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Background: There is limited data evaluating potential predictors of adherence to injection visits and the impact of late injections on viral suppression in those receiving long-acting injectable (LAI) cabotegravir/rilpivirine (CAB/RPV) for the treatment of HIV., Methods: A retrospective cohort study was conducted among adult people with HIV receiving LAI CAB/RPV for at least 6 months between May 2021 and August 2023. Data collected included demographics, office visit no-shows 1 year before switching to LAI CAB/RPV, injection visit no-shows, injections outside the dosing window, and virologic outcomes. Cox-proportional hazards regression was performed to evaluate predictors of no-show to injection visits or late injections., Results: Included were 287 people with HIV with a median follow-up time (interquartile range) of 450 days (344-548 days). Younger age [HR 0.97 (95% CI: 0.95 to 0.98)] and ≥1 office visit no-show in the year before switching to LAI CAB/RPV [HR 2.03 (1.32 to 3.12]) were associated with having a no-show to an injection visit (32.1%). Male sex assigned at birth [HR 9.18 (1.26 to 66.9)] with a trend toward younger age [HR 0.98 (0.95 to 1.0)] were associated with having a late injection (15.3%). There was no relationship between late injections and having a detectable viral load or virologic failure (n = 3) after switching to LAI CAB/RPV., Conclusions: Having office visit no-shows before switching to LAI CAB/RPV was associated with missed injection visits, and younger age was associated with both missed injection visits and late injections. Resources to reduce and manage missed injection appointments need to be considered when implementing LAI CAB/RPV., Competing Interests: L.H. is on the speaker's bureau for ViiV Healthcare. For the remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

This study aimed to identify loci (p < 1 × 10 -5 ) and gene sets (normalized enrichment score (NES) ≥ 3.0) associated with the number of times a heifer is bred to attain a successful pregnancy (TBRD) for Holstein heifers bred by artificial insemination (AI, n = 2754) or that were embryo transfer (ET, n = 1566) recipients. Eight loci were associated (p < 1 × 10 -5 ) with TBRD in AI bred heifers and four loci were associated with TBRD in ET recipients. The gene set enrichment analysis with SNP data identified one gene set enriched (NES ≥ 3.0) with TBRD in AI bred heifers and two gene sets that were enriched with TBRD in ET recipients. The estimated pseudo-heritability for times bred to AI was 0.063 and 0.043 for ET. The identification of loci associated with embryonic loss aids in the selection of Holstein heifers with higher reproductive efficiencies that are AI bred or that are ET recipients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Holly Neibergs reports financial support was provided by USDA National Institute of Food and Agriculture. If there are other authors, they 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 © 2024. Published by Elsevier Inc.)

Background: Buprenorphine is a first-line treatment for opioid use disorder (OUD), essential for reducing opioid overdose mortality and improving treatment retention. Despite federal policies that mandate the acceptance of buprenorphine in recovery residences, individuals in South Florida taking this medication often face significant barriers to admission. This study uses a secret shopper survey to examine whether federal policies regarding prescribed buprenorphine use are being violated in South Florida recovery residences., Methods: We selected recovery residences in South Florida due to the region's high opioid overdose death rate and its prominence as a recovery hub. From a list of 141 Florida Association of Recovery Residences (FARR)-certified residences in Palm Beach, Broward, and Miami-Dade, we randomly surveyed 100 programs across all treatment levels (I-IV) using a standardized script. The primary outcome was whether residences accepted individuals taking buprenorphine, classified into three categories: (1) unconditional acceptance, where any person taking buprenorphine was accepted; (2) denial, where admission was refused for all individuals taking buprenorphine; and (3) conditional acceptance, where admission was granted under specific conditions. Secondary outcomes included requirements for conditional acceptance, such as dose limits or tapering policies., Results: The distribution of the 100 surveyed recovery residences was comparable to the 141 FARR-certified facilities: 67 % were in Palm Beach, 31 % in Broward, and 2 % in Miami-Dade. Most residences (55 %) were level II certified, followed by 26 % level IV, 14 % level I, and 5 % level III. Sixteen percent of residences permitted admission of individuals taking any buprenorphine dose, 31 % had conditional policies, and 53 % prohibited buprenorphine. The maximum acceptance across all counties and levels was 20 %. No significant differences were observed by county (p = 0.61) or facility level (p = 0.29). Of 31 residences with conditional policies, 25.8 % (n = 8) required a mandatory taper, 38.7 % (n = 12) allowed a maximum 8 mg daily dosage, 12.9 % (n = 4) had a maximum 12 mg daily dosage, 6.5 % (n = 2) had a maximum 16 mg daily dosage, 6.5 % (n = 2) required a provider letter, and 9.7 % (n = 3) did not provide further information., Conclusions: Access to FARR-certified recovery residences is severely limited for individuals in South Florida taking buprenorphine. Urgent action is needed to improve access to evidence-based OUD treatments, address complexities influencing recovery residence policy and practice, and ensure appropriate allocation of public funds like State Opioid Response dollars., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Since their discovery, corticosteroids have been widely used in the treatment of several diseases, including asthma, acute lymphoblastic leukemia, chronic obstructive pulmonary disease, and many other conditions. However, it has been noted that some patients develop undesired side effects or even fail to respond to treatment. The reasons behind this have not yet been fully elucidated. This poses a significant challenge to effective treatment that needs to be addressed urgently. Recent genomic, transcriptomic, and other omics-based approximations have begun to shed light into the genetic factors influencing interindividual variability in corticosteroid efficacy and its side effects. Here, we comprehensively revise the recent literature on corticosteroid response in various critical and chronic diseases, with a focus on omics approaches, and highlight existing knowledge gaps where further investigation is urgently needed.

