinical assessment of CVD risk in men presenting with ED, especially those under 50 years.

Treatment status and progression or regression of lower urinary tract symptoms in a general adult population sample.

PURPOSE: We report progression and regression of lower urinary tract symptoms in a population based cohort by race/ethnicity, gender, age and lower urinary tract symptom medication use. MATERIALS AND METHODS: The BACH (Boston Area Community Health) Survey enrolled 5,502 participants 30 to 79 years old of black, Hispanic or white race/ethnicity. The 5-year followup interviews were completed by 1,610 men and 2,534 women for a conditional response rate of 80%. Population weighted estimates of lower urinary tract symptoms severity were assessed using the AUASI (American Urological Association symptom index) and analyzed using multivariate models. RESULTS: Symptom progression (increase in AUASI score of 3 or more points) was reported by 21% to 33% of participants and regression (decrease 3 or greater) by 30% to 44% of participants, most commonly women and Hispanic participants. Age and higher body mass index were associated with progression (p <0.01), but not with regression. Lower urinary tract symptom medication use at baseline only was associated with improved symptoms scores 5 years later (multivariate adjusted OR 3.10, 95% CI 1.28-7.51, compared to nonusers), whereas using medication at baseline and followup was associated with similar rates of progression and regression as observed among participants not using lower urinary tract symptom medication at either point. CONCLUSIONS: Lower urinary tract symptoms persisted at followup for approximately half of the population experiencing symptoms at baseline, including many men and women using lower urinary tract symptom medications. However, overall lower urinary tract symptom medication use and surgical treatment appeared beneficial for symptom control at 5-year followup. Age and body mass index were associated with symptom worsening, and Hispanic ethnicity was associated with greater symptom fluctuation. Clinicians should consider the higher likelihood of lower urinary tract symptom progression for older or heavier patients, and monitor responsiveness to lower urinary tract symptom medication.

Population-based patterns of prescription androgen use, 1976-2008.

PURPOSE: Prescription testosterone (T) has limited approved medical indications and is a controlled substance in Canada. Utilization studies in other Westernized countries have revealed sharp increases in T use in recent years. We examined medical use of androgens, including T, over a ≥30-year period among adult (18+) men in a population-based study set in a Canadian juridisdiction of universal health care. METHODS: Analyses were based on data from electronic records of dispensed prescriptions during 1976-2008 in Saskatchewan, Canada. All formulations of androgens listed in the provincial formulary (oral and injectable) were included. We examined demographics of users, androgen types used, switching patterns, and trends in the annual rate of use over time. RESULTS: There were 11 521 androgen users who were followed for an average of 11.8 years. Overall, 11 types of androgens were used, and there were 86 812 dispensing events. The mean age at first use was 56.4 years (median: 58). Men had 7.5 prescription dispensing events on average (median: 2). The most commonly used formulations were methyl-T (36.2% of users) followed by T-enanthate (32.5%), T-cypionate (22.3%), and T-undecanoate (20.0%). Most users (82%) did not switch among androgen types. The annual rate of use varied substantially over time, with a marked increase observed from 1994 to 1999 and a decrease from 2000 to 2008. CONCLUSIONS: Androgen users were largely middle aged and had relatively few dispensings. We hypothesize that observed secular trends in androgen use may align with drug treatment pattern changes for erectile dysfunction, including the advent of phosphodiesterase type 5 inhibitors.

ALS Identified: two-year findings from a sponsored ALS genetic testing program.

OBJECTIVE: To report initial results from the Amyotrophic Lateral Sclerosis (ALS) Identified genetic testing (GT) program on characteristics of individuals tested and frequency of reported disease-causing variants. METHODS: ALS Identified used the Invitae Amyotrophic Lateral Sclerosis panel (Invitae, San Francisco, CA, USA) to assay 22 ALS-associated genes. Sponsored by Biogen (Cambridge, MA, USA), the program was launched in June 2021 and was available at no charge to individuals ≥18 years in the United States and Puerto Rico with an ALS diagnosis or a known family history of ALS. Deidentified data were available to Biogen. RESULTS: As of 26 October 2023, 998 healthcare professionals ordered the panel at 681 unique care sites. Of 8054 individuals examined, 7483 (92.9%) were reported to have a clinical diagnosis of ALS, while 571 (7.1%) were asymptomatic relatives. Of the individuals with a clinical ALS diagnosis, 57.7% were male (n = 4319) and 42.3% female (n = 3164). Mean (SD) age at diagnosis is 62 (13) years. Out of the 7483 clinically diagnosed individuals, 1810 (24.2%) showed genetic variations in ALS-associated genes. Among these, 865 individuals (47.8%) carried pathogenic variants, and 44 (2.4%) had likely pathogenic variants, totaling 12.1% of the clinically diagnosed population. INTERPRETATION: Since 2021 there has been robust uptake and sustained use of the ALS Identified program, one of the largest samples of people with ALS to date across the United States, demonstrating the interest and need for genetic ALS testing.

