The mortality burden attributable to nontrauma fracture for privately insured adults with epilepsy

ObjectiveIndividuals with epilepsy have poor bone development and preservation throughout the lifespan and are vulnerable to nontrauma fracture (NTFx) and post‐NTFx complications. However, no studies have examined the contribution of NTFx to mortality among adults with epilepsy. The objective was to determine whether NTFx is a risk factor for mortality among adults with epilepsy.MethodsData from 2011 to 2016 were obtained from Optum Clinformatics Data Mart, a nationwide claims database from a single private payer in the United States. Diagnosis codes were used to identify adults (≥18 years old) with epilepsy, NTFx, and covariates (demographics and pre‐NTFx cardiovascular disease, respiratory disease, diabetes, chronic kidney disease, cancer). Crude mortality rate per 100 person‐years was estimated. Cox regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs) were determined for mortality, comparing epilepsy and NTFx (EP + NTFx; n = 11 471), epilepsy without NTFx (EP without NTFx; n = 50 384), without epilepsy and with NTFx (without EP + NTFx; n = 423 041), and without epilepsy and without NTFx (without EP without NTFx; n = 6.8 million) after adjusting for covariates.ResultsThe 3‐, 6‐, and 12‐month crude mortality rates were highest among EP + NTFx (12‐month mortality rate = 8.79), followed by without EP + NTFx (12‐month mortality rate = 4.80), EP without NTFx (12‐month mortality rate = 3.06), and without EP without NTFx (12‐month mortality rate = 0.47). After adjustments, the mortality rate was elevated for EP + NTFx for all time points compared to EP without NTFx (eg, 12‐month HR = 1.70, 95% CI = 1.58‐1.85), without EP + NTFx (eg, 12‐month HR = 1.41, 95% CI = 1.32‐1.51), and without EP without NTFx (eg, 12‐month HR = 5.23, 95% CI = 4.88‐5.60). Stratified analyses showed higher adjusted HRs of 12‐month mortality for EP + NTFx for all NTFx sites (ie, vertebral column, hip, extremities), all age categories (young, middle‐aged, older), and for both women and men.SignificanceAmong adults with epilepsy and compared to adults without epilepsy, NTFx is associated with a higher 12‐month mortality rate. Findings suggest that NTFx may be a robust risk factor for mortality among adults with epilepsy.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154895/1/epi16465.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154895/2/epi16465_am.pd

Maximize How You Supervise: Report of the 2016 ASHA Ad Hoc Committee on Supervision Training

The success of existing and future audiologists and speech-language pathologists is dependent on skilled supervision. This session presents the findings of the ASHA Ad Hoc Committee on Supervision Training, including resources to enhance supervisor/preceptor skills and strategies for growing a culture of expectation for such training

An integrated approach to identify new anti-filarial leads to treat river blindness, a neglected tropical disease

Filarial worms cause multiple debilitating diseases in millions of people worldwide, including river blindness. Currently available drugs reduce transmission by killing larvae (microfilariae), but there are no effective cures targeting the adult parasites (macrofilaricides) which survive and reproduce in the host for very long periods. To identify effective macrofilaricides, we carried out phenotypic screening of a library of 2121 approved drugs for clinical use against adul

International Coercion, Emulation and Policy Diffusion: Market-Oriented Infrastructure Reforms, 1977-1999

Why do some countries adopt market-oriented reforms such as deregulation, privatization and liberalization of competition in their infrastructure industries while others do not? Why did the pace of adoption accelerate in the 1990s? Building on neo-institutional theory in sociology, we argue that the domestic adoption of market-oriented reforms is strongly influenced by international pressures of coercion and emulation. We find robust support for these arguments with an event-history analysis of the determinants of reform in the telecommunications and electricity sectors of as many as 205 countries and territories between 1977 and 1999. Our results also suggest that the coercive effect of multilateral lending from the IMF, the World Bank or Regional Development Banks is increasing over time, a finding that is consistent with anecdotal evidence that multilateral organizations have broadened the scope of the “conditionality” terms specifying market-oriented reforms imposed on borrowing countries. We discuss the possibility that, by pressuring countries into policy reform, cross-national coercion and emulation may not produce ideal outcomes.http://deepblue.lib.umich.edu/bitstream/2027.42/40099/3/wp713.pd

A Role for Alström Syndrome Protein, Alms1, in Kidney Ciliogenesis and Cellular Quiescence

