Prodrug activation in malaria parasites mediated by an imported erythrocyte esterase, acylpeptide hydrolase (APEH).

The continued emergence of antimalarial drug resistance highlights the need to develop new antimalarial therapies. Unfortunately, new drug development is often hampered by poor drug-like properties of lead compounds. Prodrugging temporarily masks undesirable compound features, improving bioavailability and target penetration. We have found that lipophilic diester prodrugs of phosphonic acid antibiotics, such as fosmidomycin, exhibit significantly higher antimalarial potency than their parent compounds (1). However, the activating enzymes for these prodrugs were unknown. Here, we show that an erythrocyte enzyme, acylpeptide hydrolase (APEH) is the major activating enzyme of multiple lipophilic ester prodrugs. Surprisingly, this enzyme is taken up by the malaria parasite, Plasmodium falciparum, where it localizes to the parasite cytoplasm and retains enzymatic activity. Using a novel fluorogenic ester library, we characterize the structure activity relationship of APEH, and compare it to that of P. falciparum esterases. We show that parasite-internalized APEH plays an important role in the activation of substrates with branching at the alpha carbon, in keeping with its exopeptidase activity. Our findings highlight a novel mechanism for antimicrobial prodrug activation, relying on a host-derived enzyme to yield activation at a microbial target. Mutations in prodrug activating enzymes are a common mechanism for antimicrobial drug resistance (2-4). Leveraging an internalized host enzyme would circumvent this, enabling the design of prodrugs with higher barriers to drug resistance.

Isotopic Control of the Boron-Vacancy Spin Defect in Hexagonal Boron Nitride.

We report on electron spin resonance (ESR) spectroscopy of boron-vacancy (V_{B}^{-}) centers hosted in isotopically engineered hexagonal boron nitride (hBN) crystals. We first show that isotopic purification of hBN with ^{15}N yields a simplified and well-resolved hyperfine structure of V_{B}^{-} centers, while purification with ^{10}B leads to narrower ESR linewidths. These results establish isotopically purified h^{10}B^{15}N crystals as the optimal host material for future use of V_{B}^{-} spin defects in quantum technologies. Capitalizing on these findings, we then demonstrate optically induced polarization of ^{15}N nuclei in h^{10}B^{15}N, whose mechanism relies on electron-nuclear spin mixing in the V_{B}^{-} ground state. This work opens up new prospects for future developments of spin-based quantum sensors and simulators on a two-dimensional material platform.

Optically Active Spin Defects in Few-Layer Thick Hexagonal Boron Nitride.

Optically active spin defects in hexagonal boron nitride (hBN) are promising quantum systems for the design of two-dimensional quantum sensing units offering optimal proximity to the sample being probed. In this Letter, we first demonstrate that the electron spin resonance frequencies of boron vacancy centers (V_{B}^{-}) can be detected optically in the limit of few-atomic-layer thick hBN flakes despite the nanoscale proximity of the crystal surface that often leads to a degradation of the stability of solid-state spin defects. We then analyze the variations of the electronic spin properties of V_{B}^{-} centers with the hBN thickness with a focus on (i) the zero-field splitting parameters, (ii) the optically induced spin polarization rate and (iii) the longitudinal spin relaxation time. This Letter provides important insights into the properties of V_{B}^{-} centers embedded in ultrathin hBN flakes, which are valuable for future developments of foil-based quantum sensing technologies.

The Protection Gap - Diagnosis, Treatment Status, and Disease Control for People with Diabetes and Hypertension in the US-Affiliated Pacific Islands.

