Travel Surveillance and Genomics Uncover a Hidden Zika Outbreak during the Waning Epidemic.

The Zika epidemic in the Americas has challenged surveillance and control. As the epidemic appears to be waning, it is unclear whether transmission is still ongoing, which is exacerbated by discrepancies in reporting. To uncover locations with lingering outbreaks, we investigated travel-associated Zika cases to identify transmission not captured by reporting. We uncovered an unreported outbreak in Cuba during 2017, a year after peak transmission in neighboring islands. By sequencing Zika virus, we show that the establishment of the virus was delayed by a year and that the ensuing outbreak was sparked by long-lived lineages of Zika virus from other Caribbean islands. Our data suggest that, although mosquito control in Cuba may initially have been effective at mitigating Zika virus transmission, such measures need to be maintained to be effective. Our study highlights how Zika virus may still be "silently" spreading and provides a framework for understanding outbreak dynamics. VIDEO ABSTRACT.

DengueSeq: a pan-serotype whole genome amplicon sequencing protocol for dengue virus.

BACKGROUND: The increasing burden of dengue virus on public health due to more explosive and frequent outbreaks highlights the need for improved surveillance and control. Genomic surveillance of dengue virus not only provides important insights into the emergence and spread of genetically diverse serotypes and genotypes, but it is also critical to monitor the effectiveness of newly implemented control strategies. Here, we present DengueSeq, an amplicon sequencing protocol, which enables whole-genome sequencing of all four dengue virus serotypes. RESULTS: We developed primer schemes for the four dengue virus serotypes, which can be combined into a pan-serotype approach. We validated both approaches using genetically diverse virus stocks and clinical specimens that contained a range of virus copies. High genome coverage (>95%) was achieved for all genotypes, except DENV2 (genotype VI) and DENV 4 (genotype IV) sylvatics, with similar performance of the serotype-specific and pan-serotype approaches. The limit of detection to reach 70% coverage was 10-100 RNA copies/µL for all four serotypes, which is similar to other commonly used primer schemes. DengueSeq facilitates the sequencing of samples without known serotypes, allows the detection of multiple serotypes in the same sample, and can be used with a variety of library prep kits and sequencing instruments. CONCLUSIONS: DengueSeq was systematically evaluated with virus stocks and clinical specimens spanning the genetic diversity within each of the four dengue virus serotypes. The primer schemes can be plugged into existing amplicon sequencing workflows to facilitate the global need for expanded dengue virus genomic surveillance.

Introduction and Spread of Dengue Virus 3, Florida, USA, May 2022-April 2023.

During May 2022-April 2023, dengue virus serotype 3 was identified among 601 travel-associated and 61 locally acquired dengue cases in Florida, USA. All 203 sequenced genomes belonged to the same genotype III lineage and revealed potential transmission chains in which most locally acquired cases occurred shortly after introduction, with little sustained transmission.

SEIPIN Isoforms Interact with the Membrane-Tethering Protein VAP27-1 for Lipid Droplet Formation.

SEIPIN proteins are localized to endoplasmic reticulum (ER)-lipid droplet (LD) junctions where they mediate the directional formation of LDs into the cytoplasm in eukaryotic cells. Unlike in animal and yeast cells, which have single SEIPIN genes, plants have three distinct SEIPIN isoforms encoded by separate genes. The mechanism of SEIPIN action remains poorly understood, and here we demonstrate that part of the function of two SEIPIN isoforms in Arabidopsis (Arabidopsis thaliana), AtSEIPIN2 and AtSEIPIN3, may depend on their interaction with the vesicle-associated membrane protein (VAMP)-associated protein (VAP) family member AtVAP27-1. VAPs have well-established roles in the formation of membrane contact sites and lipid transfer between the ER and other organelles, and here, we used a combination of biochemical, cell biology, and genetics approaches to show that AtVAP27-1 interacts with the N termini of AtSEIPIN2 and AtSEIPIN3 and likely supports the normal formation of LDs. This insight indicates that the ER membrane tethering machinery in plant cells could play a role with select SEIPIN isoforms in LD biogenesis at the ER, and additional experimental evidence in Saccharomyces cerevisiae supports the possibility that this interaction may be important in other eukaryotic systems.

