The potential link between gas diffusion and embolism spread in angiosperm xylem: Evidence from flow-centrifuge experiments and modelling.

Understanding xylem embolism formation is challenging due to dynamic changes and multiphase interactions in conduits. Here, we hypothesise that embolism spread involves gas diffusion in xylem, and is affected by time. We measured hydraulic conductivity (Kh) in flow-centrifuge experiments over 1 h at a given pressure and temperature for stem samples of three angiosperm species. Temporal changes in Kh at 5, 22, and 35°C, and at various pressures were compared to modelled gas concentration changes in a recently embolised vessel in the centre of a centrifuge sample. Temporal changes in Kh were logarithmic and species-specific. Maximum relative increases of Kh between 6% and 40% happened at 22°C for low centrifugal speed (<3250 RPM), while maximum decreases between 41% and 61% occurred at higher speeds. These reductions in Kh were experimentally shown to be associated with a temporal increase of embolism at the centre of centrifuge samples, which was likely associated with gas concentration increases in recently embolized vessels. Although embolism is mostly pressure-driven, our experimental and modelled data indicate that time, conduit characteristics, and temperature are involved due to their potential role in gas diffusion. Gas diffusion, however, does not seem to cover the entire process of embolism spread.

Aspirin with or without Clopidogrel after Transcatheter Aortic-Valve Implantation.

BACKGROUND: The effect of single as compared with dual antiplatelet treatment on bleeding and thromboembolic events after transcatheter aortic-valve implantation (TAVI) in patients who do not have an indication for long-term anticoagulation has not been well studied. METHODS: In a randomized, controlled trial, we assigned a subgroup of patients who were undergoing TAVI and did not have an indication for long-term anticoagulation, in a 1:1 ratio, to receive aspirin alone or aspirin plus clopidogrel for 3 months. The two primary outcomes were all bleeding (including minor, major, and life-threatening or disabling bleeding) and non-procedure-related bleeding over a period of 12 months. Most bleeding at the TAVI puncture site was counted as non-procedure-related. The two secondary outcomes were a composite of death from cardiovascular causes, non-procedure-related bleeding, stroke, or myocardial infarction (secondary composite 1) and a composite of death from cardiovascular causes, ischemic stroke, or myocardial infarction (secondary composite 2) at 1 year, with both outcomes tested sequentially for noninferiority (noninferiority margin, 7.5 percentage points) and superiority. RESULTS: A total of 331 patients were assigned to receive aspirin alone and 334 were assigned to receive aspirin plus clopidogrel. A bleeding event occurred in 50 patients (15.1%) receiving aspirin alone and in 89 (26.6%) receiving aspirin plus clopidogrel (risk ratio, 0.57; 95% confidence interval [CI], 0.42 to 0.77; P = 0.001). Non-procedure-related bleeding occurred in 50 patients (15.1%) and 83 patients (24.9%), respectively (risk ratio, 0.61; 95% CI, 0.44 to 0.83; P = 0.005). A secondary composite 1 event occurred in 76 patients (23.0%) receiving aspirin alone and in 104 (31.1%) receiving aspirin plus clopidogrel (difference, -8.2 percentage points; 95% CI for noninferiority, -14.9 to -1.5; P<0.001; risk ratio, 0.74; 95% CI for superiority, 0.57 to 0.95; P = 0.04). A secondary composite 2 event occurred in 32 patients (9.7%) and 33 patients (9.9%), respectively (difference, -0.2 percentage points; 95% CI for noninferiority, -4.7 to 4.3; P = 0.004; risk ratio, 0.98; 95% CI for superiority, 0.62 to 1.55; P = 0.93). A total of 44 patients (13.3%) and 32 (9.6%), respectively, received oral anticoagulation during the trial. CONCLUSIONS: Among patients undergoing TAVI who did not have an indication for oral anticoagulation, the incidence of bleeding and the composite of bleeding or thromboembolic events at 1 year were significantly less frequent with aspirin than with aspirin plus clopidogrel administered for 3 months. (Funded by the Netherlands Organization for Health Research and Development; POPular TAVI EU Clinical Trials Register number, 2013-003125-28; ClinicalTrials.gov number, NCT02247128.).

Anticoagulation with or without Clopidogrel after Transcatheter Aortic-Valve Implantation.