Hypertension and diabetes are major causes of disability and mortality in the US-Affiliated Pacific Islands (USAPI). Control of these conditions has the potential to avert much of the burden of non-communicable diseases in the region. To realize this potential, people living with hypertension and diabetes must be identified and receive treatment of sufficient intensity to control their blood pressure and blood glucose. Data from recent cross-sectional surveys conducted in 5 jurisdictions-Pohnpei, Palau, Kosrae, Marshall Islands and American Samoa-were used to estimate the adult prevalence of hypertension and diabetes as well as diagnosis awareness, treatment, and control status of the adults with these conditions. In addition to traditional prevalence indicators, the authors provide a novel presentation of non-communicable disease (NCD) data, using the concept of "protection gaps", defined as the number of people living in a community who have an NCD for which effective control is not attained. The protection gap is determined by applying survey-derived population prevalence estimates to the community's population size using census data. The protection gap is further divided into 3 groups: (1) case-finding gap-those who are unaware of their conditions; (2) tracking and outreach gap-those who are aware of their condition but not receiving treatment; and (3) treatment efficacy gap-those who are receiving treatment but whose disease is not under control. The findings show a large protection gap, with a majority of adults living with hypertension (80.8%) and diabetes (91.6%) not having their condition under control. The case-finding gap accounts for more than half of these, followed by treatment efficacy, and tracking and outreach gaps. These findings can guide public health strategies and monitoring for control of hypertension and diabetes in the USAPI region.

Decoherence of V[Formula: see text] spin defects in monoisotopic hexagonal boron nitride.

Spin defects in hexagonal boron nitride (hBN) are promising quantum systems for the design of flexible two-dimensional quantum sensing platforms. Here we rely on hBN crystals isotopically enriched with either 10B or 11B to investigate the isotope-dependent properties of a spin defect featuring a broadband photoluminescence signal in the near infrared. By analyzing the hyperfine structure of the spin defect while changing the boron isotope, we first confirm that it corresponds to the negatively charged boron-vacancy center ([Formula: see text]). We then show that its spin coherence properties are slightly improved in 10B-enriched samples. This is supported by numerical simulations employing cluster correlation expansion methods, which reveal the importance of the hyperfine Fermi contact term for calculating the coherence time of point defects in hBN. Using cross-relaxation spectroscopy, we finally identify dark electron spin impurities as an additional source of decoherence. This work provides new insights into the properties of [Formula: see text] spin defects, which are valuable for the future development of hBN-based quantum sensing foils.

Progress and strength of response against noncommunicable diseases in the US-affiliated Pacific Island jurisdictions, 2010-2021.

Objective: To determine the effectiveness of the response to the 2010 declared regional noncommunicable diseases (NCDs) emergency in nine US-affiliated Pacific Island jurisdictions. Methods: Vital statistics and risk prevalence surveys were retrospectively reviewed using 14 standardized NCD risk, prevalence and death rate indicators to measure changes in health status over time. NCD risk and prevalence change scores were derived from subsets of these indicators, and NCD composite death rates were examined. An NCD strength-of-intervention score derived from a standardized regional monitoring tool provided measures for assessing responses aimed at curbing risk factors, prevalence and death rates. Associations between the strength-of-intervention score and changes in health status were examined. Results: Pairs of values were available for 97 of 126 individual comparisons for 14 core indicators in nine jurisdictions. The composite mean prevalence of all risk factors across the jurisdictions between baseline and follow-up (26.7% versus 24.3%, P = 0.34) and the composite mean diabetes and hypertension prevalence (28.3% versus 28.2%, P = 0.98) were unchanged, while NCD death rates increased (483.0 versus 521.9 per 100 000 per year, P < 0.01). The composite strength-of-intervention score for the region was 37.2%. Higher strength-of-intervention scores were associated with improvements in health indicators. Discussion: Despite some improvements in selected NCD indicators at the jurisdiction level, there was no significant overall change in the prevalence of risk factors, diabetes and hypertension, and death rates have continued to increase since the NCD emergency declaration. However, the adoption of public sector NCD interventions was associated with improvements in health indicators.

Innovations to maximise impact of a data for decision-making training programme in the Federated States of Micronesia.

