ASMase is Essential for the Immune Response to Partial-Tumor Radiation Exposure.

BACKGROUND/AIMS: Tumor response to radiation is thought to depend on the direct killing of tumor cells. Our laboratory has called this into question. Firstly, we showed that the biology of the host, specifically the endothelial expression of acid sphingomyelinase (ASMase), was critical in determining tumor radiocurability. Secondly, we have shown that the immune system can enhance radiation response by allowing a complete tumor control in hemi-irradiated tumors. In this paper, we focus on the integration of these two findings. METHODS: We used Lewis Lung Carcinoma (LLC) cells, injected in the flank of either: (i) ASMase knockout or (ii) WT of matched background (sv129xBl/6) or (iii) C57Bl/6 mice. Radiation therapy (RT) was delivered to 50% or 100% of the LLC tumor volume. Tumor response, immune infiltration (CD8+ T cells), ICAM-1, and STING activation were measured. Radiotherapy was also combined with methyl-cyclodextrin, to inhibit the ASMase-mediated formation of ceramide-enriched lipid rafts. RESULTS: We recapitulated our previous finding, namely that tumor hemi-irradiation was sufficient for tumor control in the LLC/C57Bl/6 model. However, in ASMase KO mice hemi-irradiation was ineffective. Likewise, pharmacological inhibition of ASMase significantly reduced the tumor response to hemi-irradiation. Further, we demonstrated elevated ICAM-1 expression, increased levels of CD8+ T cells, ICAM-1, and STING activation in tumors growing in C57Bl/6 mice, as well as the ASMase WT strain. However, no such changes were seen in tumors growing in ASMase KO mice. CONCLUSION: ASMase and ceramide generation are necessary to mediate a radiation-induced anti-tumor immune response via STING activation.

Tropical Andean climate variations since the last deglaciation.

Global warming during the Last Glacial Termination was interrupted by millennial-scale cool intervals such as the Younger Dryas and the Antarctic Cold Reversal (ACR). Although these events are well characterized at high latitudes, their impacts at low latitudes are less well known. We present high-resolution temperature and hydroclimate records from the tropical Andes spanning the past ~16,800 y using organic geochemical proxies applied to a sediment core from Laguna Llaviucu, Ecuador. Our hydroclimate record aligns with records from the western Amazon and eastern and central Andes and indicates a dominant long-term influence of changing austral summer insolation on the intensity of the South American Summer Monsoon. Our temperature record indicates a ~4 °C warming during the glacial termination, stable temperatures in the early to mid-Holocene, and slight, gradual warming since ~6,000 y ago. Importantly, we observe a ~1.5 °C cold reversal coincident with the ACR. These data document a temperature change pattern during the deglaciation in the tropical Andes that resembles temperatures at high southern latitudes, which are thought to be controlled by radiative forcing from atmospheric greenhouse gases and changes in ocean heat transport by the Atlantic meridional overturning circulation.

Atolls are globally important sites for tropical seabirds.

Seabirds play critical roles on islands. By catalysing terrestrial and marine productivity through guano nutrient input, seabirds support natural island functioning. In the Indo-Pacific, atolls comprise one-third of all islands but only ~0.02% of island area. The importance of atolls as seabird nesting grounds has been historically neglected except on a few key atolls. We compiled a global dataset of seabird surveys on atolls and modelled seabird distribution and nutrient deposition on all Indo-Pacific atolls. We found that atolls are breeding sites for 37 species, ranging from a few dozen to more than 3 million individuals per atoll. In total, an estimated 31.2 million seabirds nest on atolls, or ~25% of the tropical seabirds of the world. For 14 species, more than half of their global populations nest on atolls. Seabirds forage more than 10,000-100,000 km² around an atoll and deposit, on average, 65,000 kg N and 11,000 kg P per atoll per year, thus acting as major nutrient pumps within the tropical Indo-Pacific. Our findings reveal the global importance of atolls for tropical seabirds. Given global change, conservation will have to leverage atoll protection and restoration to preserve a relevant fraction of the tropical seabirds of the world.

Assessment of self-medication practices and safety profile of medicines utilisation among pregnant women attending antenatal clinics in Freetown, Sierra Leone: a multicentre cross-sectional study.

