Consecutive Episodes Research Articles

BS SO12 - Long-term impacts of emergency presentations following bariatric health tourism on patients and health services: A UK perspective

Abstract Background Bariatric surgery is an effective treatment for obesity. Whilst short-term complication rates are low, little is known about the longer-term impacts on patients and health services. Even less is known about the true impact of the increasing trend of Health Tourism (HT) in this field. This study aimed to explore this topic further to quantify the impact of HT on UK healthcare services and to subsequently inform future service planning. Method This was a retrospective study of consecutive emergency inpatient episodes related to bariatric surgery (presenting to ED or transferred from other hospitals) at a regional bariatric centre. The study included patients between January 2018- April 2023. Data on index procedure (type, time to presentation, location), complications (and associated management), and subsequent readmissions, diagnostic investigations, and interventions (surgical, radiological, endoscopic) following first discharge from our centre was collected. Results 308 patients (489 episodes) were included (188 patients had surgery in the UK, 77 HT, 43 unknown origin). Gastric band (50%) and gastric sleeve (39%) were the commonest causes for admission in UK and HT patients, respectively. 86 surgical interventions post discharge were required. An average of 2.0 diagnostic investigations were undertaken following discharge per patient (UK 2.3 vs HT 1.9). Following discharge, similar average rates of further readmissions (UK 0.6 v HT 0.6), surgical (UK 0.3 v HT 0.4), radiological (UK 0.2 v HT 0.2) and endoscopic interventions (UK 0.6 v HT 0.6) were seen between cohorts. Conclusion Patients presenting with emergencies following bariatric surgery require significant ongoing investigation and management following discharge from hospital. This ongoing burden is often overlooked in health services research. In our study, this demand was significantly increased by bariatric health tourism. This highlights the critical need to recognise this additional burden, improve service planning to accommodate increased service demand, and address underlying factors contributing to health tourism.

Biometrically measured sleep in medical students as a predictor of psychological health and academic experiences in the preclinical years

ABSTRACT Background Student wellness is of increasing concern in medical education. Increased rates of burnout, sleep disturbances, and psychological concerns in medical students are well documented. These concerns lead to impacts on current educational goals and may set students on a path for long-term health consequences. Methods Undergraduate medical students were recruited to participate in a novel longitudinal wellness tracking project. This project utilized validated wellness surveys to assess emotional health, sleep health, and burnout at multiple timepoints. Biometric information was collected from participant Fitbit devices that tracked longitudinal sleep patterns. Results Eighty-one students from three cohorts were assessed during the first semester of their M1 preclinical curriculum. Biometric data showed that nearly 30% of the students had frequent short sleep episodes (<6 hours of sleep for at least 30% of recorded days), and nearly 68% of students had at least one episode of three or more consecutive days of short sleep. Students that had consecutive short sleep episodes had higher rates of stress (8.3%) and depression (5.4%) symptoms and decreased academic efficiency (1.72%). Conclusions Biometric data were shown to significantly predict psychological health and academic experiences in medical students. Biometrically assessed sleep is poor in medical students, and consecutive days of short sleep duration are particularly impactful as it relates to other measures of wellness. Longitudinal, biometric data tracking is feasible and can provide students the ability to self-monitor health behaviors and allow for low-intensity health interventions.

Molecular characterisation of Mycoplasma bovis isolates from consecutive episodes of respiratory disease on Dutch veal farms