Background: In the 6 months following Hurricane Maria the number of people who died from the hurricane was much higher than was initially estimated from death certificates. Disruption of health care services and displacement led to the exacerbation of pre-existing chronic diseases. The objectives of this study were to (1) estimate the excess deaths in Puerto Rico in the 6 months following Maria, (2) identify geographical areas experiencing higher risk of chronic disease mortality following Maria and (3) identify community-level vulnerability characteristics associated with some communities being at higher risk of increased chronic disease mortality after Maria., Methods: Death records were obtained from Puerto Rico's Department of Health Demographic Registry. Mortality risks per 100 000 were calculated for chronic disease categories and all-cause mortality for the 6 months following Maria and the same months in the year before. Geospatial analysis using Getis-Ord Gi* Statistic was used to determine if mortality clusters of 6 month mortality risk following hurricane Maria by census tract were statistically significant. Multinomial logistic regression was used to model the association between census tract level social vulnerability and being classified as higher or sustained risk of mortality in the 6 months following Hurricane Maria compared to the previous year's mortality risk. Odds ratios and 95% confidence intervals were estimated to measure associations between social vulnerability and mortality risk., Results: In the 6 months following Maria there were increases in mortality risk for cardiovascular disease, Alzheimer's, diabetes, sepsis, chronic respiratory disease, hypertension and all-cause mortality. Examining community level characteristics associated with vulnerability to disasters, neighborhoods with higher proportion of people 65 and older, higher proportion of houses being multiunit structures and higher proportion of households with no vehicle, in comparison to other neighborhoods in Puerto Rico,were more likely to have sustained high risk for mortality before and after Maria or increased risk of being a hot spot for chronic disease mortality after Maria., (© 2025 The Author(s). Published by IOP Publishing Ltd.)