Background: Despite the potential foetal and maternal risks of self-medication, studies on self-medication practice and the safety profile of medicines used during pregnancy are scarce in our setting. This study determined the self-medication practice and safety profile of medicines used among pregnant women. Methods: This cross-sectional study was conducted in face-to-face interviews among 345 pregnant women at three hospitals in Sierra Leone. Data were analysed using descriptive statistics and binary logistic regression to determine the prevalence and associated factors of self-medication. Results: A total of 345 pregnant women participated in the study. The prevalence of self-medication prevalence among pregnant women with conventional and/or herbal medicine was 132 (38.3%). Also, 93 (75%) of the conventional medicines (CMs) were categorised as probably safe, of which paracetamol 36 (29.0%) was commonly used, followed by amoxicillin 23 (18.5%) and antimalarials 22 (17.7%) for common illnesses such as headache 30 (25.4%), urinary tract infection 23 (19.4%) and malaria 22 (18.6%). The most common reason for self-medication was previous experience with the disease 24 (27.3%). Luffa acutangula 19 (30.2%) was the most used herbal medicine (HM), and Oedema 30 (47.6%) was the most reported ailment. Among the HM users, 34 (54.0%) believe they are more effective than CMs. Secondary school education (AOR = 2.128, 95%CI = 1.191-3.804, p = 0.011), tertiary education (AOR = 2.915, 95%CI = 1.104-7.693, p = 0.031), monthly income of greater than NLe 1,000 (AOR = 4.084, 95% CI = 1.269-13.144, p = 0.018), and perceived maternal illness (AOR = 0.367, CI = 0.213-0.632, p = <0.001) were predictors of self-medication. Conclusion: Self-medication practice was highly prevalent and was associated with educational status, monthly income, and perceived maternal illness during pregnancy. Therefore, intervention programmes should be designed and implemented to minimise the practice and risk associated with self-medication among pregnant women.

Standardisation facilitates reliable interpretation of ETCO2 during manual cardiopulmonary resuscitation.

BACKGROUND: Interpretation of end-tidal CO2 (ETCO2) during manual cardiopulmonary resuscitation (CPR) is affected by variations in ventilation and chest compressions. This study investigates the impact of standardising ETCO2 to constant ventilation rate (VR) and compression depth (CD) on absolute values and trends. METHODS: Retrospective study of out-of-hospital cardiac arrest cases with manual CPR, including defibrillator and clinical data. ETCO2, VR and CD values were averaged by minute. ETCO2 was standardised to 10 vpm and 50 mm. We compared standardised (ETs) and measured (ETm) values and trends during resuscitation. RESULTS: Of 1,036 cases, 287 met the inclusion criteria. VR was mostly lower than recommended, 8.8 vpm, and highly variable within and among patients. CD was mostly within guidelines, 49.8 mm, and less varied. ETs was lower than ETm by 7.3 mmHg. ETs emphasized differences by sex (22.4 females vs. 25.6 mmHg males), initial rhythm (29.1 shockable vs. 22.7 mmHg not), intubation type (25.6 supraglottic vs. 22.4 mmHg endotracheal) and return of spontaneous circulation (ROSC) achieved (34.5 mmHg) vs. not (20.1 mmHg). Trends were different between non-ROSC and ROSC patients before ROSC (-0.3 vs. + 0.2 mmHg/min), and between sustained and rearrest after ROSC (-0.7 vs. -2.1 mmHg/min). Peak ETs was higher for sustained than for rearrest (53.0 vs. 42.5 mmHg). CONCLUSION: Standardising ETCO2 eliminates effects of VR and CD variations during manual CPR and facilitates comparison of values and trends among and within patients. Its clinical application for guidance of resuscitation warrants further investigation.

Weibull parametric model for survival analysis in women with endometrial cancer using clinical and T2-weighted MRI radiomic features.

