Validity of a wrist-worn consumer-grade wearable for estimating energy expenditure, sedentary behaviour, and physical activity in manual wheelchair users with spinal cord injury.

PURPOSE: To evaluate the validity of a consumer-grade wearable for estimating energy expenditure, sedentary behaviour, and physical activity in manual wheelchair users with spinal cord injury (SCI). MATERIALS AND METHODS: Fifteen manual wheelchair users with SCI (C5-L1, four female) completed activities of daily living and wheelchair propulsion (2-8 km·h-1). Wrist-worn accelerometry data were collected using consumer-grade (z-Track) and research-grade (ActiGraph GT9X) devices. Energy expenditure was measured via indirect calorimetry. Linear regression was used to evaluate the prediction of criterion metabolic equivalent of task (MET) by each accelerometer's vector magnitude (VM). Area under the receiver operating characteristic curve (ROC-AUC) evaluated the accuracy of VM for discriminating between physical activity intensities and for identifying accelerometer cut-points. RESULTS: Standardised ß-coefficients for the association between z-Track and ActiGraph VM for criterion MET were 0.791 (p < 0.001) and 0.774 (p < 0.001), respectively. The z-Track had excellent accuracy for classifying time in sedentary behaviour (ROC-AUC = 0.95) and moderate-to-vigorous physical activity (ROC-AUC = 0.93); similar values to the ActiGraph (ROC-AUC = 0.96 and 0.88, respectively). Cut-points for the z-Track were ≤37 g·min-1 for sedentary behaviour and ≥222 g·min-1 for moderate-to-vigorous physical activity. CONCLUSIONS: This study supports the validity of a consumer-grade wearable to measure sedentary time and physical activity in manual wheelchair users with SCI.

A consumer-grade wearable device provides valid estimations of sedentary time and physical activity in manual wheelchair users with spinal cord injury.Commercially available consumer-grade wearables may enable accurate self-monitoring in this population and, therefore, have potential for supporting behaviour change.

A Comparison of Clinical and Laboratory Features of Crimean-Congo Hemorrhagic Fever in Children and Adults: A Retrospective Single-Center Cohort Study and Literature Review.

Background: Crimean-Congo hemorrhagic fever (CCHF) is a major emerging infectious disease threat, and children are reported to have a milder disease course compared with adults, in contrast to other viral hemorrhagic fevers. The aim of this study was to compare adult and pediatric patients with CCHF to improve understanding of pathogenesis and the natural history of the disease. Materials and Methods: A retrospective analysis of all children and adults admitted with confirmed CCHF between 2011 and 2020. Epidemiological, clinical, and laboratory features were collated on proformas, together with clinical management details. The Severity Grading Score (SGS) system was used to stratify mortality risk. Data from children were compared with adults in the same center and with other published pediatric cohort studies. Results: A total of 47 children with a median (ranges) age of 14 (2-17) years and 176 adults with a median (ranges) age of 52 (18-83) years with confirmed CCHF were included. The most frequent symptoms in adults were fever, muscle-joint pain, headache, nausea, and vomiting; the most frequent in children were fever, anorexia, nausea, vomiting, and abdominal pain. Adults had lower lymphocyte and platelet counts and higher liver transaminase and creatinine levels than children. SGS values were lower in children, but 97.9% children received ribavirin compared with 8.5% of adults (p < 0.001), and they had associated longer median lengths of hospital admission (10 vs. 7 days, p < 0.001). Mortality of 1 out of 47 (2.1%) children was similar to 11 other cohorts reported in Türkiye and lower than 13.1% in adults (23/176) in the same center (p = 0.059). Conclusions: Children have lower CCHF-related mortality, less severe disease, and different clinical syndromes at presentation. The majority of published case definitions for screening for CCHF in the main endemic countries do not differentiate between adults and children and omit four of the five most common presenting features in children.

Ergogenic effects of spinal cord stimulation on exercise performance following spinal cord injury.