BACKGROUND: The roles of anticoagulation alone or with an antiplatelet agent after transcatheter aortic-valve implantation (TAVI) have not been well studied. METHODS: We performed a randomized trial of clopidogrel in patients undergoing TAVI who were receiving oral anticoagulation for appropriate indications. Patients were assigned before TAVI in a 1:1 ratio not to receive clopidogrel or to receive clopidogrel for 3 months. The two primary outcomes were all bleeding and non-procedure-related bleeding over a period of 12 months. Procedure-related bleeding was defined as Bleeding Academic Research Consortium type 4 severe bleeding, and therefore most bleeding at the puncture site was counted as non-procedure-related. The two secondary outcomes were a composite of death from cardiovascular causes, non-procedure-related bleeding, stroke, or myocardial infarction at 12 months (secondary composite 1) and a composite of death from cardiovascular causes, ischemic stroke, or myocardial infarction (secondary composite 2), both tested for noninferiority (noninferiority margin, 7.5 percentage points) and superiority. RESULTS: Bleeding occurred in 34 of the 157 patients (21.7%) receiving oral anticoagulation alone and in 54 of the 156 (34.6%) receiving oral anticoagulation plus clopidogrel (risk ratio, 0.63; 95% confidence interval [CI], 0.43 to 0.90; P = 0.01); most bleeding events were at the TAVI access site. Non-procedure-related bleeding occurred in 34 patients (21.7%) and in 53 (34.0%), respectively (risk ratio, 0.64; 95% CI, 0.44 to 0.92; P = 0.02). Most bleeding occurred in the first month and was minor. A secondary composite 1 event occurred in 49 patients (31.2%) receiving oral anticoagulation alone and in 71 (45.5%) receiving oral anticoagulation plus clopidogrel (difference, -14.3 percentage points; 95% CI for noninferiority, -25.0 to -3.6; risk ratio, 0.69; 95% CI for superiority, 0.51 to 0.92). A secondary composite 2 event occurred in 21 patients (13.4%) and in 27 (17.3%), respectively (difference, -3.9 percentage points; 95% CI for noninferiority, -11.9 to 4.0; risk ratio, 0.77; 95% CI for superiority, 0.46 to 1.31). CONCLUSIONS: In patients undergoing TAVI who were receiving oral anticoagulation, the incidence of serious bleeding over a period of 1 month or 1 year was lower with oral anticoagulation alone than with oral anticoagulation plus clopidogrel. (Funded by the Netherlands Organization for Health Research and Development; POPular TAVI EU Clinical Trials Register number, 2013-003125-28; ClinicalTrials.gov number, NCT02247128.).

Interdisciplinary consensus statements on imaging of DRUJ instability and TFCC injuries.

OBJECTIVES: The purpose of this agreement was to establish evidence-based consensus statements on imaging of distal radioulnar joint (DRUJ) instability and triangular fibrocartilage complex (TFCC) injuries by an expert group using the Delphi technique. METHODS: Nineteen hand surgeons developed a preliminary list of questions on DRUJ instability and TFCC injuries. Radiologists created statements based on the literature and the authors' clinical experience. Questions and statements were revised during three iterative Delphi rounds. Delphi panelists consisted of twenty-seven musculoskeletal radiologists. The panelists scored their degree of agreement to each statement on an 11-item numeric scale. Scores of "0," "5," and "10" reflected complete disagreement, indeterminate agreement, and complete agreement, respectively. Group consensus was defined as a score of "8" or higher for 80% or more of the panelists. RESULTS: Three of fourteen statements achieved group consensus in the first Delphi round and ten statements achieved group consensus in the second Delphi round. The third and final Delphi round was limited to the one question that did not achieve group consensus in the previous rounds. CONCLUSIONS: Delphi-based agreements suggest that CT with static axial slices in neutral rotation, pronation, and supination is the most useful and accurate imaging technique for the work-up of DRUJ instability. MRI is the most valuable technique in the diagnosis of TFCC lesions. The main indication for MR arthrography and CT arthrography are Palmer 1B foveal lesions of the TFCC. CLINICAL RELEVANCE STATEMENT: MRI is the method of choice for assessing TFCC lesions, with higher accuracy for central than peripheral abnormalities. The main indication for MR arthrography is the evaluation of TFCC foveal insertion lesions and peripheral non-Palmer injuries. KEY POINTS: • Conventional radiography should be the initial imaging technique in the assessment of DRUJ instability. CT with static axial slices in neutral rotation, pronation, and supination is the most accurate method for evaluating DRUJ instability. • MRI is the most useful technique in diagnosing soft-tissue injuries causing DRUJ instability, especially TFCC lesions. • The main indications for MR arthrography and CT arthrography are foveal lesions of the TFCC.