Molecular variability of the Ancylostoma secreted Protein-2 (Aca-asp-2) gene from Ancylostoma caninum contributes to expand information on population genetic studies of hookworms.

Hookworm infection is a major public health problem in many regions of the world. Given the high levels of host morbidity and even mortality of the host caused by these infections, it is crucial to understand the genetic structure of hookworm populations. This understanding can provide insights into the ecology, transmission patterns, mechanisms of drug resistance, and the development of vaccines and immunotherapeutic strategies. Previously, we examined presumably neutral molecular markers, such as microsatellites and COI (Cytochrome C oxidase subunit 1) in Brazilian populations of Ancylostoma caninum. Here we analyze the molecular variability of a genomic fragment of the Aca-asp-2 (Ancylostoma secreted protein-2) gene from Ancylostoma caninum. This gene is a highly expressed and activated following the infection of the L3 larvae in the host. We obtained individuals of A. caninum from five different geographic locations in Brazil, sequenced and analyzed parts of the gene. The results revealed extensive polymorphism at this fragment, especially in the intronic region, indicating low selective pressure acting on these sequences. However, we also observed irregular distributions of nucleotides and polymorphisms in the coding region of this gene, resulting in the identification of 27 alleles. The data presented here contribute to expanding the understanding of population genetic studies of hookworms.

Surgical evaluation in children <3 years of age with drug-resistant epilepsy: Patient characteristics, diagnostic utilization, and potential for treatment delays.

OBJECTIVE: Drug-resistant epilepsy (DRE) occurs at higher rates in children <3 years old. Epilepsy surgery is effective, but rarely utilized in young children despite developmental benefits of early seizure freedom. The present study aims to identify unique patient characteristics and evaluation strategies in children <3 years old who undergo epilepsy surgery evaluation as a means to assess contributors and potential solutions to health care disparities in this group. METHODS: The Pediatric Epilepsy Research Consortium Epilepsy Surgery Database, a multicentered, cross-sectional collaboration of 21 US pediatric epilepsy centers, collects prospective data on children <18 years of age referred for epilepsy surgery evaluation. We compared patient characteristics, diagnostic utilization, and surgical treatment between children <3 years old and those older undergoing initial presurgical evaluation. We evaluated patient characteristics leading to delayed referral (>1 year) after DRE diagnosis in the very young. RESULTS: The cohort included 437 children, of whom 71 (16%) were <3 years of age at referral. Children evaluated before the age of 3 years more commonly had abnormal neurological examinations (p = .002) and daily seizures (p = .001). At least one ancillary test was used in 44% of evaluations. Fifty-nine percent were seizure-free following surgery (n = 34), with 35% undergoing limited focal resections. Children with delayed referrals more often had focal aware (p < .001) seizures and recommendation for palliative surgeries (p < .001). SIGNIFICANCE: There are relatively few studies of epilepsy surgery in the very young. Surgery is effective, but may be disproportionally offered to those with severe presentations. Relatively low utilization of ancillary testing may contribute to reduced surgical therapy for those without evident lesions on magnetic resonance imaging. Despite this, a sizeable portion of patients have favorable outcome after focal epilepsy surgery resections.

Overnight sleeping heart rate variability of Army recruits during a 12-week basic military training course.