Cervical or upper-thoracic spinal cord injury (SCI, ≥T6) often leads to low resting blood pressure (BP) and impaired cardiovascular responses to acute exercise due to disrupted supraspinal sympathetic drive. Epidural spinal cord stimulation (invasive, ESCS) and transcutaneous spinal cord stimulation (non-invasive, TSCS) have previously been used to target dormant sympathetic circuits and modulate cardiovascular responses. This case series compared the effects of cardiovascular-optimised ESCS and TSCS versus sham ESCS and TSCS on modulating cardiovascular responses and improving submaximal upper-body exercise performance in individuals with SCI. Seven males with a chronic, motor-complete SCI between C6 and T4 underwent a mapping session to identify cardiovascular responses to spinal cord stimulation. Subsequently, four participants (two ESCS and two TSCS) completed submaximal exercise testing. Stimulation parameters (waveform, frequency, intensity, epidural electrode array configuration, and transcutaneous electrode locations in the lumbosacral region) were optimised to elevate cardiovascular responses (CV-SCS). A sham condition (SHAM-SCS) served as a comparison. Participants performed arm-crank exercise to exhaustion at a fixed workload corresponding to above ventilatory threshold, on separate days, with CV-SCS or SHAM-SCS. At rest, CV-SCS increased BP and predicted left ventricular cardiac contractility and total peripheral resistance. During exercise, CV-SCS increased time to exhaustion and peak oxygen pulse (a surrogate for stroke volume), relative to SHAM-SCS. Ratings of perceived exertion also tended to be lower with CV-SCS than SHAM-SCS. Comparable improvements in time to exhaustion with ESCS and TSCS suggest that both approaches could be promising ergogenic aids to support exercise performance or rehabilitation, along with reducing fatigue during activities of daily living in individuals with SCI.

An empirical appraisal of eLife's assessment vocabulary.

Research articles published by the journal eLife are accompanied by short evaluation statements that use phrases from a prescribed vocabulary to evaluate research on 2 dimensions: importance and strength of support. Intuitively, the prescribed phrases appear to be highly synonymous (e.g., important/valuable, compelling/convincing) and the vocabulary's ordinal structure may not be obvious to readers. We conducted an online repeated-measures experiment to gauge whether the phrases were interpreted as intended. We also tested an alternative vocabulary with (in our view) a less ambiguous structure. A total of 301 participants with a doctoral or graduate degree used a 0% to 100% scale to rate the importance and strength of support of hypothetical studies described using phrases from both vocabularies. For the eLife vocabulary, most participants' implied ranking did not match the intended ranking on both the importance (n = 59, 20% matched, 95% confidence interval [15% to 24%]) and strength of support dimensions (n = 45, 15% matched [11% to 20%]). By contrast, for the alternative vocabulary, most participants' implied ranking did match the intended ranking on both the importance (n = 188, 62% matched [57% to 68%]) and strength of support dimensions (n = 201, 67% matched [62% to 72%]). eLife's vocabulary tended to produce less consistent between-person interpretations, though the alternative vocabulary still elicited some overlapping interpretations away from the middle of the scale. We speculate that explicit presentation of a vocabulary's intended ordinal structure could improve interpretation. Overall, these findings suggest that more structured and less ambiguous language can improve communication of research evaluations.

Effects of exercise on autonomic cardiovascular control in individuals with chronic, motor-complete spinal cord injury: an exploratory randomised clinical trial.

STUDY DESIGN: Secondary analysis of a clinical trial. OBJECTIVE: To assess the impact of 6 months of arm cycle ergometry training (ACET), or body weight-supported treadmill training (BWSTT), on autonomic cardiovascular responses to a laboratory sit-up test (SUT) in individuals with chronic (≥1-year post-injury) spinal cord injury (SCI). SETTING: Tertiary Rehabilitation Centre, Vancouver, Canada. METHODS: Sixteen individuals with motor-complete (American Spinal Injury Association Impairment Scale A-B) SCI between the fourth cervical and sixth thoracic spinal cord segments, aged 39 ± 11 years, were assessed. Participants were randomized to receive 72 sessions of moderate-to-vigorous intensity ACET (n = 8) or passive BWSTT (n = 8). Changes in mean arterial pressure (finger plethysmography), hemodynamics (Modelflow® method), and heart rate/heart rate variability (HR/HRV; electrocardiography) were measured in response to a  SUT before and after 6 months of exercise training. Spontaneous cardiovagal baroreflex sensitivity (cvBRS) was assessed using the sequence method. RESULTS: Neither ACET nor BWSTT impacted hemodynamic responses to SUT or the incidence of orthostatic hypotension (all P > 0.36). ACET increased HR (P < 0.01, ηp2 = 0.34) and high frequency (HF) power HRV responses (P < 0.01, ηp2 = 0.42) to SUT following 6 months of training while BWSTT did not. Consistent with this, cvBRS improved (P < 0.05, ηp2 = 0.16) only following ACET. Improvements in cvBRS were correlated with both the HR (r = 0.726, P < 0.0001) and HF power (r = -0.484, P < 0.01) responses to SUT. CONCLUSION: Six months of ACET, but not BWSTT, improved cardiovagal baroreflex control of HR but had no effect on BP responses to SUT in individuals with chronic, motor-complete SCI. SPONSORSHIP: Canadian Institutes of Health Research (CIHR) CLINICAL TRIAL REGISTRATION: NCT01718977.