Mycoplasma bovis infections are wide spread in veal calf farms and a major contributor to respiratory disease. M. bovis are genetically diverse. It is unclear how this diversity influences the virulence and epidemiology of infections on veal calf farms over time. Therefore, the aim of this study was to follow the genetic composition of M. bovis isolates on veal farms over time in a fattening round and combine this with presence of disease and presence of other respiratory pathogens. For this, M. bovis isolates were obtained from healthy and diseased calves from ten different farms at different episodes of respiratory disease in the same groups in one fattening round. A new episode of respiratory disease was defined by the practitioner based on clinical diagnosis at least 7 days after end of a previous metaphylactic treatment. These isolates were sequenced using Illumina sequencing and analysed. This resulted in 148 sequenced isolates. The isolates belonged to 9 different clusters and to the known MLST sequence types ST4 (n=9), ST6 (n=2), ST7 (n=1), ST8 (n=1), ST21 (n=32), ST29 (n=30), ST32 (n=1), ST100 (n=36), ST122 (n=17) and ST135 (n=4), and new sequence types ST222 (n=8), ST223 (n=1), ST224 (n=5) and ST225 (n=1). Major sequence types are linked to types, found in other European countries. All farms showed presence of two or more different clusters, however with different distribution patterns. Farms did not show a major shift in type distribution over time. There was a relationship between M. bovis type and region of origin of the calves and the types differed with regards of presence of variable membrane surface lipoprotein (Vsp) genes. Types were not related to disease status of the calves or presence of other major respiratory pathogens. This study underlines the complexity of M. bovis infection on veal calf farms with persistent presence of different types together in both healthy and diseased calves with or without other respiratory pathogens. Prevention of introduction of M. bovis and biosecurity measures combined with optimisation of calf resilience should have priority.

Evaluating Indoor Air Quality in Schools: Is the Indoor Environment a Haven during High Pollution Episodes?

Pollution data were collected at five schools in Hong Kong using low-cost, sensor-based monitors both indoors and outdoors during two consecutive high pollution episodes. The pollutants monitored included NO2, O3, PM2.5, and PM10, which were also used as input to a health risk communication protocol known as Air Quality Health Index (AQHI). CO2 was also measured simultaneously. The study aimed to assess the relationship between indoor pollutant concentrations and AQHI levels with those outdoors and to evaluate the efficacy of building operating practices in protecting students from pollution exposure. The results indicate that the regular air quality monitoring stations and outdoor pollutant levels at schools exhibit similar patterns. School AQHI levels indoors were generally lower than those outdoors, with PM10 levels showing a larger proportional contribution to the calculated values indoors. NO2 levels in one school were in excess of outdoor values. CO2 monitored in classrooms commonly exceeded indoor guidelines, suggesting poor ventilation. One school that employed air filtration had lower indoor PM concentrations compared to other schools; however, they were still similar to those outdoors. O3 levels indoors were consistently lower than those outdoors. This study underscores the utility of on-site, sensor-based monitoring for assessing the health impacts of indoor and community exposure to urban air pollutants. The findings suggest a need for improved ventilation and more strategic air intake placement to enhance indoor air quality.

Hair-straightening cosmetics containing glyoxylic acid induce crystalline nephropathy

We recently reported the case of a patient who experienced three consecutive episodes of acute kidney injury, all of them following a "Brazilian" hair-straightening treatment. The cream used for the straightening procedure contained glyoxylic acid. To examine possible underlying mechanisms causing kidney injury, four groups of mice were exposed to topical application of (i) the straightening product, (ii) a cream containing 10% glyoxylic acid, (iii) a cream containing 10% glycolic acid or (iv) a control cream. Application of glycolic acid slightly increased urine oxalate excretion, while glyoxylic acid and the straightening product dramatically increased urine oxalate excretion and caused calcium oxalate nephropathy after transcutaneous absorption. Thus, glyoxylic acid was presumptively absorbed through the skin, metabolized to oxalate and promoted crystallization of calcium oxalate in urine. Hence, cosmetic products containing glyoxylic acid may induce acute kidney injury and should be discontinued. Further studies are needed to investigate the metabolism of glycolic acid and glyoxylic acid following topical application.

Effects of Intranasal Naloxone on Hypoglycemia-Associated Autonomic Failure (HAAF) in Susceptible Individuals.

