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We report here an additional HLA-B∗51 variant designated HLA-B∗5116. Detected by an abnormal serological reactivity pattern, this variant was identified as a B∗51 allele by polymerase chain reaction using sequence-specific primers (PCR-SSP) and characterized by nucleotide sequencing. The new variant sequence match closely with the classical HLA-B∗5101 excepted two adjacent nucleotide substitutions at positions 216 and 217 of the third exon and the subsequent Leucine to Glutamic acid change at codon 163 of the α2 domain (CTG→GAG). This new variant was not detected in three different ethnic groups (French, Algerian and Lebanese) suggesting a very rare frequency. [ABSTRACT FROM AUTHOR]

Hyperamylasaemia is classically associated with acute pancreatitis. Hyperamylasaemia may be associated with many other clinical conditions. However, ureteric colic has never been reported to cause hyperamylasaemia. We describe a 47-year-old woman who presented with an atypical history of left ureteric colic. Radiological investigations confirmed an upper ureteric stone with urinary extravasation. At presentation, the serum amylase was elevated but normalised after 24 h. In conclusion, ureteric colic may cause hyperamylasaemia and this is likely a result of pancreatic irritation due to urinary extravasation. Patients presenting with ureteric colic and elevated concentrations of serum amylase should raise the clinical suspicion of urinary extravasation. [ABSTRACT FROM AUTHOR]

Background: As cannabis legalization expands nationally and globally, its use for chronic pain increases, prompting people to seek information on social media platforms like YouTube. This study evaluates the accuracy and quality of information of popular YouTube videos on cannabis for chronic pain., Methods: Using search terms related to cannabis for pain, the top 66 videos by view count were selected. Each video was classified as useful, misleading, or neither. The quality and reliability of each video were assessed using the modified DISCERN, mDISCERN, score and the Global Quality Scale, GQS. The video characteristics, usefulness classification, mDISCERN scores, and GQS scores were summarized. Continuous and categorical outcomes were compared using t -test and chi-square, respectively., Results: Of the 66 videos, 22.73% (n=15) were classified as useful, and 77.27% (n=51) were classified as neither. Of useful videos, 40.00% (n=6) were uploaded by physicians, 40.00% (n=6) were uploaded by corporations, and 6.67% (n=1) were uploaded by an independent user. Of videos classified as neither useful nor misleading, news sources uploaded 27.45% (n=14) of these videos (P=0.02). Physicians uploaded 37.50% (n = 18) of videos with a GQS score ≥3 (P=0.04), while independent users uploaded significantly more videos with a mDISCERN score <3 (22.20%, P=0.02). Useful videos had a mean GQS of 4.00 ± 0.65 compared to a mean GQS of 2.76 ± 0.86 for videos deemed neither (P<0.0001)., Conclusion: This study suggests a moderate quality of YouTube content on cannabis use for chronic pain. Given cannabis's growing popularity and potential for misinformation on popular social media platforms, healthcare professionals and organizations should consider uploading educational videos on this topic on YouTube., Competing Interests: The authors declare no conflicts of interest related to this submission., (© 2024 Etumuse et al.)

Background: Gaza has long been subjected to food insecurity; however, little was known about the influence of food insecurity on the nutritional wellbeing of schoolchildren. To fill this gap, the UN Relief and Works Agency for Palestine Refugees in the Near East (UNRWA), which provides humanitarian relief to Palestine refugees, assessed the nutritional status, diet, and food security of refugee children about to enter first grade (aged 4-10 years, mean age 72·1 months) in mid-2023 during a required health examination., Methods: As part of an annual School Entrance Health Examinations that began in May, a cross-sectional food security and nutritional assessment was added from July 8, to Sept 7, 2023, during which children being examined at six study-designated UNRWA clinics across Gaza were systematically sampled (in a 1:4 ratio) and parental or guardian consent sought for their participation. Household food security was assessed by a seven-point Arab Family food Security Scale score, and respondents were asked about family receipt of food assistance. The 1-week meal patterns of the children were probed, and intake frequencies of 49 foods in the past month categorised into ten nutritious food groups to assess diet diversity. The weight, height, and haemoglobin concentrations (assessed with a photometric analyser) of the children were measured. The UNRWA Research Review Board approved all study procedures., Findings: Approximately 34 000 children underwent the annual School Entrance Health Examination in Gaza in May, 2023 and approximately 16 000 children were estimated to have completed the additional food security and nutritional assessments from July 8, to early Sept 7, 2023, of whom 3814 were systematically sampled at six UNRWA clinics across Gaza, with 3229 (84·7%) parents or guardians consenting for their children to participate. 3155 were interviewed about household food security with a seven-point Arab Family Food Security Score, and 3212 were asked about food assistance receipt. 2694 (83·9%) of 3212 households were on food assistance, 787 (24·9%) of 3155 were classified as food secure (0-2 points), 1025 (32·5%) were classified as moderately (3-5 points) food insecure, and 1343 (42·6%) as severely food insecure (6-7 points). 219 (28·5%) of 768 children reported missing breakfast and 213 (28·4%) of 750 reported missing dinner in the food-secure group, 438 (47·2%) of 928 reported missing breakfast and 426 (45·6%) of 934 reported missing dinner in the moderately food-insecure group, and 956 (75·5%) of 1267 reported missing breakfast and 951 (74·8%) of 1272 reported missing dinner in the severely food-insecure group. Lunch was missed daily by 30 (3·8%) of 786 children in the food-secure group, 54 (5·3%) of 1023 in the moderately food-insecure group, and 193 (14·5%) of 1334 in the severely food-insecure group. Diets were poor in dairy items, meat, poultry, fish, pulses, eggs, and vitamin A-rich vegetables and fruit, and 2225 (68·9%) of 3229 children did not consume a minimally diverse diet every day (≥5 nutritious food groups). 72 (2·5%) of 2913 children had stunting and 129 (4·4%) of 2913 had wasting (less than -2 Z scores), and 963 (29·8%) of 3229 had anaemia (haemoglobin <11·5 g/dL). Boys and girls were similar in their diets, anthropometric Z scores, and prevalence of anaemia., Interpretation: Gazan families with children about to enter first grade were food insecure and reliant on food assistance, possibly protecting the anthropometric status of the children, whose diets however lacked diversity., Funding: Japan Ministry of Foreign Affairs and the Vitamin Angels Alliance, USA., Translation: For the Arabic translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Lipids and their bioactive metabolites, notably lysophosphatidylcholine (LPC), are increasingly important in ischemic stroke research. Reduced plasma LPC levels have been linked to stroke occurrence and poor outcomes, positioning LPC as a potential prognostic or diagnostic marker. Nonetheless, the connection between plasma LPC levels and stroke severity remains unclear. This study aimed to elucidate this relationship by examining plasma LPC levels in conjunction with brain LPC levels to provide a deeper understanding of the underlying mechanisms. Adult male Sprague-Dawley rats underwent transient middle cerebral artery occlusion and were randomly assigned to different groups (sham-operated, vehicle, LPC supplementation, or LPC inhibition). We measured multiple LPC species in the plasma and brain, alongside assessing sensorimotor dysfunction, cerebral perfusion, lesion volume, and markers of BBB damage, inflammation, apoptosis, and oxidative stress. Among five LPC species, plasma LPC(16:0) and LPC(18:1) showed strong correlations with sensorimotor dysfunction, lesion severity, and mechanistic biomarkers in the rat stroke model. Despite notable discrepancies between plasma and brain LPC levels, both were strongly linked to functional outcomes and mechanistic biomarkers, suggesting that LPC's prognostic value is retained extracranially. This study advances the understanding of LPC as a blood marker in ischemic stroke and highlights directions for future research to further elucidate its association with stroke severity, particularly through investigations in more clinically representative models.