Epidemiologists spend a great deal of time on confounding in our teaching, in our methods development, and in our assessment of study results. This may give the impression that uncontrolled confounding is the biggest problem observational epidemiology faces, when in fact, other sources of bias such as selection bias, measurement error, missing data, and misalignment of zero time may often (especially if they are all present in a single study) lead to a stronger deviation from the truth. Compared with the amount of time we spend teaching how to address confounding in data analysis, we spend relatively little time teaching methods for simulating confounding (and other sources of bias) to learn their impact and develop plans to mitigate or quantify the bias. Here we review the accompanying paper by Desai et al (Am J Epidemiol. 2024;193(11):1600-1608), which uses simulation methods to quantify the impact of an unmeasured confounder when it is completely missing or when a proxy of the confounder is measured. We discuss how we can use simulations of sources of bias to ensure that we generate better and more valid study estimates, and we discuss the importance of simulating realistic datasets with plausible bias structures to guide data collection. This article is part of a Special Collection on Pharmacoepidemiology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Community-acquired pneumonia (CAP) is associated with high morbidity and hospitalization rate. In infectious diseases, host genetics plays a critical role in susceptibility and immune response, and the immune pathways involved are highly dependent on the microorganism and its route of infection. Here we aimed to identify genetic risk loci for CAP using a case-control genome-wide association study (GWAS)., Methods: We performed a GWAS on 3,765 Spanish individuals, including 257 adult patients hospitalized with CAP and 3,508 population controls. Pneumococcal CAP was documented in 30% of patients; the remaining 70% were selected among patients with unidentified microbiological etiology. We tested 7,6 million imputed genotypes using logistic regressions. UK Biobank GWAS of bacterial pneumonia were used for results validation. Subsequently, we prioritized genes and likely causal variants based on Bayesian fine mapping and functional evidence. Imputation and association of classical HLA alleles and amino acids were also conducted., Results: Six independent sentinel variants reached the genome-wide significance (p < 5 × 10 -8 ), three on chromosome 6p21.32, and one for each of the chromosomes 4q28.2, 11p12, and 20q11.22. Only one variant at 6p21.32 was validated in independent GWAS of bacterial and pneumococcal pneumonia. Our analyses prioritized C4orf33 on 4q28.2, TAPBP on 6p21.32, and ZNF341 on 20q11.22. Interestingly, genetic defects of TAPBP and ZNF341 are previously known inborn errors of immunity predisposing to bacterial pneumonia, including pneumococcus and Haemophilus influenzae. Associations were all non-significant for the classical HLA alleles., Conclusions: We completed a GWAS of CAP and identified four novel risk loci involved in CAP susceptibility., (© 2024. The Author(s).)

Methadone is an opioid receptor agonist medication used in the treatment of opioid use disorder (OUD). Geographic distance to opioid treatment programs (OTPs) is a major barrier to treatment, given requirements for direct observation of dosing and periodic drug screens, and 'methadone treatment deserts' are defined as a public transit threshold of 30 minutes. The purpose of this study was to examine public transit access to methadone treatment for participants of a syringe services program (SSP) in Miami-Dade County, Florida. Public transit times were calculated using the R library r5r, which facilitates multi-modal transportation network routing. General Transit Feed Specification data was combined with street network data from OpenStreetMap for Miami-Dade County. Transit times were estimated from the population-weighted centroid of each zip code (n=79) with participants of Miami's only SSP (n=1597) to the nearest OTP (n=4) using 10 departure windows aligned with OTP service hours. The mean one-way transit time from zip codes with SSP participants in Miami-Dade County to the nearest OTP was 80 minutes. 75 of the 79 (95%) zip codes with SSP participants in Miami-Dade County have a mean transit time to the closest OTP greater than 30 minutes. Transit times differ substantially between zip codes with different numbers of SSP participants, but not between departure windows. Nearly all zip codes with SSP participants in Miami-Dade County can be classified as 'methadone treatment deserts'. Geographic isolation of methadone treatment from public transit routes represents a significant barrier to equitable OUD treatment., Competing Interests: Competing interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TSB and HET receive research funding from Gilead Sciences.