Clinical and in Vitro Evidence against Placenta Infection at Term by Severe Acute Respiratory Syndrome Coronavirus 2.

Despite occasional reports of vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy, the question of placental infection and its consequences for the newborn remain unanswered. Herein, we analyzed the placentas of 31 coronavirus disease 2019-positive mothers by reverse transcriptase PCR, immunohistochemistry, and in situ hybridization. Only one case of placental infection was detected, which was associated with intrauterine demise of the fetus. Differentiated primary trophoblasts were then isolated from nonpathologic human placentas at term, differentiated, and exposed to SARS-CoV-2 virions. Unlike for positive control cells Vero E6, the virus inside cytotrophoblasts and syncytiotrophoblasts or in the supernatant 4 days after infection was undetectable. As a mechanism of defense, we hypothesized that trophoblasts at term do not express angiotensin-converting enzyme 2 and transmembrane protease serine 2 (TMPRSS2), the two main host membrane receptors for SARS-CoV-2 entry. The quantification of these proteins in the placenta during pregnancy confirmed the absence of TMPRSS2 at the surface of the syncytium. Surprisingly, a transiently induced experimental expression of TMPRSS2 did not allow the entry or replication of the virus in differentiated trophoblasts. Altogether, these results underline that trophoblasts are not likely to be infected by SARS-CoV-2 at term, but raise concern about preterm infection.

The impact of age, type 2 diabetes and hypertension on heart rate variability during rest and exercise at increasing levels of heat stress.

PURPOSE: In older adults with type 2 diabetes (T2D) and hypertension (HTN), cardiac autonomic modulation is markedly attenuated during exercise-heat stress. However, the extent to which this impairment is evident under increasing levels of heat stress remains unknown. METHODS: We examined heart rate variability (HRV), a surrogate of cardiac autonomic modulation, during incremental exercise-heat stress exposures in young (20-30 years) and middle-aged-to-older individuals (50-70 years) without and with T2D and HTN. Thirteen young and healthy (Young, n = 13) and 37 older men without (Older, n = 14) and with HTN (n = 13) or T2D (n = 10) performed 180-min treadmill walking at a fixed metabolic rate (~ 200 W/m2; ~ 3.5 METs) in a differing wet-bulb globe temperature (WBGT; 16 °C, 24 °C, 28 °C, and 32 °C). Electrocardiogram (ECG) and core temperature measurements were recorded throughout. Data were analysed using 5-min averaged epochs following 60-min exercise, which represented the last common timepoint across groups and conditions. RESULTS: Ageing did not significantly reduce HRV during increasing exercise-heat stress (all p > 0.050). However, T2D and HTN modified HRV during exercise-heat stress such that Detrended Fluctuation Analysis (DFA) α1 (p = 0.012) and the cardiac sympathetic index (p = 0.037) were decreased compared to Older in all except the warmest WBGT condition (32 °C). CONCLUSION: Our unique observations indicate that, relative to their younger counterparts, HRV in healthy older individuals is not perturbed during exercise heat-stress. However, relative to their age-matched healthy counterparts, HRV is reduced during exercise-heat stress in individuals with age-associated chronic conditions, indicative of cardiac autonomic dysfunction.

Economic feasibility of a novel tool to assist extubation decision-making: an early health economic modeling.

