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Background: Selection of appropriate trial endpoints and outcome measures is particularly important in rare disease and rapidly progressing disease such as amyotrophic lateral sclerosis (ALS) where the challenges to conducting clinical trials, are substantial: patient and disease heterogeneity, limited understanding of exact disease pathophysiology, and lack of robust and available biomarkers. To address these challenges in ALS, the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised version (ALSFRS-R) was developed and has become a key primary endpoint in ALS clinical trials to assess functional disability and disease progression, often replacing survival as a primary outcome. However, increased understanding of the ALS disease journey and improvements in assistive technology for ALS patients have exposed issues with the ALSFRS-R, including non-linearity, multidimensionality and floor and ceiling effects that could challenge its continued utility as a primary outcome measure in ALS clinical trials. Recently, other qualitative scale measures of functioning disability have been developed to help address these issues. With this in mind, we conducted a literature search aimed at identifying both established and promising new measures for potential use in clinical trials.Methods: We searched PubMed, Google, Google Scholar, and the reference sections of key studies to identify papers that discussed qualitative measures of functional status for potential use in ALS studies. We also searched clinicaltrials.gov to identify functional status and health-related quality of life (HRQoL) measures that have been used in ALS interventional studies.Results: In addition to the ALSFRS-R, we identified several newer qualitative scales including ALSFRS-EX, ALS-MITOS, CNS-BFS, DALS-15, MND-DS, and ROADS. Strengths and limitations of each measure were identified and discussed, along with their potential to act as a primary or secondary outcome to assess patient functional status in ALS clinical trials.Conclusion: This paper serves as a reference guide for researchers deciding which qualitative measures to use as endpoints in their ALS clinical trials to assess functional status. This paper also discusses the importance of including ALS HRQoL and ALS cognitive screens in future clinical trials to assess the value of a new ALS therapy more comprehensively. [ABSTRACT FROM AUTHOR]

Objective: To determine the longitudinal changes of benign prostate-specific antigen (BPSA) and [−2]proPSA and how these changes relate to the outcomes. These markers have been shown to be predictive of prostate cancer (CaP) and benign prostatic hyperplasia treatment; however, little is known about longitudinal changes in these markers. Methods: In 1990, a 25% subsample from a cohort of white men aged 40-79 years, who were randomly selected from Olmsted County, Minnesota residents, completed a detailed clinical examination. BPSA and [−2]proPSA were measured from frozen sera. The men were evaluated biennially (median follow-up 7 years; range 0-8.8). Mixed-effects regression models were used to estimate the longitudinal changes in the BPSA and [−2]proPSA levels overall and by outcomes. Spearman correlations were used to compare these changes with the baseline levels and the annualized changes in urologic measures. Results: The median and 25th and 75th percentiles annualized percent change for [−2]proPSA and BPSA was 3.7%, 2.5% and 5.2% and 7.3%, 6.8%, and 7.7%, respectively. The annualized percent change for both markers correlated with the baseline and annualized changes in PSA and prostate volume. The annualized percent change increased with increasing age decade for [−2]proPSA but not for BPSA. The rate of increase in [−2]proPSA was significantly greater for men who developed enlarged prostates (median 3.5%, 25th and 75th percentile 2.6% and 4.4%, respectively) or CaP (median 8.1%, 25th and 75th percentile 6.6% and 9.8%, respectively) compared with those who did not develop enlarged prostates (median 1.9%, 25th and 75th percentile 0.9% and 3.0%, respectively) or CaP (median 3.5%, 25th and 75th percentile 2.3% and 4.8%, respectively). Conclusion: BPSA and [−2]proPSA levels increase over time. The annualized percent change in [−2]proPSA increases with age and might be a useful predictor of CaP development. [ABSTRACT FROM AUTHOR]

Study Type – Prognosis (cohort) Level of Evidence 2a OBJECTIVES To measure prostate volume doubling times (PVDTs) for a large sample of community men followed serially by transrectal ultrasonography (TRUS), and to determine whether specific characteristics are associated with a rapid PVDT. SUBJECTS AND METHODS A subsample of 446 subjects from a larger cohort of American white men aged 40–79 years were evaluated biennially for a median (range) follow-up of 10 (3–14) years. Mixed-effects regression models were used to estimate prostate growth rates and PVDT for subjects with three or more or with five or more serial biennial TRUS PV measurements. RESULTS The median (25–75th percentile) PVDT was 32.6 (24.6–44.0) years. The average annual increase in PV was 2.2%. The PVDT distribution was constant in men of all age groups studied ( r < 0.001, P = 0.99). The factor most strongly associated with PVDT was baseline transition zone volume ( r = −0.55, P < 0.001). Baseline total prostate-specific antigen (PSA) level, free PSA and total PV were also significantly inversely associated with PVDT ( r = −0.30, −0.44 and −0.32, respectively, all P < 0.001). Age, baseline anthropomorphic measurements, hormone levels and specific lifestyle characteristics were not significantly correlated with PVDT. CONCLUSION These data indicate that PVDT might be a useful future measure of benign prostatic growth. They provide a basis to forecast PV at 10, 20, or 30 years later, after one baseline TRUS measurement of prostate volume, and can be presented in a simple nomogram. [ABSTRACT FROM AUTHOR]