Study Objectives: To characterize children and youth newly diagnosed with insomnia and to describe their use of sleep and other related prescription medications., Methods: Within a commercial claims database (January 1, 2016-December 31, 2021), we identified children and youth (2-24 years) with a newly recorded insomnia diagnosis (G47.0x; F51.0x) and examined psychiatric diagnoses in the prior 6 months. We evaluated sleep and related prescription medications dispensed in the week after new insomnia diagnoses (i.e. trazodone, other antidepressants, hydroxyzine, alpha-agonists, benzodiazepines, non-benzodiazepine hypnotics "z-drugs," antipsychotics, and others). Analyses were stratified by age and psychiatric comorbidities., Results: Among 68 698 children and 108 118 older youth (18-24 years) with a new insomnia diagnosis, three-quarters had a diagnosed comorbid psychiatric condition; anxiety disorders, depression, and ADHD were the most common. Among those without comorbid psychiatric diagnoses, 20.2% of children and 37.4% of older youth had a sleep or related medication dispensed in the following week. In children without a comorbid psychiatric diagnosis, alpha-agonists, hydroxyzine, and trazodone were the most common medications; in older youth, trazodone was the most common medication followed by hydroxyzine, z-drugs, and SSRIs. Sleep and related prescription medications were more commonly dispensed to those with psychiatric comorbidities. From 2017 to 2021, there was an increase in hydroxyzine prescriptions following a new insomnia diagnosis and decline in z-drug and benzodiazepine prescriptions., Conclusions: Our findings from a nationwide sample of young people with insomnia highlight the high prevalence of psychiatric comorbidities and variety of sleep and related medications they receive. Characterizing prescribing tendencies informs guideline development and future research., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: People who inject drugs (PWID) remain a high priority population under the federal Ending the HIV Epidemic initiative with 11% of new HIV infections attributable to injection drug use. There is a critical need for innovative, efficacious, scalable, and community-driven models of healthcare in non-stigmatizing settings for PWID. We seek to test a Comprehensive-TeleHarm Reduction (C-THR) intervention for HIV prevention services delivered via a syringe services program (SSP)., Methods: The CHARIOT trial is a hybrid type I effectiveness-implementation study using a parallel two-arm randomized controlled trial design. Participants (i.e., PWID; n = 350) will be recruited from a syringe services program (SSP) in Miami, Florida. Participants will be randomized to receive either C-THR or non-SSP clinic referral and patient navigation. The objectives are: (1) to determine if the C-THR intervention increases engagement in HIV prevention (i.e., HIV pre-exposure prophylaxis; PrEP or medications for opioid use disorder; MOUD) compared to non-SSP clinic referral and patient navigation, (2) to examine the long-term effectiveness and cost-effectiveness of the C-THR intervention, and (3) to assess the barriers and facilitators to implementation and sustainment of the C-THR intervention. The co-primary outcomes are PrEP or MOUD engagement across follow-up at 3, 6, 9 and 12 months. For PrEP, engagement is confirmed by tenofovir on dried blood spot or cabotegravir injection within the previous 8 weeks. For MOUD, engagement is defined as screening positive for norbuprenorphine or methadone on urine drug screen; or naltrexone or buprenorphine injection within the previous 4 weeks. Secondary outcomes include PrEP adherence, engagement in HCV treatment and sustained virologic response, and treatment of sexually transmitted infections. The short and long term cost-effectiveness analyses and mixed-methods implementation evaluation will provide compelling data on the sustainability and possible impact of C-THR on comprehensive HIV prevention delivered via SSPs., Discussion: The CHARIOT trial will be the first to our knowledge to test the efficacy of an innovative, peer-led telehealth intervention with PWID at risk for HIV delivered via an SSP. This innovative healthcare model seeks to transform the way PWID access care by bypassing the traditional healthcare system, reducing multi-level barriers to care, and meeting PWID where they are., Trial Registration: ClinicalTrials.gov NCT05897099. Trial registry name: Comprehensive HIV and Harm Prevention Via Telehealth (CHARIOT). Registration date: 06/12/2023., (© 2024. The Author(s).)

Background: Tele-harm reduction (THR) is a telehealth-enhanced, peer-led, harm reduction intervention delivered within a trusted syringe services program (SSP) venue. The primary goal of THR is to facilitate linkage to care and rapid, enduring virologic suppression among people who inject drugs (PWID) with HIV. An SSP in Miami, Florida, developed THR to circumvent pervasive stigma within the traditional healthcare system., Methods: During intervention development, we conducted in-depth interviews with PWID with HIV (n = 25) to identify barriers and facilitators to care via THR. We employed a general inductive approach to transcripts guided by iterative readings of the raw data to derive the concepts, themes, and interpretations of the THR intervention., Results: Of the 25 PWID interviewed, 15 were in HIV care and adherent to medication; 4 were in HIV care but non-adherent; and 6 were not in care. Themes that emerged from the qualitative analysis included the trust and confidence PWID have with SSP clinicians as opposed to professionals within the traditional healthcare system. Several barriers to treatment were reported among PWID, including perceived and actual discrimination by friends and family, negative internalized behaviors, denial of HIV status, and fear of engaging in care. Facilitators to HIV care included empathy and respect by SSP staff, flexibility of telehealth location, and an overall destigmatizing approach., Conclusion: PWID identified barriers and facilitators to receipt of HIV care through the THR intervention. Interviews helped inform THR intervention development, centered on PWID in the destigmatizing environment of an SSP., (© 2024. The Author(s).)