Background: Acute liver injury (ALI) that progresses into acute liver failure (ALF) is a life-threatening condition with an increasing incidence and associated costs. Acetaminophen (N-acetyl-p-aminophenol, APAP) overdosing is among the leading causes of ALI and ALF in the Northern Hemisphere. Brain dysfunction defined as hepatic encephalopathy is one of the main diagnostic criteria for ALF. While neuroinflammation and brain metabolic alterations significantly contribute to hepatic encephalopathy, their evaluation at early stages of ALI remained challenging. To provide insights, we utilized post-mortem analysis and non-invasive brain micro positron emission tomography (microPET) imaging of mice with APAP-induced ALI., Methods: Male C57BL/6 mice were treated with vehicle or APAP (600 mg/kg, i.p.). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver damage (using H&E staining), hepatic and serum IL-6 levels, and hippocampal IBA1 (using immunolabeling) were evaluated at 24h and 48h. Vehicle and APAP treated animals also underwent microPET imaging utilizing a dual tracer approach, including [ 11 C]-peripheral benzodiazepine receptor ([ 11 C]PBR28) to assess microglia/astrocyte activation and [ 18 F]-fluoro-2-deoxy-2-D-glucose ([ 18 F]FDG) to assess energy metabolism. Brain images were pre-processed and evaluated using conjunction and individual tracer uptake analysis., Results: APAP-induced ALI and hepatic and systemic inflammation were detected at 24h and 48h by significantly elevated serum ALT and AST levels, hepatocellular damage, and increased hepatic and serum IL-6 levels. In parallel, increased microglial numbers, indicative for neuroinflammation were observed in the hippocampus of APAP-treated mice. MicroPET imaging revealed overlapping increases in [ 11 C]PBR28 and [ 18 F]FDG uptake in the hippocampus, thalamus, and habenular nucleus indicating microglial/astroglial activation and increased energy metabolism in APAP-treated mice (vs. vehicle-treated mice) at 24h. Similar significant increases were also found in the hypothalamus, thalamus, and cerebellum at 48h. The individual tracer uptake analyses (APAP vs vehicle) at 24h and 48h confirmed increases in these brain areas and indicated additional tracer- and region-specific effects including hippocampal alterations., Conclusion: Peripheral manifestations of APAP-induced ALI in mice are associated with brain neuroinflammatory and metabolic alterations at relatively early stages of disease progression, which can be non-invasively evaluated using microPET imaging and conjunction analysis. These findings support further PET-based investigations of brain function in ALI/ALF that may inform timely therapeutic interventions.

Background: Scaphoid nonunion advanced collapse (SNAC) injuries are frequently associated with irreversible degenerative wrist arthritic changes that necessitate surgical intervention. Midcarpal fusion remains the mainstay of the management of SNAC II and III injuries. A successful four-corner fusion (4CF) relies on a stable lunate-capitate fusion (LCF). There have been reports of management relying solely on LCF. The outcomes of LC- and 4 C-fusions in SNAC injuries were not widely documented. The objective of this research is to provide valuable insights into the effectiveness of both fusion procedures in the management of SNAC II and III wrist injuries, with a focus on reporting associated complications, functional and radiological outcomes., Patients and Methods: This retrospective study encompassed 65 patients diagnosed with SNAC II and III wrist injuries who underwent limited wrist fusion procedures between 2015 and 2024, with a minimum of 2 years of postoperative follow-up. Exclusion criteria encompassed patients with carpal instability, prior wrist surgical interventions, and scapholunate advanced collapse. Following the fusion procedure performed, patients were stratified into two groups: the LCF group consisting of 31 patients, and the 4CF group comprising 34 patients. Preoperative and intraoperative data were retrieved from the patient's medical records. At their final follow-up appointments, patients underwent comprehensive radiographic and clinical evaluations. Clinical outcomes including hand grip strength, range of motion, the Disabilities of the Arm, Shoulder, and Hand Score, and the Mayo Modified Wrist Score, were compared between groups. Any associated complications were reported., Results: The average healing time was 74.7 ± 15.6 and 72.2 ± 13.2 days for the LCF and 4CF groups, respectively. At the final visit, all patients showed functional improvement relative to their preoperative status, with comparable wrist range of motions observed in both groups. The functional wrist scores were slightly better in the LCF patients (P > 0.05). The average grip strength was significantly greater in the LCF group (P = 0.04), with mean strength values of 86.8% and 82.1% of the contralateral side, for the LCF and 4CF groups, respectively., Conclusion: The LCF is not less efficient than the 4CF in the treatment of SNAC II and III wrist injuries. Through a less time-consuming procedure, LCF can efficiently provide comparable results to 4CF., Level of Evidence: level IV evidence., (© 2024. The Author(s).)