New tree height allometries derived from terrestrial laser scanning reveal substantial discrepancies with forest inventory methods in tropical rainforests.

Tree allometric models, essential for monitoring and predicting terrestrial carbon stocks, are traditionally built on global databases with forest inventory measurements of stem diameter (D) and tree height (H). However, these databases often combine H measurements obtained through various measurement methods, each with distinct error patterns, affecting the resulting H:D allometries. In recent decades, terrestrial laser scanning (TLS) has emerged as a widely accepted method for accurate, non-destructive tree structural measurements. This study used TLS data to evaluate the prediction accuracy of forest inventory-based H:D allometries and to develop more accurate pantropical allometries. We considered 19 tropical rainforest plots across four continents. Eleven plots had forest inventory and RIEGL VZ-400(i) TLS-based D and H data, allowing accuracy assessment of local forest inventory-based H:D allometries. Additionally, TLS-based data from 1951 trees from all 19 plots were used to create new pantropical H:D allometries for tropical rainforests. Our findings reveal that in most plots, forest inventory-based H:D allometries underestimated H compared with TLS-based allometries. For 30-metre-tall trees, these underestimations varied from -1.6 m (-5.3%) to -7.5 m (-25.4%). In the Malaysian plot with trees reaching up to 77 m in height, the underestimation was as much as -31.7 m (-41.3%). We propose a TLS-based pantropical H:D allometry, incorporating maximum climatological water deficit for site effects, with a mean uncertainty of 19.1% and a mean bias of -4.8%. While the mean uncertainty is roughly 2.3% greater than that of the Chave2014 model, this model demonstrates more consistent uncertainties across tree size and delivers less biased estimates of H (with a reduction of 8.23%). In summary, recognizing the errors in H measurements from forest inventory methods is vital, as they can propagate into the allometries they inform. This study underscores the potential of TLS for accurate H and D measurements in tropical rainforests, essential for refining tree allometries.

Selective pressures for public antibiotic resistance.

The rapid increase of antibiotic-resistant pathogens is severely limiting our current treatment possibilities. An important subset of the resistance mechanisms conferring antibiotic resistance have public effects, allowing otherwise susceptible bacteria to also survive antibiotic treatment. As susceptible bacteria can survive treatment without bearing the metabolic cost of producing the resistance mechanism, there is potential to increase their relative frequency in the population and, as such, select against resistant bacteria. Multiple studies showed that this altered selection for resistance is dependent on various environmental and treatment parameters. In this review, we provide a comprehensive overview of their most important findings and describe the main factors impacting the selection for resistance. In-depth understanding of the driving forces behind selection can aid in the design and implementation of alternative treatments which limit the risk of resistance development.

Greater aperture counteracts effects of reduced stomatal density on WUE: a case study on sugarcane and meta-analysis.

Stomata regulate CO2 and water vapor exchange between leaves and the atmosphere. Stomata are a target for engineering to improve crop intrinsic water use efficiency (iWUE). One example is by expressing genes that lower stomatal density (SD) and reduce stomatal conductance (gsw). However, the quantitative relationship between reduced SD, gsw, and the mechanisms underlying it is poorly understood. We addressed this knowledge gap using low-SD sugarcane (Saccharum spp. hybrid) as a case study alongside a meta-analysis of data from 10 species. Transgenic expression of EPIDERMAL PATTERNING FACTOR 2 from Sorghum bicolor (SbEFP2) in sugarcane reduced SD by 26-38% but did not affect gsw compared to wildtype. Further, no changes occurred in stomatal complex size or proxies for photosynthetic capacity. Measurements of gas exchange at low CO2 concentrations that promote complete stomatal opening to normalize aperture size between genotypes were combined with modeling of maximum gsw from anatomical data. These data suggest that increased stomatal aperture is the only possible explanation for maintaining gsw when SD is reduced. Meta-analysis across C3 dicots, C3 monocots, and C4 monocots revealed engineered reductions in SD are strongly correlated with lower gsw (r2=0.60-0.98), but this response is damped relative to the change in anatomy.

