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BackgroundChronic low back pain (CLBP) is a major economic and social problem worldwide. Despite the variety of recommended treatments, long-term self-management of this condition is complex and requires the development of innovative interventions. Mobile health (mHealth) technologies hold great promise for the management of chronic pain, particularly to support physical activity. However, their implementation is challenged by a lack of user compliance and limited engagement, which may be due to insufficient consideration of the needs of potential users during development. ObjectiveThis study aims to explore the needs of people with CLBP and health care professionals regarding mHealth technologies to support self-managed physical activity, and to delineate design recommendations based on identified needs. MethodsA participatory study was conducted using a 3-phase, user-centered design approach: needs investigation with a group of experts in a workshop (phase 1), needs exploration with end users in focus groups (phase 2), and validation of needs using Delphi questionnaires followed by the development of a set of recommendations (phase 3). ResultsA total of 121 people with CLBP, expert patients, health care professionals, rehabilitation researchers, and biomechanical engineers participated in this study. The results indicated how technology could help people with CLBP overcome their difficulties with managing physical activity. Specific needs were formulated concerning device objectives, expected strategies, functionalities, technical features, conditions of use, and potential facilitators and barriers to use. These needs were validated by consensus from the potential end users and translated into design recommendations. ConclusionsThis study provides design recommendations for the development of an mHealth device specifically adapted for people with CLBP.

Abstract Precisely timed and reliably emitted spikes are hypothesized to serve multiple functions, including improving the accuracy and reproducibility of encoding stimuli, memories, or behaviours across trials. When these spikes occur as a repeating sequence, they can be used to encode and decode a potential time series. Here, we show both analytically and in simulations that the error incurred in approximating a time series with precisely timed and reliably emitted spikes decreases linearly with the number of neurons or spikes used in the decoding. This was verified numerically with synthetically generated patterns of spikes. Further, we found that if spikes were imprecise in their timing, or unreliable in their emission, the error incurred in decoding with these spikes would be sub-linear. However, if the spike precision or spike reliability increased with network size, the error incurred in decoding a time-series with sequences of spikes would maintain a linear decrease with network size. The spike precision had to increase linearly with network size, while the probability of spike failure had to decrease with the square-root of the network size. Finally, we identified a candidate circuit to test this scaling relationship: the repeating sequences of spikes with sub-millisecond precision in area HVC (proper name) of the zebra finch. This scaling relationship can be tested using both neural data and song-spectrogram-based recordings while taking advantage of the natural fluctuation in HVC network size due to neurogenesis.

Background/Objectives: In connection with previous work on V-shaped polycyclic thiazolo[5,4-f]quinazolin-9-one and [5,4-f]quinazoline derivatives that can modulate the activity of various kinases, the synthesis of straight thiazole-fused [4,5-g] or [5,4-g]quinazolin-8-ones and quinazoline derivatives hitherto undescribed was envisioned. Methods: An innovative protocol allowed to obtain the target structures. The synthesis of inverted thiazolo[4,5-h] and [5,4-h]quinazolin-8-one derivatives was also explored with the aim of comparing biological results. The compounds obtained were tested against a representative panel of eight mammalian protein kinases of human origin: CDK9/CyclinT, Haspin, Pim-1, GSK-3β, CK-1ε, JAK3, CLK1 and DYRK1A. Results and Conclusions: The results obtained show that the novel linear thiazoloquinazolines are not kinase inhibitors. The cytotoxicity of these newly synthesized compounds was assessed against seven representative tumor cell lines (human cancers: Huh7-D12, Caco-2, HCT-116, MCF-7, MDA-MB-231, MDA-MB-468 and PC-3). The majority of these novel molecules proved capable of inhibiting the growth of the tested cells. The 7-Benzyl-8-oxo-7,8-dihydrothiazolo[5,4-g]quinazolinones 5b and 6b are the most potent, with IC50 values in the micromolar range. None of these compounds showed toxicity against normal cells. A larger program of investigations will be launched to investigate the real potential interest of such compounds in anticancer applications.

Two new fusarochromanone derivatives, deacetylfusarochromene (1) and deacetamidofusarochrom-2′,3-diene (2), along with the previously reported metabolites fusarochromanone TDP-2 (3), fusarochromene (4), 2,2-dimethyl-5-amino-6-(2′E-ene-4′-hydroxylbutyryl)-4-chromone (5), fusarochromanone (6), (−)-chrysogine (7), and equisetin (8), were isolated from the marine fungus Fusarium equiseti UBOCC-A-117302. The structures of the compounds were determined by extensive spectrometric (HRMS) and spectroscopic (1D and 2D NMR) analyses, as well as specific rotation. Among them, 2 and 5 showed inhibition of three protein kinases with IC50 values ranging from 1.42 to 25.48 μM. Cytotoxicity and antimicrobial activity of all isolated compounds were also evaluated. Six fusarochromanone derivatives (1–6) exhibited diverse activities against three cell lines, RPE-1, HCT-116, and U2OS (IC50 values ranging from 0.058 to 84.380 μM). Equisetin (8) showed bactericidal activities against Bacillus cereus and Listeria monocytogenes (MBC values of 7.8 and 31.25 µM, respectively), and bacteriostatic activity against Enterococcus faecalis (MIC value of 31.25 µM). Compounds 2 and 4 showed bacteriostatic activities against Listeria monocytogenes (MIC of 125 µM).