Premature truncation alleles in the ALMS1 gene are a frequent cause of human Alström syndrome. Alström syndrome is a rare disorder characterized by early obesity and sensory impairment, symptoms shared with other genetic diseases affecting proteins of the primary cilium. ALMS1 localizes to centrosomes and ciliary basal bodies, but truncation mutations in Alms1/ALMS1 do not preclude formation of cilia. Here, we show that in vitro knockdown of Alms1 in mice causes stunted cilia on kidney epithelial cells and prevents these cells from increasing calcium influx in response to mechanical stimuli. The stunted-cilium phenotype can be rescued with a 5′ fragment of the Alms1 cDNA, which resembles disease-associated alleles. In a mouse model of Alström syndrome, Alms1 protein can be stably expressed from the mutant allele and is required for cilia formation in primary cells. Aged mice developed specific loss of cilia from the kidney proximal tubules, which is associated with foci of apoptosis or proliferation. As renal failure is a common cause of mortality in Alström syndrome patients, we conclude that this disease should be considered as a further example of the class of renal ciliopathies: wild-type or mutant alleles of the Alström syndrome gene can support normal kidney ciliogenesis in vitro and in vivo, but mutant alleles are associated with age-dependent loss of kidney primary cilia

Exceptionally preserved fossil assemblages through geologic time and space

Geologic deposits containing fossils with remains of non-biomineralized tissues (i.e. Konservat-Lagerstätten) provide key insights into ancient organisms and ecosystems. Such deposits are not evenly distributed through geologic time or space, suggesting that global phenomena play a key role in exceptional fossil preservation. Nonetheless, establishing the influence of global phenomena requires documenting temporal and spatial trends in occurrences of exceptionally preserved fossil assemblages. To this end, we compiled and analyzed a dataset of 694 globally distributed exceptional fossil assemblages spanning the history of complex eukaryotic life (~ 610 to 3 Ma). Our analyses demonstrate that assemblages with similar ages and depositional settings commonly occur in clusters, each signifying an ancient geographic region (up to hundreds of kilometers in scale), which repeatedly developed conditions conducive to soft tissue preservation. Using a novel hierarchical clustering approach, we show that these clusters decrease in number and shift from open marine to transitional and non-marine settings across the Cambrian-Ordovician interval. Conditions conducive to exceptional preservation declined worldwide during the early Paleozoic in response to transformations of near-surface environments that promoted degradation of tissues and curbed authigenic mineralization potential. We propose a holistic explanation relating these environmental transitions to ocean oxygenation and bioturbation, which affected virtually all taphonomic pathways, in addition to changes in seawater chemistry that disproportionately affected processes of soft tissue conservation. After these transitions, exceptional preservation rarely occurred in open marine settings, excepting times of widespread oceanic anoxia, when low oxygen levels set the stage. With these patterns, non-marine cluster count is correlated with non-marine rock quantity, and generally decreases with age. This result suggests that geologic processes, which progressively destroy terrestrial rocks over time, limit sampling of non-marine deposits on a global scale. Future efforts should aim to assess the impacts of such phenomena on evolutionary and ecological patterns in the fossil record

Short-course quinazoline drug treatments are effective in the Litomosoides sigmodontis and Brugia pahangi jird models

The quinazolines CBR417 and CBR490 were previously shown to be potent anti-wolbachials that deplete Wolbachia endosymbionts of filarial nematodes and present promising pre-clinical candidates for human filarial diseases such as onchocerciasis. In the present study we tested both candidates in two models of chronic filarial infection, namely the Litomosoides sigmodontis and Brugia pahangi jird model and assessed their long-term effect on Wolbachia depletion, microfilariae counts and filarial embryogenesis 16-18 weeks after treatment initiation (wpt). Once per day (QD) oral treatment with CBR417 (50 mg/kg) for 4 days or twice per day (BID) with CBR490 (25 mg/kg) for 7 days during patent L. sigmodontis infection reduced the Wolbachia load by >99% and completely cleared peripheral microfilaremia from 10-14 wpt. Similarly, 7 days of QD treatments (40 mg/kg) with CBR417 or CBR490 cleared >99% of Wolbachia from B. pahangi and reduced peritoneal microfilariae counts by 93% in the case of CBR417 treatment. Transmission electron microscopy analysis indicated intensive damage to the B. pahangi ovaries following CBR417 treatment and in accordance filarial embryogenesis was inhibited in both models after CBR417 or CBR490 treatment. Suboptimal treatment regimens of CBR417 or CBR490 did not lead to a maintained reduction of the microfilariae and Wolbachia load. In conclusion, CBR417 or CBR490 are pre-clinical candidates for filarial diseases, which achieve long-term clearance of Wolbachia endosymbionts of filarial nematodes, inhibit filarial embryogenesis and clear microfilaremia with treatments as short as 7 days

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570