Familial hemiplegic migraine type 3 (FHM3) is a severe autosomal dominant migraine disorder caused by mutations in the voltagegated sodium channel Nav1.1 encoded by SCN1A. We determined the functional consequences of three mutations linked to FHM3 (L263V, Q1489K, and L1649Q) in an effort to identify molecular defects that underlie this inherited migraine disorder. Only L263V and Q1489K generated quantifiable sodium currents when coexpressed in tsA201 cells with the human β1 and β2 accessory subunits. The third mutant, L1649Q, failed to generate measurable whole-cell current because of markedly reduced cell surface expression. Compared to WT-Nav1.1. Q1489K exhibited increased persistent current but also enhanced entry into slow inactivation as well as delayed recovery from fast and slow inactivation, thus resulting in a predominantly loss-of-function phenotype further demonstrated by a greater loss of channel availability during repetitive stimulation. In contrast, L263V exhibited gain-of-function features, including delayed entry into, as well as accelerated recovery from, fast inactivation; depolarizing shifts in the steady-state voltage dependence of fast and slow inactivation; increased persistent current; and delayed entry into slow inactivation. Notably, the two mutations (Q1489K and L1649Q) that exhibited partial or complete loss of function are linked to typical FHM, whereas the gain-of-function mutation L263V occurred in a family having both FHM and a high incidence of generalized epilepsy. We infer from these data that a complex spectrum of Nav1.1 defects can cause FHM3. Our results also emphasize the complex relationship between migraine and epilepsy and provide further evidence that both disorders may share common molecular mechanisms. [ABSTRACT FROM AUTHOR]

Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel α1 subunit (NaV1.1), are associated with genetic forms of epilepsy, including generalized epilepsy with febrile seizures plus (GEFS+ type 2), severe myoclonic epilepsy of infancy (SMEI) and related conditions. Several missense SCN1A mutations have been identified in probands affected by the syndrome of intractable childhood epilepsy with generalized tonic–clonic seizures (ICEGTC), which bears similarity to SMEI. To test whether ICEGTC arises from molecular mechanisms similar to those involved in SMEI, we characterized eight ICEGTC missense mutations by whole-cell patch clamp recording of recombinant human SCN1A heterologously expressed in cultured mammalian cells. Two mutations (G979R and T1709I) were non-functional. The remaining alleles (T808S, V983A, N1011I, V1611F, P1632S and F1808L) exhibited measurable sodium current, but had heterogeneous biophysical phenotypes. Mutant channels exhibited lower (V983A, N1011I and F1808L), greater (T808S) or similar (V1611F and P1632S) peak sodium current densities compared with wild-type (WT) SCN1A. Three mutations (V1611F, P1632S and F1808L) displayed hyperpolarized conductance–voltage relationships, while V983A exhibited a strong depolarizing shift in the voltage dependence of activation. All mutants except T808S had hyperpolarized shifts in the voltage dependence of steady-state channel availability. Three mutants (V1611F, P1632S and F1808L) exhibited persistent sodium current ranging from ∼1–3% of peak current amplitude that was significantly greater than WT-SCN1A. Several mutants had impaired slow inactivation, with V983A showing the most prominent effect. Finally, all of the functional alleles exhibited reduced use-dependent channel inhibition. In summary, SCN1A mutations associated with ICEGTC result in a wide spectrum of biophysical defects, including mild-to-moderate gating impairments, shifted voltage dependence and reduced use dependence. The constellation of biophysical abnormalities for some mutants is distinct from those previously observed for GEFS+ and SMEI, suggesting possible, but complex, genotype–phenotype correlations. [ABSTRACT FROM AUTHOR]

Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel α1 subunit (Nav1.1), are associated with at least two forms of epilepsy, generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy of infancy (SMEI). We examined the functional properties of five SMEI mutations by using whole-cell patch-clamp analysis of heterologously expressed recombinant human SCN1A. Two mutations (F902C and G1674R) rendered SCN1A channels nonfunctional, and a third allele (G1749E) exhibited minimal functional alterations. However, two mutations within or near the S4 segment of the fourth repeat domain (R1648C and F1661S) conferred significant impairments in fast inactivation, including persistent noninactivating channel activity resembling the pattern of channel dysfunction observed for alleles associated with generalized epilepsy with febrile seizures plus. Our data provide evidence for a range of SCNIA functional abnormalities in SMEI, including gain-of-function defects that were not anticipated in this disorder. Our results further indicate that a complex relationship exists between phenotype and aberrant sodium channel function in these inherited epilepsies. [ABSTRACT FROM AUTHOR]