PURPOSE: This study aimed to quantify sleeping heart rate (HR) and HR variability (HRV) alongside circulating tumor necrosis factor alpha (TNFα) concentrations during 12-week Basic Military Training (BMT). We hypothesised that, despite a high allostatic load, BMT would increase cardiorespiratory fitness and HRV, while lowering both sleeping HR and TNFα in young healthy recruits. METHODS: Sixty-three recruits (18-43 years) undertook ≥ 2 overnight cardiac frequency recordings in weeks 1, 8 and 12 of BMT with 4 h of beat-to-beat HR collected between 00:00 and 06:00 h on each night. Beat-to-beat data were used to derive HR and HRV metrics which were analysed as weekly averages (totalling 8 h). A fasted morning blood sample was collected in the equivalent weeks for the measurement of circulating TNFα concentrations and predicted VO2max was assessed in weeks 2 and 8. RESULTS: Predicted VO2max was significantly increased at week 8 (+ 3.3 ± 2.6 mL kg-1 min-1; p < 0.001). Sleeping HR (wk1, 63 ± 7 b min-1) was progressively reduced throughout BMT (wk8, 58 ± 6; wk12, 55 ± 6 b min-1; p < 0.01). Sleeping HRV reflected by the root mean square of successive differences (RMSSD; wk1, 86 ± 50 ms) was progressively increased (wk8, 98 ± 50; wk12, 106 ± 52 ms; p < 0.01). Fasted circulating TNFα (wk1, 9.1 ± 2.8 pg/mL) remained unchanged at wk8 (8.9 ± 2.5 pg/mL; p = 0.79) but were significantly reduced at wk12 (8.0 ± 2.4 pg/mL; p < 0.01). CONCLUSION: Increased predicted VO2max, HRV and reduced HR during overnight sleep are reflective of typical cardiorespiratory endurance training responses. These results indicate that recruits are achieving cardiovascular health benefits despite the high allostatic load associated with the 12-week BMT.

Comparison of Military Recruit and Incumbent Physical Characteristics and Performance: Potential Implications for Through-Career Individual Readiness and Occupational Performance.

ABSTRACT: Drain, JR, Debenedictis, T, Bulmer, S, and Michael, S. comparison of military recruit and incumbent physical characteristics and performance: Potential implications for through-career individual readiness and occupational performance. J Strength Cond Res 36(9): 2536-2543, 2022-After basic military training, physical training practices among incumbent personnel differ substantially, potentially precipitating varied physical capacity and operational readiness. The purpose of this retrospective investigation was to compare physical characteristics and physical performance between recruits and incumbent personnel. Data were collected for 222 army recruits (REC: 197 men/25 women) nearing completion of basic training and 280 incumbent army personnel from combat arms (CA: 142 men) and noncombat arms trades (NCA: 113 men/25 women). Height, mass, and body mass index (BMI) were recorded together with performance measures including predicted V̇ o2 max and 1 repetition maximum box lift. Compared with REC, male incumbents were older (21.8 ± 0.6 vs. 27.6 ± 1.2 years; mean ± 95% confidence interval), had greater body mass (77.6 ± 1.3 vs. 82.6 ± 1.5 kg) and BMI (24.2 ± 0.3 vs. 25.8 ± 0.5 kg·m -2 ), similar relative V̇ o2 max, and lower box lift (49.7 ± 1.4 vs. 47.2 ± 2.4 kg). Male CA demonstrated greatest physical performance while male NCA demonstrated the highest BMI and poorest physical performance. Compared with REC, female incumbents were older (22.8 ± 1.6 vs. 31.9 ± 4.4 years), had similar body mass, higher BMI (24.1 ± 0.7 vs. 26.1 ± 2.4 kg·m -2 ), as well as lower V̇ o2 max (42.0 ± 1.3 vs. 37.9 ± 2.1 ml·kg· -1 ·min -1 ) and box lift (27.8 ± 2.1 vs. 23.3 ± 2.4 kg). More than 97% of men and approximately 75% of women were able to achieve the box lift and V̇ o2 max baseline standards. The older age category (26 + vs. 18-25 years) typically demonstrated higher BMI and lower physical performance. Through-career maintenance of physical capacity is important for military personnel to support individual readiness and occupational performance, preserve health, and mitigate musculoskeletal injury risk.

A cohort study of men infected with COVID-19 for presence of SARS-CoV-2 virus in their semen.