OBJECTIVES: To estimate the minimum percent change in failed extubation to make a tool designed to reduce extubation failure (Extubation Advisor [EA]) economically viable. METHODS: We conducted an early return on investment (ROI) analysis using data from intubated intensive care unit (ICU) patients at a large Canadian tertiary care hospital. We obtained input parameters from the hospital database and published literature. We ran generalized linear models to estimate the attributable length of stay, total hospital cost, and time to subsequent extubation attempt following failure. We developed a Markov model to estimate the expected ROI and performed probabilistic sensitivity analyses to assess the robustness of findings. Costs were presented in 2020 Canadian dollars (C$). RESULTS: The model estimated a 1 percent reduction in failed extubation could save the hospital C$289 per intubated patient (95 percent CI: 197, 459). A large center seeing 2,500 intubated ICU patients per year could save C$723,124/year/percent reduction in failed extubation. At the current annual price of C$164,221, the EA tool must reduce extubation failure by at least 0.24 percent (95 percent CI: .14, .41) to make the tool cost-effective at our site. CONCLUSIONS: Clinical decision-support tools like the EA may play an important role in reducing healthcare costs by reducing the rate of extubation failure, a costly event in the ICU.

Prism adaptation effects in complex regional pain syndrome: A therapo-physiological single case experimental design exploratory report.

Complex Regional Pain Syndrome (CRPS) is an invalidating chronic condition that can occur after an acute peripheral lesion. Prism adaptation therapy is regarded as a promising tool to improve chronic pain in this syndrome but the mechanisms which lead to pain amelioration remain unknown. In this exploratory report we performed a retrospective analysis of longitudinal data collected from a single, atypical patient, who showed hyper-attention toward her affected (left) hand. Repeated assessments of pain and spatial neglect made during the course of the prism adaptation treatment revealed differential contributions of the two hands to adaptation-induced pain reduction. Treatment response appeared to be associated with a relative modification of the spatial behaviour of the two hands. This case study provides a new example of pain relief following prismatic deviation away from the pathological side.

Spontaneous Selection of Cryptosporidium Drug Resistance in a Calf Model of Infection.

The intestinal protozoan Cryptosporidium is a leading cause of diarrheal disease and mortality in young children. There is currently no fully effective treatment for cryptosporidiosis, which has stimulated interest in anticryptosporidial development over the last ∼10 years, with numerous lead compounds identified, including several tRNA synthetase inhibitors. Here, we report the results of a dairy calf efficacy trial of the methionyl-tRNA (Cryptosporidium parvum MetRS [CpMetRS]) synthetase inhibitor 2093 and the spontaneous emergence of drug resistance. Dairy calves experimentally infected with Cryptosporidium parvum initially improved with 2093 treatment, but parasite shedding resumed in two of three calves on treatment day 5. Parasites shed by each recrudescent calf had different amino acid-altering mutations in the gene encoding CpMetRS (CpMetRS), yielding either an aspartate 243-to-glutamate (D243E) or a threonine 246-to-isoleucine (T246I) mutation. Transgenic parasites engineered to have either the D243E or T246I CpMetRS mutation using CRISPR/Cas9 grew normally but were highly 2093 resistant; the D243E and T246I mutant-expressing parasites, respectively, had 2093 half-maximal effective concentrations (EC50s) that were 613- and 128-fold that of transgenic parasites with wild-type CpMetRS. In studies using recombinant enzymes, the D243E and T246I mutations shifted the 2093 IC50 >170-fold. Structural modeling of CpMetRS based on an inhibitor-bound Trypanosoma brucei MetRS crystal structure suggested that the resistance mutations reposition nearby hydrophobic residues, interfering with compound binding while minimally impacting substrate binding. This is the first report of naturally emerging Cryptosporidium drug resistance, highlighting the need to address the potential for anticryptosporidial resistance and establish strategies to limit its occurrence.

Pore constrictions in intervessel pit membranes provide a mechanistic explanation for xylem embolism resistance in angiosperms.

Embolism spreading in angiosperm xylem occurs via mesoporous pit membranes between vessels. Here, we investigate how the size of pore constrictions in pit membranes is related to pit membrane thickness and embolism resistance. Pit membranes were modelled as multiple layers to investigate how pit membrane thickness and the number of intervessel pits per vessel determine pore constriction sizes, the probability of encountering large pores, and embolism resistance. These estimations were complemented by measurements of pit membrane thickness, embolism resistance, and number of intervessel pits per vessel in stem xylem (n = 31, 31 and 20 species, respectively). The modelled constriction sizes in pit membranes decreased with increasing membrane thickness, explaining the measured relationship between pit membrane thickness and embolism resistance. The number of pits per vessel affected constriction size and embolism resistance much less than pit membrane thickness. Moreover, a strong relationship between modelled and measured embolism resistance was observed. Pore constrictions provide a mechanistic explanation for why pit membrane thickness determines embolism resistance, which suggests that hydraulic safety can be uncoupled from hydraulic efficiency. Although embolism spreading remains puzzling and encompasses more than pore constriction sizes, angiosperms are unlikely to have leaky pit membranes, which enables tensile transport of water.