Background: Inflammation is pathogenically implicated in pulmonary arterial hypertension; however, it has not been adequately targeted therapeutically. We investigated whether neuromodulation of an anti-inflammatory neuroimmune pathway involving the splenic nerve using noninvasive, focused ultrasound stimulation of the spleen (sFUS) can improve experimental pulmonary hypertension., Methods: Pulmonary hypertension was induced in rats either by Sugen 5416 (20 mg/kg SQ) injection, followed by 21 (or 35) days of hypoxia (sugen/hypoxia model), or by monocrotaline (60 mg/kg IP) injection (monocrotaline model). Animals were randomized to receive either 12-minute-long sessions of sFUS daily or sham stimulation for 14 days. Catheterizations, echocardiography, indices of autonomic function, lung and heart histology and immunohistochemistry, spleen flow cytometry, and lung single-cell RNA sequencing were performed after treatment to assess the effects of sFUS., Results: Splenic denervation right before induction of pulmonary hypertension results in a more severe disease phenotype. In both sugen/hypoxia and monocrotaline models, sFUS treatment reduces right ventricular systolic pressure by 25% to 30% compared with sham treatment, without affecting systemic pressure, and improves right ventricular function and autonomic indices. sFUS reduces wall thickness, apoptosis, and proliferation in small pulmonary arterioles, suppresses CD3 + and CD68 + cell infiltration in lungs and right ventricular fibrosis and hypertrophy and lowers BNP (brain natriuretic peptide). Beneficial effects persist for weeks after sFUS discontinuation and are more robust with early and longer treatment. Splenic denervation abolishes sFUS therapeutic benefits. sFUS partially normalizes CD68 + and CD8 + T-cell counts in the spleen and downregulates several inflammatory genes and pathways in nonclassical and classical monocytes and macrophages in the lung. Differentially expressed genes in those cell types are significantly enriched for human pulmonary arterial hypertension-associated genes., Conclusions: sFUS causes dose-dependent, sustained improvement of hemodynamic, autonomic, laboratory, and pathological manifestations in 2 models of experimental pulmonary hypertension. Mechanistically, sFUS normalizes immune cell populations in the spleen and downregulates inflammatory genes and pathways in the lung, many of which are relevant in human disease., Competing Interests: Disclosures None.

Objectives: Low-intensity, focused ultrasound (FUS) is an emerging noninvasive neuromodulation approach, with improved spatial and temporal resolution and penetration depth compared to other noninvasive electrical stimulation strategies. FUS has been used to modulate circuits in the brain and the peripheral nervous system, however, its potential to modulate spinal circuits is unclear. In this study, we assessed the effect of trans-spinal FUS (tsFUS) on spinal reflexes in healthy rats., Materials and Methods: tsFUS targeting different spinal segments was delivered for 1 minute, under anesthesia. Monosynaptic H-reflex of the sciatic nerve, polysynaptic flexor reflex of the sural nerve, and withdrawal reflex tested with a hot plate were measured before, during, and after tsFUS., Results: tsFUS reversibly suppresses the H-reflex in a spinal segment-, acoustic pressure- and pulse-repetition frequency (PRF)-dependent manner. tsFUS with high PRF augments the degree of homosynaptic depression of the H-reflex observed with paired stimuli. It suppresses the windup of components of the flexor reflex associated with slower, C-afferent, but not faster, A- afferent fibers. Finally, it increases the latency of the withdrawal reflex. tsFUS does not elicit neuronal loss in the spinal cord., Conclusions: Our study provides evidence that tsFUS reversibly suppresses spinal reflexes and suggests that tsFUS could be a safe and effective strategy for spinal cord neuromodulation in disorders associated with hyperreflexia, including spasticity after spinal cord injury and painful syndromes., Competing Interests: Conflict of Interest The authors reported no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The outcomes of traumatic brain injury (TBI) exhibit variance contingent upon biological sex. Although female sex hormones exert neuroprotective effects, the administration of estrogen and progesterone has not yielded conclusive results. Hence, it is conceivable that additional mediators, distinct from female sex hormones, merit consideration due to their potential differential impact on TBI outcomes. Calcitonin gene-related peptide (CGRP) exhibits sexually dimorphic expression and demonstrates neuroprotective effects in acute brain injuries. In this study, we aimed to examine sex-based variations in TBI structural and functional outcomes with respect to CGRP expression., Methods: Male and female Sprague Dawley rats were exposed to controlled cortical impact to induce severe TBI, followed by interventions with and without CGRP inhibition. In the acute phase of TBI, the study centered on elucidating the influence of CGRP on oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) and endothelial nitric oxide synthase (eNOS) signaling in the peri-impact tissue. Subsequently, during the chronic phase of TBI, the investigation expanded to evaluate CGRP expression in relation to lesion volume, microvascular dysfunction, and white matter injury, as well as working and spatial memory, anxiety-like, and depression-like behaviors in subjects of both sexes., Results: Female rats exhibited elevated levels of CGRP in the peri-impact brain tissue during both baseline conditions and in the acute and chronic phases of TBI, in comparison to age-matched male counterparts. Enhanced CGRP levels in specific brain sub-regions among female rats correlated with superior structural and functional outcomes following TBI compared to their male counterparts. CGRP inhibition induced heightened oxidative stress and a reduction in the expression of Nrf2 and eNOS in both male and female rats, with the observed alteration being more pronounced in females than in males., Conclusions: This study marks the inaugural identification of CGRP as a downstream mediator contributing to the sexually dimorphic response observed in TBI outcomes., (© 2024. The Author(s).)

Acetylcholine is produced in the spleen in response to vagus nerve activation; however, the effects on antibody production have been largely unexplored. Here, we use a chronic vagus nerve stimulation (VNS) mouse model to study the effect of VNS on T-dependent B cell responses. We observed lower titers of high-affinity IgG and fewer antigen-specific germinal center (GC) B cells. GC B cells from chronic VNS mice exhibited altered mRNA and protein expression suggesting increased apoptosis and impaired plasma cell differentiation. Follicular dendritic cell (FDC) cluster dispersal and altered gene expression suggested poor function. The absence of acetylcholine-producing CD4 + T cells diminished these alterations. In vitro studies revealed that α7 and α9 nicotinic acetylcholine receptors (nAChRs) directly regulated B cell production of TNF, a cytokine crucial to FDC clustering. α4 nAChR inhibited coligation of CD19 to the B cell receptor, presumably decreasing B cell survival. Thus, VNS-induced GC impairment can be attributed to distinct effects of nAChRs on B cells.