Hypoglycemia-associated autonomic failure (HAAF), defined as blunting of counter-regulatory hormone and symptom responses to recurrent hypoglycemia, remains a therapeutic challenge in diabetes treatment. The opioid system may play a role in HAAF pathogenesis since activation of opioid receptors induces HAAF. Blockade of opioid receptors with intravenous naloxone ameliorates HAAF experimentally, yet is not feasible therapeutically. To investigate the effects of opioid receptor blockade with intranasal naloxone on experimentally-induced HAAF. Randomized, double-blinded, placebo-controlled crossover study. Academic research center. Healthy non-diabetic volunteers. Paired two-day studies, 5-10 weeks apart, each consisting of three consecutive hypoglycemic episodes (hyperinsulinemic hypoglycemic clamps, glucose nadir: 54 mg/dL): two on day 1 with administration of intranasal naloxone vs. placebo, followed by the third episode on day 2. Differences in counter-regulatory hormones responses and hypoglycemia symptoms between first and third hypoglycemic episodes in naloxone vs. placebo studies. Out of 17 participants, 9 developed HAAF, confirming variable inter-individual susceptibility. Among participants susceptible to HAAF, naloxone maintained some hormonal and symptomatic responses to hypoglycemia and prevented the associated requirement for increased glucose infusion. Unexpectedly, naloxone reduced plasma epinephrine and growth hormone responses to the first hypoglycemic episode but prevented further reduction with subsequent hypoglycemia. This is the first study to report that intranasal naloxone, a widely used opioid receptor antagonist, may ameliorate some features of HAAF. Further investigation is warranted into mechanisms of variable inter-individual susceptibility to HAAF and the effects of intranasal naloxone in people with diabetes at risk for HAAF.

Null models confirm nest site fidelity by male smallmouth bass, Micropterus dolomieu

BackgroundMany animals appear to preferentially renest in proximity to a site they previously occupied. Evidence of nest fidelity is often inferred from a right skewed distribution of distances between the nests of individuals that breed in two consecutive reproduction episodes, where many individuals nest some arbitrarily close distance to their prior nest and others, in the extended right tail of the distribution, nest far from the nest they previously occupied. Because right skewed distributions of inter-nest distances can arise even when individuals choose nest locations randomly, however, such inferences are prone to error. The importance of null models—used to generate patterns of individual inter-nest distances by processes that do not involve site attachment—for inferences about site fidelity has been known for decades but is still often unappreciated or ignored.MethodsThe right skewed distributions of inter-nest distances observed in two earlier studies of male smallmouth bass (Micropterus dolomieu) suggest prima facie that males exhibit nest site fidelity between annual reproduction episodes, but patterns of inter-nest distances have yet to be compared to an adequate null model. Here, we evaluate the nest site fidelity of marked male M. dolomieu in a decade-long dataset, where we apply a randomization procedure based on the rencontre probability problem to generate null models. Eight observed distributions of individual, annual inter-nest distances are compared to a year-specific null model to determine whether random processes are sufficient to explain the observed distributions of inter-nest distances.ResultsThrough contrasts between observed annual inter-nest distances and results derived from null models that imposed realistic constraints on behavior, we show that some males were undoubtedly nest-site faithful. To reinforce the utility of null models and to make these kinds of models more accessible, we also provide a supplemental tutorial. The tutorial illustrates how random site choices, subject to common ecological and behavioral constraints, and even how distance is measured, can produce patterns of inter-nest distances that falsely imply nest site fidelity, or a lack of fidelity. The R code needed to reproduce these null models is included. The inference errors evident in our examples generalize to other forms of site fidelity, such as the apparent patch fidelity of certain sea bird foragers.ConclusionsThe comparisons of observed distributions of inter-nest distances with those generated by null models imply that, as suggested in prior studies, male M. dolomieu indeed exhibit annual nest site fidelity. Procedures like those we apply are necessary first steps in analyses when distributions of distances between the nests of individuals in consecutive reproduction episodes are used to infer nest-site fidelity. Why male M. dolomieu are site faithful is a question yet to be answered.

Safe online optimization of motor speed synchronization control with incremental Q-learning

Reinforcement learning (RL) is promising for online controller optimization. However, its practical application has been hindered by safety issues. This paper proposes an algorithm named Incremental Q-learning (IQ) and applies it to the online optimization of motor speed synchronization control. IQ ensures safe learning by adopting so-called incremental action variables which represent incremental change rather than absolute magnitude, and dividing the one-round learning process in the classic Q-learning (in this paper referred to as Absolute Q-learning, AQ) into multiple consecutive ones with the Q table getting reset at the beginning of each round. Since the permitted interval of change is restricted to be very small, the agent can learn its way safely, steadily, and robustly towards the optimal policy. Simulation results show that IQ is advantageous to AQ in optimality, safety, and adaptability. IQ converges to better final performances with significantly smaller performance variance along the whole learning process, smaller torque trajectory deviation between consecutive episodes and adapts to unknown disturbances faster. It is of great potential for online controller optimization/tuning in practical engineering projects. Source code and demos are provided.