Interdisciplinary consensus statements on imaging of scapholunate joint instability.

OBJECTIVES: The purpose of this agreement was to establish evidence-based consensus statements on imaging of scapholunate joint (SLJ) instability by an expert group using the Delphi technique. METHODS: Nineteen hand surgeons developed a preliminary list of questions on SLJ instability. Radiologists created statements based on the literature and the authors' clinical experience. Questions and statements were revised during three iterative Delphi rounds. Delphi panellists consisted of twenty-seven musculoskeletal radiologists. The panellists scored their degree of agreement to each statement on an eleven-item numeric scale. Scores of '0', '5' and '10' reflected complete disagreement, indeterminate agreement and complete agreement, respectively. Group consensus was defined as a score of '8' or higher for 80% or more of the panellists. RESULTS: Ten of fifteen statements achieved group consensus in the second Delphi round. The remaining five statements achieved group consensus in the third Delphi round. It was agreed that dorsopalmar and lateral radiographs should be acquired as routine imaging work-up in patients with suspected SLJ instability. Radiographic stress views and dynamic fluoroscopy allow accurate diagnosis of dynamic SLJ instability. MR arthrography and CT arthrography are accurate for detecting scapholunate interosseous ligament tears and articular cartilage defects. Ultrasonography and MRI can delineate most extrinsic carpal ligaments, although validated scientific evidence on accurate differentiation between partially or completely torn or incompetent ligaments is not available. CONCLUSIONS: Delphi-based agreements suggest that standardized radiographs, radiographic stress views, dynamic fluoroscopy, MR arthrography and CT arthrography are the most useful and accurate imaging techniques for the work-up of SLJ instability. KEY POINTS: • Dorsopalmar and lateral wrist radiographs remain the basic imaging modality for routine imaging work-up in patients with suspected scapholunate joint instability. • Radiographic stress views and dynamic fluoroscopy of the wrist allow accurate diagnosis of dynamic scapholunate joint instability. • Wrist MR arthrography and CT arthrography are accurate for determination of scapholunate interosseous ligament tears and cartilage defects.

The impact of surgical subspecialization on patient outcomes following emergency colorectal resections in the north of England: a retrospective cohort study.

AIM: Emergency colorectal surgery is associated with significant morbidity and mortality. Most general surgeons have a subspecialty, which forms the focus of their elective work, allowing development of specialist skill sets. The aim of this study was to assess the impact of consultant subspecialization on patient outcomes following emergency colorectal resections. METHODS: Data were requested for all emergency admissions under a general surgeon between 1 January 2002 and 31 December 2016 within the north of England. These were acquired from individual Trusts following Caldicott approval. Data included demographics, diagnoses and any procedures undertaken. Patients were assigned to cohorts based on the subspecialist interest of the consultant they were under the care of. The primary outcome of interest was 30-day postoperative mortality. Categorical data were compared with the chi-squared test, and continuous data with the t test or ANOVA. A logistic regression model determined factors associated with 30-day in-hospital mortality. RESULTS: Overall, 7648 emergency colorectal resections were performed with a 30-day postoperative mortality of 13.8%. This was significantly lower if the responsible consultant was a colorectal surgeon compared with other general surgery subspecialties (11.8% vs. 15.2%, P < 0.001). This was significant on univariate analysis (OR 0.75, P < 0.001); however, following multivariable adjustment, this was not statistically significant (P = 0.380). The colorectal specialists had a higher laparoscopy rate than their colleagues-9.8% versus 6.8% (P < 0.001). Stoma rates were also lower (46.9% vs. 51.0%, P = 0.001) and anastomosis rates higher (55.9% vs. 49.3%, P < 0.001) amongst colorectal surgeons. CONCLUSION: These findings add to the growing body of evidence that patient outcomes may be improved by involving subspecialists in colorectal emergencies.