Introduction: Acupuncture is commonly used to treat chronic pain. Patients often access public social media platforms for healthcare information when querying acupuncture. Our study aims to appraise the utility, accuracy, and quality of information available on YouTube, a popular social media platform, on acupuncture for chronic pain treatment., Methods: Using search terms such as "acupuncture for chronic pain" and "acupuncture pain relief", the top 54 videos by view count were selected. Included videos were >1 minute duration, contained audio in English, had >7000 views, and was related to acupuncture. One primary outcome of interest was categorizing each video's usefulness as useful, misleading, or neither. Another primary outcome of interest was the quality and reliability of each video using validated instruments, including the modified DISCERN (mDISCERN) tool and the Global Quality Scale (GQS). The means were calculated for the video production characteristics, production sources, and mDISCERN and GQS scores. Continuous and categorical outcomes were compared using Student's t -test and chi-square test, respectively., Results: Of the 54 videos, 57.4% were categorized as useful, 14.8% were misleading, and 27.8% were neither. Useful videos had a mean GQS and mDISCERN score of 3.77±0.67 and 3.48±0.63, respectively, while misleading videos had mean GQS and mDISCERN score of 2.50±0.53 and 2.38±0.52, respectively. 41.8% of the useful videos were produced by a healthcare institution while none of the misleading videos were produced by a healthcare institution. However, 87.5% of the misleading videos were produced by health media compared to only 25.8% of useful videos from health media., Discussion: As patients increasingly depend on platforms like YouTube for trustworthy information on complementary health practices such as acupuncture, our study emphasizes the critical need for more higher-quality videos from unbiased healthcare institutions and physicians to ensure patients are receiving reliable information regarding this topic., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Greer et al.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in multiple inflammatory and non-inflammatory diseases, including liver injury induced by acetaminophen (APAP) overdose. Multiple small molecule inhibitors of MIF have been described, including the clinically available anti-rheumatic drug T-614 (iguratimod); however, this drug's mode of inhibition has not been fully investigated., Methods: We conducted in vitro testing including kinetic analysis and protein crystallography to elucidate the interactions between MIF and T-614. We also performed in vivo experiments testing the efficacy of T-614 in a murine model of acetaminophen toxicity. We analyzed survival in lethal APAP overdose with and without T-614 and using two different dosing schedules of T-614. We also examined MIF and MIF inhibition effects on hepatic hydrogen peroxide (H 2 O 2 ) as a surrogate of oxidative stress in non-lethal APAP overdose., Results: Kinetic analysis was consistent with a non-competitive type of inhibition and an inhibition constant (K i ) value of 16 µM. Crystallographic analysis revealed that T-614 binds outside of the tautomerase active site of the MIF trimer, with only the mesyl group of the molecule entering the active site pocket. T-614 improved survival in lethal APAP overdose when given prophylactically, but this protection was not observed when the drug was administered late (6 h after APAP). T-614 also decreased hepatic hydrogen peroxide concentrations during non-lethal APAP overdose in a MIF-dependent fashion., Conclusions: T-614 is an allosteric inhibitor of MIF that prevented death and decreased hepatic hydrogen peroxide concentrations when given prophylactically in a murine model of acetaminophen overdose. Further studies are needed to elucidate the mechanistic role of MIF in APAP toxicity., (© 2024. The Author(s).)

Antiviral therapy based on neuraminidase (oseltamivir) or polymerase (baloxavir marboxil) inhibitors plays an important role in the management of influenza infections. However, the emergence of drug resistance and the uncontrolled inflammatory response are major limitations in the treatment of severe influenza disease. Protectins D1 (PD1) and DX (PDX), part of a family of pro-resolving mediators, have previously demonstrated anti-influenza activity as well as anti-inflammatory properties in various clinical contexts. Herein, we synthetized a series of simplified PDX analogs and assessed their in vitro antiviral activity against influenza A(H1N1) viruses, including oseltamivir- and baloxavir-resistant variants. In ST6GalI-MDCK cells, the PDX analog AN-137B reduced viral replication in a dose-dependent manner with IC 50 values of 23.8 for A/Puerto Rico/8/1934 (H1N1) and between 32.6 and 36.7 µM for susceptible and resistant A(H1N1)pdm09 viruses. In MTS-based cell viability experiments, AN-137B showed a 50% cellular cytotoxicity (CC 50 ) of 638.7 µM with a resulting selectivity index of 26.8. Of greater importance, the combination of AN-137B with oseltamivir or baloxavir resulted in synergistic and additive in vitro effects, respectively. Treatment of lipopolysaccharide (LPS)-stimulated macrophages with AN-137B resulted in a decrease of iNOS activity as shown by the reduction of nitrite production, suggesting an anti-inflammatory effect. In conclusion, our results indicate that the protectin analog AN-137B constitutes an interesting therapeutic modality against influenza A virus, warranting further evaluation in animal models., (© 2024 Wiley Periodicals LLC.)

Introduction: Antenatal care is an essential component of primary healthcare, providing opportunities to screen, prevent, and treat morbidity to preserve the health of mothers and offspring. The World Health Organization now recommends a minimum of eight antenatal care contacts, instead of four, which is challenging in countries exposed to political violence and structural disparities in access to social, economic and healthcare resources as exist in Palestine. This study examines the compliance of the recommend standard of antenatal care in Palestine., Methods: We analyzed data from the UNICEF's Palestinian Multiple Indicator Cluster Survey (MICS) 2019-2020. The eligible sample consisted of 2,028 women, 15-49 years of age, living in Palestine, on whom data were available on reported antenatal care services received during the most recent pregnancy within the last two years. Outcome variables of interest were the reported frequencies of antenatal care visits, gestational timing of 1st visit, and services received. Potential risk factors were assessed in women attending less than eight versus eight or more antenatal contacts, as recommended by WHO, by estimating prevalence ratios with 95% Confidence Intervals., Results: Overall, 28% of women did not meet the WHO's recommendation of eight or more antenatal contacts, varying from 18% in Central West Bank to 33% in South West Bank across the four areas of Palestine (North, Central, and South West Bank and Gaza Strip). Twelve percent of women reported having had no antenatal contacts in the 1st trimester, and these women were two- to three-folds more unlikely to meet WHO recommendation of antenatal contacts than mothers who initiated the antenatal contact in the 1st trimester. Women who had less than eight antenatal contacts were generally poorer, higher in parity, lived in North and South West Bank, sought ANC from either doctor or nurse/midwife only, and initiated antenatal contact in 2nd-to-3rd trimesters., Conclusion: There were considerable socioeconomic and geographic inequalities in the prevalence of not meeting WHO recommended number of antenatal contacts in Palestine, offering the opportunity to inform, improve and continuously reassess coverage of antenatal care., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Horino et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Nearly 5 decades ago, the effect of trigeminal nerve stimulation (TNS) on cerebral blood flow was observed for the first time. This implication directly led to further investigations and TNS' success as a therapeutic intervention. Possessing unique connections with key brain and brainstem regions, TNS has been observed to modulate cerebral vasodilation, brain metabolism, cerebral autoregulation, cerebral and systemic inflammation, and the autonomic nervous system. The unique range of effects make it a prime therapeutic modality and have led to its clinical usage in chronic conditions such as migraine, prolonged disorders of consciousness, and depression. This review aims to present a comprehensive overview of TNS research and its broader therapeutic potentialities. For the purpose of this review, PubMed and Google Scholar were searched from inception to August 28, 2023 to identify a total of 89 relevant studies, both clinical and pre-clinical. TNS harnesses the release of vasoactive neuropeptides, modulation of neurotransmission, and direct action upon the autonomic nervous system to generate a suite of powerful multitarget therapeutic effects. While TNS has been applied clinically to chronic pathological conditions, these powerful effects have recently shown great potential in a number of acute/traumatic pathologies. However, there are still key mechanistic and methodologic knowledge gaps to be solved to make TNS a viable therapeutic option in wider clinical settings. These include bimodal or paradoxical effects and mechanisms, questions regarding its safety in acute/traumatic conditions, the development of more selective stimulation methods to avoid potential maladaptive effects, and its connection to the diving reflex, a trigeminally-mediated protective endogenous reflex. The address of these questions could overcome the current limitations and allow TNS to be applied therapeutically to an innumerable number of pathologies, such that it now stands at the precipice of becoming a ground-breaking therapeutic modality., (© 2023. The Author(s).)