Reasons for encounters, diagnoses, and admission rate among emergency referrals at an urban primary care clinic in Japan: A retrospective cohort study

AbstractBackgroundComprehensive understanding of emergency referrals (EmR), encompassing reasons for encounters (RFEs) and diagnoses, is crucial for primary care physicians (PCPs). Comparing EmR rates and subsequent admission rates can potentially enhance the quality of primary care for EmR practice. However, no study has evaluated RFEs among patients with EmRs. This study aimed to identify RFE/diagnosis in relation to subsequent admission among patients receiving EmR.MethodsWe conducted a retrospective cohort study at an urban family physician teaching clinic in Kawasaki City, Japan. Our cohort recruited consecutive EmR episodes with their medical records and admissions confirmed through response letters from receiving hospitals. Using the 2nd edition of the International Classification of Primary Care, we explored the frequency of RFEs and diagnoses, calculating EmR rates and admission rates as primary outcomes. Bivariate analyses were employed to compare admission and non‐admission cases.ResultsThe present study encompassed 162 EmR episodes out of 47,901 visits, yielding an EmR rate of 3.38/1000 visits. Among 153 completely followed episodes, 99 patients were emergently admitted, resulting in a 64.7% admission rate. The admission group exhibited significantly higher age and a greater prevalence of dementia. Descriptive analysis revealed fever and pneumonia as the most frequent RFE and diagnosis, respectively, with significant differences between admission and non‐admission groups.ConclusionsThe present study reports EmR and admission rates following EmR, highlighting differences in patient characteristics, RFEs, and diagnoses. The findings offer insights to enhance PCPs' EmR practices and serve as a benchmark for the scope of EmR practice.

Observational analysis of surface ozone variability in China from 2015 to 2020: Insights from consecutive ENSO episodes

Utilizing daily surface ozone (O3) concentration data (MDA8-O3) from nearly 1500 monitoring stations across mainland China, complemented by gridded atmospheric reanalysis data, this study conducts a comprehensive analysis of O3 concentration, anomalies, and oscillations. Employing regression and composite analyses, we investigate the potential linkage between O3 variations and the phase and strength of El Niño-Southern Oscillation (ENSO) across diverse regions and seasons in China. Noteworthy findings include the identification of regions exhibiting peak O3 concentrations in autumn or spring, deviating from the typical seasonal cycle, as well as regions exhibiting varying strengths of seasonal and semi-annual O3 oscillations. Moreover, the study unveils the spatiotemporal patterns of synoptic and intra-seasonal O3 oscillations. The analyses reveal a prevailing inverse association between O3 anomalies and ENSO in most Chinese regions except for the southern and southeastern coastal areas. The potential impacts of ENSO on O3 are elucidated by anomalous atmospheric conditions linked to ENSO, the nature of which strongly depends on the region and season. In northern China, anomalous temperature and solar radiation related to ENSO exert a more pronounced influence on O3 anomalies. On the other hand, in southern China, anomalies in wind speed/direction and precipitation associated with anomalous atmospheric circulations play a more predominant role. These findings contribute valuable insights to the nuanced understanding of O3 variability, paving the way for the development of sophisticated O3 forecasting approaches tailored to different regions and seasons across China.

Are any specific respiratory viruses more severe than others in recipients of allogeneic stem cell transplantation? A focus on lower respiratory tract disease.