Plague is a flea-borne fatal disease caused by the bacterium Yersinia pestis, which persists in rural Madagascar. Although fleas parasitizing rats are considered the primary vectors of Y. pestis, the human flea, Pulex irritans, is abundant in human habitations in Madagascar, and has been found naturally infected by the plague bacterium during outbreaks. While P. irritans may therefore play a role in plague transmission if present in plague endemic areas, the factors associated with infestation and human exposure within such regions are little explored. To determine the socio-ecological risk factors associated with P. irritans infestation in rural households in plague-endemic areas of Madagascar, we used a mixed-methods approach, integrating results from P. irritans sampling, a household survey instrument, and an observational checklist. Using previously published vectorial capacity data, the minimal P. irritans index required for interhuman bubonic plague transmission was modeled to determine whether household infestations were enough to pose a plague transmission risk. Socio-ecological risk factors associated with a high P. irritans index were then identified for enrolled households using generalized linear models. Household flea abundance was also modeled using the same set of predictors. A high P. irritans index occurred in approximately one third of households and was primarily associated with having a traditional dirt floor covered with a plant fiber mat. Interventions targeting home improvement and livestock housing management may alleviate flea abundance and plague risk in rural villages experiencing high P. irritans infestation. As plague-control resources are limited in developing countries such as Madagascar, identifying the household parameters and human behaviors favoring flea abundance, such as those identified in this study, are key to developing preventive measures that can be implemented at the community level.

There is a growing interest in wearable inertial sensors to monitor and analyze the movements of pregnant women. The noninvasive and discrete nature of these sensors, integrated into devices accumulating large datasets, offers a unique opportunity to study the dynamic changes in movement patterns during the rapid physical transformations induced by pregnancy. However, the final cut of the third trimester of pregnancy, particularly the first stage of labor up to delivery, remains underexplored. The growing popularity of “walking epidural”, a neuraxial analgesia method allowing motor function preservation, ambulation, and free movement throughout labor and during delivery, opens new opportunities to study the biomechanics of labor using inertial sensors. Critical research gaps exist in parturient fall prediction and detection during walking epidural and understanding pain dynamics during labor, particularly in the presence of pelvic girdle pain. The analysis of fetal descent, upright positions, and their relationship with dynamic pelvic movements facilitated by walking during labor is another area where inertial sensors can play an interesting role. Moreover, as contemporary obstetrics advocate for less restricted or non-restricted movements during labor, the role of inertial sensors in objectively measuring the quantity and quality of women’s movements becomes increasingly important. This includes studying the impact of epidural analgesia on maternal mobility, walking patterns, and associated obstetrical outcomes. In this paper, the potential use of wearable inertial sensors for gait analysis in the first stage of labor is discussed.

Mice were immunized with a combination of self-amplifying (sa) RNA constructs for the F1 and V antigens of Yersinia pestis at a dose level of 1 μg or 5 μg or with the respective protein sub-units as a reference vaccine. The immunization of outbred OF1 mice on day 0 and day 28 with the lowest dose used (1 μg) of each of the saRNA constructs in lipid nanoparticles protected 5/7 mice against subsequent sub-cutaneous challenge on day 56 with 180 cfu (2.8 MLD) of a 2021 clinical isolate of Y. pestis termed 10-21/S whilst 5/7 mice were protected against 1800cfu (28MLD) of the same bacteria on day 56. By comparison, only 1/8 or 1/7 negative control mice immunized with 10 μg of irrelevant haemagglutin RNA in lipid nanoparticles (LNP) survived the challenge with 2.8 MLD or 28 MLD Y. pestis 10-21/S, respectively. BALB/c mice were also immunized with the same saRNA constructs and responded with the secretion of specific IgG to F1 and V, neutralizing antibodies for the V antigen and developed a recall response to both F1 and V. These data represent the first report of an RNA vaccine approach using self-amplifying technology and encoding both of the essential virulence antigens, providing efficacy against Y. pestis. This saRNA vaccine for plague has the potential for further development, particularly since its amplifying nature can induce immunity with less boosting. It is also amenable to rapid manufacture with simpler downstream processing than protein sub-units, enabling rapid deployment and surge manufacture during disease outbreaks.

Abstract BackgroundIn recent years, researchers have been advocating for the integration of ambulatory gait monitoring as a complementary approach to traditional fall risk assessments. However, current research relies on dedicated inertial sensors that are fixed on a specific body part. This limitation impacts the acceptance and adoption of such devices. ObjectiveOur study objective is twofold: (1) to propose a set of step-based fall risk parameters that can be obtained independently of the sensor placement by using a ubiquitous step detection method and (2) to evaluate their association with prospective falls. MethodsA reanalysis was conducted on the 1-week ambulatory inertial data from the StandingTallSmartstep, ResultsThe built model had an area under the curve of 0.69, which is comparable to models exclusively built on fixed sensor placement. A higher fall risk was noted with higher gait variability (coefficient of variance of stride time), intensity (cadence), and quantity (number of steps) and lower gait complexity (sample entropy and fractal exponent). ConclusionsThese findings highlight the potential of our method for comprehensive and accurate fall risk assessments, independent of sensor placement. This approach has promising implications for ambulatory gait monitoring and fall risk monitoring using consumer-grade devices.

PurposeAccelerometers can be used to objectively measure physical activity. They could be offered to people with chronic low back pain (CLBP) who are encouraged to maintain an active lifestyle. The aim of this study was to examine the use of accelerometers in studies of people with CLBP and to synthesize the main results regarding the measurement of objective physical activity.MethodsA scoping review was conducted following Arksey and O'Malley's framework. Relevant studies were collected from 4 electronic databases (PubMed, Embase, CINHAL, Web of Science) between January 2000 and July 2023. Two reviewers independently screened all studies and extracted data.Results40 publications out of 810 citations were included for analysis. The use of accelerometers in people with CLBP differed across studies; the duration of measurement, physical activity outcomes and models varied, and several limitations of accelerometry were reported. The main results of objective physical activity measures varied and were sometimes contradictory. Thus, they question the validity of measurement methods and provide the opportunity to discuss the objective physical activity of people with CLBP.ConclusionsAccelerometers have the potential to monitor physical performance in people with CLBP; however, important technical limitations must be overcome.