Accurate and timely health information is an essential foundation for strengthening health systems. Data for decision making (DDM) is a training curriculum designed to enhance capacity of health department staff to capture and use high-quality data to address priority health issues. In 2013, the Pacific Public Health Surveillance Network adapted and piloted the DDM curriculum as an 'at work, from work, for work' field epidemiology training programme component for low-income and middle-income Pacific Island jurisdictions. Based on lessons learned from the pilot, we made several innovations, including delivery on-site at each district (rather than bringing trainees to a central location), conducting pre-DDM consultations and ongoing contact with health leaders across the programme, taking more care in selecting trainees and enrolling a larger cohort of students from within each health department. The decentralised programme was delivered in-country at four sites (both at national and state levels) in the Federated States of Micronesia. Following delivery, we performed an external evaluation of the programme to assess student outcomes, benefits to the health department and general programme effectiveness. Of the 48 trainees who completed all four classroom modules, 40 trainees participated in the evaluation. Thirty-two of these trainees completed the programme's capstone field project. Eighteen of these projects directly contributed to changes in legislation, revised programme budgets, changes in programme strategy to augment outreach and to target disease and risk factor 'hot spots'.

'Hybrid Survey' approach to non-communicable disease surveillance in the US-Affiliated Pacific Islands.

In 2010 the US-Affiliated Pacific Islands (USAPI) declared a regional state of health emergency due to the epidemic of non-communicable disease (NCD) and an NCD monitoring and surveillance framework was developed that includes adult NCD risk factor and disease prevalence indicators to be collected every 5 years using a population-based survey. On evaluation of existing data from adult population-based NCD surveys, it was found that there was a lack of valid, available and consistently collected data. Therefore, a new model was developed to combine various indicators and survey tools from different partner agencies into one survey. After the report was endorsed by local health leadership, a dissemination workshop was conducted. In 2015 (baseline for Hybrid Survey implementation), three out of nine jurisdictions (33.3%) had completed a population-based survey in the past 5 years. Four (44.4%) had no adult prevalence data at all, two (22.2%) had data sets from their surveys and four (44.4%) had at least two surveys ever collected that could be used for comparison. As of 2020, all nine jurisdictions have, or are in the process of completing an adult population-based survey. Eight (88.9%) have data sets from their surveys, and five (55.6%) have at least two surveys collected that can be used for comparison. This Hybrid Survey model has helped to improve adult NCD surveillance in the USAPI by more efficiently using limited resources. This model could be considered in other small island nations, or rural areas where adult NCD surveillance is challenging.

Characterization of Agfa Structurix series D4 and D3sc x-ray films in the 0.7-4.6 keV energy range.

X-ray films remain a key asset for high-resolution x-ray spectral imaging in high-energy-density experiments conducted at the National Ignition Facility (NIF). The soft x-ray Opacity Spectrometer (OpSpec) fielded at the NIF has an elliptically shaped crystal design that measures x rays in the 900-2100 eV range and currently uses an image plate as the detecting medium. However, Agfa D4 and D3sc x-ray films' higher spatial resolution provides increased spectral resolution to the data over the IP-TR image plates, driving the desire for regular use of x-ray film as a detecting medium. The calibration of Agfa D4 x-ray film for use in the OpSpec is communicated here. These calibration efforts are vital to the accuracy of the NIF opacity measurements and are conducted in a previously un-studied x-ray energy range under a new film development protocol required by NIF. The absolute response of Agfa D4 x-ray film from 705 to 4620 eV has been measured using the Nevada National Security Site Manson x-ray source. A broader range of energies was selected to compare results with previously published data. The measurements were taken using selected anodes, filters, and applied voltages to produce well-defined energy lines.

Upgrades and redesign of the National Ignition Facility's soft x-ray opacity spectrometer (OpSpec).

The soft x-ray Opacity Spectrometer (OpSpec) used on the National Ignition Facility (NIF) has recently incorporated an elliptically shaped crystal. The original OpSpec used two convex cylindrical crystals for time-integrated measurements of point-projection spectra from 540 to 2100 eV. However, with the convex geometry, the low-energy portion of the spectrum suffered from high backgrounds due to scattered x-rays as well as reflections from alternate crystal planes. An elliptically shaped crystal allows an acceptance aperture at the crossover focus between the crystal and the detector, which reduces background and eliminates nearly all reflections from alternate crystal planes. The current elliptical design is an improvement from the convex cylindrical design but has a usable energy range from 900 to 2100 eV. In addition, OpSpec is currently used on 18 NIF shots/year, in which both crystals are typically damaged beyond reuse, so efficient production of 36 crystals/year is required. Design efforts to improve the existing system focus on mounting reliability, reducing crystal strain to increase survivability between mounting and shot time, and extending the energy range of the instrument down to 520 eV. The elliptical design, results, and future options are presented.