Association of lower urinary tract symptoms and the metabolic syndrome: results from the Boston area community health survey.

PURPOSE: In this study we investigated the relationship between lower urinary tract symptoms as defined by the American Urological Association symptom index and the metabolic syndrome, and determined the relationship between individual symptoms comprising the American Urological Association symptom index and the metabolic syndrome. MATERIALS AND METHODS: The Boston Area Community Health Survey used a 2-stage cluster design to recruit a random sample of 2,301 men 30 to 79 years old. Analyses were conducted on 1,899 men who provided blood samples. Urological symptoms comprising the American Urological Association symptom index were included in the analysis. The metabolic syndrome was defined using a modification of the Adult Treatment Panel III guidelines. The association between lower urinary tract symptoms and the metabolic syndrome was assessed using odds ratios and 95% confidence intervals estimated using logistic regression models. RESULTS: Increased odds of the metabolic syndrome were observed in men with mild to severe symptoms (American Urological Association symptom index 2 to 35) compared to those with an American Urological Association symptom index score of 0 or 1 (multivariate OR 1.68, 95% CI 1.21-2.35). A statistically significant association was observed between the metabolic syndrome and a voiding symptom score of 5 or greater (multivariate adjusted OR 1.73, 95% CI 1.06-2.80) but not for a storage symptom score of 4 or greater (multivariate adjusted OR 0.94, 95% CI 0.66-1.33). Increased odds of the metabolic syndrome were observed even with mild symptoms, primarily for incomplete emptying, intermittency and nocturia. These associations were observed primarily in younger men (younger than 60 years) and were null in older men (60 years old or older). CONCLUSIONS: The observed association between urological symptoms and the metabolic syndrome provides further evidence of common underlying factors between lower urinary tract symptoms and chronic conditions outside the urinary tract.

Common prescription medication use and erectile dysfunction: results from the Boston Area Community Health (BACH) survey.

OBJECTIVE: To investigate the association of erectile dysfunction (ED) with commonly used medications including antihypertensive treatment (AHT), psychoactive medication and pain and anti-inflammatory medication. SUBJECTS AND METHODS: The Boston Area Community Health (BACH) survey used a multistage stratified design to recruit a random sample of 2301 men aged 30-79 years. ED was assessed using the five-item International Index of Erectile Function (IIEF-5). Prescription medications, captured using a combination of drug inventory and self-report with a prompt by indication, included in this analysis comprised AHT, psychoactive medication, and pain and anti-inflammatory medication. Logistic regression was used to estimate the odds ratios (ORs) of the association of medication use with ED and to adjust for potential confounders including age, comorbid conditions and sociodemographic and lifestyle factors. RESULTS: Multivariable analyses showed benzodiazepines (adjusted OR = 2.34, 95% confidence interval [CI]: 1.03, 5.31) and tricyclic antidepressants (adjusted OR = 3.35, 95% CI: 1.09, 10.27) were associated with ED, while no association was observed for serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors and atypical antipsychotics. The use of AHT, whether in monotherapy or in conjunction with other AHTs, and pain or anti-inflammatory medications were not associated with ED after accounting for confounding factors. CONCLUSIONS: Results of the BACH survey suggest adverse effects of some psychoactive medications (benzodiazepines and tricyclic antidepressants). No evidence of an association of AHT or pain and anti-inflammatory medication with ED was observed.

Estimated Familial Amyotrophic Lateral Sclerosis Proportion: A Literature Review and Meta-analysis.

Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder. Familial (fALS) cases are usually reported to constitute 5%-10% of all ALS cases; however, no recent literature review or meta-analysis of this proportion (referred to throughout as "proportion fALS") has been conducted. Our objective was to estimate the proportion fALS by geographic region and to assess the effect of study characteristics on the estimates. Methods: A comprehensive literature review was performed to identify all original studies reporting the number of fALS cases in an ALS cohort. The results were stratified by geographic region, study design (case series or population-based), and decade of study publication. Subgroup analyses were conducted according to family history criteria used to define fALS. We report pooled estimates of the proportion fALS from random-effects meta-analyses when >2 studies are available and I2 is < 90%; weighted averages and ranges are otherwise presented. Results: The overall pooled proportion fALS based on a total 165 studies was 8% (0%, 71%). The proportion fALS was 9% (0%, 71%) among 107 case series and 5% (4%, 6%) among 58 population-based studies. Among population-based studies, proportion fALS by geographic region was 6% (5%, 7%; N = 37) for Europe, 5% (3%, 7%; N = 5) for Latin America, and 5% (4%, 7%; N = 12) for North America. Criteria used to define fALS were reported by 21 population-based studies (36%), and proportion fALS was 5% (4%, 5%; N = 9) for first-degree relative, 7% (4%, 11%; N = 4) for first or second-degree relative, and 11% (N = 1) for more distant ALS family history. Population-based studies published in the 2000s or earlier generated a lower pooled proportion fALS than studies published in the 2010s or later. Discussion: The results suggest that variability in the reported proportion fALS in the literature may be, in part, due to the differences in geography, study design, fALS definition, and decade of case ascertainment. Few studies outside of European ancestral populations were available. The proportion fALS was marginally higher among case series compared with population-based studies, likely because of referral bias. Criteria used to define fALS were largely unreported. Consensus criteria for fALS and additional population-based studies in non-European ancestral populations are needed.

Increased Risk of Venous Thromboembolism in Patients With Amyotrophic Lateral Sclerosis: Results From a US Insurance Claims Database Study.

Background and Objectives: Reduced mobility in patients with amyotrophic lateral sclerosis (ALS) is hypothesized to increase the risk of venous thromboembolism (VTE). A few small, single-center studies have investigated the risk of VTE in patients with ALS. Given the high morbidity and mortality associated with VTE, further understanding of the risk in patients with ALS may inform clinical care. The objective of this study was to investigate the incidence of VTE in patients with ALS compared with controls without ALS. Methods: Patients were identified from a US health insurance claims database, Optum's deidentified Clinformatics Data Mart Database, between 2004 and 2019. ALS cases were defined as patients aged 18 years or older with (1) 2 or more ALS claims at least 27 days apart including at least 1 claim from a neurologist visit or (2) 1 or more ALS claims and a prescription for riluzole or edaravone. Each ALS case was matched on age and sex to 5 controls without ALS. VTE was defined as at least 1 claim for VTE and at least 1 anticoagulant prescription or VTE-related procedure within 7 days before and 30 days after a VTE claim date. Incidence rates were reported per 1,000 person-years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazards model. Results: Among 4,205 ALS cases and 21,025 controls, incident VTE occurred in 132 ALS cases (3.1%) and 244 controls (1.2%). Incidence rates of VTE were 19.9 per 1,000 person-years (95% CI 16.7-23.6) in ALS cases compared with 6.0 per 1,000 person-years (95% CI 5.0-7.1) in controls. ALS cases were about 3 times more likely to develop VTE (HR 3.3, 95% CI 2.6-4.0), with similar results among men and women. The median time to first VTE was 10 months from the initial ALS claim in ALS cases. Discussion: Consistent with previous smaller studies, a higher incidence rate of VTE was observed in a large sample of patients with ALS from across the United States, as compared to matched controls. The markedly increased risk underscores the importance of preventive efforts and careful monitoring for VTE in patients with ALS and may have implications for the management of ALS.

Are physical activity, smoking and alcohol consumption associated with lower urinary tract symptoms in men or women? Results from a population based observational study.