Potassium 6-oxo-7,13,16,22-tetraazatetracyclo[12.6.2.18,12.017,21]tricosa-1(20),8(23),9,11,14,16,18,21-octaen-2-yne-15-carboxylate was synthesized through a multi-step pathway, starting from commercially available 3-iodo-1,2-phenylenediamine. Structure characterization of this new substituted macrocyclic quinoxaline compound was achieved using 1H NMR, 13C NMR, and HRMS spectral analysis. This new macrocyclic derivative demonstrated submicromolar potency on both Pim-1 and Pim-2 isoforms, with an interesting selectivity profile against a selected panel of human kinases.

TOPOVIBL and REC114 are required for meiotic DNA double-strand breaks (DSBs). This study shows that TOPOVIBL forms a complex with REC114 and mice carrying mutations that disrupt the interaction show DSB defects with distinct outcomes in males and females.

ABSTRACT Eimeria tenella is an obligate intracellular parasite responsible for avian coccidiosis. Like other apicomplexan parasites, such as Toxoplasma gondii, cell invasion and intracellular development rely on apical organelle content discharge, named micronemes and rhoptries. Some rhoptry (ROP) kinases (ROPK) are key virulence factors in T. gondii. To date, among the 28 ropk genes carried by E. tenella, only two to four were confirmed by proteomic analysis or immunostaining to be expressed at the sporozoite stage. We have previously shown that EtROP1 is implicated in the inhibition of host cell apoptosis by interacting with the cellular p53. This work functionally described the second ROP kinase expressed at the sporozoite stage in E. tenella. EtROP2 is an active kinase that phosphorylates cell substrates of approximately 50 kDa. Its overexpression leads to the shortening of the prepatent period and to the early development of first-generation schizonts. Conduction of RNA sequencing analysis and reverse transcriptase quantitative PCR (RT-qPCR) on the host cell allowed us to identify the mitogen-activated protein kinase (MAPK) pathway and the transcription factor cFos to be upregulated by EtROP2. We also showed by immunofluorescence assay that the active kinase EtROP2 is implicated in the p38 MAPK pathway activation. We established here that EtROP2 activates the p38 MAPK pathway through a direct or indirect phosphorylation, leading to the overexpression of the master transcription factor cFos known to be implicated in E. tenella development. IMPORTANCE Rhoptries are specialized secretory organelles found in zoite stages of apicomplexan parasites. In addition to well-conserved rhoptry neck proteins, their protein consists mostly of kinase proteins, highly divergent from eukaryotic kinases. Some of those kinases are described as major virulence factors in Toxoplasma gondii, secreted into the host cell to hijack signaling pathways. Most of those kinases remain to be characterized in Eimeria tenella. Deciphering their cellular function is a prerequisite to supporting their relevance as a druggable target in development of new means of Eimeria tenella control. Secreted divergent kinases that interact with host cell partners to modulate pathways are good candidates, as they coevolve with their host targets to ensure their function within the host and are less prone to mutations that would lead to drug resistance. The absence of any orthologous kinase in host cells makes these parasite kinases a promising drug target candidate.

Evidence suggests that whole-body angular momentum (WBAM) is a highly controlled mechanical variable for performing our daily motor activities safely and efficiently. Recent findings have revealed that, compared to young adults, older adults exhibit larger range of WBAM during various motor tasks, such as walking and stepping. However, it remains unclear whether these age-related changes are ascribed to a poorer control of WBAM with age or not. The purpose of the present study was to examine the effect of normal aging on WBAM control during stepping. Twelve young adults and 14 healthy older adults performed a series of volitional stepping at their preferred selected speed. An Uncontrolled Manifold (UCM) analysis was conducted to explore the presence of synergies among the angular momenta of the body segments (elemental variables) to control WBAM (performance variable); i.e., to stabilize or destabilize it. Results revealed the existence of a stronger synergy destabilizing the WBAM in the sagittal-plane older adults compared to young adults during stepping, while there was no difference between the two groups in the frontal and transversal planes. Although older participants also had a larger range of WBAM in the sagittal plane compared to young adults, we found no significant correlation between synergy index and the range of WBAM in the sagittal plane. We concluded that the age-related changes in WBAM during stepping are not ascribed to alterations in the ability to control this variable with aging.

Abstract Hemodialysis (HD) patients are at risk for severe COVID-19 and cannot comply with social distancing. SARS-COV2 seroprevalence in French patients and caregivers after the first wave of COVID-19 is unknown. SeroCOVIDial is a prospective study conducted between June and December 2020. SARS-COV2 seroprevalence was evaluated by a rapid serological test (BIOSYNEX) in HD patients and caregivers, and the presence or not of anti-SARS-COV2 neutralizing or non-neutralizing antibodies in patients was also determined by ELISA and seroneutralization. In June 2020, 451 HD patients and 238 caregivers were included. Overall SARS-COV2 seroprevalence was 8.4% (patients) and 6.7% (caregivers), and was 87.1% (patients) and 90.0% (caregivers) in participants with a previously documented SARS-COV2 infection. Overall seroprevalence reached 13.8% (patients) and 12.6% (caregivers) following the second epidemic wave. During the follow-up, 38 (8.4%) patients died (9 of COVID-19). Among the 44 (10.6%) patients who became infected, only two were seropositive at M0. The levels of anti-SARS-COV2 antibodies decreased over time in patients and caregivers. The BIOSYNEX test showed 82.9% sensitivity and 97.7% specificity. Prevalence of anti-SARS-COV2 antibodies was low in HD patients and caregivers after the first epidemic wave but rose after the second wave. A rapid serological test showed good performances and could be useful for future monitoring of anti-SARS-COV2 antibodies.