In the general population, influenza virus, respiratory syncytial virus, and SARS-CoV-2 are considered the most severe community-acquired respiratory viruses (CARVs). However, allogeneic stem cell transplant (allo-SCT) recipients may also face severe courses from other CARVs. This retrospective study compared outcomes of various CARV lower respiratory tract diseases (LRTD) in 235 adult allo-SCT recipients, excluding co-infection episodes. We included 235 adults allo-SCT recipients experiencing 353 CARV LRTD consecutive episodes (130 rhinovirus, 63 respiratory syncytial virus, 43 influenza, 43 human parainfluenza virus, 23 human metapneumovirus, 19 Omicron SARS-CoV-2, 17 common coronavirus, 10 adenovirus and 5 human bocavirus) between December 2013 and June 2023. Day 100 overall survival ranged from 78% to 90% without significant differences among CARV types. Multivariable analysis of day 100 all-cause mortality identified corticosteroid use of >1 to <30 mg/d [Hazard ratio (HR) 2.45, p = 0.02) and ≥30 mg/d (HR 2.20, p = 0.015) along with absolute lymphocyte count <0.2 × 109/L (HR 5.82, p < 0.001) and number of CARV episodes as a continuous variable per one episode increase (HR 0.48, p = 0.001) as independent risk factors for all-cause mortality. Degree of immunosuppression, rather than intrinsic CARV virulence, has the most significant impact on mortality in allo-SCT recipients with CARV-LRTD.

Safety of empirical antibiotic therapy discontinuing for fever of unknown origin during high-risk neutropenia in children

ECIL-2021 recommends discontinuing empirical antibiotic therapy (EAT) in febrile-neutropenic children after 72h of treatment and at least 24-48h of apyrexia in the case of fever of unknown origin (FUO). These guidelines are rarely applied to high-risk children's neutropenia. We retrospectively included all consecutive FUO episodes occurring during profound neutropenia ≥10 days in children in our institution. We evaluated the safety of EAT discontinuation in patients for whom the ECIL guidelines were followed compared to those for whom they didn't. We used a combined criterion of mortality and intensive care unit admission at 30 days. We identified risk factors for recurrent fever after EAT discontinuation. Fifty-one FUO episodes occurred in 37 patients. EAT discontinuation followed ECIL guidelines in 19 (37%) episodes. No deaths and-or transfers in ICU occurred in the ECIL group. The duration of EAT was shorter by nine days in the group following ECIL guidelines (p<0.001). We observed 14 (27%) episodes of recurrent fever. Mucositis was significantly associated with recurrent fever (p<0.01). EAT discontinuation seems feasible and safe in FUO during prolonged febrile neutropenia in children. However, mucosal lesions should prompt thorough surveillance due to the risk of recurrent fever.

Impact of therapeutic plasma exchange on intact protein S, apolipoproteins, and thrombin generation

IntroductionTherapeutic plasma exchange (TPE), with solvent/detergent (S/D)-treated plasma as replacement fluid, is an extracorporeal blood purification technique with major impact on both coagulation and lipids. Our previous in vitro study showed that S/D-plasma enhances thrombin generation by lowering intact protein S (PS) levels. Aims: To evaluate the impact of altered lipid balance on coagulation phenotype during heparin-anticoagulated TPE with S/D-plasma, and to investigate whether the lowered intact PS levels with concomitant procoagulant phenotype, are recapitulated in vivo. Methods: Coagulation biomarkers, thrombin generation with Calibrated Automated Thrombogram (CAT), and lipid levels were measured before and after the consecutive 1st, 3rd and 5th episodes of TPE performed to six patients with Guillain-Barré syndrome or myasthenia gravis. The effects of in vitro dilution of S/D-plasma on thrombin generation were explored with CAT to mimic TPE. Results: Patients did not have coagulation disorders, except elevated FVIII. Intact PS, lipoproteins, especially LDL, Apolipoprotein CIII (ApoC3) and ApoB/ApoA1 ratio declined (p < 0.05). In contrast, VLDL and triglyceride levels stayed intact. CAT lag time shortened (p < 0.05). In vitro dilution of S/D plasma with co-transfused Ringer's lactate and 4% albumin partially reduced its procoagulant phenotype in CAT, which is mainly seen as peak thrombin, and modestly shortened lag time. Conclusions: After the five settings of TPE using S/D-plasma in vivo, which associated with heparinization and reduced coagulation factor activities, our observations of declining natural anticoagulant intact PS and apolipoproteins refer to rebalance of the hemostatic and lipid profiles.