PURPOSE: Lower urinary tract symptoms are highly prevalent and reduce quality of life. Lifestyle behaviors and the development of lower urinary tract symptoms have been largely unexamined. We investigated physical activity, smoking and alcohol drinking in relation to the development of lower urinary tract symptoms in men and women. MATERIALS AND METHODS: Data were obtained from the BACH (Boston Area Community Health) Survey, a longitudinal observational study. Baseline (2002 to 2005) in-person interviews assessed activity, smoking and alcohol consumption. Five-year followup interviews (2006 to 2010 in 4,145) assessed new reports of moderate to severe lower urinary tract symptoms defined by the AUASI (AUA symptom index). Analysis was conducted using multivariable logistic regression. RESULTS: Lower urinary tract symptoms developed in 7.7% and 12.7% of at-risk men and women, respectively. Women were 68% less likely to experience lower urinary tract symptoms (OR 0.32; 95% CI 0.17, 0.60; p <0.001) if they had high vs low levels of physical activity. Although the association was similar among men, it was not statistically significant upon adjustment for medical or sociodemographic characteristics in the multivariable model. Women smokers were twice as likely to experience lower urinary tract symptoms, particularly storage symptoms (OR 2.15; 95% CI 1.30, 3.56; p = 0.003), compared to never smokers. Among men, smoking was not associated with lower urinary tract symptoms. Results for alcohol intake were inconsistent by intake level and symptom subtype. CONCLUSIONS: A low level of physical activity was associated with a 2 to 3 times greater likelihood of lower urinary tract symptoms. Smoking may contribute to the development of lower urinary tract symptoms in women but not in men. Clinicians should continue to promote physical activity and smoking cessation, noting the additional potential benefits of the prevention of lower urinary tract symptoms, particularly for women.

Association of overactive bladder and C-reactive protein levels. Results from the Boston Area Community Health (BACH) Survey.

OBJECTIVE: • To investigate the association between overactive bladder (OAB) and C-reactive protein (CRP) in a population-based sample of men and women. SUBJECTS AND METHODS: • Epidemiological survey of urological symptoms among men and women aged 30-79 years. A multi-stage stratified cluster design was used to randomly sample 5503 adults from the city of Boston. Analyses were conducted on 1898 men and 1854 women with available CRP levels. • The International Continence Society defines OAB as 'Urgency with or without urge incontinence, usually with frequency and nocturia.' OAB was defined as: (1) urgency, (2) urgency with frequency, and (3) urgency with frequency and nocturia. • Odds ratios (OR) and 95% confidence intervals (95% CI) of the CRP and OAB association were estimated using logistic regression. RESULTS: • Prevalence of OAB increased with CRP levels in both men and women. • In men, adjusted ORs (95% CI) per log(10) (CRP) levels were 1.90 (1.26-2.86) with OAB defined as urgency, 1.65 (1.06-2.58) with OAB defined as urgency and frequency, and 1.92 (1.13-3.28) with OAB defined as urgency, frequency and nocturia. • The association was more modest in women with ORs (95% CI) of 1.53 (1.07-2.18) for OAB as defined urgency, 1.51 (1.02-2.23) for OAB defined as urgency and frequency, and 1.34 (0.85-2.12) for OAB defined as urgency, frequency and nocturia. CONCLUSIONS: • Results show a consistent association of increasing CRP levels and OAB among both men and women. • These results support our hypothesis for the role of inflammation in the development of OAB and a possible role for anti-inflammatory agents in its treatment.

Incidence of Aicardi-Goutières syndrome and KCNT1-related epilepsy in Denmark.