INTRODUCTION: Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be detected in semen and transmitted sexually is a vital question that has, thus far, been inconclusive. Prior studies, with limited numbers, have included men in various stages of infection with most in the recovery phase of the illness. The timing of test results and severity of illness has made recruiting study participants a significant challenge. Our pilot study will examine semen from men with a recent diagnosis of COVID-19 as well as those in the convalescent phase to determine if SARS-CoV-2 can be detected and its relationship, if any, with the severity of the disease. METHODS: Eighteen men with a median age of 32 (range, 24-57) who tested positive for COVID-19 by rt-PCR analysis were enrolled and provided a semen sample. The study group demonstrated symptoms of COVID-19 ranging from asymptomatic to moderate and none required hospitalization. Samples were subjected to viral RNA extraction and then processed by real-time RT-PCR using the US Centers for Disease Control and Prevention (CDC, USA) panel of 2019-Novel Coronavirus (2019-nCoV) primers and probes to detect the presence of SARS-CoV-2 RNA. RESULTS: Length of time from diagnosis to providing a specimen ranged from 1 to 28 days (median, 6 days). Fifteen participants were symptomatic and three were asymptomatic, including recovering men, at the time of semen collection. No SARS-CoV-2 was detected in any of the semen samples. CONCLUSION: Based on these preliminary results and consistent with prior findings, we suggest SARS-CoV-2 is not present in semen during the acute or convalescent phase of COVID-19.

The Chemistry of the Ketogenic Diet: Updates and Opportunities in Organic Synthesis.

The high-fat, low-carbohydrate (ketogenic) diet has grown in popularity in the last decade as a weight loss tool. Research into the diet's effects on the body have revealed a variety of other health benefits. The use of exogenous ketone supplements to confer the benefits of the diet without strict adherence to it represents an exciting new area of focus. Synthetic ketogenic compounds are of particular interest that has received very little emphasis and is an untapped area of focus for chemical synthesis. In this review, we summarize the chemical basis for ketogenicity and opportunities for further advancement of the field.

Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia.

Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. GPAA1 (glycosylphosphatidylinositol anchor attachment 1) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT, and PIGU (phosphatidylinositol-glycan biosynthesis classes K, S, T, and U, respectively). This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum. Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families. Using whole-exome sequencing, we identified two frameshift mutations (c.981_993del [p.Gln327Hisfs∗102] and c.920delG [p.Gly307Alafs∗11]), one intronic splicing mutation (c.1164+5C>T), and six missense mutations (c.152C>T [p.Ser51Leu], c.160_161delinsAA [p.Ala54Asn], c.527G>C [p.Trp176Ser], c.869T>C [p.Leu290Pro], c.872T>C [p.Leu291Pro], and c.1165G>C [p.Ala389Pro]). Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia. The splicing mutation was found to decrease GPAA1 mRNA. Moreover, flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system.

Variable Inhibition of Zika Virus Replication by Different Wolbachia Strains in Mosquito Cell Cultures.

Mosquito-borne arboviruses are a major source of human disease. One strategy to reduce arbovirus disease is to reduce the mosquito's ability to transmit virus. Mosquito infection with the bacterial endosymbiont Wolbachia pipientis wMel is a novel strategy to reduce Aedes mosquito competency for flavivirus infection. However, experiments investigating cyclic environmental temperatures have shown a reduction in maternal transmission of wMel, potentially weakening the integration of this strain into a mosquito population relative to that of other Wolbachia strains. Consequently, it is important to investigate additional Wolbachia strains. All Zika virus (ZIKV) suppression studies are limited to the wMel Wolbachia strain. Here we show ZIKV inhibition by two different Wolbachia strains: wAlbB (isolated from Aedes albopictus mosquitoes) and wStri (isolated from the planthopper Laodelphax striatellus) in mosquito cells. Wolbachia strain wStri inhibited ZIKV most effectively. Single-cycle infection experiments showed that ZIKV RNA replication and nonstructural protein 5 translation were reduced below the limits of detection in wStri-containing cells, demonstrating early inhibition of virus replication. ZIKV replication was rescued when Wolbachia was inhibited with a bacteriostatic antibiotic. We observed a partial rescue of ZIKV growth when Wolbachia-infected cells were supplemented with cholesterol-lipid concentrate, suggesting competition for nutrients as one of the possible mechanisms of Wolbachia inhibition of ZIKV. Our data show that wAlbB and wStri infection causes inhibition of ZIKV, making them attractive candidates for further in vitro mechanistic and in vivo studies and future vector-centered approaches to limit ZIKV infection and spread.IMPORTANCE Zika virus (ZIKV) has swiftly spread throughout most of the Western Hemisphere. This is due in large part to its replication in and spread by a mosquito vector host. There is an urgent need for approaches that limit ZIKV replication in mosquitoes. One exciting approach for this is to use a bacterial endosymbiont called Wolbachia that can populate mosquito cells and inhibit ZIKV replication. Here we show that two different strains of Wolbachia, wAlbB and wStri, are effective at repressing ZIKV in mosquito cell lines. Repression of virus growth is through the inhibition of an early stage of infection and requires actively replicating Wolbachia Our findings further the understanding of Wolbachia viral inhibition and provide novel tools that can be used in an effort to limit ZIKV replication in the mosquito vector, thereby interrupting the transmission and spread of the virus.