IntroductionKidney transplant recipients (KTRs) are at high risk of severe COVID-19, even when they are fully vaccinated. Additional booster vaccinations or passive immunization with prophylactic monoclonal antibodies are recommended to increase their protection against severe COVID-19.MethodsHere, we describe the neutralization of SARS-CoV-2 Delta, Omicron BA.1, BA.2, BA.4, and BA.5 variants, firstly by 39 serum samples from vaccinated KTRs exhibiting anti-spike antibody concentrations ≥264 binding antibody units (BAU)/mL and, secondly, by tixagevimab/cilgavimab.ResultsNo neutralization was observed for 18% of the KTRs, while serum from only 46% of patients could neutralize the five variants. Cross-neutralization of the Delta and Omicron variants occurred for 65–87% of sera samples. The anti-spike antibody concentration correlated with neutralization activity for all the variants. The neutralization titers against the Delta variant were higher in vaccinated KTRs who had previously presented with COVID-19, compared to those KTRs who had only been vaccinated. Breakthrough infections occurred in 39% of the KTRs after the study. Tixagevimab/cilgavimab poorly neutralizes Omicron variants, particularly BA.5, and does not neutralize BQ.1, which is currently the most prevalent strain.DiscussionAs a result, sera from seropositive vaccinated KTRs had poor neutralization of the successive Omicron variants. Several Omicron variants are able to escape tixagevimab/cilgavimab.

High dose methotrexate (HD-MTX) based chemoimmunotherapy is a central part of the standard approach to treatment of primary central nervous system lymphoma (PCNSL). Renal dysfunction leads to delayed MTX complete elimination and critical MTX concentration. Despite the recommendations, hemodialysis status should not exclude HD-MTX.We report the case of a 64 years old woman on chronic hemodialysis with PCNSL successfully treated with HD-MTX-based chemoimmunotherapy with an adjusted dose of 100 mg/m2, instead of the usual dose of 3500 mg/m2, and daily hemodialysis started 24 h later. The patient had no significant toxicity and was in complete remission at 1 year after the end of the treatment.We argue that ESRD is not an absolute pitfall to the use of HD-MTX for hematological malignancies. Experts should consider the use of adjusted dose at 100 mg/m2 as a viable therapeutic modality in ESRD patients. Resumen: La quimioinmunoterapia basada en una dosis elevada de metotrexato (HD-MTX) es una parte central del enfoque terapéutico estándar del linfoma primario del sistema nervioso central (PCNSL). La insuficiencia renal causa la demora de la eliminación completa de MTX, así como la concentración crítica del mismo. A pesar de las recomendaciones, el estatus de hemodiálisis no debería excluir la HD-MTX.Reportamos el caso de una mujer de 64 años con PCNSL y tratamiento de hemodiálisis crónica que fue exitosamente tratada con quimioinmunoterapia basada en HD-MTX con una dosis ajustada de 100 mg/m2, en lugar de la dosis habitual de 3.500 mg/m2, iniciándose la hemodiálisis diaria al cabo de 24 h. La paciente no reflejó toxicidad significativa y experimentó remisión completa al cabo de un año desde la finalización del tratamiento.Nosotros argumentamos que la enfermedad renal en etapa terminal (ESRD) no constituye un escollo en absoluto para utilizar la HD-MTX para neoplasias hematológicas. Los expertos deberían considerar el uso de una dosis ajustada a 100 mg/m2 como modalidad terapéutica viable en los pacientes de ESRD.

Food fortification is an effective approach to improve vitamin D (VD) concentrations in foods. Eggs are a useful food vehicle for enrichment with VD via its hydroxylated metabolite, 25-hydroxyvitamin D (25-D3), in hen feed. This study determined the impact of time of lay, storage conditions (ambient and refrigeration) and common cooking methods (boiling, frying, scrambling, poaching and microwaving) on the vitamin D metabolite concentration of eggs enriched with 25-D3. Processed samples were freeze-dried and analysed for D3 and 25-D3 using an HPLC-MS(/MS) method. The results indicated that storage and cooking practices influence VD metabolites, with 25-D3 showing true retention of 72–111% and concentrations of 0.67–0.96 µg/100 g of whole egg. Vitamin D3 showed true retention of 50–152% and concentrations of 0.11–0.61 µg/100 g of whole egg. Depending on the storage and method of cooking applied, the calculated total VD activity of enriched eggs ranged from 3.45 to 5.43 µg/100 g of whole egg and was 22–132% higher in comparison to standardised VD content for non-enriched British eggs. The study suggests that 25-D3 is a stable metabolite in eggs following storage and cooking, and that 25-D3-enriched eggs may serve as a potent dietary source of VD.

Kinematic analysis of the upper extremity can be useful to assess the performance and skill levels of athletes during combat sports such as boxing. Although marker-based approach is widely used to obtain kinematic data, it is not suitable for “in the field” activities, i.e., when performed outside the laboratory environment. Markerless video-based systems along with deep learning-based pose estimation algorithms show great potential for estimating skeletal kinematics. However, applicability of these systems in assessing upper-limb kinematics remains unexplored in highly dynamic activities. This study aimed to assess kinematics of the upper limb estimated with a markerless motion capture system (2D video cameras along with commercially available pose estimation software Theia3D) compared to those measured with marker-based system during “in the field” boxing. A total of three elite boxers equipped with retroreflective markers were instructed to perform specific sequences of shadow boxing trials. Their movements were simultaneously recorded with 12 optoelectronic and 10 video cameras, providing synchronized data to be processed further for comparison. Comparative assessment showed higher differences in 3D joint center positions at the elbow (more than 3 cm) compared to the shoulder and wrist (