Background: The noradrenergic innervation of the spleen is implicated in the autonomic control of inflammation and has been the target of neurostimulation therapies for inflammatory diseases. However, there is no real-time marker of its successful activation, which hinders the development of anti-inflammatory neurostimulation therapies and mechanistic studies in anti-inflammatory neural circuits., Methods: In mice, we performed fast-scan cyclic voltammetry (FSCV) in the spleen during intravenous injections of norepinephrine (NE), and during stimulation of the vagus, splanchnic, or splenic nerves. We defined the stimulus-elicited charge generated at the oxidation potential for NE (~ 0.88 V) as the "NE voltammetry signal" and quantified the dependence of the signal on NE dose and intensity of neurostimulation. We correlated the NE voltammetry signal with the anti-inflammatory effect of splenic nerve stimulation (SpNS) in a model of lipopolysaccharide- (LPS) induced endotoxemia, quantified as suppression of TNF release., Results: The NE voltammetry signal is proportional to the estimated peak NE blood concentration, with 0.1 μg/mL detection threshold. In response to SpNS, the signal increases within seconds, returns to baseline minutes later, and is blocked by interventions that deplete NE or inhibit NE release. The signal is elicited by efferent, but not afferent, electrical or optogenetic vagus nerve stimulation, and by splanchnic nerve stimulation. The magnitude of the signal during SpNS is inversely correlated with subsequent TNF suppression in endotoxemia and explains 40% of the variance in TNF measurements., Conclusions: FSCV in the spleen provides a marker for real-time monitoring of anti-inflammatory activation of the splenic innervation during autonomic stimulation., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The emerging field of bioelectronic medicine (BEM) is poised to make a significant impact on the treatment of several neurological and inflammatory disorders. With several BEM therapies being recently approved for clinical use and others in late-phase clinical trials, the 2022 BEM summit was a timely scientific meeting convening a wide range of experts to discuss the latest developments in the field. The BEM Summit was held over two days in New York with more than thirty-five invited speakers and panelists comprised of researchers and experts from both academia and industry. The goal of the meeting was to bring international leaders together to discuss advances and cultivate collaborations in this emerging field that incorporates aspects of neuroscience, physiology, molecular medicine, engineering, and technology. This Meeting Report recaps the latest findings discussed at the Meeting and summarizes the main developments in this rapidly advancing interdisciplinary field. Our hope is that this Meeting Report will encourage researchers from academia and industry to push the field forward and generate new multidisciplinary collaborations that will form the basis of new discoveries that we can discuss at the next BEM Summit., (© 2023. Feinstein Institute for Medical Research.)

Background: Cardiac arrest (CA) can lead to neuronal degeneration and death through various pathways, including oxidative, inflammatory, and metabolic stress. However, current neuroprotective drug therapies will typically target only one of these pathways, and most single drug attempts to correct the multiple dysregulated metabolic pathways elicited following cardiac arrest have failed to demonstrate clear benefit. Many scientists have opined on the need for novel, multidimensional approaches to the multiple metabolic disturbances after cardiac arrest. In the current study, we have developed a therapeutic cocktail that includes ten drugs capable of targeting multiple pathways of ischemia-reperfusion injury after CA. We then evaluated its effectiveness in improving neurologically favorable survival through a randomized, blind, and placebo-controlled study in rats subjected to 12 min of asphyxial CA, a severe injury model., Results: 14 rats were given the cocktail and 14 received the vehicle after resuscitation. At 72 h post-resuscitation, the survival rate was 78.6% among cocktail-treated rats, which was significantly higher than the 28.6% survival rate among vehicle-treated rats (log-rank test; p = 0.006). Moreover, in cocktail-treated rats, neurological deficit scores were also improved. These survival and neurological function data suggest that our multi-drug cocktail may be a potential post-CA therapy that deserves clinical translation., Conclusions: Our findings demonstrate that, with its ability to target multiple damaging pathways, a multi-drug therapeutic cocktail offers promise both as a conceptual advance and as a specific multi-drug formulation capable of combatting neuronal degeneration and death following cardiac arrest. Clinical implementation of this therapy may improve neurologically favorable survival rates and neurological deficits in patients suffering from cardiac arrest.

Seasonal influenza A and B viruses may cause severe infections requiring therapeutic interventions. Baloxavir, the latest antiviral drug approved against those infections, targets the endonuclease activity encoded by the polymerase acidic (PA) protein. While appearing effective at cessation of viral shedding, baloxavir demonstrated a low barrier of resistance. Herein, we aimed to assess the impact of PA-I38T substitution, a major marker of baloxavir-resistance, on the fitness of contemporary influenza B viruses. Recombinant wild-type (WT) influenza B/Phuket/2073/13 (B/Yamagata/16/88-like) and B/Washington/02/19 (B/Victoria/2/87-like) viruses and their respective PA-I38T mutants were used to evaluate replication kinetics in vitro, using A549 and Calu3 cells, and ex vivo, using nasal human airway epithelium (HAE) cells. Infectivity was also assessed in guinea pigs. In the B/Washington/02/19 background, there were no major differences between the recombinant WT virus and its I38T mutant when viral replication kinetics were evaluated in human lung cell lines and HAE as well as in nasal washes of experimentally infected guinea pigs. By contrast, the I38T mutation moderately impacted the B/Phuket/2073/13 viral fitness. In conclusion, contemporary influenza B viruses that may acquire baloxavir-resistance through the PA-I38T substitution could retain a significant level of fitness, highlighting the importance of monitoring the emergence of such variant.