Reducing stomatal density by expression of a synthetic Epidermal Patterning Factor increases leaf intrinsic water use efficiency and reduces plant water use in a C4 crop.

Enhancing crop water use efficiency (WUE) is a key target trait for climatic resilience and expanding cultivation on marginal lands. Engineering lower stomatal density to reduce stomatal conductance (gs) has improved WUE in multiple C3 crop species. However, reducing gs in C3 species often reduces photosynthetic carbon gain. A different response is expected in C4 plants because they possess specialized anatomy and biochemistry which concentrates CO2 at the site of fixation. This modifies the photosynthesis (AN) relationship with intracellular CO2 concentration (ci) so that photosynthesis is CO2-saturated and reductions in gs are unlikely to limit AN. To test this hypothesis, genetic strategies were investigated to reduce stomatal density in the C4 crop sorghum. Constitutive expression of a synthetic epidermal patterning factor (EPF) transgenic allele in sorghum, led to reduced stomatal densities, reduced gs, reduced plant water use and avoidance of stress during a period of water deprivation. In addition, moderate reduction in stomatal density did not increase stomatal limitation to AN. However, these positive outcomes were associated with negative pleiotropic effects on reproductive development and photosynthetic capacity. Avoiding pleiotropy by targeting expression of the transgene to specific tissues could provide a pathway to improved agronomic outcomes.

Gastrointestinal and Neuropsychological Symptoms Are Associated With Distinct Vomiting Profiles in Patients Receiving Chemotherapy.

OBJECTIVES: To identify subgroups of patients with distinct chemotherapy-induced vomiting (CIV) profiles; determine how these subgroups differ on several demographic, clinical, and symptom characteristics; and evaluate factors associated with chemotherapy-induced nausea and CIV profiles. SAMPLE & SETTING: Adult patients (N = 1,338) receiving cancer chemotherapy. METHODS & VARIABLES: Data were collected on demographic, clinical, and symptom characteristics. Differences among subgroups of patients with distinct CIV profiles were evaluated using parametric and nonparametric tests. RESULTS: Three CIV profiles (None, Decreasing, and Increasing) were identified. Compared with the None class, Decreasing and Increasing classes were more likely to have lower household income and a higher comorbidity burden, as well as to report higher rates of dry mouth, nausea, diarrhea, depression, anxiety, sleep disturbance, morning fatigue, and pain interference. IMPLICATIONS FOR NURSING: Clinicians need to assess common and distinct risk factors for CIV and chemotherapy-induced nausea.

Expanding the data Ark: an attempt to make the data from highly cited social science papers publicly available.

Access to scientific data can enable independent reuse and verification; however, most data are not available and become increasingly irrecoverable over time. This study aimed to retrieve and preserve important datasets from 160 of the most highly-cited social science articles published between 2008-2013 and 2015-2018. We asked authors if they would share data in a public repository-the Data Ark-or provide reasons if data could not be shared. Of the 160 articles, data for 117 (73%, 95% CI [67%-80%]) were not available and data for 7 (4%, 95% CI [0%-12%]) were available with restrictions. Data for 36 (22%, 95% CI [16%-30%]) articles were available in unrestricted form: 29 of these datasets were already available and 7 datasets were made available in the Data Ark. Most authors did not respond to our data requests and a minority shared reasons for not sharing, such as legal or ethical constraints. These findings highlight an unresolved need to preserve important scientific datasets and increase their accessibility to the scientific community.

The lifetime risk of surgery in England: a nationwide observational cohort study.