The metabolic syndrome, which is a set of lipid and nonlipid risk factors of metabolic origin linked with insulin resistance, is believed to be associated with an elevated risk for cardiovascular disease, but few have studied this association in prospective long-term cardiovascular outcomes trials. Placebo data from the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) were used post hoc to estimate the long-term relative risk of major coronary events (MCEs) associated with the metabolic syndrome, after excluding diabetes mellitus. In 4S and AFCAPS/TexCAPS, respectively, placebo-treated patients with the metabolic syndrome were 1.5 (95% confidence interval 1.2 to 1.8) and 1.4 (95% confidence interval 1.04 to 1.9) times more likely to have MCEs than those without it. Of the components of the metabolic syndrome, low high-density lipoprotein levels were associated with elevated risk of MCEs in both studies, whereas high triglycerides in 4S and elevated blood pressure and obesity in AFCAPS/TexCAPS were associated with significantly increased relative risk. Patients with the metabolic syndrome showed increased risk of MCEs irrespective of their Framingham-calculated 10-year risk score category (>20% vs ≤20%). These data demonstrate that the metabolic syndrome is associated with increased risk of MCEs in both hypercholesterolemic patients with coronary heart disease in 4S and in those with low high-density lipoprotein cholesterol but without coronary heart disease in AFCAPS/TexCAPS. It appears that the metabolic syndrome is associated with risk that is not entirely accounted for by traditional risk scoring paradigms. [Copyright &y& Elsevier]

Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel α[sub1] subunit (Na[subv]1.1), are associated with at least two forms of epilepsy, generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). We examined the functional properties of four GEFS+ alleles and one SMEI allele using whole-cell patch-clamp analysis of heterologously expressed recombinant human SCN1A. One previously reported GEFS+ mutation (I1656M) and an additional novel allele (R1657C), both affecting residues in a voltage-sensing S4 segment, exhibited a similar depolarizing shift in the voltage dependence of activation. Additionally, R1657C showed a 50% reduction in current density and accelerated recovery from slow inactivation. Unlike three other GEFS+ alleles that we recently characterized, neither R1657C nor 11656M gave rise to a persistent, noninactivating current. In contrast, two other GEFS + mutations (A1685V and V1353L) and L986F, an SMEI-associated allele, exhibited complete loss of function. In conclusion, our data provide evidence for a wide spectrum of sodium channel dysfunction in familial epilepsy and demonstrate that both GEFS+ and SMEI can be associated with nonfunctional SCN1A alleles. [ABSTRACT FROM AUTHOR]

Background: Naproxen strongly inhibits platelet aggregation. Objective: To examine the risk of acute thromboembolic cardiovascular events (TCEs) (myocardial infarction, sudden death, and stroke) with current naproxen use among patients with rheumatoid arthritis. Methods: We studied patients aged 40 to 79 years with rheumatoid arthritis in the British General Practice Research Database, excluding those with a prior TCE and potentially confounding conditions. We matched up to 4 controls by sex, age, and site of medical practice to cases with first incident TCEs. The case diagnosis date was designated as the index date for each case and his or her controls. We categorized naproxen according to the most recent prescription prior to the index date as being current (≤30 days), past (>30 days but <365 days), or none (≥365 days before index date). Using conditional logistic regression, we conducted a matched case-control analysis with adjustment for potential confounders. Results: We identified 809 cases. Current naproxen use was more common among controls (5.7%) than cases (3.2%). Adjusting for calendar year of treatment start, systemic corticosteroid use, diabetes, and comorbidity, we found that the odds ratio (95% confidence interval) for current naproxen use was 0.61 (0.39-0.94) while that for past use was 0.87 (0.65-1.16). Secondary and sensitivity analyses supported these results. Conclusions: In this case-control study, patients with rheumatoid arthritis and a current prescription for naproxen had a reduced risk of acute major TCEs relative to those with no naproxen prescription in the past year. These results are consistent with the ability of naproxen to inhibit platelet aggregation. [ABSTRACT FROM AUTHOR]

Presents research which determined the pore stoichiometry of a C1C isoform, human C1C-1. What ion channels are; Role of pores in channels; Features of chloride channels in the C1C family; Blockage of C1C-1 channels; Effects of the placement of thiol chains; Human C1C-1 having a single functional pore.

Studies the limnological effects of natural forest disturbance and succession in Mud Pond, Maine. Examination of the chemistry, charcoal, pollen, chrysophytes, and diatoms in sediments deposited in Mud Pond; Locality and bathymetry of Mud Pond; Physical and chemical characteristics of Mud Pond; Ages of Mud Pond sediment.