Objective: This study aimed to analyse the patterns of the irrational use of medicines in Arab countries and to determine the factors contributing to these patterns., Methods: A systematic literature review was conducted using two major databases: PubMed and Scopus. The systematic search targeted original studies conducted in Arab countries from 2000 to 2019. A conceptual framework was adopted from a previous study and was utilized to assess the irrational use of medicines and its influencing factors., Results: A total of 136 studies from 16 Arab countries were included. Almost all were cross-sectional studies. Most focused on evaluating the irrational use of medicines rather than investigating the cause. The number of medications per encounter was 2.3 which is within the limits of developed countries (2.7). The percentage of antibiotics per 100 encounter was 50.1% and the percentage of injections prescribed per 100 encounter was 15.2%. The consumption of antibiotic and injections was much higher than that recommended by WHO. At the same time, the review identified that one fourth of all medications were unnecessarily prescribed., Summary: The literature review revealed that the irrational use of medicine is prevalent in most Arab countries. Excessive use of antibiotics was the most commonly observed pattern. Therefore, there is a need to conduct further research to identify the factors that drive the irrational use of medicines in Arab countries and then to make recommendations to mitigate this issue., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Vagal fibers travel inside fascicles and form branches to innervate organs and regulate organ functions. Existing vagus nerve stimulation (VNS) therapies activate vagal fibers non-selectively, often resulting in reduced efficacy and side effects from non-targeted organs. The transverse and longitudinal arrangement of fibers inside the vagal trunk with respect to the functions they mediate and organs they innervate is unknown, however it is crucial for selective VNS. Using micro-computed tomography imaging, we tracked fascicular trajectories and found that, in swine, sensory and motor fascicles are spatially separated cephalad, close to the nodose ganglion, and merge caudad, towards the lower cervical and upper thoracic region; larynx-, heart- and lung-specific fascicles are separated caudad and progressively merge cephalad. Using quantified immunohistochemistry at single fiber level, we identified and characterized all vagal fibers and found that fibers of different morphological types are differentially distributed in fascicles: myelinated afferents and efferents occupy separate fascicles, myelinated and unmyelinated efferents also occupy separate fascicles, and small unmyelinated afferents are widely distributed within most fascicles. We developed a multi-contact cuff electrode to accommodate the fascicular structure of the vagal trunk and used it to deliver fascicle-selective cervical VNS in anesthetized and awake swine. Compound action potentials from distinct fiber types, and physiological responses from different organs, including laryngeal muscle, cough, breathing, and heart rate responses are elicited in a radially asymmetric manner, with consistent angular separations that agree with the documented fascicular organization. These results indicate that fibers in the trunk of the vagus nerve are anatomically organized according to functions they mediate and organs they innervate and can be asymmetrically activated by fascicular cervical VNS., Competing Interests: Declaration of competing of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Autoinflammatory diseases, a diverse group of inherited conditions characterized by excessive innate immune activation, have limited therapeutic options. Neuroimmune circuits of the inflammatory reflex control innate immune overactivation and can be stimulated to treat disease using the acetylcholinesterase inhibitor galantamine., Methods: We tested the efficacy of galantamine in a rodent model of the prototypical autoinflammatory disease familial Mediterranean fever (FMF). Multiple chronic disease markers were evaluated in animals that received long-term galantamine treatment compared to vehicle., Results: Long-term treatment with galantamine attenuated the associated splenomegaly and anemia which are characteristic features of this disease. Further, treatment reduced inflammatory cell infiltration into affected organs and a subcutaneous air pouch., Conclusions: These findings suggest that galantamine attenuates chronic inflammation in this mouse model of FMF. Further research is warranted to explore the therapeutic potential of galantamine in FMF and other autoinflammatory diseases., (© 2022. The Author(s).)

Purpose: This study aimed to explore the perspectives of policymakers and patients on breast cancer (BC) management in the Gaza Strip., Methods: A descriptive qualitative study design was employed using semi-structured in-depth interviews with 13 policymakers and focus group discussions with 19 BC patients. The four criteria presented by Lincoln and Guba were used to evaluate the validity and reliability. Data were analysed using conventional content analysis approach., Results: Three categories were generated from the qualitative data analysis: (1) limited human resources in the BC management, (2) inadequate institutional level service provision in the BC management, and (3) a lack of policy level support for the BC management. The current health services provided to Gazan BC patients are either fragmented or partially unavailable. The roles and responsibilities at the policy, system and individual levels were ambiguous. Policymakers attributed the fragmented BC services to the shortage of qualified healthcare professionals, inadequate training programmes for the staff, and lack of coordination among health institutions. Some patients expressed an insufficient knowledge about cancer screening tests, while others ignored screening for cultural reasons., Conclusion: Gaza's BC services are fragmented and not well-organised and they have received inadequate attention at the leadership and governance levels. The government in the Gaza Strip should strengthen its leadership to upgrade and develop the policies and strategies necessary for proper BC management, including an improved information system and cooperation with national and international institutions to secure funding for developing BC services and ensure medication availability., Competing Interests: Declaration of competing interest The authors declare that there are no potential conflicts of interest with respect to research, authorship, financial interests or publication of this article., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Brain metabolic alterations and neuroinflammation have been reported in several peripheral inflammatory conditions and present significant potential for targeting with new diagnostic approaches and treatments. However, non-invasive evaluation of these alterations remains a challenge., Methods: Here, we studied the utility of a micro positron emission tomography (microPET) dual tracer ([ 11 C]PBR28 - for microglial activation and [ 18 F]FDG for energy metabolism) approach to assess brain dysfunction, including neuroinflammation in murine endotoxemia. MicroPET imaging data were subjected to advanced conjunction and individual analyses, followed by post-hoc analysis., Results: There were significant increases in [ 11 C]PBR28 and [ 18 F]FDG uptake in the hippocampus of C57BL/6 J mice 6 h following LPS (2 mg/kg) intraperitoneal (i.p.) administration compared with saline administration. These results confirmed previous postmortem observations. In addition, patterns of significant simultaneous activation were demonstrated in the hippocampus, the thalamus, and the hypothalamus in parallel with other tracer-specific and region-specific alterations. These changes were observed in the presence of robust systemic inflammatory responses manifested by significantly increased serum cytokine levels., Conclusions: Together, these findings demonstrate the applicability of [ 11 C]PBR28 - [ 18 F]FDG dual tracer microPET imaging for assessing neuroinflammation and brain metabolic alterations in conditions "classically" characterized by peripheral inflammatory and metabolic pathogenesis., (© 2022. The Author(s).)

Peptides, polymers of amino acids, comprise a vital and expanding therapeutic approach. Their rapid degradation by proteases, however, represents a major limitation to their therapeutic utility and chemical modifications to native peptides have been employed to mitigate this weakness. Herein, we describe functionalized thiocarbazate scaffolds as precursors of aza-amino acids, that, upon activation, can be integrated in a peptide sequence to generate azapeptides using conventional peptide synthetic methods. This methodology facilitates peptide editing-replacing targeted amino acid(s) with aza-amino acid(s) within a peptide-to form azapeptides with preferred therapeutic characteristics (extending half-life/bioavailability, while at the same time typically preserving structural features and biological activities). We demonstrate the convenience of this azapeptide synthesis platform in two well-studied peptides with short half-lives: FSSE/P5779, a tetrapeptide inhibitor of HMGB1/MD-2/TLR4 complex formation, and bradykinin, a nine-residue vasoactive peptide. This bench-stable thiocarbazate platform offers a robust and universal approach to optimize peptide-based therapeutics., (© 2022. The Author(s).)