The compatibility of concurrent high intensity interval training and resistance training for muscular strength and hypertrophy: a systematic review and meta-analysis.

The purpose of this systematic review and meta-analysis is to assess the effect of concurrent high intensity interval training (HIIT) and resistance training (RT) on strength and hypertrophy. Five electronic databases were searched using terms related to HIIT, RT, and concurrent training. Effect size (ES), calculated as standardised differences in the means, were used to examine the effect of concurrent HIIT and RT compared to RT alone on muscle strength and hypertrophy. Sub-analyses were performed to assess region-specific strength and hypertrophy, HIIT modality (cycling versus running), and inter-modal rest responses. Compared to RT alone, concurrent HIIT and RT led to similar changes in muscle hypertrophy and upper body strength. Concurrent HIIT and RT resulted in a lower increase in lower body strength compared to RT alone (ES = -0.248, p = 0.049). Sub analyses showed a trend for lower body strength to be negatively affected by cycling HIIT (ES = -0.377, p = 0.074) and not running (ES = -0.176, p = 0.261). Data suggests concurrent HIIT and RT does not negatively impact hypertrophy or upper body strength, and that any possible negative effect on lower body strength may be ameliorated by incorporating running based HIIT and longer inter-modal rest periods.

Driving in an urban environment, the stress response and effects of exercise.

Driving may be detrimental to health, with one hypothesis suggesting that driving may elicit an acute stress response and, with repeated exposures, may become a chronic stressor. The present study examined the stress response to driving and the effectiveness of a prior exercise bout in dampening this response. Twenty healthy adults performed three tasks: control, driving and exercise plus driving. Heart rate (HR), heart rate variability (HRV), blood pressure (BP) and cortisol were measured to quantify the acute stress response to each condition. Data indicated a stress response to driving: HR was elevated and HRV was reduced during the driving task compared with control. HR was elevated and HRV was reduced comparing the exercise plus driving with the driving condition. BP and cortisol were not different among conditions. The potential of interventions, such as exercise, to counter daily stressors should be evaluated to safeguard long-term health. Practitioner Summary: this study confirms that driving induces a stress response, with the exercise intervention providing mixed results (an increase in cardiovascular measures and a decrease in cortisol measure trending significance). Given the known consequences of stress and evidence that exercise can mitigate acute stress, further evaluation of exercise interventions is recommended.

Longer exercise duration delays post-exercise recovery of cardiac parasympathetic but not sympathetic indices.