BACKGROUND: The average number of times a person will have surgery in their lifetime, and the amount of surgical healthcare resources they use, is unknown. Lifetime risk is a measure of the risk of an average person having a specific event within their lifetime. We report the lifetime risk of surgery and the change observed during the first year of the COVID-19 pandemic. METHODS: We conducted a population cohort study using hospital episode statistics to identify all patients undergoing surgery between January 1, 2016, and December 31, 2020, in England. We calculated age- and sex-specific incidence rates of surgery and combined these with routinely available population and mortality data from the Office for National Statistics. We computed the probability of requiring surgery stratified by 5-yr epochs (age 0-4 to ≥90 yr). Our primary analysis calculated lifetime risk for all surgery using the life table method. We assessed the impact of the COVID-19 pandemic, comparing a pre-pandemic and a pandemic period. RESULTS: Between 2016 and 2020, 23 427 531 patients underwent surgery, of which 11 937 062 were first surgeries. The average denominator population for England was 55.9 million. The lifetime risk of first surgery was 60.2% (95% confidence interval 55.1-65.4%) for women and 59.1% (95% confidence interval 54.2-64.1%) for men. The COVID-19 pandemic decreased the lifetime risk of first surgery by 32.3% for women and by 31.7% for men. This estimated lifetime risk should only be applied to the English population. CONCLUSIONS: This population epidemiological analysis suggests that approximately 60% of people in England will undergo surgery in their lifetime.

Enhancing Spinal Cord Injury Care: Using Wearable Technologies for Physical Activity, Sleep, and Cardiovascular Health.

Wearable devices have the potential to advance health care by enabling real-time monitoring of biobehavioral data and facilitating the management of an individual's health conditions. Individuals living with spinal cord injury (SCI) have impaired motor function, which results in deconditioning and worsening cardiovascular health outcomes. Wearable devices may promote physical activity and allow the monitoring of secondary complications associated with SCI, potentially improving motor function, sleep, and cardiovascular health. However, several challenges remain to optimize the application of wearable technologies within this population. One is striking a balance between research-grade and consumer-grade devices in terms of cost, accessibility, and validity. Additionally, limited literature supports the validity and use of wearable technology in monitoring cardio-autonomic and sleep outcomes for individuals with SCI. Future directions include conducting performance evaluations of wearable devices to precisely capture the additional variation in movement and physiological parameters seen in those with SCI. Moreover, efforts to make the devices small, lightweight, and inexpensive for consumer ease of use may affect those with severe motor impairments. Overcoming these challenges holds the potential for wearable devices to help individuals living with SCI receive timely feedback to manage their health conditions and help clinicians gather comprehensive patient health information to aid in diagnosis and treatment.

Microbial symbionts buffer hosts from the demographic costs of environmental stochasticity.

Species' persistence in increasingly variable climates will depend on resilience against the fitness costs of environmental stochasticity. Most organisms host microbiota that shield against stressors. Here, we test the hypothesis that, by limiting exposure to temporally variable stressors, microbial symbionts reduce hosts' demographic variance. We parameterized stochastic population models using data from a 14-year symbiont-removal experiment including seven grass species that host Epichloë fungal endophytes. Results provide novel evidence that symbiotic benefits arise not only through improved mean fitness, but also through dampened inter-annual variance. Hosts with "fast" life-history traits benefited most from symbiont-mediated demographic buffering. Under current climate conditions, contributions of demographic buffering were modest compared to benefits to mean fitness. However, simulations of increased stochasticity amplified benefits of demographic buffering and made it the more important pathway of host-symbiont mutualism. Microbial-mediated variance buffering is likely an important, yet cryptic, mechanism of resilience in an increasingly variable world.

Lived Experiences of Sexuality and Sexual Functioning in Males with SCI: A Mixed-Methods Study.