Objective: To estimate the incidence of Aicardi-Goutières syndrome (AGS) and potassium sodium-activated channel subfamily T member 1 (KCNT1)-related epilepsy in Denmark and to characterize the patients diagnosed with AGS and KCNT1-related epilepsy. Background: AGS and KCNT1-related epilepsy are 2 distinct rare genetic disorders. Due to the rarity of AGS and KCNT1-related epilepsy, the epidemiology remains unclear. The incidences for these diseases or the carriers with disease-related genetic variants remain unknown. Materials and methods: This is a retrospective, non-interventional, population-based study using aggregate data from the Danish population register and hospital-based patient-level data in Denmark to identify persons with genetically confirmed AGS between January 2010 to December 2020 and KCNT1-related epilepsies between January 2012 to December 2020. Cases of these disorders were identified from in-hospital databases, and pathogenic variants were identified and confirmed by Sanger and/or whole exome (panel-based) sequencing. The incidence of AGS and KCNT1-related epilepsy were estimated in separate statistical analyses. Results: A total of 7 AGS patients were identified. The mean age at AGS diagnosis was 19.4 months (median age 14 months). TREX1 (n < 5) and RNASEH2B (n ≥ 5) genes were reported with confirmed pathogenic variants. The birth incidence of AGS was <0.7600 per 100,000 live births. The average annual incidence rate was calculated as 0.0539 (95% CI: 0.0217-0.1111) per 100,000 persons per year in the total population < 18 years (n = 7); the average annual incidence rate was <0.7538 per 100,000 persons per year (n < 5) in the population < 12 months, and the average annual incidence rate in the population ≥ 12 months and < 18 years was <0.0406 per 100,000 persons per year (n < 5). A total of 14 KCNT1-related epilepsy cases were identified during the study period (n = 5 in 2016, remaining 9 cases in 2013 and 2015). The mean age at diagnosis was 20.6 years (median 19 years) for KCNT1 cases. A total of 8 cases (57.1%) were ≥ 18 years, and 6 (42.9%) were < 18 years at diagnosis. The phenotype autosomal dominant or sporadic sleep-related hypermotor epilepsy (ADSHE) (n = 10, 71.4%) was most reported; the remaining 4 cases had either epilepsy of infancy with migrating focal seizures (EIMFS) or an unclassifiable developmental and epileptic encephalopathy (DEE). The birth incidence of KCNT1-related epilepsy was ≤1.1205 per 100,000 live births. The average annual incidence rates per 100,000 persons per year during the study period were 0.0431 (95% confidence interval [CI]: 0.0236-0.0723; n = 14) in the overall population ≤ 50 years, 0.0568 (95% CI: 0.0209-0.1237; n = 6) in the population < 18 years, and 0.0365 (95% CI: 0.0157-0.0718; n = 8) in the population ≥ 18 and ≤ 50 years. There were 3 families with at least 2 cases diagnosed with KCNT1-related epilepsies (on average 3.3 cases per family), indicating 10 cases in total within the 3 families. All KCNT1 cases of ADSHE phenotype came from the 3 families. The higher incidence of older ages and ADSHE cases compared with previous KCNT1 studies is likely due to the capture of prevalent and familial previously undiagnosed cases. Excluding these family cases, the average annual incidence was 0.0123 (95% CI: 0.0034-0.0315, n = 4) per 100,000 persons per year in the population ≤ 50 years during 2012-2020. Conclusions: AGS and KCNT1-related epilepsy are particularly rare diseases. The annual average incidence rate of AGS was 0.0539 per 100,000 persons per year in the population < 18 years and birth incidence was <0.7600 per 100,000 live births during 2010-2020. The average annual incidence rate of KCNT1-related epilepsy was 0.0431 per 100,000 persons per year in the population ≤ 50 years and the birth incidence was ≤1.1205 per 100,000 live births during 2012-2020. Given similar healthcare systems and genetic pools, these findings may provide insight on the incidence of these rare diseases in the Nordics.

Comparative All-Cause Mortality Among a Large Population of Patients with Spinal Muscular Atrophy Versus Matched Controls.

INTRODUCTION: There is little information about survival of spinal muscular atrophy (SMA) patients into adulthood, in particular from population-based samples. We estimated and compared age-specific, all-cause mortality rates in patients with SMA and matched controls in a large, retrospective cohort study using electronic health records (EHRs) from the pre-treatment era. METHODS: The US Optum® de-identified EHR database contains EHRs for ~ 104 million persons (study period: January 1, 2007-December 22, 2016). SMA cases were identified by one or more International Classification of Diseases, Ninth/Tenth Edition codes for SMA. Controls with no SMA diagnosis code were matched 10:1 to SMA cases based on birth year, gender, and first diagnostic code date. For both groups, ≥ 1 month of observation and (if deceased) a valid date of death were required for inclusion. Age-specific mortality rates per person-year (PY) and hazard ratios were calculated. RESULTS: Five thousand one hundred seventy-nine SMA cases and 51,152 controls were analyzed. The overall hazard ratio comparing cases with controls was 1.76 (95% CI 1.63-1.90). In patients with SMA type III diagnostic codes only, the all-age mortality rate was 1059/100,000 PYs in cases and 603/100,000 PYs in controls. In older age groups (13-20, 21-30, 31-40, 41-50, 51-60, and > 60 years), age-specific mortality rates for cases consistently exceeded those of controls. Limitations of this study included the inability to confirm the SMA diagnosis or SMA type by genetic or clinical confirmation. CONCLUSION: Patients with SMA of all ages, including adults and type III patients, had a higher all-cause mortality rate as compared to age-matched controls during the pre-treatment era.

Nonsteroidal antiinflammatory drug use and lower urinary tract symptoms: results from the Boston area community health survey.