Background: Gankyrin is an ankyrin-repeat protein that promotes cell proliferation, tumor development and cancer progression when overexpressed. Aim: To design and synthesize a novel series of gankyrin-binding small molecules predicated on a 2,5-pyrimidine scaffold. Materials & methods: The synthesized compounds were evaluated for their antiproliferative activity, ability to bind gankyrin and effects on cell cycle progression and the proteasomal degradation pathway. Results: Compounds 188 and 193 demonstrated the most potent antiproliferative activity against MCF7 and A549 cells, respectively. Both compounds also demonstrated the ability to effectively bind gankyrin, disrupt proteasomal degradation and inhibit cell cycle progression. Conclusion: The 2,5-pyrimidine scaffold exhibits a novel and promising strategy for binding gankyrin and inhibiting cancer cell proliferation.

Background: Most studies assessing the safety of parental drug exposures during pregnancy and around the time of conception describe the effects of maternal exposure. Recent publications have raised awareness of the need for additional research regarding the safety of paternal drug exposures on pregnancy outcomes., Objectives: To identify and describe studies that use secondary databases in paternal drug safety studies and to describe the secondary databases that were used., Methods: A systematic review of studies assessing paternal medication exposure and pregnancy and infant outcomes using secondary databases was performed. In addition, the secondary databases used for these studies was described. Literature search was conducted using Embase, Web of Science, and PubMed, over the period January 1, 2012 to April 30, 2023. For each eligible study, paternal drug exposure, outcome, and data source characteristics were extracted in a data extraction form., Results: After reviewing the literature, 17 studies met inclusion criteria. The medications assessed for paternal safety were anti-rheumatic drugs (n = 10), anti-depressants (n = 3), anticonvulsants (n = 2), and anti-diabetes medications (n = 2). Pregnancy safety outcomes included congenital malformations, birth weight, and developmental disorders. The studies used five different databases across Europe and North America. The included studies used databases from Denmark (n = 12), Norway (n = 2), Sweden (n = 1), Canada (n = 1), and the United States (n = 1). The European studies utilized national patient registers that linked fathers to births and prescription histories. The North American databases used included insurance claims and electronic health records., Conclusions: Our review shows that few studies have been completed on paternal medication exposures and pregnancy outcomes, despite the availability of secondary databases that contain data necessary to link fathers to infants. More research on the potential adverse impacts of paternal medication exposures is needed., (© 2024 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Inflatable fabric beams (IFBs) integrating pleat folds can generate complex motion by modifying the pleat characteristics (e.g., dimensions, orientations). However, the capability of the IFB to return to the folded configuration relies upon the elasticity of the fabrics, requiring additional pressure inputs or complementary mechanisms. Using soft compliant elements (SCEs) assembled onto pleat folds is an appealing approach to improving the IFB elasticity and providing a range of spatial configurations when pressurized. This study introduces an actuator comprising an IFB with pleat folds and SCEs. By methodologically assembling the SCEs onto the pleat folds, we constrain the IFB unfolding to achieve out-of-plane motion at 5 kPa. Besides, the proposed actuator can generate angular displacement by regulating the input pressure ( > 5 kPa). A matrix-based representation and model are proposed to analyze the actuator motion. We experimentally study the actuator's angular displacement by modifying SCE shapes, fold dimensions, and assembly distances of SCEs. Moreover, we analyze the effects of incorporating two SCEs onto a pleat fold. Our results show that the actuator motion can be tuned by integrating SCEs with different stiffness and varying the pleat fold dimensions. In addition, we demonstrate that the integration of two SCEs onto the pleat fold permits the actuator to return to its folded configuration when depressurized. In order to demonstrate the versatility of the proposed actuator, we devise and conduct experiments showcasing the implementation of a planar serial manipulator and a soft gripper with two grasping modalities., Competing Interests: The 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 © 2024 Huaroto, Suarez, Kim and Vela.)

Background: We aimed to report the preliminary xylazine prevalence among people who inject drugs (PWID) treated at a student-run free clinic in Miami, FL, USA and to identify characteristics associated with screening positive for xylazine., Methods: A retrospective chart review of 59 patients presenting to a syringe services program (SSP) clinic in was conducted between April 27th and August 17th, 2023. We measured presence of xylazine with rapid visual immunoassay strips on patient urine samples., Results: Xylazine was present in 55.9 % (33/59) of urine samples including 2 without detected opioids. Xylazine presence was significantly associated with unsheltered homelessness ( p  = 0.018), presence of wound(s) ( p  = 0.008), and testing positive for hepatitis C antibody ( p  = 0.014), fentanyl ( p  = 0.005) and MDMA ( p  = 0.002)., Conclusions: A high prevalence of xylazine in the Southeastern United States furthers evidence of the geographical spread of xylazine and rapidly evolving illicit drug supply. Widespread xylazine screening is urgently needed to inform people who inject drugs and to studyinterventions to minimize harms associated with xylazine., Competing Interests: None., (© 2023 The Authors. Published by Elsevier B.V.)