Background: Sexual dysfunction is highly prevalent in males with spinal cord injury (SCI) and has been recognized to be a key recovery priority. Objectives: This cross-sectional, mixed-methods study aimed to investigate the major themes linked to sexual functioning in males with chronic (>1 year) SCI. Methods: Twenty male participants with SCI, aged 25 to 59 years, completed validated questionnaires exploring sexual function/satisfaction and health-related quality of life and a semi-structured interview with an experienced sexual medicine physician. Sex hormone concentrations and metabolic biomarkers, along with body composition and habitual physical activity levels, were assessed. Interview recordings were transcribed and thematic analysis performed using combined COM-B (Capability, Opportunity, Motivation, and Behavior) and biopsychosocial models to identify and organize major contributors and barriers to sexual functioning. Results: Metabolic and hormonal biomarkers largely fell within normal physiological ranges despite reduced sexual functioning reported in our cohort (19/20 participants reported some degree of erectile dysfunction). Qualitative analysis of interview transcripts revealed 24 themes. Adaptability was important for improving sexual satisfaction. Attraction and attentiveness to sex and partners remained stable over time, while the desire for intimacy increased post injury. Sexual social norms, and comparisons to the able-bodied population, provided challenges for sexual activity and partnership. Environmental concerns regarding access to sexual health resources and accessible physical spaces during intimacy were relevant. Mood disorders and general life stressors negatively impacted sexual desire, while physical activity encouraged sexual activity. Conclusion: By considering a holistic view of sexuality in males with SCI, we identified key contributors and barriers to sexual functioning for the cohort studied.

Cerebrovascular Reactivity Following Spinal Cord Injury.

Background: Spinal cord injuries (SCI) often result in cardiovascular issues, increasing the risk of stroke and cognitive deficits. Objectives: This study assessed cerebrovascular reactivity (CVR) using functional magnetic resonance imaging (fMRI) during a hypercapnic challenge in SCI participants compared to noninjured controls. Methods: Fourteen participants were analyzed (n = 8 with SCI [unless otherwise noted], median age = 44 years; n = 6 controls, median age = 33 years). CVR was calculated through fMRI signal changes. Results: The results showed a longer CVR component (tau) in the grey matter of SCI participants (n = 7) compared to controls (median difference = 3.0 s; p < .05). Time since injury (TSI) correlated negatively with steady-state CVR in the grey matter and brainstem of SCI participants (RS = -0.81, p = .014; RS = -0.84, p = .009, respectively). Lower steady-state CVR in the brainstem of the SCI group (n = 7) correlated with lower diastolic blood pressure (RS = 0.76, p = .046). Higher frequency of hypotensive episodes (n = 7) was linked to lower CVR outcomes in the grey matter (RS = -0.86, p = .014) and brainstem (RS = -0.89, p = .007). Conclusion: Preliminary findings suggest a difference in the dynamic CVR component, tau, between the SCI and noninjured control groups, potentially explaining the higher cerebrovascular health burden in SCI individuals. Exploratory associations indicate that longer TSI, lower diastolic blood pressure, and more hypotensive episodes may lead to poorer CVR outcomes. However, further research is necessary to establish causality and support these observations.

Assessment of ICD eligibility in non-ischaemic cardiomyopathy patients: a position statement by the Task Force of the Dutch Society of Cardiology.

International guidelines recommend implantation of an implantable cardioverter-defibrillator (ICD) in non-ischaemic cardiomyopathy (NICM) patients with a left ventricular ejection fraction (LVEF) below 35% despite optimal medical therapy and a life expectancy of more than 1 year with good functional status. We propose refinement of these recommendations in patients with NICM, with careful consideration of additional risk parameters for both arrhythmic and non-arrhythmic death. These additional parameters include late gadolinium enhancement on cardiac magnetic resonance imaging and genetic testing for high-risk genetic variants to further assess arrhythmic risk, and age, comorbidities and sex for assessment of non-arrhythmic mortality risk. Moreover, several risk modifiers should be taken into account, such as concomitant arrhythmias that may affect LVEF (atrial fibrillation, premature ventricular beats) and resynchronisation therapy. Even though currently no valid cut-off values have been established, the proposed approach provides a more careful consideration of risks that may result in withholding ICD implantation in patients with low arrhythmic risk and substantial non-arrhythmic mortality risk.

Long-term reliability of the phospholamban (PLN) p.(Arg14del) risk model in predicting major ventricular arrhythmia: a landmark study.