Broad Diversity of Near-Infrared Single-Photon Emitters in Silicon.

We report the detection of individual emitters in silicon belonging to seven different families of optically active point defects. These fluorescent centers are created by carbon implantation of a commercial silicon-on-insulator wafer usually employed for integrated photonics. Single photon emission is demonstrated over the 1.1-1.55 µm range, spanning the O and C telecom bands. We analyze their photoluminescence spectra, dipolar emissions, and optical relaxation dynamics at 10 K. For a specific family, we show a constant emission intensity at saturation from 10 K to temperatures well above the 77 K liquid nitrogen temperature. Given the advanced control over nanofabrication and integration in silicon, these individual artificial atoms are promising systems to investigate for Si-based quantum technologies.

Signaling pathway deregulation and molecular alterations across pediatric medulloblastomas.

Medulloblastomas (MBs) account for 15% of brain tumors in children under the age of 15. To date, the overall 5-year survival rate for all children is only around 60%. Recent advances in cancer genomics have led to a fundamental change in medulloblastoma classification and is evolving along with the genomic discoveries, allowing to regularly reclassify this disease. The previous molecular classification defined 4 groups (WNT-activated MB, SHH-activated MB and the groups 3 and 4 characterized partially by NMYC and MYC driven MBs). This stratification moved forward recently to better define these groups and their correlation to outcome. This new stratification into 7 novel subgroups was helpful to lay foundations and complementary data on the understanding regarding molecular pathways and gene mutations underlying medulloblastoma biology. This review was aimed at answering the recent key questions on MB genomics and go further in the relevance of those genes in MB development as well as in their targeted therapies.

Impact of malpractice liability among spine surgeons: A national survey of French private neurosurgeons.

PURPOSE: In the general context of medical judicialization, spine surgeons are impacted by the part that medical responsibility and the risk of malpractice play in their actions and decisions. Our aim was to evaluate possible shifts in practices among private neurosurgeons who are highly exposed to this judicial risk and detect alterations in their pleasure in exercising their profession. We present the first national survey on French physicians' perception of surgical judicialization and consequences on their practice. METHODS: An online survey was submitted to the 121 members of the French Society of Private Neurosurgery, who represent 29.1% of the total number of spine surgeons and perform 36.0% of the national total spine surgery activity. The French law (no-fault out-of-court scheme) significantly impacts these surgeons in the event of litigation. RESULTS: A total of 78 surveys were completed (64.5% response rate): 89.7% of respondents experienced alteration of doctor-patient relationship related to judicialization and 60.2% had already refused to perform risky surgeries. Fear of being sued added negative pressure during surgery for 55.1% of respondents and 37.2% of them had already considered stopping their practice because of this litigation context. CONCLUSION: The increasing impact of medical liability is prompting practitioners to change their practice and perceptions. The doctor-patient relationship appears to be altered, negative pressure is placed on physicians and defensively, some neurosurgeons may refuse high-risk patients and procedures. This situation causes professional disenchantment and can ultimately prove disadvantageous for both doctors and patients.

Baseline status of policy and legislation actions to address non communicable diseases crisis in the Pacific.