Background: Vagal reflexes regulate homeostasis in visceral organs and systems through afferent and efferent neurons and nerve fibers. Small, unmyelinated, C-type afferents comprise over 80% of fibers in the vagus and form the sensory arc of autonomic reflexes of the gut, lungs, heart and vessels and the immune system. Selective bioelectronic activation of C-afferents could be used to mechanistically study and treat diseases of peripheral organs in which vagal reflexes are involved, but it has not been achieved., Methods: We stimulated the vagus in rats and mice using trains of kHz-frequency stimuli. Stimulation effects were assessed using neuronal c-Fos expression, physiological and nerve fiber responses, optogenetic and computational methods., Results: Intermittent kHz stimulation for 30 min activates specific motor and, preferentially, sensory vagus neurons in the brainstem. At sufficiently high frequencies (>5 kHz) and at intensities within a specific range (7-10 times activation threshold, T, in rats; 15-25 × T in mice), C-afferents are activated, whereas larger, A- and B-fibers, are blocked. This was determined by measuring fiber-specific acute physiological responses to kHz stimulus trains, and by assessing fiber excitability around kHz stimulus trains through compound action potentials evoked by probing pulses. Aspects of selective activation of C-afferents are explained in computational models of nerve fibers by how fiber size and myelin shape the response of sodium channels to kHz-frequency stimuli., Conclusion: kHz stimulation is a neuromodulation strategy to robustly and selectively activate vagal C-afferents implicated in physiological homeostasis and disease, over larger vagal fibers., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SZ and YCC have a provisional patent application that includes aspects of the research presented in this paper. The other authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Baloxavir marboxil (BXM) is an antiviral drug that targets the endonuclease of the influenza polymerase acidic (PA) protein. Antiviral resistance, mainly mediated by the I38T PA substitution, readily occurs in both A(H1N1) and A(H3N2) viruses following a single dose of BXM. Influenza B resistance to BXM remains poorly documented. We aimed to generate baloxavir-resistant contemporary influenza B/Yamagata/16/1988- and B/Victoria/2/1987-like viruses by in vitro passages under baloxavir acid (BXA) pressure to identify resistance mutations and to characterize the fitness of drug-resistant variants. Influenza B/Phuket/3073/2013 recombinant virus (rg-PKT13, a B/Yamagata/16/1988-like virus) and B/Quebec/MCV-11/2019 (MCV19, a B/Victoria/2/1987-like isolate) were passaged in ST6GalI-MDCK cells in the presence of increasing concentrations of BXA. At defined passages, viral RNA was extracted for sequencing the PA gene. The I38T PA substitution was selected in MCV19 after six passages in presence of BXA whereas no PA change was detected in rg-PKT13. The I38T substitution increased the BXA IC 50 value by 13.7-fold in the MCV19 background and resulted in reduced viral titers compared to the wild type (WT) at early time points in ST6GalI-MDCK and at all time-points in human epithelial cells. By contrast, the I38T substitution had no impact on MCV19 polymerase activity, and this mutation was genetically stable over four passages. In conclusion, our results show a similar pathway of resistance to BXA in influenza B viruses highlighting the major role of the I38T PA substitution and suggest that I38T may differently impact the fitness of influenza variants depending on the viral type, subtype, or lineage.

Anemia of inflammation, also known as anemia of chronic disease, is refractory to erythropoietin (EPO) treatment, but the mechanisms underlying the EPO refractory state are unclear. Here, we demonstrate that high mobility group box-1 protein (HMGB1), a damage-associated molecular pattern molecule recently implicated in anemia development during sepsis, leads to reduced expansion and increased death of EPO-sensitive erythroid precursors in human models of erythropoiesis. HMGB1 significantly attenuates EPO-mediated phosphorylation of the Janus kinase 2/STAT5 and mTOR signaling pathways. Genetic ablation of receptor for advanced glycation end products, the only known HMGB1 receptor expressed by erythroid precursors, does not rescue the deleterious effects of HMGB1 on EPO signaling, either in human or murine precursors. Furthermore, surface plasmon resonance studies highlight the ability of HMGB1 to interfere with the binding between EPO and the EPOR. Administration of a monoclonal anti-HMGB1 antibody after sepsis onset in mice partially restores EPO signaling in vivo. Thus, HMGB1-mediated restriction of EPO signaling contributes to the chronic phase of anemia of inflammation., (© 2022 by The American Society of Hematology.)

Novel research in the field of bioelectronic medicine requires neuromodulation systems that pair high-performance neurostimulation and bio-signal acquisition hardware with advanced signal processing and control algorithms. Although mice are the most commonly used animal in medical research, the size, weight, and power requirements of such bioelectronic systems either preclude use in mice or impose significant constraints on experimental design. Here, a fully-implantable recording and stimulation neuromodulation system suitable for use in mice is presented, measuring 2.2 cm 3 and weighing 2.8 g. The bidirectional wireless interface allows simultaneous readout of multiple physiological signals and complete control over stimulation parameters, and a wirelessly rechargeable battery provides a lifetime of up to 5 days on a single charge. The device was implanted to deliver vagus nerve stimulation (n = 12 animals) and a functional neural interface (capable of inducing acute bradycardia) was demonstrated with lifetimes exceeding three weeks. The design utilizes only commercially-available electrical components and 3D-printed packaging, with the goal of facilitating widespread adoption and accelerating discovery and translation of future bioelectronic therapeutics., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Hepatic ischemia and reperfusion (I/R) injury is commonly associated with surgical liver resection or transplantation, and represents a major cause of liver damage and graft failure. Currently, there are no effective therapies to prevent hepatic I/R injury other than ischemic preconditioning and some preventative strategies. Previously, we have revealed the anti-inflammatory activity of a sweat gland-derived peptide, dermcidin (DCD), in macrophage/monocyte cultures. Here, we sought to explore its therapeutic potential and protective mechanisms in a murine model of hepatic I/R., Methods: Male C57BL/6 mice were subjected to hepatic ischemia by clamping the hepatic artery and portal vein for 60 min, which was then removed to initiate reperfusion. At the beginning of reperfusion, 0.2 ml saline control or solution of DCD (0.5 mg/kg BW) or DCD-C34S analog (0.25 or 0.5 mg/kg BW) containing a Cys (C)→Ser (S) substitution at residue 34 was injected via the internal jugular vein. For survival experiments, mice were subjected to additional resection to remove non-ischemic liver lobes, and animal survival was monitored for 10 days. For mechanistic studies, blood and tissue samples were collected at 24 h after the onset of reperfusion, and subjected to measurements of various markers of inflammation and tissue injury by real-time RT-PCR, immunoassays, and histological analysis., Results: Recombinant DCD or DCD-C34S analog conferred a significant protection against lethal hepatic I/R when given intravenously at the beginning of reperfusion. This protection was associated with a significant reduction in hepatic injury, neutrophilic CXC chemokine (Mip-2) expression, neutrophil infiltration, and associated inflammation. Furthermore, the administration of DCD also resulted in a significant attenuation of remote lung inflammatory injury. Mechanistically, DCD interacted with epidermal growth factor receptor (EGFR), a key regulator of liver inflammation, and significantly inhibited hepatic I/R-induced phosphorylation of EGFR as well as a downstream signaling molecule, protein kinase B (AKT). The suppression of EGFR expression by transducing Egfr-specific shRNA plasmid into macrophages abrogated the DCD-mediated inhibition of nitric oxide (NO) production induced by a damage-associated molecular pattern (DAMP), cold-inducible RNA-binding protein, CIRP., Conclusions: The present study suggests that human DCD and its analog may be developed as novel therapeutics to attenuate hepatic I/R-induced inflammatory injury possibly by impairing EGFR signaling., Competing Interests: PW and HW are co-inventors of a patent entitled “Use of dermcidin in sterile anti-inflammatory conditions” (US15/769,800). PW is a co-founder of TheraSource LLC, which has an option to license the relevant technology. MB is a part-time employee of TheraSource LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Qiang, Li, Zhu, He, Chen, Al-Abed, Brenner, Tracey, Wang and Wang.)