Background: Proton-pump inhibitors (PPIs) are widely prescribed as acid-suppression therapy. Some observational studies suggest that long-term use of PPIs is potentially associated with certain adverse kidney outcomes. We conducted a systematic literature review to assess potential bias in non-randomized studies reporting on putative associations between PPIs and adverse kidney outcomes (acute kidney injury, acute interstitial nephritis, chronic interstitial nephritis, acute tubular necrosis, chronic kidney disease, and end-stage renal disease). Methods: We searched the medical literature within 10 years of 17 December 2020. Pre-specified criteria guided identification of relevant English language articles for assessment. Risk of bias on an outcome-specific basis was evaluated using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool by two independent reviewers. Results: Of 620 initially identified records, 26 studies met a priori eligibility criteria and underwent risk of bias assessment. Nineteen studies were judged as having a moderate risk of bias for reported adverse kidney outcomes, while six studies were judged as having a serious risk of bias (mainly due to inadequate control of confounders and selection bias). We were unable to determine the overall risk of bias in two studies (one of which was assessed as having a moderate risk of bias for a different adverse kidney outcome) due to insufficient information presented. Effect estimates for PPIs in relation to adverse kidney outcomes varied widely (0.24–7.34) but associations mostly showed increased risk. Conclusion: Using ROBINS-I, we found that non-randomized observational studies suggesting kidney harm by PPIs have moderate to serious risk of bias, making it challenging to establish causality. Additional high-quality, real-world evidence among generalizable populations are needed to better understand the relation between PPI treatment and acute and chronic kidney outcomes, accounting for the effects of varying durations of PPI treatment, self-treatment with over-the-counter PPIs, and potential critical confounders. [ABSTRACT FROM AUTHOR]

BACKGROUND. Previous studies investigating the prevalence of male pattern hair loss (MPHL) typically used biased samples of men recruited from clinical populations which may limit generalizability of findings to broader populations. OBJECTIVE. To obtain an updated and improved estimate of the occurrence of MPHL in healthy men residing in the community. METHODS. Community-based sample of healthy men aged 18-49 years participated in a study investigating the effects of MPHL. Participants completed a brief questionnaire self reporting degree of hair loss, general health-related quality of life (HRQL) and hair-loss-specific measures. A trained observer also rated each participant using standardized classification for MPHL. RESULTS. The proportion of men with moderate to extensive hair loss (type III or greater) was 42%. The proportion of men with moderate to extensive hair loss increased with increasing age, ranging from 16% for men 18-29 years of age to 53% of men 40-49. Twelve percent of the men were classified as having predominantly frontal baldness (type A variants). CONCLUSIONS. MPHL, especially frontal baldness, may be more common than previously reported. [ABSTRACT FROM AUTHOR]

Background: The rising prevalence of adolescent mild depression in the UK and the paucity of evidence-based interventions in non-specialist sectors where most cases present, creates an urgent need for early psychological interventions. Randomised controlled trials (RCTs) are considered the gold standard for obtaining unbiased estimates of intervention effectiveness. However, the complexity of mental health settings poses great challenges for effectiveness evaluations. This paper reports learning from an embedded process evaluation of the ICALM RCT which tested the feasibility of delivering Interpersonal Counselling for Adolescents (IPC-A) plus Treatment as Usual (TAU) versus TAU only for adolescent (age 12–18) mild depression by non-qualified mental health professionals in non-specialist sectors. Methods: A qualitative mixed methods process evaluation, drawing on Bronfenbrenner's socioecological model to investigate key influences on trial delivery across macro-(e.g. policy), meso-(e.g. service characteristics) and micro-(e.g. on-site trial processes) contextual levels. Data collection methods included 9 site questionnaires, 4 observations of team meetings, policy documents, and 18 interviews with stakeholders including therapists, heads of service and managers. Thematic analysis focused on understanding how contextual features shaped trial implementation. Results: The ICALM trial concluded in 2022 having only randomised 14 out of the target 60 young people. At a macro-level, trial delivery was impacted by the COVID-19 pandemic, with services reporting a sharp increase in cases of (social) anxiety over low mood, and backlogs at central referral points which prolonged waiting times for mild cases (e.g. low mood). An interaction between high demand and lack of capacity at a meso-service level led to low prioritisation of trial activities at a micro-level. Unfamiliarity with research processes (e.g. randomisation) and variation in TAU support also accentuated the complexities of conducting an RCT in this setting. Conclusions: Conducting a RCT of IPC-A in non-specialist services is not feasible in the current context. Failure to conduct effectiveness trials in this setting has clinical implications, potentially resulting in escalation of mild mental health problems. Research done in this setting should adopt pragmatic and innovative recruitment and engagement approaches (e.g. creating new referral pathways) and consider alternative trial designs, e.g. cluster, stepped-wedge or non-controlled studies using complex systems approaches to embrace contextual complexity. Trial registration: ISRCTN registry, ISRCTN82180413. Registered on 31 December 2019. [ABSTRACT FROM AUTHOR]

The article presents the results of a study on the relationship of indices of insulin secretion in response to two challenges in persons with normal and abnormal glucose tolerances. Subjects were given an oral glucose tolerance test (OGTT) and a standardized mixed meal tolerance test (MTT). Insulin and glucose were determined at time 0, 30, 60, 90, 120 minutes post-challenge. The study concluded that there appears to be good correlation among indices of insulin secretion for the two challenges.