AIMS: Recently, a genetic variant-specific prediction model for phospholamban (PLN) p.(Arg14del)-positive individuals was developed to predict individual major ventricular arrhythmia (VA) risk to support decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts major VA risk from baseline data, but iterative evaluation of major VA risk may be warranted considering that the risk factors for major VA are progressive. Our aim is to evaluate the diagnostic performance of the PLN p.(Arg14del) risk model at 3-year follow-up. METHODS AND RESULTS: We performed a landmark analysis 3 years after presentation and selected only patients with no prior major VA. Data were collected of 268 PLN p.(Arg14del)-positive subjects, aged 43.5 ± 16.3 years, 38.9% male. After the 3 years landmark, subjects had a mean follow-up of 4.0 years (± 3.5 years) and 28 (10%) subjects experienced major VA with an annual event rate of 2.6% [95% confidence interval (CI) 1.6-3.6], defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. The PLN p.(Arg14del) risk score yielded good discrimination in the 3 years landmark cohort with a C-statistic of 0.83 (95% CI 0.79-0.87) and calibration slope of 0.97. CONCLUSION: The PLN p.(Arg14del) risk model has sustained good model performance up to 3 years follow-up in PLN p.(Arg14del)-positive subjects with no history of major VA. It may therefore be used to support decision-making for primary prevention ICD implantation not merely at presentation but also up to at least 3 years of follow-up.

Clomiphene Citrate Administered in Periconception Phase Causes Fetal Loss and Developmental Impairment in Mice.

Clomiphene citrate is a common treatment for ovulation induction in subfertile women, but its use is associated with elevated risk of adverse perinatal outcomes and birth defects. To investigate the biological plausibility of a causal relationship, this study investigated the consequences in mice for fetal development and pregnancy outcome of periconception clomiphene citrate administration at doses approximating human exposures. A dose-dependent adverse effect of clomiphene citrate given twice in the 36 hours after mating was seen, with a moderate dose of 0.75 mg/kg sufficient to cause altered reproductive outcomes in 3 independent cohorts. Viable pregnancy was reduced by 30%, late gestation fetal weight was reduced by 16%, and ∼30% of fetuses exhibited delayed development and/or congenital abnormalities not seen in control dams, including defects of the lung, kidney, liver, eye, skin, limbs, and umbilicus. Clomiphene citrate also caused a 30-hour average delay in time of birth, and elevated rate of pup death in the early postnatal phase. In surviving offspring, growth trajectory tracking and body morphometry analysis at 20 weeks of age showed postweaning growth and development similar to controls. A dysregulated inflammatory response in the endometrium was observed and may contribute to the underlying pathophysiological mechanism. These results demonstrate that in utero exposure to clomiphene citrate during early pregnancy can compromise implantation and impact fetal growth and development, causing adverse perinatal outcomes. The findings raise the prospect of similar iatrogenic effects in women where clomiphene citrate may be present in the periconception phase unless its use is well-supervised.

Impact of a Chronic Total Coronary Occlusion on the Incidence of Appropriate Implantable Cardioverter-Defibrillator Shocks and Mortality: A Substudy of the Dutch Outcome in ICD Therapy (DO-IT)) Registry.

BACKGROUND: Chronic total coronary occlusions (CTO) substantially increase the risk for sudden cardiac death. Among patients with chronic ischemic heart disease at risk for sudden cardiac death, an implantable cardioverter defibrillator (ICD) is the favored therapy for primary prevention of sudden cardiac death. This study sought to investigate the impact of CTOs on the risk for appropriate ICD shocks and mortality within a nationwide prospective cohort. METHODS AND RESULTS: This is a subanalysis of the nationwide Dutch-Outcome in ICD Therapy (DO-IT) registry of primary prevention ICD recipients in The Netherlands between September 2014 and June 2016 (n=1442). We identified patients with chronic ischemic heart disease (n=663) and assessed available coronary angiograms for CTO presence (n=415). Patients with revascularized CTOs were excluded (n=79). The primary end point was the composite of all-cause mortality and appropriate ICD shocks. Clinical follow-up was conducted for at least 2 years. A total of 336 patients were included, with an average age of 67±9 years, and 20.5% was female (n=69). An unrevascularized CTO was identified in 110 patients (32.7%). During a median follow-up period of 27 months (interquartile range, 24-32), the primary end point occurred in 21.1% of patients with CTO (n=23) compared with 11.9% in patients without CTO (n=27; P=0.034). Corrected for baseline characteristics including left ventricular ejection fraction, and the presence of a CTO was an independent predictor for the primary end point (hazard ratio, 1.82 [95% CI, 1.03-3.22]; P=0.038). CONCLUSIONS: Within this nationwide prospective registry of primary prevention ICD recipients, the presence of an unrevascularized CTO was an independent predictor for the composite outcome of all-cause mortality and appropriate ICD shocks.