Abstract Background Muscle strength decreases as kidney failure progresses. Low muscle strength affects more than 50% of hemodialysis patients and leads to daily life activities impairment. In the general population, numerous studies have linked low 25OH-vitamin D (25OHD) concentrations to the loss of the muscle strength and low physical performances. Data on native vitamin D and muscle function are scarce in the chronic kidney disease (CKD) population, but low 25OHD levels have been associated with poor muscle strength. We present in this article the protocol of an ongoing study named VITADIAL testing if cholecalciferol supplementation in hemodialysis patients with low 25OHD improves their muscle strength. Methods/design VITADIAL is a prospective open randomized French multicenter study. All patients will have 25OHD levels ≤50nmol/L at randomization. One group will receive 100,000 UI cholecalciferol once a month during 6 months; the other group will receive no treatment during 6 months. In order to randomize patients with 25OHD ≤50nmol/L, supplemented patients will undergo a 3 months wash-out period renewable 3 times (maximum of 12 months wash-out) until 25OHD reaches a level ≤50nmol/L. The main objective of this study is to analyze if a 6-month period of oral cholecalciferol (i.e., native vitamin D) supplementation improves muscle strength of hemodialysis patients with low 25OHD vitamin D levels. Muscle strength will be assessed at 0, 3, and 6 months, by handgrip strength measured with a quantitative dynamometer. Secondary objectives are (1) to analyze 25OHD plasma levels after vitamin D wash-out and/or supplementation, as well as factors associated with 25OHD lowering speed during wash-out, and (2) to analyze if this supplementation improves patient’s autonomy, reduces frailty risk, and improves quality of life. Fifty-four patients are needed in each group to meet our main objective. Discussion In the general population, around 30 randomized studies analyzed the effects of vitamin D supplementation on muscle strength. These studies had very different designs, sizes, and studied population. Globally, these studies and the meta-analysis of studies favor a beneficial effect of vitamin D supplementation on muscle strength, but this effect is mainly found in the subgroup of aged patients and those with the lowest 25OHD concentrations at inclusion. We reported a positive independent association between 25OHD and handgrip strength in a population of 130 hemodialysis patients in a dose-dependent manner. In our cohort, a plateau effect was observed above 75 nmol/L. Only two randomized studies analyzed the effect of native vitamin D supplementation on muscle strength in hemodialysis patients, but unfortunately, these two studies were underpowered. VITADIAL is a trial specifically designed to assess whether cholecalciferol might benefit to hemodialysis patient’s muscle strength. Trial registration ClinicalTrials.gov NCT04262934 . Registered on 10 February 2020 - Retrospectively registered.

Abstract Background Rural-urban health care disparities are an important topic in health services research. Hence, developing valid and reliable tools to measure rurality is needed to support high quality research. However, Japan, has no index to measure rurality for health care research. In this study, we conducted a systematic scoping review to identify the important factors and methodological approaches to consider in a rurality index to inform the development of a rurality index for Japan. Methods For our review, we searched six bibliographic databases (MEDLINE, PubMed, CINAHIL, ERIC, Web of Science and the Grey Literature Report) and official websites of national governments such as Government and Legislative Libraries Online Publications Portal (GALLOP), from 1 January 1989 to 31 December 2018. We extracted relevant variables used in the development of rurality indices, the formulas used to calculate indices, and any measures for reliability and validity of these indices. Results We identified 17 rurality indices from 7 countries. These indices were primarily developed to assess access to health care or to determine eligibility for incentives for health care providers. Frequently used factors in these indices included population size/density and travel distance/time to emergency care or referral centre. Many indices did not report reliability or validity measures. Conclusions While the concept of rurality and concerns about barriers to access to care for rural residents is shared by many countries, the operationalization of rurality is highly context-specific, with few universal measures or approaches to constructing a rurality index. The results will be helpful in the development of a rurality index in Japan and in other countries.

Abstract Background Rhabdomyolysis is a life-threatening disease that can lead to severe hyperkalemia, acute kidney injury (AKI) and hypovolemic shock. The predictive factors of AKI and acute to chronic kidney disease (CKD) transition remain poorly described. Methods This multicenter retrospective study enrolled 387 patients with severe rhabdomyolysis (CPK > 5000 U/L). Primary end-point was the development of severe AKI, defined as stage 2 or 3 of KDIGO classification. Secondary end-points included the incidence of AKI to CKD transition. Results Among the 387 patients, 315 (81.4%) developed AKI, including 171 (44.1%) with stage 3 AKI and 103 (26.6%) requiring RRT. Stage 2–3 AKI was strongly correlated with serum phosphate, potassium and bicarbonate at admission, as well as myoglobin over 8000 U/L and the need for mechanical ventilation. 42 patients (10.8%) died before day 28. In the 80 patients with available eGFR values both before and 3 months after the rhabdomyolysis, the decrease in eGFR (greater than 20 mL/min/1.73 m2 in 23 patients; 28.8%) was correlated to the severity of the AKI and serum myoglobin levels > 8000 U/L at admission. Conclusions Severe rhabdomyolysis leads to AKI in most patients admitted to an ICU. Mechanical ventilation and severity of the rhabdomyolysis, including myoglobin level, are associated with the risk of stage 2–3 AKI. The long-term renal decline is correlated to serum myoglobin at admission.

Abstract Device‐encapsulated human stem cell‐derived pancreatic endoderm (PE) can generate functional β‐cell implants in the subcutis of mice, which has led to the start of clinical studies in type 1 diabetes. Assessment of the formed functional β‐cell mass (FBM) and its correlation with in vivo metabolic markers can guide clinical translation. We recently reported ex vivo characteristics of device‐encapsulated human embryonic stem cell‐derived (hES)‐PE implants in mice that had established a metabolically adequate FBM during 50‐week follow‐up. Cell suspensions from retrieved implants indicated a correlation with the number of formed β cells and their maturation to a functional state comparable to human pancreatic β cells. Variability in metabolic outcome was attributed to differences in number of PE‐generated β cells. This variability hinders studies on processes involved in FBM‐formation. This study reports modifications that reduce variability. It is undertaken with device‐encapsulated human induced pluripotent stem cell‐derived‐PE subcutaneously implanted in mice. Cell mass of each cell type was determined on intact tissue inside the device to obtain more precise data than following isolation and dispersion. Implants in a preformed pouch generated a glucose‐controlling β‐cell mass within 20 weeks in over 60% of recipients versus less than 20% in the absence of a pouch, whether the same or threefold higher cell dose had been inserted. In situ analysis of implants indicated a role for pancreatic progenitor cell expansion and endocrine differentiation in achieving the size of β‐ and α‐cell mass that correlated with in vivo markers of metabolic control. Stem Cells Translational Medicine 2019;8:1296&1305