Variability Predictors of Vasospasm in Subarachnoid Hemorrhage: A Feasibility Study.

BACKGROUND: Mean cerebral blood flow velocity (mean-CBFV) obtained from Transcranial Doppler (TCD) poorly predicts cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage (aSAH). Variability descriptors of mean-CBFV obtained during extended TCD recordings may improve this prediction. We assessed the feasibility of generating reliable linear and non-linear descriptors of mean-CBFV variability using extended recordings in aSAH patients and in healthy controls. We also explored which of those metrics might have the ability to discriminate between aSAH patients and healthy controls, and among patients who would go on to develop vasospasm and those who would not. METHODS: Bilateral mean-CBFV, blood pressure, and heart rate were continuously recorded for 40 minutes in aSAH patients (n = 8) within the first 5 days after ictus, in age-matched healthy controls (n = 8) and in additional young controls (n = 8). We obtained linear [standard deviation, coefficient of variations, and the very-low (0.003-0.040 Hz), low (0.040-0.150 Hz), and high-frequency (0.15-0.4 Hz) power spectra] and non-linear (Fractality, deterministic Chaos analyses) variability metrics. RESULTS: We successfully obtained TCD recordings from patients and healthy controls and calculated the desired metrics of mean-CBFV variability. Differences were appreciable between aSAH patients and healthy controls, as well as between aSAH patients who later developed vasospasm and those who did not. CONCLUSIONS: A 40-minute TCD recording provides reliable variability metrics in aSAH patients and healthy controls. Future studies are required to determine if mean-CBFV variability metrics remain stable over time, and whether they may serve to identify patients who are at greatest risk of developing cerebral vasospasm after aSAH.

First evidence that intrinsic fetal heart rate variability exists and is affected by hypoxic pregnancy.

KEY POINTS: We introduce a technique to test whether intrinsic fetal heart rate variability (iFHRV) exists and we show the utility of the technique by testing the hypothesis that iFHRV is affected by chronic fetal hypoxia, one of the most common adverse outcomes of human pregnancy complicated by fetal growth restriction. Using an established late gestation ovine model of fetal development under chronic hypoxic conditions, we identify iFHRV in isolated fetal hearts and show that it is markedly affected by hypoxic pregnancy. Therefore, the isolated fetal heart has intrinsic variability and carries a memory of adverse intrauterine conditions experienced during the last third of pregnancy. ABSTRACT: Fetal heart rate variability (FHRV) emerges from influences of the autonomic nervous system, fetal body and breathing movements, and from baroreflex and circadian processes. We tested whether intrinsic heart rate variability (iHRV), devoid of any external influences, exists in the fetal period and whether it is affected by chronic fetal hypoxia. Chronically catheterized ewes carrying male singleton fetuses were exposed to normoxia (n = 6) or hypoxia (10% inspired O2 , n = 9) for the last third of gestation (105-138 days of gestation (dG); term ∼145 dG) in isobaric chambers. At 138 dG, isolated hearts were studied using a Langendorff preparation. We calculated basal intrinsic FHRV (iFHRV) indices reflecting iFHRV's variability, predictability, temporal symmetry, fractality and chaotic behaviour, from the systolic peaks within 15 min segments in each heart. Significance was assumed at P < 0.05. Hearts of fetuses isolated from hypoxic pregnancy showed approximately 4-fold increases in the Grid transformation as well as the AND similarity index (sgridAND) and a 4-fold reduction in the scale-dependent Lyapunov exponent slope. We also detected a 2-fold reduction in the Recurrence quantification analysis, percentage of laminarity (pL) and recurrences, maximum and average diagonal line (dlmax, dlmean) and the Multiscale time irreversibility asymmetry index. The iHRV measures dlmax, dlmean, pL and sgridAND correlated with left ventricular end-diastolic pressure across both groups (average R2  = 0.38 ± 0.03). This is the first evidence that iHRV originates in fetal life and that chronic fetal hypoxia significantly alters it. Isolated fetal hearts from hypoxic pregnancy exhibit a time scale-dependent higher complexity in iFHRV.

Instanton theory of ground-state tunneling splittings with general paths.