Background: At the start of the pandemic, relaxation of buprenorphine prescribing regulations created an opportunity to create new models of medications for opioid use disorder (MOUD) delivery and care. To expand and improve access to MOUD, we adapted and implemented the Tele-Harm Reduction (THR) intervention; a multicomponent, telehealth-based and peer-driven intervention to promote HIV viral suppression among people who inject drugs (PWID) accessing a syringe services program (SSP). This study examined buprenorphine initiation and retention among PWID with opioid use disorder who received the adapted THR intervention at the IDEA Miami SSP. Methods: A retrospective chart review of participants who received the THR intervention for MOUD was performed to examine the impact of telehealth on buprenorphine retention. Our primary outcome was three-month retention, defined as three consecutive months of buprenorphine dispensed from the pharmacy. Results: A total of 109 participants received the adapted THR intervention. Three-month retention rate on buprenorphine was 58.7%. Seeing a provider via telehealth at baseline or any follow up visit (aOR = 7.53, 95% CI: [2.36, 23.98]) and participants who had received an escalating dose of buprenorphine after baseline visit (aOR = 8.09, 95% CI: [1.83, 35.87]) had a higher adjusted odds of retention at three months. Participants who self-reported or tested positive for a stimulant (methamphetamine, amphetamine, or cocaine) at baseline had a lower adjusted odds of retention on buprenorphine at three months (aOR = 0.29, 95% CI: [0.09, 0.93]). Conclusions: Harm reduction settings can adapt dynamically to the needs of PWID in provision of critical lifesaving buprenorphine in a truly destigmatising approach. Our pilot suggests that an SSP may be an acceptable and feasible venue for delivery of THR to increase uptake of buprenorphine by PWID and promote retention in care.KEY MESSAGESThe Tele-Harm Reduction intervention can be adapted for initiating and retaining people who inject drugs with opioid use disorder on buprenorphine within a syringe services program settingUsing telehealth was associated with increased three-month buprenorphine retentionBaseline stimulant use was negatively associated with three-month buprenorphine retention.

Dravet syndrome is a rare form of severe genetic epilepsy characterized by recurrent and long-lasting seizures. It appears around the first year of life, with a quick evolution toward an increase in the frequency of the seizures, accompanied by a delay in motor and cognitive development, and does not respond well to antiepileptic medication. Most patients carry a mutation in the gene SCN1A encoding the α subunit of the voltage-gated sodium channel Nav1.1, resulting in hyperexcitability of neural circuits and seizure onset. In this work, we applied transcranial static magnetic stimulation (tSMS), a non-invasive, safe, easy-to-use and affordable neuromodulatory tool that reduces neural excitability in a mouse model of Dravet syndrome. We demonstrate that tSMS dramatically reduced the number of crises. Furthermore, crises recorded in the presence of the tSMS were shorter and less intense than in the sham condition. Since tSMS has demonstrated its efficacy at reducing cortical excitability in humans without showing unwanted side effects, in an attempt to anticipate a possible use of tSMS for Dravet Syndrome patients, we performed a numerical simulation in which the magnetic field generated by the magnet was modeled to estimate the magnetic field intensity reached in the cerebral cortex, which could help to design stimulation strategies in these patients. Our results provide a proof of concept for nonpharmacological treatment of Dravet syndrome, which opens the door to the design of new protocols for treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Vascular endothelial cells have important functions in fibrosis via direct and indirect methods and in regeneration through secretion of tissue-specific, paracrineacting angiocrine factors. In the salivary gland, endothelial cells are required for proper development, but their roles within adult glands are largely unknown. The goal of this work was to identify ligand-receptor interactions between endothelial cells and other cell types that are important during homeostasis, fibrosis, and regeneration. To model salivary gland fibrosis and regeneration, we utilized a reversible ductal ligation. To induce injury, a clip was applied to the primary ducts for 14 days, and to induce a regenerative response, the clip was subsequently removed for 5 days. To identify endothelial cell-produced factors, we used single-cell RNA-sequencing of stromal-enriched cells from adult submandibular and sublingual salivary glands. Transcriptional profiles of homeostatic salivary gland endothelial cells were compared to endothelial cells of other organs. Salivary gland endothelial cells were found to express unique genes and displayed the highest overlap in gene expression with other fenestrated endothelial cells from the colon, small intestine, and kidney. Comparison of the 14-day ligated, mock ligated, and 5-day deligated stromal-enriched transcripts and lineage tracing were used to identify evidence for a partial endoMT phenotype, which was observed in a small number of endothelial cell subsets with ligation. CellChat was used to predict changes in ligand-receptor interactions in response to ligation and deligation. CellChat predicted that after ligation, endothelial cells are sources of protein tyrosine phosphatase receptor type m, tumor necrosis factor ligand superfamily member 13, and myelin protein zero signaling and targets for tumor necrosis factor signaling. Following deligation, CellChat predicted that endothelial cells are sources of chemokine (C-X-C motif) and EPH signaling to promote regenerative responses. These studies will inform future endothelial cell-based regenerative therapies., Competing Interests: Conflict of Interest The authors declare no financial or non-financial conflicts of interest.