Abstract Background CDK10 is a poorly known cyclin M (CycM)‐dependent kinase. Loss‐of‐function mutations in the genes encoding CycM or CDK10 cause, respectively, STAR or Al Kaissi syndromes, which present a constellation of malformations and dysfunctions. Most reported mutations abolish gene expression, but two mutations found in 3’ exons could allow the expression of CDK10 and CycM truncated variants. Methods We built a structural model that predicted a preserved ability of both variants to form a CDK10/CycM heterodimer. Hence, we functionally characterized these two truncated variants by determining their capacity to heterodimerize and form an active protein kinase when expressed in insect cells, by examining their two‐hybrid interaction profiles when expressed in yeast, and by observing their expression level and stability when expressed in human cells. Results Both truncated variants retain their ability to form a CDK10/CycM heterodimer. While the CycM variant partially activates CDK10 activity in vitro, the CDK10 variant remains surprisingly inactive. Expression in human cells revealed that the CDK10 and CycM variants are strongly and partially degraded by the proteasome, respectively. Conclusion Our results point to a total loss of CDK10/CycM activity in the Al Kaissi patient and a partial loss in the STAR patients.

Three series of our lead CLK1 inhibitor DB18 have been designed, synthetized and tested against CLKs and DYRK1A kinases. Their cytotoxicity was subsequently measured on seven representative cancer cell lines. Guided by docking experiments, we focused on the less constrained part of the scaffold, and showed that drastically different substituents can be tolerated here. This work ended with the discovery of another promising derivative 12g, with IC50 = 0.004 µM in the inhibition of HsCLK1 and IC50 = 3.94 µM for the inhibition of HsDYRK1A. The SAR results are discussed in the light of extensive molecular modeling analyses. Finally, a kinome scan (463 human kinases) confirmed the outstanding selectivity of our lead compound DB18, suggesting that this scaffold is of prominent interest for selective CLK inhibitors. Altogether, these results pave the way for the development of inhibitors with novel selectivities in this family of kinases.

Summary: Basal breast cancer is associated with younger age, early relapse, and a high mortality rate. Here, we use unbiased droplet-based single-cell RNA sequencing (RNA-seq) to elucidate the cellular basis of tumor progression during the specification of the basal breast cancer subtype from the luminal progenitor population in the MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mammary tumor model. We find that basal-like cancer cells resemble the alveolar lineage that is specified upon pregnancy and encompass the acquisition of an aberrant post-lactation developmental program of involution that triggers remodeling of the tumor microenvironment and metastatic dissemination. This involution mimicry is characterized by a highly interactive multicellular network, with involution cancer-associated fibroblasts playing a pivotal role in extracellular matrix remodeling and immunosuppression. Our results may partially explain the increased risk and poor prognosis of breast cancer associated with childbirth.

Meiotic recombination starts with the formation of DNA double-strand breaks (DSBs) at specific genomic locations that correspond to PRDM9-binding sites. The molecular steps occurring from PRDM9 binding to DSB formation are unknown. Using proteomic approaches to find PRDM9 partners, we identified HELLS, a member of the SNF2-like family of chromatin remodelers. Upon functional analyses during mouse male meiosis, we demonstrated that HELLS is required for PRDM9 binding and DSB activity at PRDM9 sites. However, HELLS is not required for DSB activity at PRDM9-independent sites. HELLS is also essential for 5-hydroxymethylcytosine (5hmC) enrichment at PRDM9 sites. Analyses of 5hmC in mice deficient for SPO11, which catalyzes DSB formation, and in PRDM9 methyltransferase deficient mice reveal that 5hmC is triggered at DSB-prone sites upon PRDM9 binding and histone modification, but independent of DSB activity. These findings highlight the complex regulation of the chromatin and epigenetic environments at PRDM9-specified hotspots.

Cyclin-dependent kinases (CDKs) constitute a family of 20 serine/threonine protein kinases that play pivotal roles in the regulation of numerous important molecular and cellular processes. CDKs have long been considered promising therapeutic targets in a variety of pathologies, and the recent therapeutic success of CDK4/6 inhibitors in breast cancers has renewed interest in their therapeutic potential. Small-molecule inhibitors have been identified for every human CDK, except for CDK10. The only recent discovery of an activating cyclin (CycM) for CDK10 enabled us to identify its first phosphorylation substrates and gain insights into its biological functions. Yet, our knowledge of this kinase remains incomplete, despite it being the only member of its family that causes severe human developmental syndromes, when mutated either on the cyclin or the CDK moiety. CDK10 small-molecule inhibitors would be useful in exploring the functions of this kinase and gauging its potential as a therapeutic target for some cancers. Here, we report the identification of an optimized peptide phosphorylation substrate of CDK10/CycM and the development of the first homogeneous, miniaturized CDK10/CycM in vitro kinase assay. We reveal the ability of known CDK inhibitors, among which clinically tested SNS-032, riviciclib, flavopiridol, dinaciclib, AZD4573 and AT7519, to potently inhibit CDK10/CycM. We also show that NVP-2, a strong, remarkably selective CDK9 inhibitor is an equally potent CDK10/CycM inhibitor. Finally, we validate this kinase assay for applications in high-throughput screening campaigns to discover new, original CDK10 inhibitors.