Changing trends in clinical characteristics and in-hospital mortality of patients with infective endocarditis over four decades

BackgroundInfective endocarditis continues to be a significant concern and may be undergoing an epidemiological transition. MethodsWere studied 1804 consecutive episodes of infective endocarditis between 1978 and 2022. The mean age was 48 ( ± 19), and 1162 (64%) patients were male. Temporal trends in demographic data, comorbidities, predisposing conditions, microorganisms, complications and in-hospital death have been studied over the decades (1978–1988, 1989–1999, 2000–2010 and 2011–2022). The outcomes and clinical characteristics were modeled using nonlinear cubic spline functions. FindingsValve surgery was performed in 50% of the patients and overall in-hospital mortality was 30%. From the first to the fourth decade studied, the average age of patients increased from 29 to 57 years (p < 0.001), with significant declines in the occurrence of rheumatic valvular heart disease (15% to 6%; p < 0.001) and streptococcal infections (46% to 33%; p < 0.001). Healthcare-associated infections have increased (9% to 21%; p < 0.001), as have prosthetic valve endocarditis (26% to 53%; p < 0.001), coagulase-negative staphylococcal infections (4% to 11%; p < 0.001), and related-complications (heart failure, embolic events, and perivalvular abscess; p < 0.001). These changes were associated with a decline in adjusted in-hospital mortality from 34% to 25% (p = 0.019). InterpretationIn the 44 years studied, there was an increase in the mean age of patients, healthcare-related, prosthetic valve, coagulase-negative staphylococci/MRSA infections, and related complications. Notably, these epidemiological changes were associated with a decline in the adjusted in-hospital mortality.

Repeated hypoxic episodes allow hematological and physiological habituation in rainbow trout.

Introduction: Under climate change, the increase in temperature in aquatic environments may induce oxygen depletion. In extreme cases, low oxygen may become a limiting factor for fish, thus generating stress. In addition, consecutive hypoxic episodes may complicate the recovery of individuals and hinder their ability to modulate physiological and biochemical responses to maintain homeostasis. Thus, the aim of this study was to determine the hematological and physiological responses of rainbow trout under a condition of repeated hypoxic and manipulation stresses at three different time points. Methods: Every hypoxic episode consisted of exposing the fish to low dissolved oxygen concentrations (2 mgO2/L for 1 h). Following the exposure, the fish were allowed to recover for 1 h, after which they were sampled to investigate hematological and physiological parameters. Results and discussion: The results showed a pattern of habituation reflected by values of hematocrit, hemoglobin, and mean corpuscular volume, indicating a certain ability of rainbow trout to resist this type of repeated hypoxic events, provided that the fish can have some recovery time between the exposures.

Bacterial Vaginosis and Vulvovaginal Candidiasis Pathophysiologic Interrelationship.

Among the infectious causes of vulvovaginal symptoms, bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC) dominate. Apart from infrequent mixed infections, both are considered independent and caused by unrelated pathogenic mechanisms. Clinical experience, however, is strongly suggestive that in some populations these infections are linked with recurrent BV (RBV) serving as the dominant etiopathogenic trigger for development of recurrent VVC (RVVC) with profound clinical and therapeutic consequences. The biologic basis for this critical interrelationship is discussed and suggests that as a consequence of BV dysbiosis, and not necessarily because of antibiotics prescribed, immune defenses are compromised, neutralizing vaginal yeast tolerance. The consequent BV-induced vaginal proinflammatory environment predisposes to mixed infection or consecutive episodes of post-treatment VVC. Recurrent BV and repeated antimicrobial drug exposure also predispose to acquired fluconazole resistance in C. albicans isolates, contributing to refractory vulvovaginal candidiasis.

Decreased risk of underdosing with continuous infusion versus intermittent administration of cefotaxime in patients with sickle cell disease and acute chest syndrome.