Acute respiratory distress syndrome (ARDS) is a life-threatening lung condition that arises from multiple causes, including sepsis, pneumonia, trauma, and severe coronavirus disease 2019 (COVID-19). Given the heterogeneity of causes and the lack of specific therapeutic options, it is crucial to understand the genetic and molecular mechanisms that underlie this condition. The identification of genetic risks and pharmacogenetic loci, which are involved in determining drug responses, could help enhance early patient diagnosis, assist in risk stratification of patients, and reveal novel targets for pharmacological interventions, including possibilities for drug repositioning. Here, we highlight the basis and importance of the most common genetic approaches to understanding the pathogenesis of ARDS and its critical triggers. We summarize the findings of screening common genetic variation via genome-wide association studies and analyses based on other approaches, such as polygenic risk scores, multi-trait analyses, or Mendelian randomization studies. We also provide an overview of results from rare genetic variation studies using Next-Generation Sequencing techniques and their links with inborn errors of immunity. Lastly, we discuss the genetic overlap between severe COVID-19 and ARDS by other causes.

We report the two cases in which femtosecond laser (FSL) technology used to manage visually significant retained host's Descemet's membrane (RHDM) after penetrating keratoplasty (PKP). FSL-assisted descemetorhexis was done first, then membrane removal with intraocular forceps. Both patients had advanced keratoconus and were managed with PKP. In the first patient, FSL descemetorhexis of RHDM was incomplete. It was augmented manually, and then, the removal of the retained membrane was done with an intraocular forceps, whereas, a complete and central 5.5 mm FSL descemetorhexis was created in the second case. Then, it was pulled out with intraocular forceps. Postoperatively, the best-corrected visual acuity was 20/40, with an intraocular pressure (IOP) of 18 mmHg. In the second case, best-corrected visual acuity and IOP were 20/70 and 16 mmHg, respectively. In conclusion, FSL technology can be an alternative to manual or neodymiumdoped yttrium - aluminum garnet membranotomy for the management of RHDM after PKP., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Middle East African Journal of Ophthalmology.)