We derive a multidimensional instanton theory for calculating ground-state tunneling splittings in Cartesian coordinates for general paths. It is an extension of the method by Mil'nikov and Nakamura [J. Chem. Phys. 115, 6881 (2001)] to include asymmetric paths that are necessary for calculating tunneling splitting patterns in multi-well systems, such as water clusters. The approach avoids multiple expensive matrix diagonalizations to converge the fluctuation prefactor in the ring-polymer instanton (RPI) method, and instead replaces them by an integration of a Riccati differential equation. When combined with the string method for locating instantons, we avoid the need to converge the calculation with respect to the imaginary time period of the semiclassical orbit, thereby reducing the number of convergence parameters of the optimized object to just one: the number of equally spaced system replicas used to represent the instanton path. The entirety of the numerical effort is thus concentrated in optimizing the shape of the path and evaluating hessians along the path, which is a dramatic improvement over RPI. In addition to the standard instanton approximations, we neglect the coupling of vibrational modes to external rotations. The method is tested on the model potential of malonaldehyde and on the water dimer and trimer, giving close agreement with RPI at a much-reduced cost.

Age differences in cardiac autonomic regulation during intermittent exercise in the heat.

PURPOSE: This study aimed to detect potential differences in heart-rate variability (HRV) during a moderate-intensity intermittent exercise in the heat among physically active young (25.8 ± 1.9 years), middle-aged (43.5 ± 2.8 years), and older (62.9 ± 3.7 years) men. METHODS: Thirty-three participants (11/group) performed four successive bouts of 15-min cycling at a moderate fixed rate of metabolic heat production of ~ 400 W; each separated by a 15-min recovery with 1 h of final recovery in a hot and dry environment (35 °C, 20% relative humidity). Twelve HRV indices were computed that have been commonly described in the literature, and characterized various domains of the variability and complexity of heart rate. RESULTS: Cardiac autonomic regulation during intermittent exercise in the heat, as well as during pre-exercise rest and recovery was significantly affected by age, as changes were observed among the three different aged groups in five indices (p ≤ 0.05). Similarly, time influenced cardiac autonomic regulation as three indices showed changes across time (p ≤ 0.05) during intermittent exercise, whilst five indices displayed significant changes (p ≤ 0.05) during rest and recovery in the heat. CONCLUSIONS: This study supports that moderate-intensity intermittent exercise in the heat is associated with significant cardiac autonomic dysregulation in older men, as compared to young and middle-aged men, yet it highlights the importance of developing preventative health strategies for heat-related illness in aged individuals.

Heart rate variability in older workers during work under the Threshold Limit Values for heat exposure.

BACKGROUND: The Threshold Limit Values (TLV) of the American Conference of Governmental and Industrial Hygienists indicate the levels of heat stress that all workers may be repeatedly exposed to without adverse health effects. In this study, we evaluated heart rate variability (HRV) during moderate-to-heavy work performed continuously or according to different TLV work-rest (WR) allocations in healthy physically active older workers. METHODS: Nine healthy older (58 ± 5 years) males performed three different 120-minute conditions in accordance with TLV guidelines for moderate-to-heavy intensity work (360 W fixed rate of heat production) in different wet-bulb globe temperatures (WBGT): continuous cycling at 28°C WBGT (CON), as well as intermitted work performed at WR of 3:1 in 29°C WBGT (WR3:1), and at WR of 1:1 at 30°C (WR1:1). Rectal temperature and HRV (3-lead electrocardiogram [ECG]) were assessed throughout. RESULTS: Coefficient of Variation, Poincaré SD2, and Shannon Entropy were decreased during the CON compared with the WR3:1 when core temperature exceeded 38°C and after 1 hour of continuous work (P < .05). Also, 4 of the 12 HRV indices studied were reduced at CON compared with WR1:1 after 2 hours of accumulated work time (P < .05). Participants worked longer before core temperature reached 38°C during the WR1:1 and the WR3:1, compared with CON (P < .05). CONCLUSIONS: Incorporating breaks during moderate-to-heavy work in the heat for older adults can reduce autonomic stress and prolong the work performed at safe core temperature levels. The TLV WR1:1 provides increased cardiac protection for older workers, as compared with the CON and the WR3:1.

Heart rate variability in older men on the day following prolonged work in the heat.