Underdosing of antibiotics is common in patients with sickle cell disease (SCD). We hypothesized that in critically-ill patients with SCD receiving cefotaxime during acute chest syndrome, the continuous infusion may outperform the intermittent administration in achieving pharmacokinetic/pharmacodynamic targets. Prospective before-after study. Intensive-care unit of a French teaching hospital and sickle cell disease referral center. Sixty consecutive episodes of severe acute chest syndrome in 58 adult patients with sickle cell disease. Patients were treated with intermittent administration during the first period (April 2016 -April 2018) and with continuous infusion during the second period (May 2018 -August 2019). We included 60 episodes of acute chest syndrome in 58 patients (29 [25-34] years, 37/58 (64%) males). Daily dose of cefotaxime was similar between groups (59 [48-88] vs. 61 [57-64] mg/kg/day, p = 0.84). Most patients (>75%) presented a glomerular hyperfiltration with no difference between groups (p = 0.25). More patients had a cefotaxime trough level ≥2 mg/L with continuous infusion than intermittent administration: 28 (93%) vs. 5 (16%), p<0.001. The median residual concentration was higher in the continuous infusion than intermittent administration group: 10.5 [7.4-13.3] vs. 0 [0-0] mg/L, p<0.001. No infection relapse was observed in the entire cohort. Hospital length of stay was similar between groups. As compared to intermittent administration, continuous infusion of cefotaxime maximizes the pharmacokinetic/pharmacodynamic parameters in patients with SCD. The clinical outcome did not differ between the two administration methods; however, the study was underpowered to detect such a difference.

Contrasting the form and strength of pre- and postcopulatory sexual selection in a flatworm.

Sexual traits may be selected during multiple consecutive episodes of selection, occurring before, during, or after copulation. The overall strength and form of selection acting on traits may thus be determined by how selection (co-)varies along different episodes. However, it is challenging to measure pre- and postcopulatory phenotypic traits alongside variation in fitness components at each different episode. Here, we used a transgenic line of the transparent flatworm Macrostomum lignano expressing green fluorescent protein (GFP) in all cell types, including sperm cells, enabling in vivo sperm tracking. We assessed the mating success, sperm-transfer efficiency, and sperm fertilizing efficiency of GFP(+) focal worms in which we measured 13 morphological traits. We found linear selection on sperm production rate arising from pre- and postcopulatory components and on copulatory organ shape arising from sperm fertilizing efficiency. We further found nonlinear (mostly concave) selection on combinations of copulatory organ and sperm morphology traits arising mostly from sperm-transfer efficiency and sperm fertilizing efficiency. Our study provides a fine-scale quantification of sexual selection, showing that both the form and strength of selection can change across fitness components. Quantifying how sexual selection builds up along episodes of selection allows us to better understand the evolution of sexually selected traits.

Final Report: Somatic Mutations and HMGCLL1 Haplotype Are Not Associated with Molecular Relapse-Free Survival in Patients with Chronic Myeloid Leukemia Who Attempt Treatment-Free Remission