BACKGROUND: Semiparametric survival analysis such as the Cox proportional hazards (CPH) regression model is commonly employed in endometrial cancer (EC) study. Although this method does not need to know the baseline hazard function, it cannot estimate event time ratio (ETR) which measures relative increase or decrease in survival time. To estimate ETR, the Weibull parametric model needs to be applied. The objective of this study is to develop and evaluate the Weibull parametric model for EC patients' survival analysis. METHODS: Training (n = 411) and testing (n = 80) datasets from EC patients were retrospectively collected to investigate this problem. To determine the optimal CPH model from the training dataset, a bi-level model selection with minimax concave penalty was applied to select clinical and radiomic features which were obtained from T2-weighted MRI images. After the CPH model was built, model diagnostic was carried out to evaluate the proportional hazard assumption with Schoenfeld test. Survival data were fitted into a Weibull model and hazard ratio (HR) and ETR were calculated from the model. Brier score and time-dependent area under the receiver operating characteristic curve (AUC) were compared between CPH and Weibull models. Goodness of the fit was measured with Kolmogorov-Smirnov (KS) statistic. RESULTS: Although the proportional hazard assumption holds for fitting EC survival data, the linearity of the model assumption is suspicious as there are trends in the age and cancer grade predictors. The result also showed that there was a significant relation between the EC survival data and the Weibull distribution. Finally, it showed that Weibull model has a larger AUC value than CPH model in general, and it also has smaller Brier score value for EC survival prediction using both training and testing datasets, suggesting that it is more accurate to use the Weibull model for EC survival analysis. CONCLUSIONS: The Weibull parametric model for EC survival analysis allows simultaneous characterization of the treatment effect in terms of the hazard ratio and the event time ratio (ETR), which is likely to be better understood. This method can be extended to study progression free survival and disease specific survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT03543215, https://clinicaltrials.gov/ , date of registration: 30th June 2017.

A 1 Ma sedimentary ancient DNA (sedaDNA) record of catchment vegetation changes and the developmental history of tropical Lake Towuti (Sulawesi, Indonesia).

Studying past ecosystems from ancient environmental DNA preserved in lake sediments (sedaDNA) is a rapidly expanding field. This research has mainly involved Holocene sediments from lakes in cool climates, with little known about the suitability of sedaDNA to reconstruct substantially older ecosystems in the warm tropics. Here, we report the successful recovery of chloroplast trnL (UAA) sequences (trnL-P6 loop) from the sedimentary record of Lake Towuti (Sulawesi, Indonesia) to elucidate changes in regional tropical vegetation assemblages during the lake's Late Quaternary paleodepositional history. After the stringent removal of contaminants and sequence artifacts, taxonomic assignment of the remaining genuine trnL-P6 reads showed that native nitrogen-fixing legumes, C3 grasses, and shallow wetland vegetation (Alocasia) were most strongly associated with >1-million-year-old (>1 Ma) peats and silts (114-98.8 m composite depth; mcd), which were deposited in a landscape of active river channels, shallow lakes, and peat-swamps. A statistically significant shift toward partly submerged shoreline vegetation that was likely rooted in anoxic muddy soils (i.e., peatland forest trees and wetland C3 grasses (Oryzaceae) and nutrient-demanding aquatic herbs (presumably Oenanthe javanica)) occurred at 76 mcd (~0.8 Ma), ~0.2 Ma after the transition into a permanent lake. This wetland vegetation was most strongly associated with diatom ooze (46-37 mcd), thought to be deposited during maximum nutrient availability and primary productivity. Herbs (Brassicaceae), trees/shrubs (Fabaceae and Theaceae), and C3 grasses correlated with inorganic parameters, indicating increased drainage of ultramafic sediments and laterite soils from the lakes' catchment, particularly at times of inferred drying. Downcore variability in trnL-P6 from tropical forest trees (Toona), shady ground cover herbs (Zingiberaceae), and tree orchids (Luisia) most strongly correlated with sediments of a predominantly felsic signature considered to be originating from the catchment of the Loeha River draining into Lake Towuti during wetter climate conditions. However, the co-correlation with dry climate-adapted trees (i.e., Castanopsis or Lithocarpus) plus C4 grasses suggests that increased precipitation seasonality also contributed to the increased drainage of felsic Loeha River sediments. This multiproxy approach shows that despite elevated in situ temperatures, tropical lake sediments potentially comprise long-term archives of ancient environmental DNA for reconstructing ecosystems, which warrants further exploration.

An Assessment of Medication Errors Among Pediatric Patients in Three Hospitals in Freetown Sierra Leone: Findings and Implications for a Low-Income Country.