Purpose: Mutations in SCN1A, encoding the human NaV1.1 neuronal voltage-gated sodium channel, cause the syndrome of severe myoclonic epilepsy of infancy (SMEI). Most SMEI-associated mutations are predicted to truncate the SCN1A protein, likely causing a loss of sodium channel function. However, many missense or in-frame deletion SCN1A mutations have also been reported in this disorder, but their functional impact is largely unknown. Here we report the functional characterization of eight SCN1A mutations (G177E, I227S, R393H, Y426N, H939Q, C959R, delF1289, and T1909I) previously identified in SMEI probands. Methods: SCN1A mutants were constructed in a recombinant human SCN1A and then heterologously expressed in human tsA201 cells along with the human β1 and β2 sodium channel accessory subunits. Whole-cell patch-clamp recording was used to define biophysical properties of each mutant and for comparison with the wild-type (WT) channel. Results: Six of the mutants were nonfunctional, but Y426N and T1909I generated measurable sodium channel activity. Cells expressing Y426N and T1909I had significantly lower current densities compared with WT-SCN1A. In addition, other biophysical abnormalities were observed for the two functional mutants including decreased channel availability (Y426N) and increased persistent sodium current (T1909I). Conclusions: We conclude that SMEI is caused either by complete loss of SCN1A function, or by dysfunctional sodium channels exhibiting mixed biophysical properties. This wide spectrum of functional defects observed among SCN1A mutations suggests that SMEI may result from more than a single molecular or cellular mechanism, or require other factors for pathogenesis. [ABSTRACT FROM AUTHOR]

Mutations in genes encoding neuronal voltage-gated sodium channel subunits have been linked to inherited forms of epilepsy. The majority of mutations (>100) associated with generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI) occur in SCN1A encoding the Nav1.1 neuronal sodium channel α-subunit. Previous studies demonstrated functional heterogeneity among mutant SCN1A channels, revealing a complex relationship between clinical and biophysical phenotypes. To further understand the mechanisms responsible for mutant SCN1A behavior; we performed a comprehensive analysis of the single-channel properties of heterologously expressed recombinant WT-SCN1A channels. Based on these data, we then determined the mechanisms for dysfunction of two GEFS+-associated mutations (R1648H, R1657C) both affecting the S4 segment of domain 4. WT-SCN1A has a slope conductance (17 pS) similar to channels found in native mammalian neurons. The mean open time is ∼0.3 ms in the -30 to - 10 mV range. The R1648H mutant, previously shown to display persistent sodium current in whole-cell recordings, exhibited similar slope conductance but had an increased probability of late reopening and a subfraction of channels with prolonged open times. We did not observe bursting behavior and found no evidence for a gating mode shift to explain the increased persistent current caused by R1648H. Cells expressing R1657C exhibited conductance, open probability mean open time, and latency to first opening similar to WT channels but reduced whole-cell current density, suggesting decreased number of functional channels at the plasma membrane. In summary, our findings define single-channel properties for WT-SCN1A, detail the functional phenotypes for two human epilepsy-associated sodium channel mutants, and clarify the mechanism for increased persistent sodium current induced by the R1648H allele. [ABSTRACT FROM AUTHOR]

: ObjectivesTo investigate the longitudinal changes in the International Prostate Symptom Score (IPSS), bother score, and quality-of-life index in a community-based study in Japan.: MethodsOf 289 men between 40 and 79 years of age who were analyzed in the first community-based study, 223 (77.2%) participated in a follow-up study conducted 3 years later. The IPSS, bother score, and quality-of-life index, as well as medical histories and current medication use, were evaluated.: ResultsNeither the average IPSS, bother score, nor quality-of-life index significantly changed after 3 years in any age decade. However, changes in the IPSS varied among individuals, because 32%, 35%, and 33% of the men reported improved, stable, and worsened IPSS, respectively. Transurethral resection of the prostate was performed on 0%, 4%, and 21% of the men in the mild (0 to 7), moderate (8 to 19), and severe (20 to 35) IPSS categories, respectively. Neither prostate volume nor peak urinary flow rate significantly predicted progression of the IPSS after 3 years.: ConclusionsAlthough no definite general symptomatic progression was observed in the participants during 3 years, changes in subjective urinary symptoms varied among individuals ranging from improvement to worsening. The men with a more severe IPSS had a greater chance of transurethral resection of the prostate within 3 years. [Copyright &y& Elsevier]