Background Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder resulting from the BCR::ABL1 rearrangement. Patients with CML have a comparable life expectancy to that of age-matched individuals in the general population when they achieve an optimal response with tyrosine kinase inhibitor (TKI) therapy. With the aim of improving the quality of life of patients who are significantly affected by drug-related adverse events and financial burden, the practical goal of CML treatment has shifted to treatment-free remission (TFR), defined as the successful discontinuation (DISC) of TKI therapy without losing leukemia control. TKI treatment DISC is a safe procedure but requires appropriate candidate selection and frequent molecular monitoring. Several biomarkers were investigated, but no definite biomarker has yet been successfully identified and validated. We have investigated somatic mutations before TKI discontinuation and HMGCLL1 haplotype as a potential biomarker for TFR, given that they were previously described as predictors of CML outcomes. Patients and methods A total of 155 patients who attempted TKI discontinuation for TFR from 5 countries were included: Canada (n=71), Brazil (n=30), Argentina (n=28), Italy (n=23), and the Czech Republic (n=3). We applied our in-house single molecule-molecular inversion probe (smMIP) panel which is a barcoded error-corrected DNA-based sequencing with a limit of detection up to 0.2%. The panel encompasses 40 genes with 332 amplicon probes: epigenetic modifiers (n=7), activation signaling (n=12), myeloid transcription factor (TF; n=5), spliceosome (n=3), tumor suppressor (n=3), cohesion (n=4), miscellaneous (n=3) and 8 HMGCLL1 single nucleotide polymorphisms (SNPs). Two groups were constructed based on these eight SNPs: group 1: CTCAGGCA (C- haplotype) or group 2: ACGTAATG (A-haplotype). Samples were collected prior to TKI DISC when patients met the criteria for TFR attempt. Molecular relapse-free survival (mRFS) was calculated from the date of TKI DISC to the date of confirmed loss of deep molecular response (DMR). Loss of DMR includes single-time loss of major molecular response (MMR) or two consecutive episodes of loss of molecular response 4 log or deeper response (MR4). Kaplan-Meier survival estimate was used to evaluate mRFS and Cox's proportional hazard regression model was applied. Results The median MR4 duration prior to TKI DISC was 7.2 years (range 4.7-9.3), while overall TKI treatment duration was 8.5 years (range 6.0-11.6). With a median follow-up of 831 days (range: 460-1,415), out of the 155 patients, 68 (43.9%) lost response, among whom 6 lost MMR only, 12 lost MR4 only, and 50 lost MMR and MR4, both. Median time to MMR loss was 95 days (range 83.5-137). A total of 71 mutations were detected in 51 patients (32.9%). TET2 mutation was the most frequent mutation, detected in 17 cases (24%) followed by ASXL1 (n=14; 20%) and DNMT3A (n=12; 17%). When grouped by relevant biological pathways involved, mutations in epigenetic genes (n=42, 61%) were the most frequently involved. mRFS rate was 64% (95% CI [55.8-71.1%]) and 56% [48.2-64.0%] at 6 and 12 months, respectively. During the univariate analysis, no significant difference was observed in mRFS according to the presence, number, or type of somatic mutations, or the HMGCLL1 haplotype. Additionally, there were no significant differences in mRFS based on age, sex, Sokal risk group, line of TKI therapy, or TKI drug type prior to TKI DISC. However, MR4 duration prior to TKI DISC was associated with mRFS rate: patients with≥7.3 years (n=71) showed higher mRFS: 74.09% [62.05-82.82%] compared to those &amp;lt;7.3 years (n=74) with mRFS rate of 44.36% [32.54 -55.51] (p &amp;lt;0.01, HR 0.36 [0.21-0.63]). In addition, a longer duration of TKI treatment before TKI DISC was associated with higher mRFS: patients with ≥ 8.3 years of treatment (n=85) showed 71.8% mRFS [60.4-80.4], compared to 42.5% mRFS [30.5-54.0%] in those with &amp;lt;8.3 years (n=71) (p&amp;lt;0.01, HR 0.48 [0.31-0.74]). Multivariate analyses for mRFS confirmed that MR4 duration and the total duration of TKI treatment before TKI DISC were associated with TFR outcomes, but not the presence of epigenetic mutations, any mutation, or HMGCLL1 haplotype (Table1). Conclusion In CML, somatic mutations before attempting TFR are frequently observed. However, our current study does not support their prognostic significance as TFR-predictive biomarkers.

End-to-End Autonomous Navigation Based on Deep Reinforcement Learning with a Survival Penalty Function.

An end-to-end approach to autonomous navigation that is based on deep reinforcement learning (DRL) with a survival penalty function is proposed in this paper. Two actor-critic (AC) frameworks, namely, deep deterministic policy gradient (DDPG) and twin-delayed DDPG (TD3), are employed to enable a nonholonomic wheeled mobile robot (WMR) to perform navigation in dynamic environments containing obstacles and for which no maps are available. A comprehensive reward based on the survival penalty function is introduced; this approach effectively solves the sparse reward problem and enables the WMR to move toward its target. Consecutive episodes are connected to increase the cumulative penalty for scenarios involving obstacles; this method prevents training failure and enables the WMR to plan a collision-free path. Simulations are conducted for four scenarios-movement in an obstacle-free space, in a parking lot, at an intersection without and with a central obstacle, and in a multiple obstacle space-to demonstrate the efficiency and operational safety of our method. For the same navigation environment, compared with the DDPG algorithm, the TD3 algorithm exhibits faster numerical convergence and higher stability in the training phase, as well as a higher task execution success rate in the evaluation phase.