Background: Pediatric patients are prone to medicine-related problems like medication errors (MEs), which can potentially cause harm. Yet, this has not been studied in this population in Sierra Leone. Therefore, this study investigated the prevalence and nature of MEs, including potential drug-drug interactions (pDDIs), in pediatric patients. Methods: The study was conducted in three hospitals among pediatric patients in Freetown and consisted of two phases. Phase one was a cross-sectional retrospective review of prescriptions for completeness and accuracy based on the global accuracy score against standard prescription writing guidelines. Phase two was a point prevalence inpatient chart review of MEs categorized into prescription, administration, and dispensing errors and pDDIs. Data was analyzed using frequency, percentages, median, and interquartile range. Kruskal-Wallis H and Mann-Whitney U-tests were used to compare the prescription accuracy between the hospitals, with p<0.05 considered statistically significant. Results: Three hundred and sixty-six (366) pediatric prescriptions and 132 inpatient charts were reviewed in phases one and two of the study, respectively. In phase one, while no prescription attained the global accuracy score (GAS) gold standard of 100%, 106 (29.0%) achieved the 80-100% mark. The patient 63 (17.2%), treatment 228 (62.3%), and prescriber 33 (9.0%) identifiers achieved an overall GAS range of 80-100%. Although the total GAS was not statistically significant (p=0.065), the date (p=0.041), patient (p=<0.001), treatment (p=0.022), and prescriber (p=<0.001) identifiers were statistically significant across the different hospitals. For phase two, the prevalence of MEs was 74 (56.1%), while that of pDDIs was 54 (40.9%). There was a statistically positive correlation between the occurrence of pDDI and number of medicines prescribed (r=0.211, P=0.015). Conclusion: A Low GAS indicates poor compliance with prescription writing guidelines and high prescription errors. Medication errors were observed at each phase of the medication use cycle, while clinically significant pDDIs were also reported. Thus, there is a need for training on prescription writing guidelines and medication errors.

Metrics of impulsiveness of manual chest compressions for out-of-hospital cardiopulmonary resuscitation.

Aim: Propose new metrics of impulsiveness of manual chest compressions (CCs) that account for shape and duration, separate the characteristics of the compressive part of the CC cycle from those of the recoil part, and are uncorrelated to CC depth and rate. Methods: We conducted a retrospective analysis of adult out-of-hospital cardiac arrest monitor-defibrillator recordings having CPR data. Specifically, episodes of adult patients with ≥ 1000 compressions free of leaning were examined. CCs were obtained from the depth signal of the valid episodes, and we calculated the novel metrics: compression area index (CAI), recoil area index (RAI), compression impulsiveness index (CII) and recoil impulsiveness index (RII). Generalized linear mixed-effects models and Jonckheere-Terpstra trend analyses were employed to measure differences between populations and trends, and the absolute value of Pearson's correlation coefficient |r| was used to report dependence between variables. Statistics are reported as median and interquartile range. Results: We analyzed 982,340 CCs corresponding to 453 episodes, for which we calculated their CAI, RAI and duty cycle (DC). We analyzed the metrics for various populations: age, sex, any ROSC achieved and disposition, and found that CAI was significantly different according to patient disposition and RAI relative to age and sex (p<0.05). None of the metrics was correlated strongly to depth or rate (|r| values of 0.22 or smaller), and all of them varied for CC series corresponding to the same rescuer over the course of resuscitation (ptrend<0.05). However, we observed that the metrics are not balanced, in that for any value of DC, CAI and RAI span almost their entire ranges. Conclusion: The proposed metrics correctly and completely describe manual CC waveforms, improve upon the DC, since they depend on the signal waveform, and provide additional information to current indicators of quality CPR, depth and rate. Furthermore, they allow to differentiate the compressive and recoil parts of the CC cycle, reflecting influence of the rescuer (via CAI or CII) and of the biomechanics of the patient's chest (via RAI or RII). Thus, they have the potential to contribute to better understanding CPR dynamics and, eventually, to enhanced quality of CPR practice as additional indicators of proper manual CC technique.

Prevalence of hypertension, diabetes mellitus, and their risk factors in an informal settlement in Freetown, Sierra Leone: a cross-sectional study.