Introduction: There is a need for treatment guidelines and prognostic factor identification in children with primary IgA nephropathy. We analyzed the causative effect of steroids and the applicability of the Oxford classification. Methods: A total of 82 consecutive children (mean 10.6 years; median follow-up 3.3 years) were reviewed; 21 patients (25.6%) presented with acute kidney injury, and 6 (7.3%) with nephrotic syndrome. Renal biopsies were scored for Oxford classification and podocytopathic features in 2 groups: a group treated with steroid therapy (some in association with cyclophosphamide) and supportive care (renin angiotensin system blockade) and a group treated by supportive care alone. Results: The 2 groups were not comparable because baseline clinical data were different. Estimated glomerular filtration rate (eGFR) in immunosupressive group significantly improved between M0 (at onset) and M6 (6 months after treatment) from 89.9 [61.2–114.5] to 110.5 [93.7–120] ml/min per 1.73 m2, P

Summary: Human stem cells represent a potential source for implants that replace the depleted functional beta cell mass (FBM) in diabetes patients. Human embryonic stem cell-derived pancreatic endoderm (hES-PE) can generate implants with glucose-responsive beta cells capable of reducing hyperglycemia in mice. This study with device-encapsulated hES-PE (4 × 106 cells/mouse) determines the biologic characteristics at which implants establish metabolic control during a 50-week follow-up. A metabolically adequate FBM was achieved by (1) formation of a sufficient beta cell number (>0.3 × 106/mouse) at >50% endocrine purity and (2) their maturation to a functional state comparable with human pancreatic beta cells, as judged by their secretory responses during perifusion, their content in typical secretory vesicles, and their nuclear NKX6.1-PDX1-MAFA co-expression. Assessment of FBM in implants and its correlation with in vivo metabolic markers will guide clinical translation of stem cell-derived grafts in diabetes. : In this article, Pipeleers and colleagues demonstrate that subcutaneous implants of device-encapsulated human stem cell-derived pancreatic endoderm can generate a functional beta cell mass that establishes sustained glucose control in mice. They identified their biologic characteristics and correlation with in vivo outcome. Data and methods are expected to guide clinical translation to beta cell replacement therapy in diabetes. Keywords: stem cell-derived pancreatic endoderm, stem cell therapy, diabetes, encapsulation, differentiation, functional maturation, functional beta cell mass, metabolic control

Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[b,d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC50 value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure–activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and Galleria mellonella larvae testing for acute toxicity.

The purpose of this work is to investigate the protein kinase inhibitory activity of constituents from Acacia auriculiformis stem bark. Column chromatography and NMR spectroscopy were used to purify and characterize betulin from an ethyl acetate soluble fraction of acacia bark. Betulin, a known inducer of apoptosis, was screened against a panel of 16 disease-related protein kinases. Betulin was shown to inhibit Abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase, casein kinase 1ε (CK1ε), glycogen synthase kinase 3α/β (GSK-3 α/β), Janus kinase 3 (JAK3), NIMA Related Kinase 6 (NEK6), and vascular endothelial growth factor receptor 2 kinase (VEGFR2) with activities in the micromolar range for each. The effect of betulin on the cell viability of doxorubicin-resistant K562R chronic myelogenous leukemia cells was then verified to investigate its putative use as an anti-cancer compound. Betulin was shown to modulate the mitogen-activated protein (MAP) kinase pathway, with activity similar to that of imatinib mesylate, a known ABL1 kinase inhibitor. The interaction of betulin and ABL1 was studied by molecular docking, revealing an interaction of the inhibitor with the ABL1 ATP binding pocket. Together, these data demonstrate that betulin is a multi-target inhibitor of protein kinases, an activity that can contribute to the anticancer properties of the natural compound and to potential treatments for leukemia.

Abstract Background Sickle cell trait is not completely benign, and some renal complications can occur. The baseline rate of admission for gross hematuria in normal males carrying the sickle cell trait is 2%. Case presentation A 35-year-old non-smoking African man experienced a 2-week history of painless, profuse and persistent gross hematuria. Laboratory tests showed normal renal function, hematuria and mild proteinuria. Abdominal ultrasonography and computed tomography angiography revealed no renal abnormalities; the bladder appeared pristine under cystoscopy. The diagnosis of sickle cell trait associated with gross hematuria was made using hemoglobin electrophoresis; renal biopsy and its complications were avoided. Urine was clear after 2 weeks of oral hydration and gamma epsilon-aminocaproic acid. Conclusion Hemoglobin electrophoresis should be performed in cases of gross hematuria. Coupled with other non-invasive evaluation, this could avoid renal biopsy and its associated complications.

Proviral integration site for Moloney murine leukemia virus (Pim)-1/2 kinase overexpression has been identified in a variety of hematologic (e.g., multiple myeloma or acute myeloid leukemia (AML)) and solid (e.g., colorectal carcinoma) tumors, playing a key role in cancer progression, metastasis, and drug resistance, and is linked to poor prognosis. These kinases are thus considered interesting targets in oncology. We report herein the design, synthesis, structure–activity relationships (SAR) and in vitro evaluations of new quinoxaline derivatives, acting as dual Pim1/2 inhibitors. Two lead compounds (5c and 5e) were then identified, as potent submicromolar Pim-1 and Pim-2 inhibitors. These molecules were also able to inhibit the growth of the two human cell lines, MV4-11 (AML) and HCT-116 (colorectal carcinoma), expressing high endogenous levels of Pim-1/2 kinases.

The kinesin-3 family member Unc-104/KIF1A is required for axonal transport of many presynaptic components to synapses, and mutation of this gene results in synaptic dysfunction in mice, flies and worms. Our studies at the Drosophila neuromuscular junction indicate that many synaptic defects in unc-104-null mutants are mediated independently of Unc-104’s transport function, via the Wallenda (Wnd)/DLK MAP kinase axonal damage signaling pathway. Wnd signaling becomes activated when Unc-104’s function is disrupted, and leads to impairment of synaptic structure and function by restraining the expression level of active zone (AZ) and synaptic vesicle (SV) components. This action concomitantly suppresses the buildup of synaptic proteins in neuronal cell bodies, hence may play an adaptive role to stresses that impair axonal transport. Wnd signaling also becomes activated when pre-synaptic proteins are over-expressed, suggesting the existence of a feedback circuit to match synaptic protein levels to the transport capacity of the axon.