Epilepsy is a common neurological condition that reflects neuronal hyperexcitability arising from largely unknown cellular and molecular mechanisms. In generalized epilepsy with febrile seizures plus, an autosomal dominant epilepsy syndrome, mutations in three genes coding for voltage-gated sodium channel α or β1 subunits (SCN1A, SCN2A, SCN1B) and one GABA receptor subunit gene (GABRG2) have been identified. Here, we characterize the functional effects of three mutations in the human neuronal sodium channel α subunit SCN1A by heterologous expression with its known accessory subunits, β1 and β2, in cultured mammalian cells. SCN1A mutations alter channel inactivation, resulting in persistent inward sodium current. This gain-of-function abnormality will likely enhance excitability of neuronal membranes by causing prolonged membrane depolarization, a plausible underlying biophysical mechanism responsible for this inherited human epilepsy. [Copyright &y& Elsevier]

Objective: To estimate the maternity-related cost of health care services in women with and without severe maternal morbidity (SMM). Methods: Women with a live inpatient birth in the calendar year 2013 were identified in the MarketScan® Commercial and Medicaid health insurance claims databases. Costs were defined as the amounts paid by insurers plus out-of-pocket and third-party payments. Costs were calculated as total maternity-related costs and categorized as prenatal, delivery, and postpartum costs. SMM was identified using the CDC algorithm of 25 ICD-9 diagnostic and procedural codes. Variables associated with higher delivery costs were determined by multivariable linear regression analysis. Results: A total of 750 women met the criteria for SMM in the Commercial population. The total, per-patient mean costs of care for women without and with SMM were $14,840 and $20,380, respectively. Delivery hospitalization costs were 76-77% of total mean costs for women without and with SMM. A total of 99 women met the criteria for SMM in the Medicaid population. The total, per-patient mean costs of care for women without and with SMM were $6894 and $10,134, respectively. Delivery costs were 71–72% of total costs. Variables independently predictive of increased delivery costs in both Commercial and Medicaid populations were delivery by cesarean section, multifetal gestation, gestational hypertension/preeclampsia, and obstetric infection. Conclusions: The occurrence of SMM was associated with an increase in maternity-related costs of 37% in the Commercial and 47% in the Medicaid population. Some of the factors associated with increased delivery hospitalization costs may be prevented. [ABSTRACT FROM AUTHOR]

Background: Epidemiology of patients with worsening heart failure and reduced ejection fraction (HFrEF) in the real-world setting is not well described.Objectives: The purpose of this study was to describe incidence, clinical characteristics, treatment, and outcomes of patients with HFrEF who develop worsening heart failure (HF) in the real-world setting.Methods: Data on patients with incident HFrEF from the National Cardiovascular Data Registry PINNACLE were linked to pharmacy, private practitioner, and hospital claims databases. Incidence, clinical characteristics, treatment (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blocker, and mineralocorticoid receptor antagonist) and outcomes of patients with worsening HF, defined as ≥90 days of stable HF with subsequent worsening requiring intravenous diuretic agents, were assessed.Results: Of 11,064 HFrEF patients, 1,851 (17%) developed worsening HF on average 1.5 years following initial HF diagnosis. Patients who developed worsening HF were more likely to be African American, be octogenarians, and have higher comorbidity burden (p < 0.001). At the onset of worsening HF, 42.4% of patients were on monotherapy, 43.4% were on dual therapy, and 14.1% were on triple therapy. A total of 48%, 61%, and 98% of patients were on >50% target dose for angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blocker, and mineralocorticoid receptor antagonist, respectively. The 2-year mortality rate was 22.5%, and 56% of patients were rehospitalized within 30 days of the worsening HF event.Conclusions: In the real-world setting, 1 in 6 patients with HFrEF develop worsening HF within 18 months of HF diagnosis. These patients have a high risk for 2-year mortality and recurrent HF hospitalizations. The use of standard-of-care therapies both before and after the onset of worsening HF is low. With high unmet medical need, patients with worsening HF require novel treatment strategies as well as greater optimization of existing guideline-directed therapy. [ABSTRACT FROM AUTHOR]

Objective: To determine the longitudinal changes of benign prostate-specific antigen (BPSA) and [-2]proPSA and how these changes relate to the outcomes. These markers have been shown to be predictive of prostate cancer (CaP) and benign prostatic hyperplasia treatment; however, little is known about longitudinal changes in these markers.Methods: In 1990, a 25% subsample from a cohort of white men aged 40-79 years, who were randomly selected from Olmsted County, Minnesota residents, completed a detailed clinical examination. BPSA and [-2]proPSA were measured from frozen sera. The men were evaluated biennially (median follow-up 7 years; range 0-8.8). Mixed-effects regression models were used to estimate the longitudinal changes in the BPSA and [-2]proPSA levels overall and by outcomes. Spearman correlations were used to compare these changes with the baseline levels and the annualized changes in urologic measures.Results: The median and 25th and 75th percentiles annualized percent change for [-2]proPSA and BPSA was 3.7%, 2.5% and 5.2% and 7.3%, 6.8%, and 7.7%, respectively. The annualized percent change for both markers correlated with the baseline and annualized changes in PSA and prostate volume. The annualized percent change increased with increasing age decade for [-2]proPSA but not for BPSA. The rate of increase in [-2]proPSA was significantly greater for men who developed enlarged prostates (median 3.5%, 25th and 75th percentile 2.6% and 4.4%, respectively) or CaP (median 8.1%, 25th and 75th percentile 6.6% and 9.8%, respectively) compared with those who did not develop enlarged prostates (median 1.9%, 25th and 75th percentile 0.9% and 3.0%, respectively) or CaP (median 3.5%, 25th and 75th percentile 2.3% and 4.8%, respectively).Conclusion: BPSA and [-2]proPSA levels increase over time. The annualized percent change in [-2]proPSA increases with age and might be a useful predictor of CaP development. [ABSTRACT FROM AUTHOR]