BACKGROUND: Noncommunicable diseases (NCDs), especially hypertension and diabetes mellitus are on the increase in sub-Saharan Africa (SSA). Informal settlement dwellers exhibit a high prevalence of behavioural risk factors and are highly vulnerable to hypertension and diabetes. However, no study has assessed the prevalence of hypertension, diabetes, and NCDrisk factors among informal settlement dwellers in Sierra Leone. We conducted a study in June 2019 to determine the prevalence of hypertension, diabetes, and NCD risk factors among adults living in the largest Sierra Leonean informal settlement (KrooBay). METHODS AND MATERIALS: We conducted a community-based cross-sectional survey among adults aged ≥ 35 years in the KrooBay community. Trained healthcare workers collected data on socio-demographic characteristics and self-reported health behaviours using the World Health Organization STEPwise surveillance questionnaire for chronic disease risk factors. Anthropometric, blood glucose, and blood pressure measurements were performed following standard procedures. Logistics regression was used for analysis and adjusted odd ratios with 95% confidence intervals were calculated to identify risk factors associated with hypertension. RESULTS: Of the 418 participants, 242 (57%) were females and those below the age of 45 years accounted for over half (55.3%) of the participants. The prevalence of smoking was 18.2%, alcohol consumption was 18.8%, overweight was 28.2%, obesity was 17.9%, physical inactivity was 81.5%, and inadequate consumption of fruits and vegetables was 99%. The overall prevalence of hypertension was 45.7% (95% CI 41.0-50.5%), systolic hypertension was 34.2% (95% CI 29.6-38.8%), diastolic blood pressure was 39.9% (95% CI 35.2-44.6), and participants with diabetes were 2.2% (95% CI 0.7-3.6%). Being aged ≥ 55 years (AOR = 7.35, 95% CI 1.49-36.39) and > 60 years (AOR 8.05; 95% CI 2.22-29.12), separated (AOR = 1.34; 95% 1.02-7.00), cohabitating (AOR = 6.68; 95% CL1.03-14.35), vocational (AOR = 3.65; 95% CI 1.81-7.39 ) and having a university education (AOR = 4.62; 95% CI 3.09-6.91) were found to be independently associated with hypertension. CONCLUSION: The prevalence of hypertension,and NCD risk factors was high among the residents of the Kroobay informal settlement. We also noted a low prevalence of diabetes. There is an urgent need for the implementation of health education, promotion, and screening initiatives to reduce health risks so that these conditions will not overwhelm health services.

Skin keratinocyte-derived SIRT1 and BDNF modulate mechanical allodynia in mouse models of diabetic neuropathy.

Diabetic neuropathy is a debilitating disorder characterized by spontaneous and mechanical allodynia. The role of skin mechanoreceptors in the development of mechanical allodynia is unclear. We discovered that mice with diabetic neuropathy had decreased sirtuin 1 (SIRT1) deacetylase activity in foot skin, leading to reduced expression of brain-derived neurotrophic factor (BDNF) and subsequent loss of innervation in Meissner corpuscles, a mechanoreceptor expressing the BDNF receptor TrkB. When SIRT1 was depleted from skin, the mechanical allodynia worsened in diabetic neuropathy mice, likely due to retrograde degeneration of the Meissner-corpuscle innervating Aß axons and aberrant formation of Meissner corpuscles which may have increased the mechanosensitivity. The same phenomenon was also noted in skin-keratinocyte specific BDNF knockout mice. Furthermore, overexpression of SIRT1 in skin induced Meissner corpuscle reinnervation and regeneration, resulting in significant improvement of diabetic mechanical allodynia. Overall, the findings suggested that skin-derived SIRT1 and BDNF function in the same pathway in skin sensory apparatus regeneration and highlighted the potential of developing topical SIRT1-activating compounds as a novel treatment for diabetic mechanical allodynia.

Using a targeted metabolomics approach to explore differences in ARDS associated with COVID-19 compared to ARDS caused by H1N1 influenza and bacterial pneumonia.

RATIONALE: Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome commonly associated with infections such as COVID-19, influenza, and bacterial pneumonia. Ongoing research aims to improve our understanding of ARDS, including its molecular mechanisms, individualized treatment options, and potential interventions to reduce inflammation and promote lung repair. OBJECTIVE: To map and compare metabolic phenotypes of different infectious causes of ARDS to better understand the metabolic pathways involved in the underlying pathogenesis. METHODS: We analyzed metabolic phenotypes of 3 ARDS cohorts caused by COVID-19, H1N1 influenza, and bacterial pneumonia compared to non-ARDS COVID-19-infected patients and ICU-ventilated controls. Targeted metabolomics was performed on plasma samples from a total of 150 patients using quantitative LC-MS/MS and DI-MS/MS analytical platforms. RESULTS: Distinct metabolic phenotypes were detected between different infectious causes of ARDS. There were metabolomics differences between ARDSs associated with COVID-19 and H1N1, which include metabolic pathways involving taurine and hypotaurine, pyruvate, TCA cycle metabolites, lysine, and glycerophospholipids. ARDSs associated with bacterial pneumonia and COVID-19 differed in the metabolism of D-glutamine and D-glutamate, arginine, proline, histidine, and pyruvate. The metabolic profile of COVID-19 ARDS (C19/A) patients admitted to the ICU differed from COVID-19 pneumonia (C19/P) patients who were not admitted to the ICU in metabolisms of phenylalanine, tryptophan, lysine, and tyrosine. Metabolomics analysis revealed significant differences between C19/A, H1N1/A, and PNA/A vs ICU-ventilated controls, reflecting potentially different disease mechanisms. CONCLUSION: Different metabolic phenotypes characterize ARDS associated with different viral and bacterial infections.