Susceptibility to heat illness during physically demanding work in hot environments is greater on the second of two consecutive workdays. While it has been demonstrated that heat storage is exacerbated on the second compared to first workday in older workers (50-65 yr), the effects on heart rate variability (HRV), an established surrogate of cardiac autonomic modulation, remain unclear. This study evaluated HRV in older workers on the day following prolonged work in the heat. Electrocardiogram was recorded in nine older (53-64 yr) males at rest, during three 30-min bouts of semi-recumbent cycling at fixed rates of metabolic heat production (150, 200, 250 W/m2), each separated by 15-min recovery. Experiments were conducted in hot-dry conditions (40 °C, 20% relative humidity), immediately prior to (Day 1), and on the day following (Day 2), a prolonged work simulation (∼7.5 hr) involving moderate intensity intermittent exercise in hot-dry conditions (38 °C, 34% relative humidity). Core temperature, as well as time, frequency, and nonlinear HRV indices were derived for analysis during rest, the final 5-min of exercise at the highest heat production and recovery. The change in core temperature at the end of work (mean ±SD) was significantly greater on Day 2 (1.0 °C ±0.3) relative to Day 1 (0.8 °C ±0.2; p < 0.01). Heart rate, however, did not significantly differ between days 1 and 2 at rest (Day 1, 59 ±11 bpm; Day 2, 62 ±13 bpm), during exercise (Day 1, 113 ±21 bpm; Day 2, 114 ±18 bpm ) and at the end of recovery (Day 1, 75 ±16 bpm; Day 2, 76 ±12 bpm). Likewise, there were no significant differences in any HRV indices derived from time, frequency, and nonlinear domains (all p > 0.05). Prolonged work in the heat did not modulate next-day heart rhythms, as reflected by HRV, despite augmented core temperature. While HRV can reflect physiological aspects of cardiac autonomic stressors, these findings indicate it does not provide a means to identify exacerbated heat strain in older workers over consecutive work shifts in the heat.

Epidemiological studies of natural sources of radiation and childhood cancer: current challenges and future perspectives.

The empirical estimation of cancer risks in children associated with low-dose ionising radiation (<100 mSv) remains a challenge. The main reason is that the required combination of large sample sizes with accurate and comprehensive exposure assessment is difficult to achieve. An international scientific workshop, 'Childhood cancer and background radiation', organised by the Institute of Social and Preventive Medicine of the University of Bern, brought together researchers in this field to evaluate how epidemiological studies of background radiation and childhood cancer can best improve our understanding of the effects of low-dose ionising radiation. This review summarises and evaluates the findings of these studies with regard to their methodological differences, identifies key limitations and challenges, and proposes ways to move forward. Large childhood cancer registries, such as those in Great Britain, France and Germany, now permit the conducting of studies that should have sufficient statistical power to detect the effects predicted by standard risk models. Nevertheless, larger studies or pooled studies will be needed to investigate disease subgroups. The main challenge is to accurately assess children's individual exposure to radiation from natural sources and from other sources, as well as potentially confounding non-radiation exposures, in such large study populations. For this, the study groups should learn from each other to improve exposure estimation and develop new ways to validate exposure models with personal dosimetry.

Optimization of Methionyl tRNA-Synthetase Inhibitors for Treatment of Cryptosporidium Infection.

Cryptosporidiosis is one of the leading causes of moderate to severe diarrhea in children in low-resource settings. The therapeutic options for cryptosporidiosis are limited to one drug, nitazoxanide, which unfortunately has poor activity in the most needy populations of malnourished children and HIV-infected persons. We describe here the discovery and early optimization of a class of imidazopyridine-containing compounds with potential for treating Cryptosporidium infections. The compounds target the Cryptosporidium methionyl-tRNA synthetase (MetRS), an enzyme that is essential for protein synthesis. The most potent compounds inhibited the enzyme with Ki values in the low picomolar range. Cryptosporidium cells in culture were potently inhibited with 50% effective concentrations as low as 7 nM and >1,000-fold selectivity over mammalian cells. A parasite persistence assay indicates that the compounds act by a parasiticidal mechanism. Several compounds were demonstrated to control infection in two murine models of cryptosporidiosis without evidence of toxicity. Pharmacological and physicochemical characteristics of compounds were investigated to determine properties that were associated with higher efficacy. The results indicate that MetRS inhibitors are excellent candidates for development for anticryptosporidiosis therapy.