For over 50 years of azapeptide synthetic techniques, developments have renewed the field of peptidomimetic therapeutics. Azapeptides are close surrogates of natural peptides: they contain a substitution of the amino acid α-carbon by a nitrogen atom. Goserelin (1989) and Atazanavir (2003) are two well-known, FDA-approved azapeptide-based drugs for the treatment of cancers and HIV infection, providing evidence for the successful clinical implementation of this class of therapeutic. This review highlights the azapeptides in recent medicinal chemistry applications and synthetic milestones. We describe the current techniques for azapeptide bond formation by introducing azapeptide coupling reagents and chain elongation methods both in solution and solid-phase strategies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The prevalence of nonalcoholic steatohepatitis (NASH) and liver cancer is increasing. De novo lipogenesis and fibrosis contribute to disease progression and cancerous transformation. Here, we found that β2-spectrin (SPTBN1) promotes sterol regulatory element (SRE)–binding protein (SREBP)–stimulated lipogenesis and development of liver cancer in mice fed a high-fat diet (HFD) or a western diet (WD). Either hepatocyte-specific knockout of SPTBN1 or siRNA-mediated therapy protected mice from HFD/WD-induced obesity and fibrosis, lipid accumulation, and tissue damage in the liver. Biochemical analysis suggested that HFD/WD induces SPTBN1 and SREBP1 cleavage by CASPASE-3 and that the cleaved products interact to promote expression of genes with sterol response elements. Analysis of human NASH tissue revealed increased SPTBN1 and CASPASE-3 expression. Thus, our data indicate that SPTBN1 represents a potential target for therapeutic intervention in NASH and liver cancer.

The polymerase acidic (PA) I38T substitution is a dominant marker of resistance to baloxavir. We evaluated the impact of I38T on the fitness of a contemporary influenza A(H3N2) virus. Influenza A/Switzerland/9715293/2013 (H3N2) wild-type (WT) virus and its I38T mutant were rescued by reverse genetics. Replication kinetics were compared using ST6GalI-MDCK and A549 cells and infectivity/contact transmissibility were evaluated in guinea pigs. Nasal wash (NW) viral titres were determined by TCID50 ml -1 in ST6GalI-MDCK cells. Competition experiments were performed and the evolution of viral population was assessed by droplet digital RT-PCR. I38T did not alter in vitro replication. I38T induced comparable titres vs the WT in guinea pigs NWs and the two viruses transmitted equally by direct contact. However, a 50 %:50 % mixture inoculum evolved to mean WT/I38T ratios of 71 %:29 % and 66.4 %:33.6 % on days 4 and 6 p.i., respectively. Contemporary influenza A(H3N2)-I38T PA variants may conserve a significant level of viral fitness.

Of the 486,000 burn injuries that required medical treatment in the United States in 2016, 40,000 people were hospitalized, with >3,000 fatalities. After burn injury, humans are at increased risk of sepsis and mortality from infections caused by Pseudomonas aeruginosa, an opportunistic pathogen. We hypothesize that systemic events were initiated from the burn that increased the host's susceptibility to P. aeruginosa. A nonlethal 10% total body surface area (TBSA), full-thickness flame burn was performed in CD-1 mice without and with subsequent P. aeruginosa (strain M2) infection. The 50% lethal dose for subcutaneous infection with P. aeruginosa M2 at the burn site immediately after the burn decreased by 6 log, with mortality occurring between 18 and 26 h, compared with P. aeruginosa-infected mice without burn injury. Bacteria in distal organs were detected by 18 h, concurrent with the onset of clinical symptoms. Serum proinflammatory cytokines (interleukin-6 [IL-6], IL-1β, gamma interferon, and tumor necrosis factor alpha) and the anti-inflammatory cytokine IL-10 were first detected at 12 h postburn with infection and continued to increase until death. Directly after burn alone, serum levels of HMGB1, a danger-associated molecular pattern and TLR4 agonist, transiently increased to 50 ng/ml before returning to 20 ng/ml. Burn with P. aeruginosa infection increased serum HMGB1 concentrations >10-fold (250 ng/ml) at the time of death. This HMGB1-rich serum stimulated TLR4-mediated NF-κB activation in a TLR4 reporter cell line. Treatment of infected burned mice with P5779, a peptide inhibitor of HMGB1, increased the mean survival from 23 to 42 h ( P  < 0.0001). We conclude that the high level of serum HMGB1, which preceded the increase in proinflammatory cytokines, is associated with postburn mortality.

Fetal hemoglobin (HbF) induction constitutes a valuable and validated approach to treat the symptoms of sickle cell disease (SCD). Here, we synthesized pomalidomide-nitric oxide (NO) donor derivatives (3a-f) and evaluated their suitability as novel HbF inducers. All compounds demonstrated different capacities of releasing NO, ranging 0.3-30.3%. Compound 3d was the most effective HbF inducer for CD34 + cells, exhibiting an effect similar to that of hydroxyurea. We investigated the mode of action of compound 3d for HbF induction by studying the in vitro alterations in the levels of transcription factors (BCL11A, IKAROS, and LRF), inhibition of histone deacetylase enzymes (HDAC-1 and HDAC-2), and measurement of cGMP levels. Additionally, compound 3d exhibited a potent anti-inflammatory effect similar to that of pomalidomide by reducing the TNF-α levels in human mononuclear cells treated with lipopolysaccharides up to 58.6%. Chemical hydrolysis studies revealed that compound 3d was stable at pH 7.4 up to 24 h. These results suggest that compound 3d is a novel HbF inducer prototype with the potential to treat SCD symptoms., (Copyright © 2021 Elsevier Inc. All rights reserved.)