Prevalence and correlates of metabolic syndrome among adults in freetown, Sierra Leone: A comparative analysis of NCEP ATP III, IDF and harmonized ATP III criteria.

Background: Metabolic syndrome (MetS) is a global health concern, especially for low and middle-income countries with limited resources and information. The study's objective was to assess the prevalence of MetS in Freetown, Sierra Leone, using the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III), International Diabetes Federation (IDF) and Harmonize ATP III. Additionally, we aimed to establish the concordance between these three different criteria used. Methods: This community-based health screening survey was conducted from October 2019 to October 2022. A multistage stratified random design was used to select adults aged 20 years and above. Mean, interquartile range (IQR), and logistic regression were used for statistical analysis. The kappa coefficient statistics resolved the agreement between these defined criteria. Results: The prevalence for NCEP ATP III, Harmonize ATP III and IDF criteria was 11.8 % (95 % CI: 9.0-15.15), 14.3 % (95 % CI: 11.3-18.0), and 8.5 % (95 % CI: 6.2-11.2), respectively for the 2394 selected adults. The kappa coefficient (κ) agreement between the MetS is: Harmonized ATP III and IDF criteria = [(208 (60.8 %); (κ = 0.62)]; Harmonized ATP III and NCEP ATP III = [(201 (58.7 %); (κ = 0.71)]; while IDF and NCEP ATP III was [(132 (38.6 %); (κ = 0.52)]. In the multivariable regression analysis, waist circumference correlated with all three MetS criteria: ATP III [AOR = 0.85; C.I 95 %: (0.40-1.78), p = 0.032], Harmonized ATP III [AOR = 1.14; C.I 95 %: (0.62-2.11), p = 0.024], IDF [AOR = 1.06; C.I 95 % (0.52-2.16), p = 0.018]. Conclusion: We reported a high prevalence of MetS in Freetown, Sierra Leone and identified waist circumference as a major risk factor for MetS. This underscores the crucial role of health education and effective management of MetS in Sierra Leone.

NAD+ Precursors Reverse Experimental Diabetic Neuropathy in Mice.

Abnormal NAD+ signaling has been implicated in axonal degeneration in diabetic peripheral neuropathy (DPN). We hypothesized that supplementing NAD+ precursors could alleviate DPN symptoms through increasing the NAD+ levels and activating the sirtuin-1 (SIRT1) protein. To test this, we exposed cultured Dorsal Root Ganglion neurons (DRGs) to Nicotinamide Riboside (NR) or Nicotinamide Mononucleotide (NMN), which increased the levels of NAD+, the SIRT1 protein, and the deacetylation activity that is associated with increased neurite growth. A SIRT1 inhibitor blocked the neurite growth induced via NR or NMN. We then induced neuropathy in C57BL6 mice with streptozotocin (STZ) or a high fat diet (HFD) and administered NR or NMN for two months. Both the STZ and HFD mice developed neuropathy, which was reversed through the NR or NMN administration: sensory function improved, nerve conduction velocities normalized, and intraepidermal nerve fibers were restored. The NAD+ levels and SIRT1 activity were reduced in the DRGs from diabetic mice but were preserved with the NR or NMN treatment. We also tested the effect of NR or NMN administration in mice that overexpress the SIRT1 protein in neurons (nSIRT1 OE) and found no additional benefit from the addition of the drug. These findings suggest that supplementing with NAD+ precursors or activating SIRT1 may be a promising treatment for DPN.

2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia.