BACKGROUND: Non-Communicable Diseases (NCD) are the leading cause of death in the Pacific Island Countries and Territories (PICTs) accounting for approximately 70% of mortalities. Pacific leaders committed to take action on the Pacific NCD Roadmap, which specifies NCD policy and legislation. To monitor progress against the NCD Roadmap, the Pacific Monitoring Alliance for NCD Action (MANA) was formed and the MANA dashboard was developed. This paper reports on the first status assessment for all 21 PICTs. METHODS: The MANA Dashboard comprises 31 indicators across the domains of leadership and governance, preventive policies, health system response and monitoring processes, and uses a 'traffic light' rating scheme to track progress. The dashboard indicators draw on WHO's best-buy interventions and track highly cost-effective interventions for addressing NCDs. The MANA coordination team in collaboration with national NCD focal points completed Dashboards for all 21 PICTs between 2017 and 2018 in an agreed process. The data were analysed and presented within each area of the MANA dashboard. RESULTS: This assessment found that PICTs are at varying stages of developing and implementing NCD policy and legislation. Some policy and legislation are in place in most PICTs e.g. smoke free environment (18 PICTs), alcohol licensing (19 PICTs), physical education in schools (14 PICTs), reduction of population salt consumption (14 PICTs) etc. However, no PICTs has policy or legislation on tobacco industry interference, controlling marketing of foods and drinks to children, and reducing trans-fats in the food supply, and only 7 PICTs have policies restricting alcohol advertising. Eighteen PICTs implement tobacco taxation measures, however only five were defined as having strong measures in place. Nineteen PICTs have alcohol taxation mechanisms and 13 PICTs have fiscal policies on foods to promote healthier diets. CONCLUSION: This baseline assessment fills a knowledge gap on current strengths and areas where more action is needed to scale up NCD action in a sustained 'whole of government and whole of society approach' in PICTs. The findings of this assessment can be used to identify priority actions, and as a mutual accountability mechanism to track progress on implementation of NCD policy and legislation at both national and Pacific level.

Photolytic degradation of molecular iodine adsorbed on model SiO2 particles.

A molecular derivatization method followed by gas chromatographic separation coupled with mass spectrometric detection was used to study photolytic degradation of I2 adsorbed on solid SiO2 particles. This heterogeneous photodegradation of I2 is studied at ambient temperature in synthetic air to better understand I2 atmospheric dispersion and environmental fate. The obtained laboratory results show a considerably enhanced atmospheric lifetime of molecular iodine adsorbed on solid media. The heterogeneous atmospheric residence time (τ) of I2 is calculated to be τ ≈ 187 min, i.e., τ ≈ 3 h. The obtained heterogeneous lifetime of I2 is shown to be considerably longer than its destruction by its principal atmospheric sink, namely, photolysis. The observed enhanced atmospheric lifetime of I2 on heterogeneous media will likely have direct consequences on the atmospheric transport of I2 that influences the toxicity or the oxidative capacity of the atmosphere.

[Causes, diagnosis and treatments of circulatory shocks]. / États de choc : grands cadres étiologiques, prise en charge initiale.

Shock states are the leading causes of intensive care admission and are nowadays associated with high morbidity and mortality. They are driven by a complex physiopathology and most frequently a multifactorial mechanism. They can be separated in whether a decrease of oxygen delivery (quantitative shock) or an abnormal cell distribution of cardiac output (distributive shock). Septic, cardiogenic and hypovolemic shocks represent more than 80% of shock etiologies. Clinical presentation is mostly characterized by frequent arterial hypotension and sign of poor clinical perfusion. Hyperlactatemia occurs in most of shock states. The diagnostic of shock or earlier reversible "pre-shock" states is urgent in order to initiate adequate therapy. Therefore, orientation and therapies must be discussed with intensive care physiologists in a multidisciplinary approach. Etiologic investigation and correction is a primary concern. Hemodynamic and respiratory support reflect another part of initial therapy toward normalization of cell oxygenation. Fluid resuscitation is the corner stone part of initial therapy of any form of shock. Vasoconstrictive drugs or inotropic support still often remain necessary. The primary goal of initial resuscitation should be not only to restore blood arterial pressure but also to improve clinical perfusion markers. On the biological side, decrease of lactate concentration is associated with better outcome.

[Do caregivers of non-dependent elderly have specific characteristics? Study among 876 elderly-caregiver dyads]. / Les aidants de personnes âgées non dépendantes ont-ils des spécificités ? Étude auprès de 876 dyades personnes âgées-aidants.