Introduction: We compared post-prandial insulin and glucose results from an Oral Glucose Tolerance Test (OGTT) to a standardized mixed meal tolerance test (MTT) in a representative sample of subjects categorized by OGTT as normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes (DM). Methods: 208 participants, aged 40 to 65 years, randomly selected through the Hoorn municipal registry, were included in this study: 163 NGT, 19 IGT, and 23 DM. Subjects were given a 75-glucose/carbohydrates OGTT and MTT (fat 49 g, carbohydrates 75 g, protein 25 g) at separate visits in random order. Blood samples were drawn for glucose at 0 (fasting), 30, 60, 90 and 120 minutes. ANOVA and paired t-tests were used to test for differences between meals. Results: Glucose levels at 2 hours were fairly comparable for OGTT vs MTT within IGT and NGT groups. Insulin was significantly higher for NGT and IGT subjects at 30 minutes than for DM (p<0.01), and for MTT vs OGTT within NGT (p<0.01) and IGT (p<0.05) groups. The much lower early insulin response for DM showed significant differences for MTT vs OGTT (p<0.05) at 30 minutes, and significant glucose differences at 2 hours (p<0.01). Conclusions: In a representative sample, glucose values for all groups rise to higher levels at 30 minutes following OGTT (glucose load) vs MTT despite similar glycemic content. The reduced early insulin response in DM is associated with higher 2-hour glucose levels and significant differences between OGTT and MTT, while the greater early insulin response for NGT and IGT results in comparable 2-hour glucose values for NGT and IGT. [ABSTRACT FROM AUTHOR]

Abstract: This study compared classical and model-based beta-cell responses during an oral glucose tolerance test (OGTT) and a meal tolerance test (MTT) in a population-based cohort. Individuals with normal glucose metabolism (NGM, n =161), impaired glucose metabolism (IGM, n =19) and type 2 diabetes mellitus (DM, n =20) underwent a 75g-OGTT and an MTT (75g carbohydrates, 50g fat, 24g proteins). Classical estimates of beta-cell function (insulinogenic index and the ratio of areas under insulin and glucose curves) were calculated. Mathematical modelling was used to determine beta-cell glucose sensitivity, rate sensitivity and potentiation. Insulin sensitivity was characterized by three surrogate estimates. Both classical and model-based estimates of beta-cell function were higher during MTT than during OGTT (P <0.05). Regarding the model-based parameters, especially beta-cell sensitivity was increased following MTT as compared with OGTT (P <0.05). Both during OGTT and MTT, across most parameters describing beta-cell function, the largest reduction in beta-cell response occurred between IGM and DM, while the largest reduction in insulin sensitivity occurred between NGM and IGM. We conclude that beta-cell response is stronger after a mixed meal than after an OGTT with equal carbohydrate quantity, both for classical and model-based parameters. The higher response was mostly explained by higher beta-cell sensitivity during the meal. [Copyright &y& Elsevier]

Objectives: We evaluated the hypothesis that plasma levels of adiponectin and leptin are independently but oppositely associated with coronary artery calcification (CAC), a measure of subclinical atherosclerosis. In addition, we assessed which biomarkers of adiposity and insulin resistance are the strongest predictors of CAC beyond traditional risk factors, metabolic syndrome, and plasma C-reactive protein (CRP). Background: Adipokines are fat-secreted biomolecules with pleiotropic actions that converge in diabetes and cardiovascular disease. Methods: We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, nondiabetic participants in the SIRCA (Study of Inherited Risk of Coronary Atherosclerosis). Results: Plasma adiponectin and leptin levels had opposite and distinct associations with adiposity, insulin resistance, and inflammation. Plasma leptin was positively (top vs. bottom quartile) associated with higher CAC after adjustment for age, gender, traditional risk factors, and Framingham risk scores (tobit regression ratio 2.42 (95% confidence interval [CI]: 1.48 to 3.95; p = 0.002) and further adjustment for metabolic syndrome and CRP (tobit regression ratio: 2.31; 95% CI: 1.36 to 3.94; p = 0.002). In contrast, adiponectin levels were not associated with CAC. Comparative analyses suggested that levels of leptin, interleukin-6, and soluble tumor necrosis factor receptor-2, as well as the homeostasis model assessment of insulin resistance (HOMA-IR) index, predicted CAC scores, but only leptin and HOMA-IR provided value beyond risk factors, metabolic syndrome, and CRP. Conclusions: In SIRCA, although both leptin and adiponectin levels were associated with metabolic and inflammatory markers, only leptin was a significant independent predictor of CAC. Of several metabolic markers, leptin and the HOMA-IR index had the most robust, independent associations with CAC. [Copyright &y& Elsevier]