In the case of disequilibrium, the capacity to step quickly is critical to avoid falling for elderly. This capacity can be simply assessed through the choice stepping reaction time test (CSRT), where elderly fallers (F) take longer to step than elderly non-fallers (NF). However, reasons why elderly F elongate their stepping time remain unclear. The purpose of this study is to assess the characteristics of anticipated postural adjustments (APA) that elderly F develop in a stepping context and their consequences on the dynamic stability. 44 community-dwelling elderly subjects (20 F and 22 NF) performed a CSRT where kinematics and ground reaction forces were collected. Variables were analyzed using two-way repeated measures ANOVAs. Results for F compared to NF showed that stepping time is elongated, due to a longer APA phase. During APA, they seem to use two distinct balance strategies, depending on the axis: in the anteroposterior direction, we measured a smaller backward movement and slower peak velocity of the center of pressure (CoP); in the mediolateral direction, the CoP movement was similar in amplitude and peak velocity between groups but lasted longer. The biomechanical consequence of both strategies was an increased margin of stability (MoS) at foot-off, in the respective direction. By elongating their APA, elderly F use a safer balance strategy that prioritizes dynamic stability conditions instead of the objective of the task. Such a choice in balance strategy probably comes from muscular limitations and/or a higher fear of falling and paradoxically indicates an increased risk of fall.

Human balance recovery from external disturbances is a complex process, and simulating it remains an open challenge. In particular, there still is a need for a comprehensive numerical tool capable of predicting the outcome of a balance perturbation, including in particular the three elementary recovery strategies: ankle, hip and stepping with variable step duration. In order to fill this gap we further developed a previously proposed multiple step balance recovery prediction tool to include the use of the hip strategy and variable step duration. Simulated recovery reactions are compared against observations from different experimental situations from the literature. Reasonable accuracy in terms of step positions and durations were obtained for these different situations using a single set of controller parameters. Moreover, variations in the use of the hip strategy and the step duration between situations were consistent with biomechanical observations. Such a model could be useful to better understand the balance recovery mechanisms, and could also be used to identify potentially hazardous situations.

Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.

Many therapies using mesenchymal stem cells (MSC) rely on their ability to produce and release paracrine signals with chemotactic and pro-angiogenic activity. These characteristics, however, are mostly studied under standard in vitro culture conditions. In contrast, various novel cell-based therapies imply pre-seeding MSC into bio-artificial scaffolds. Here we describe human bone marrow-derived MSC seeded in Integra matrices, a common type of scaffold for dermal regeneration (SDR). We show and measured the distribution of MSC within the SDR, where cells clearly establish physical interactions with the scaffold, exhibiting constant metabolic activity for at least 15 days. In the SDR, MSC secrete VEGF and SDF-1 and induce transwell migration of CD34+ hematopoietic/endothelial progenitor cells, which is inhibited in the presence of a CXCR4/SDF-1 antagonist. MSC in SDR respond to hypoxia by altering levels of angiogenic signals such as Angiogenin, Serpin-1, uPA and IL-8. Finally, we show that MSC-containing SDR that have been pre-incubated in hypoxia show higher infiltration of endothelial cells after implantation into immune deficient mice. Our data show that MSC are fully functional ex vivo when implanted into SDR. In addition, our results strongly support the notion of hypoxic pre-conditioning MSC-containing SDR, in order to promote angiogenesis in the wounds.

Genome duplication requires the coordinated activity of a multi-component machine, the replisome. In contrast to the background of metabolic diversity across the bacterial domain, the composition and architecture of the bacterial replisome seems to have suffered few changes during evolution. This immutability underlines the replisome’s efficiency in copying the genome. It also highlights the success of various strategies inherent to the replisome for responding to stress and avoiding problems during critical stages of DNA synthesis. Here we summarise current understanding of bacterial replisome architecture and highlight the known variations in different bacterial taxa. We then look at the mechanisms in place to ensure that the bacterial replisome is assembled appropriately on DNA, kept together during elongation, and disassembled upon termination. We put forward the idea that the architecture of the replisome may be more flexible that previously thought and speculate on elements of the replisome that maintain its stability to ensure a safe journey from origin to terminus.

This paper outlines the way in which various concepts measuring doctor reactions to their jobs and careers (e.g., satisfaction, burnout, etc.) have been developed. The variety of measures, methods, and models reflect differing disciplinary and theoretical approaches and research traditions. In order to identify productive ways to advance the field, this paper presents a proposal for how multi-disciplinary, cross-national comparative research might be conducted to resolve some of the issues linking medical care organization, physicians' experiences, and patient outcomes. In seeking buy-in from stakeholders, researchers need to be cognizant that various ideologies and agendas shape the nature of the concerns that these interest groups (e.g., professional associations, clinical managers, payers, patient advocates, etc.) have about physician satisfaction, its precursors, and its consequences. Keywords: Physician satisfaction, burnout, measurement, methodology, medical autonomy

Little is known about differences between induced pluripotent stem cells produced from tissues originating from the same germ layer. We have generated human myoblast-derived iPS cells by retroviral transduction of human primary myoblasts with the OCT3/4, SOX2, KLF4 and MYC coding sequences and compared them to iPS produced from human primary fibroblasts. When cultivated in vitro, these iPS cells proved similar to human embryonic stem cells in terms of morphology, expression of embryonic stemness markers and gene promoter methylation patterns. Embryonic bodies were derived that expressed endodermal, mesodermal as well as ectodermal markers. A comparative analysis of transcription patterns revealed significant differences in the gene expression pattern between myoblast- and fibroblast-derived iPS cells. However, these differences were reduced in the mesenchymal stem cells derived from the two iPS cell types were compared.