RATIONALE: New evidence is available examining the use of corticosteroids in sepsis, acute respiratory distress syndrome (ARDS) and community-acquired pneumonia (CAP), warranting a focused update of the 2017 guideline on critical illness-related corticosteroid insufficiency. OBJECTIVES: To develop evidence-based recommendations for use of corticosteroids in hospitalized adults and children with sepsis, ARDS, and CAP. PANEL DESIGN: The 22-member panel included diverse representation from medicine, including adult and pediatric intensivists, pulmonologists, endocrinologists, nurses, pharmacists, and clinician-methodologists with expertise in developing evidence-based Clinical Practice Guidelines. We followed Society of Critical Care Medicine conflict of interest policies in all phases of the guideline development, including task force selection and voting. METHODS: After development of five focused Population, Intervention, Control, and Outcomes (PICO) questions, we conducted systematic reviews to identify the best available evidence addressing each question. We evaluated the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach and formulated recommendations using the evidence-to-decision framework. RESULTS: In response to the five PICOs, the panel issued four recommendations addressing the use of corticosteroids in patients with sepsis, ARDS, and CAP. These included a conditional recommendation to administer corticosteroids for patients with septic shock and critically ill patients with ARDS and a strong recommendation for use in hospitalized patients with severe CAP. The panel also recommended against high dose/short duration administration of corticosteroids for septic shock. In response to the final PICO regarding type of corticosteroid molecule in ARDS, the panel was unable to provide specific recommendations addressing corticosteroid molecule, dose, and duration of therapy, based on currently available evidence. CONCLUSIONS: The panel provided updated recommendations based on current evidence to inform clinicians, patients, and other stakeholders on the use of corticosteroids for sepsis, ARDS, and CAP.

Impact of COVID-19 on the Utilization of HIV Testing and Linkage Services in Sierra Leone: Experience from Three Public Health Facilities in Freetown.

The COVID-19 pandemic adversely affected the delivery of essential health services globally. In this study, we aimed to assess the impact of the pandemic on HIV testing and linkage services at three public health facilities in Freetown, Sierra Leone. We conducted a retrospective study to assess the impact of COVID-19 on HIV testing and linkage to treatment services (HTS) at Connaught Hospital (CH-tertiary), Lumley Government Hospital (LGH-secondary) and George Brooke Community Health Center (GBC-primary) in Freetown. Statistical analyses were conducted in Stata (16.1, StataCorp LLC, College Station, TX). Intra-pandemic HTS (2020) and HTS during recovery (2021) were compared with pre-pandemic HTS (2019). Of the 8538 people tested for HIV in the three facilities, 4929 (57.5%) visited CH. Only 2249 people were tested for HIV in 2020 compared to 3825 in 2019 (difference: - 41.2%, P < 0.001). Fewer people were also tested in 2021 (difference: - 35.6% P < 0.001). The largest reductions in testing in 2020 occurred in women (- 47.7%), children under 15 (- 95.2%), married people (- 42.6%), and CH (- 46.2%). Overall, 1369 (16.0%) people were positive for HIV; CH (878, 17.9%), LGH (469, 15.6%) and GBC (22, 3.5%). The likelihood of a positive HIV test was 26% lower in 2020 than 2019 (PR 0.74; 95% CI 0.64-0.85; P < 0.001), but 16% higher in 2021 than 2019 (PR 1.16; 95% CI 1.03-1.30; P < 0.05). Of the 1369 HIV diagnosis, 526 (38.4%) were linked to care. We found significant disruptions in HIV testing and linkage services at different levels of service delivery during the COVID-19 pandemic, underscoring the need to strengthen essential health services during public health emergencies.

Barley MLA3 recognizes the host-specificity effector Pwl2 from Magnaporthe oryzae.

Plant nucleotide-binding leucine-rich repeat (NLRs) immune receptors directly or indirectly recognize pathogen-secreted effector molecules to initiate plant defense. Recognition of multiple pathogens by a single NLR is rare and usually occurs via monitoring for changes to host proteins; few characterized NLRs have been shown to recognize multiple effectors. The barley (Hordeum vulgare) NLR gene Mildew locus a (Mla) has undergone functional diversification, and the proteins encoded by different Mla alleles recognize host-adapted isolates of barley powdery mildew (Blumeria graminis f. sp. hordei [Bgh]). Here, we show that Mla3 also confers resistance to the rice blast fungus Magnaporthe oryzae in a dosage-dependent manner. Using a forward genetic screen, we discovered that the recognized effector from M. oryzae is Pathogenicity toward Weeping Lovegrass 2 (Pwl2), a host range determinant factor that prevents M. oryzae from infecting weeping lovegrass (Eragrostis curvula). Mla3 has therefore convergently evolved the capacity to recognize effectors from diverse pathogens.