PURPOSE: This study investigated non-invasive indices of post-exercise parasympathetic reactivation (using heart rate variability, HRV) and sympathetic withdrawal (using systolic time intervals, STI) following different exercise durations. METHODS: 13 healthy males (age 26.4 ± 4.7 years) cycled at 70% heart rate (HR) reserve for two durations-8 min (SHORT) and 32 min (LONG)-on separate occasions: HRV (including natural logarithm of root mean square of successive differences, Ln-RMSSD) and STI (including pre-ejection period, PEP) were assessed throughout 10 min seated recovery. RESULTS: Exercise HR was similar between SHORT and LONG (146 ± 7 and 147 ± 6 b min-1, respectively; p = 0.173), as was HR deceleration during 10 min recovery (p = 0.199). HR remained elevated above baseline (p < 0.001) throughout recovery for both trials (SHORT 82 ± 13 b min-1; LONG 86 ± 10 b min-1, at 10 min post-exercise). Ln-RMSSD was similar at end-exercise between trials (SHORT 1.10 ± 0.30 ms; LONG 1.05 ± 0.73 ms; p = 0.656), though it recovered more rapidly following SHORT (p = 0.010), with differences apparent from 1 min (SHORT 2.29 ± 1.08 ms; LONG 1.85 ± 0.82 ms; p = 0.005) to 10 min post-exercise (SHORT 2.89 ± 0.80 ms; LONG 2.46 ± 0.70 ms; p = 0.007). Ln-RMSSD remained suppressed below baseline throughout recovery following both trials (p < 0.001). PEP was the same at end exercise for both trials (70 ± 6 ms), with exercise duration having no effect on recovery (p = 0.659). By 10 min post-exercise, PEP increased to 130 ± 21 ms (SHORT) and 131 ± 20 ms (LONG), which was similar to baseline (p ≥ 0.143). CONCLUSIONS: Prolonged exercise duration attenuated the recovery of HRV indices of parasympathetic reactivation, but did not influence STI indices of sympathetic withdrawal. Therefore, duration must be considered when investigating post-exercise HRV. Monitoring these measures simultaneously can provide insights not revealed by underlying HR or either measure alone.

Accuracy in Estimating Repetitions to Failure During Resistance Exercise.

Hackett, DA, Cobley, SP, Davies, TB, Michael, SW, and Halaki, M. Accuracy in estimating repetitions to failure during resistance exercise. J Strength Cond Res 31(8): 2162-2168, 2017-The primary aim of this study was to assess the accuracy in estimation of repetitions to failure (ERF) during resistance exercise. Furthermore, this investigation examined whether the accuracy in ERF was affected by training status, sex, or exercise type. Eighty-one adults (men, n = 53 and women, n = 28) with broad range of resistance training experience participated in this study. Subjects performed up to 10 sets of 10 repetitions at 70% 1 repetition maximum (1RM) and 80% 1RM for the chest press and leg press, respectively. At the completion of each set, subjects reported their ERF and then continued repetitions to failure to determine actual repetitions to failure (ARF). The accuracy (amount of error) of ERF was determined over an ARF 0-10. Significant differences were found for error of ERF among ARF (p < 0.001), with the error of ERF ∼1 repetition at ARF 0-5 compared with >2 repetitions at ARF 7-10. Greater accuracy was found for the chest press compared with leg press, with the error of ERF ≤1 repetition for ARF 0-5 and ARF 0-3, respectively (p = 0.012). Men were found to be more accurate than women at specific ARFs for the leg press (p = 0.008), whereas no interaction was found for the chest press. Resistance training experience did not affect the accuracy in ERF. These results suggest that resistance trainers can accurately estimate repetitions to failure when close to failure and that ERF could importantly be practically used for prescription and monitoring of resistance exercise.

Heart-Rate Variability Threshold as an Alternative for Spiro-Ergometry Testing: A Validation Study.

Mankowski, RT, Michael, S, Rozenberg, R, Stokla, S, Stam, HJ, and Praet, SFE. Heart-rate variability threshold as an alternative for spiro-ergometry testing: a validation study. J Strength Cond Res 31(2): 474-479, 2017-Although spiro-ergometry is the established "gold standard" for determination of the second ventilatory threshold (VT2), it is a costly and rather time-consuming method. Previous studies suggest that assessing the second anaerobic threshold (AT2) on the basis of heart rate variability (HRV) during exercise may be a more cost-effective and noninvasive manner. However, appropriate validation studies, are still lacking. Eleven healthy, moderately trained subjects underwent 3 incremental exercise tests. Ventilation, oxygen uptake (V[Combining Dot Above]O2), CO2 production (V[Combining Dot Above]CO2), and HRV were measured continuously. Exercise testing was performed in 3 oxygen (FiO2) conditions of inspired air (14, 21, and 35% of oxygen). Participants and assessors were blinded to the FiO2 conditions. Two research teams assessed VT2s and HRVT2s independently from each other. Mean workloads corresponding to VT2 and HRVT2 in hypoxia were, respectively, 19 ± 17% (p = 0.01) and 15 ± 15% (p = 0.1) lower in comparison with hyperoxic conditions. Bland-Altman analysis showed low estimation bias (2.2%) and acceptably precise 95% limits of agreement for workload -15.7% to 20.1% for all FiO2 conditions. Bias was the lowest under normoxic conditions (1.1%) in comparison with hypoxia (3.7%) and hyperoxia (4.7%). Heart rate variability-based AT2 assessment had a most acceptable agreement with VT2 under normoxic conditions. This simple HRVT2 assessment may have potential applications for exercise monitoring in commercial fitness settings.