BACKGROUND: The increase in life expectancy and the aging of the population have a significant impact on the informal care provided by caregivers. Protecting caregivers against excessive burden has become a public health priority. The majority of studies target only those providing care for dependent elderly people. The aim of this study was to describe the characteristics of informal caregivers of non-dependent elderly persons, their difficulties and their level of burden. METHODS: A cross-sectional study was conducted among 876 dyads: elderly people (over 70 years of age, non-dependent, living at home and having requested assistance from CARSAT South-East) and their caregivers. Two questionnaires were administered: one for the elderly (including the Frailty Group Iso-Resource Evaluation) and one for caregivers (including the Mini-Zarit Scale). A multi-component analysis and a logistic regression were performed. RESULTS: The elderly were mainly women (77.6%) with a mean age of 82.2±5.8 years and most were frail (94.7%). Most of the caregivers were women (64.5%) with a mean age of 62.7±13.7 years. The multi-component analysis showed three categories of caregivers: spouses, children and others. Among them, spouses performed the most tasks (4.8±2.6) and had the greatest burden. Caregivers in the "others" category were the least burdened and were the least impacted in their daily life. The children category caregivers were divided into two subgroups: those with characteristics similar to "others" caregivers and those with characteristics similar to "spouse" caregivers. Heavy burden was related to greater impact on daily life, poor relationships with the elderly and caregivers' difficulties in performing their role. CONCLUSION: This study confirms the heterogeneous nature of informal caregiver profiles. It also shows that the characteristic features and the burden of these caregivers are similar whether the elderly person is dependent or non-dependent but frail.

The symbiotic complex of Dendroctonus simplex: implications in the beetle attack and its life cycle.

The eastern larch beetle (Dendroctonus simplex Le Conte) is recognized as a serious destructive forest pest in the upper part of North America. Under epidemic conditions, this beetle can attack healthy trees, causing severe damages to larch stands. Dendroctonus species are considered as holobionts, as they engage in multipartite interactions with microorganisms, such as bacteria, filamentous fungi, and yeasts, which are implicated in physiological processes of the insect, such as nutrition. They also play a key role in the beetle's attack, as they are responsible for the detoxification of the subcortical environment and weaken the tree's defense mechanisms. The eastern larch beetle is associated with bacteria and fungi, but their implication in the success of the beetle remains unknown. Here, we investigated the bacterial and fungal microbiota of this beetle pest throughout its ontogeny (pioneer adults, larvae and pupae) by high-throughput sequencing. A successional microbial assemblage was identified throughout the beetle developmental stages, reflecting the beetle's requirements. These results indicate that a symbiotic association between the eastern larch beetle and some of these microorganisms takes place and that this D. simplex symbiotic complex is helping the insect to colonize its host tree and survive the conditions encountered.

High Prevalence of Non-Communicable Disease Risk Factors among Adolescents in Pohnpei, Micronesia.

Non-communicable disease (NCD) related behaviors among adolescents are on the rise globally and in the Pacific region. To better understand and elucidate the prevalence of NCD risk factors among adolescents in Pohnpei state, Federated States of Micronesia, a cross-sectional study was conducted among secondary school students. Of 2965 students enrolled in the 2015-2016 academic year, 2555 (86.2%) completed the survey, and 2386 (80.5%) were included in the final analysis. Of the survey respondents, 21.7% of students self-reported smoking tobacco in the past 30 days, 30.3% self-reported drinking alcohol in the past 30 days, 40.9% self-reported chewing betel nut in the past 30 days, and 21.2% self-reported chewing tobacco with or without betel nut in the last 30 days. Male students, older students, and public school students had higher prevalence of substance use. Additionally, about 17.3% of students were overweight and 10.1% were obese according to physical measures of height and weight. Female students and private school students had higher prevalence of overweight and obesity than male students, and prevalence of overweight was higher in older age groups. These findings indicate a cohort of adolescents at substantial risk for the development of NCDs and signal an urgent need for public health interventions to address NCD risk factors.