• Objectives: To evaluate the cross-sectional association between lower urinary tract symptoms (LUTS) severity and sexual function in a population-based sample of men and the extent to which this association might be explained by age. • Subjects and Methods: Subjects in The Olmsted County Study of Urinary Symptoms and Health Status Among Men (55% participation rate) included 2115 white men aged 40 to 79 years; subjects were recruited on January 1, 1990, from a random sample identified through the Rochester Epidemiology Project. At baseline in 1990 and biennially thereafter, these men completed a self administered questionnaire that assessed LUTS severity with questions similar to those of the American Urological Association Symptom Index. At the 6-year follow-up, 11 previously validated questions about male sexual function from the Brief Sexual Function Inventory were added. • Results: Overall, each of the sexual function domains (sexual drive, erectile function, ejaculatory function, problem assessment, and overall sexual satisfaction) was inversely associated with the severity of LUTS, with Spearman correlation coefficients ranging from -0.21 to -0.31 (all P<.001). In age-adjusted analyses, the ejaculatory function and problem assessment domains were most strongly associated with overall LUTS severity, whereas the association with sexual drive was substantially diminished. Little difference was noted in the magnitude of association between sexual function and either obstructive or irritative symptoms. • Conclusions: The cross-sectional data suggest that sexual function is inversely associated with LUTS severity and that this association is only partially attributable to the confounding effects of age. [ABSTRACT FROM AUTHOR]

Sick sinus syndrome (SSS) describes an arrhythmia phenotype attributed to sinus node dysfunction and diagnosed by electrocardiographic demonstration of sinus bradycardia or sinus arrest. Although frequently associated with underlying heart disease and seen most often in the elderly, SSS may occur in the fetus, infant, and child without apparent cause. In this setting, SSS is presumed to be congenital. Based on prior associations with disorders of cardiac rhythm and conduction, we screened the alpha subunit of the cardiac sodium channel (SCN5A) as a candidate gene in ten pediatric patients from seven families who were diagnosed with congenital SSS during the first decade of life. Probands from three kindreds exhibited compound heterozygosity for six distinct SCN5A alleles, including two mutations previously associated with dominant disorders of cardiac excitability. Biophysical characterization of the mutants using heterologously expressed recombinant human heart sodium channels demonstrate loss of function or significant impairments in channel gating (inactivation) that predict reduced myocardial excitability. Our findings reveal a molecular basis for some forms of congenital SSS and define a recessive disorder of a human heart voltage-gated sodium channel. [ABSTRACT FROM AUTHOR]

Studies the patterns of vegetation change in the glaciated northeastern United States. Increase in the abundance of Picea; Decrease in the abundance of Tsuga canadensis and Fagus grandifolia; Increase in the abundance of Betula in response to forest disturbance; Decrease of T. canadensis caused by tanning industry.

We studied whether parameters of beta cell function were similar during an oral glucose tolerance test (OGTT) and a -physiologically more relevant-mixed meal tolerance test (MTT) in different glucose tolerance groups. Individuals with normal glucose tolerance (NGT, n=150), intermediate hyperglycaemia (IH, n=19) and diabetes (DM, n=19) underwent an OGTT and an MTT, both containing 75g carbohydrates. The meal also contained 50g fat and 24g proteins. Plasma glucose, insulin and C-peptide were sampled before and 15, 30, 60, 90 and 120 minutes after OGTT and MTT. Insulin secretion rate (ISR) and beta cell function parameters were calculated from C-peptide using a mathematical model. These parameters included beta cell glucose sansitivity, i.e., the slope of the glucose concentration - ISR relationship and potentiation, which expresses a relative increase of ISR from the beginning to the end of the test. ANOVA and dependent t-tests with Bonferroni corrections were used to test for differences. Beta cell glucose sensitivity was higher during MTT than during OGTT in all groups (Table 1). Diabetic subjects had significantly lower beta cell glucose sensitivity than IH- and NGT-subjects. Potentiation was similar (NGT-or DM-subjects) or slightly higher (IH-subjects) during MTT. Beta cells were more sensitive to glucose (i.e. insulin secretion per glucose unit was higher) during a mixed meal load than during a glucose load while the ability to modulate this relationship (potentiation) was similar or slightly higher. Individuals with IH, unlike diabetic subjects, did not have lower beta cell sensitivity than NGT-individuals. We conclude that beta cell response is stronger after a mixed meal than after an OGTT with equal-carbohydrate quantity. [ABSTRACT FROM AUTHOR]