A novel de novo dominant negative mutation in DNM1L impairs mitochondrial fission and presents as childhood epileptic encephalopathy.

DNM1L encodes dynamin-related protein 1 (DRP1/DLP1), a key component of the mitochondrial fission machinery that is essential for proper functioning of the mammalian brain. Previously reported probands with de novo missense mutations in DNM1L presented in the first year of life with severe encephalopathy and refractory epilepsy, with several dying within the first several weeks after birth. In contrast, we report identical novel missense mutations in DNM1L in two unrelated probands who experienced normal development for several years before presenting with refractory focal status epilepticus and subsequent rapid neurological decline. We expand the phenotype of DNM1L-related mitochondrial fission defects, reveal common unique clinical characteristics and imaging findings, and compare the cellular impact of this novel mutation to the previously reported A395D lethal variant. We demonstrate that our R403C mutation, which resides in the assembly region of DRP1, acts by a dominant-negative mechanism and reduces oligomerization, mitochondrial fission activity, and mitochondrial recruitment of DRP1, but to a lesser extent compared to the A395D mutation. In contrast to the initial report of neonatal lethality resulting from DNM1L mutation and DRP1 dysfunction, our results show that milder DRP1 impairment is compatible with normal early development and subsequently results in a distinct set of neurological findings. In addition, we identify a common pathogenic mechanism whereby DNM1L mutations impair mitochondrial fission. © 2016 Wiley Periodicals, Inc.

Submaximal exercise intensity modulates acute post-exercise heart rate variability.

PURPOSE: This study investigated whether short-term heart rate variability (HRV) can be used to differentiate between the immediate recovery periods following three different intensities of preceding exercise. METHODS: 12 males cycled for 8 min at three intensities: LOW (40-45 %), MOD (75-80 %) and HIGH (90-95 %) of heart rate (HR) reserve. HRV was assessed during exercise and throughout 10-min seated recovery. RESULTS: 1-min HR recovery was reduced following greater exercise intensities when expressed as R-R interval (RRI, ms) (p < 0.001), but not b min(-1) (p = 0.217). During exercise, the natural logarithm of root mean square of successive differences (Ln-RMSSD) was higher during LOW (1.66 ± 0.47 ms) relative to MOD (1.14 ± 0.32 ms) and HIGH (1.30 ± 0.25 ms) (p ≤ 0.037). Similar results were observed for high-frequency spectra (Ln-HF-LOW: 2.9 ± 1.0; MOD: 1.6 ± 0.6; HIGH: 1.6 ± 0.3 ms(2), p < 0.001). By 1-min recovery, higher preceding exercise intensities resulted in lower HRV amongst all three intensities for Ln-RMSSD (LOW: 3.45 ± 0.58; MOD: 2.34 ± 0.81; HIGH: 1.66 ± 0.78 ms, p < 0.001) and Ln-HF (LOW: 6.0 ± 1.0; MOD: 4.3 ± 1.4; HIGH: 2.8 ± 1.4 ms(2), p < 0.001). Similarly, by 1-min recovery 'HR-corrected' HRV (Ln-RMSSD: RRI × 10(3)) was different amongst all three intensities (LOW: 3.64 ± 0.49; MOD: 2.90 ± 0.65; HIGH: 2.40 ± 0.67, p < 0.001). These differences were maintained throughout 10-min recovery (p ≤ 0.027). CONCLUSION: Preceding exercise intensity has a graded effect on recovery HRV measures reflecting cardiac vagal activity, even after correcting for the underlying HR. The immediate recovery following exercise is a potentially useful period to investigate autonomic activity, as multiple levels of autonomic activity can be clearly differentiated between using HRV. When investigating post-exercise HRV it is critical to account for the relative exercise intensity.