There is evidence for a role of inflammation in the etiology of lower urinary tract symptoms (LUTS), raising the possibility that use of nonsteroidal antiinflammatory drugs (NSAIDs) may inhibit the development or progression of LUTS. The authors examined the association between use of prescription and over-the-counter NSAIDs and LUTS among 1,974 men and 2,661 women in the Boston Area Community Health Survey (2002-2005). Multivariable-adjusted logistic regression was used to estimate odds ratios and 95% confidence intervals for LUTS, voiding symptoms, storage symptoms, and nocturia. There was no clear association between use of prescription or over-the-counter NSAIDs (compared with no NSAID use) and overall LUTS, voiding symptoms, or nocturia in men or women. However, over-the-counter NSAID use was positively associated with storage symptoms in women (odds ratio = 1.37, 95% confidence interval: 1.03, 1.83), and there was a positive association between over-the-counter NSAID use and overall LUTS among women with a history of arthritis (odds ratio = 2.09, 95% confidence interval: 1.20, 3.64). These results do not provide strong support for an association between NSAIDs and LUTS. However, the associations between over-the-counter NSAID use and certain urologic symptoms, particularly among women with arthritis, and the potential mechanisms involved should be evaluated in future studies.

Association of nocturia and mortality: results from the Third National Health and Nutrition Examination Survey.

PURPOSE: Nocturia, a common problem in men and women, has been associated with chronic illnesses such as heart disease and hypertension. Using data from the Third National Health and Nutrition Examination Survey we investigated the association of nocturia with subsequent mortality risk. MATERIALS AND METHODS: NHANES III is a national probability survey of the United States between 1988 and 1994. Mortality data were obtained by linkage of NHANES III to the National Death Index. Cox proportional hazards regression models were used to assess the association between nocturia and all cause mortality, controlling for potential confounders in a sample of 15,988 men and women 20 years old or older. RESULTS: The prevalence of nocturia, defined as 2 or more voiding episodes nightly, was 15.5% in men and 20.9% in women. Multivariate analyses showed a statistically significant trend of increased mortality risk with increased number of voiding episodes in men and women. The magnitude of the nocturia and mortality association was greater in those younger than 65 years with attenuated associations in the 65 years old or older age group. CONCLUSIONS: Nocturia is a strong predictor of mortality, more so in younger men and women than in the elderly, with a dose-response pattern in increased mortality risk with increasing number of voiding episodes nightly. Potential underlying mechanisms of the observed association of nocturia and increased mortality risk include sleep disruption and subsequent development of related comorbid conditions.

Prevalence of post-micturition symptoms in association with lower urinary tract symptoms and health-related quality of life in men and women.

OBJECTIVE: • To estimate the prevalence of post-micturition symptoms (a feeling of incomplete emptying following urination and post-micturition dribble) in a population-based sample of men and women, and to examine overlap with storage and voiding LUTS and associations with health-related quality of life (HRQL). PATIENTS AND METHODS: • Data were obtained by in-person interview in the Boston Area Community Health survey, a population-based random sample of 2301 men and 3202 women aged 30-79 years in the USA. • Lower urinary tract symptoms (LUTS) were defined using the International Prostate Symptom Score and standardized terminology. • Multivariate linear regression was used to evaluate associations between urological symptoms and validated HRQL measures (SF-12 and activities interference) cross-sectionally. RESULTS: • The overall prevalence of post-micturition symptoms was 11.8% in men and 8.5% in women. • The prevalence increased with age in men but not women. • In men, post-void dribbling contributed to much of the post-micturition symptoms, whereas, in women, incomplete emptying was more common. • For both genders, over 50% with voiding symptoms also had post-micturition symptoms, compared to less than 50% of respondents who reported storage symptoms. • The presence of post-micturition symptoms, particularly incomplete emptying, was indicative of mildly impaired physical HRQL and activities interference in men and women, and mental HRQL in men (P < 0.01). CONCLUSIONS: • Post-micturition symptoms were more prevalent than any individual voiding symptom and commonly overlapped with other LUTS. • Over half of men and women with a voiding symptom also had a post-micturition symptom. • The presence of post-micturition symptoms was indicative of impaired HRQL.

14-Year Changes in Plasma Neurofilament Levels Among Men: A Pilot Study.

Little is known about the feasibility of using long-term stored blood samples to measure neurofilament levels and about long-term changes in neurofilament levels among healthy individuals. We performed a pilot study among 26 adult men in preparation for a larger-scale study of the natural history of neurofilament levels. Median change over 14 years in pNf-H was 97.1 pg/mL (IQR: 5.0 to 242.0 pg/mL) and in Nf-L was 2.117 pg/mL (IQR: -2.691 to 3.393 pg/mL). We demonstrated the feasibility of measuring neurofilament concentrations in stored blood samples and found a trend between age and increases in Nf-L levels among adults.