3-O-sulfogalactosylceramide, or sulfatide, is a prominent myelin glycosphingolipid reduced in the normal appearing white matter (NAWM) in Multiple Sclerosis (MS), indicating that sulfatide reduction precedes demyelination. Using a mouse model that is constitutively depleted of sulfatide, we previously demonstrated that sulfatide is essential during development for the establishment and maintenance of myelin and axonal integrity and for the stable tethering of certain myelin proteins in the sheath. Here, using an adult-onset depletion model of sulfatide, we employ a combination of ultrastructural, immunohistochemical and biochemical approaches to analyze the consequence of sulfatide depletion from the adult CNS. Our findings show a progressive loss of axonal protein domain organization, which is accompanied by axonal degeneration, with myelin sparing. Similar to our previous work, we also observe differential myelin protein anchoring stabilities that are both sulfatide dependent and independent. Most notably, stable anchoring of neurofascin155, a myelin paranodal protein that binds the axonal paranodal complex of contactin/Caspr1, requires sulfatide. Together, our findings show that adult-onset sulfatide depletion, independent of demyelination, is sufficient to trigger progressive axonal degeneration. Although the pathologic mechanism is unknown, we propose that sulfatide is required for maintaining myelin organization and subsequent myelin-axon interactions and disruptions in these interactions results in compromised axon structure and function.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that affect different anatomical locations. Despite this heterogeneity, HNSCC treatment depends on the anatomical location, TNM stage and resectability of the tumor. Classical chemotherapy is based on platinum-derived drugs (cisplatin, carboplatin and oxaliplatin), taxanes (docetaxel, paclitaxel) and 5-fluorouracil 1 . Despite advances in HNSCC treatment, the rate of tumor recurrence and patient mortality remain high. Therefore, the search for new prognostic identifiers and treatments targeting therapy-resistant tumor cells is vital. Our work demonstrates that there are different subgroups with high phenotypic plasticity within the CSC population in HNSCC. CD10, CD184, and CD166 may identify some of these CSC subpopulations with NAMPT as a common metabolic gene for the resilient cells of these subpopulations. We observed that NAMPT reduction causes a decrease in tumorigenic and stemness properties, migration capacity and CSC phenotype through NAD pool depletion. However, NAMPT-inhibited cells can acquire resistance by activating the NAPRT enzyme of the Preiss-Handler pathway. We observed that coadministration of the NAMPT inhibitor with the NAPRT inhibitor cooperated inhibiting tumor growth. The use of an NAPRT inhibitor as an adjuvant improved NAMPT inhibitor efficacy and reduced the dose and toxicity of these inhibitors. Therefore, it seems that the reduction in the NAD pool could have efficacy in tumor therapy. This was confirmed by in vitro assays supplying the cells with products of inhibited enzymes (NA, NMN or NAD) and restoring their tumorigenic and stemness properties. In conclusion, the coinhibition of NAMPT and NAPRT improved the efficacy of antitumor treatment, indicating that the reduction in the NAD pool is important to prevent tumor growth., (© 2023. The Author(s).)

Paliperidone was approved by the US FDA in 2006 as an extended-release (ER) tablet (Invega ® ) for the once-daily treatment of schizophrenia. This osmotic-controlled release oral delivery system (OROS) offers advantages, such as the prevention of plasma concentration fluctuation and reduced dosing frequency. The administration of the ER after a high-fat/high-calorie meal leads to increased maximum plasma concentration and area under the curve values by 60% and 54%, respectively. Food has various effects on gastrointestinal (GI) physiology, including changed transit times, changed volumes, altered pH in different GI compartments, secretion of bile salts, and increased hepatic blood flow. This may affect solubility, the dissolution rate, absorption, and the pharmacokinetics. The aim of this study was to apply physiologically based absorption modeling (PBAM) to provide insights on paliperidone ER absorption under fed and fasting conditions. The PBAM adequately predicted absorption from the OROS formulation under both conditions. Absorption primarily occurs in the ascending colon and caecum. After a high-fat/high-calorie meal, absorption is increased through the jejunum, ileum, and colon due to either increased solubilization or the better efficiency of the OROS technology. PBAM-guided approaches can improve the understanding of branded drugs and thereby aid in guiding the development of generic formulations or formulation alternatives.

Background: The resurgence of HIV outbreaks and rising prevalence among people who inject drugs (PWID) remain exigent obstacles to Ending the HIV Epidemic in the USA. Adapting a low threshold, comprehensive treatment model for PWID with HIV can leverage syringe services programs (SSPs) to increase availability and accessibility of antiretrovirals (ART), medications for opioid use disorder (MOUD), and hepatitis C cure. We developed Tele-Harm Reduction, a telehealth-enhanced, harm reduction intervention delivered within an SSP venue., Methods: The T-SHARP trial is an open-label, multi-site, randomized controlled superiority trial with two parallel treatment arms. Participants (n=240) recruited from SSPs in Miami, Ft. Lauderdale, and Tampa, Florida, who are PWID with uncontrolled HIV (i.e., HIV RNA>200) will be randomized to Tele-Harm Reduction or off-site linkage to HIV care. The primary objective is to compare the efficacy of Tele-Harm Reduction for initiation of ART at SSPs vs. off-site linkage to an HIV clinic with respect to viral suppression across follow-up (suppression at 3, 6, and 12 months post randomization). Participants with HIV RNA<200 copies/ml will be considered virally suppressed. The primary trial outcome is time-averaged HIV viral suppression (HIV RNA <200 copies/ml) over 3-, 6-, and 12-month follow-up. Secondary outcomes include initiation of MOUD measured by urine drug screen and HCV cure, defined as achieving 12-week sustained virologic response (negative HCV RNA at 12 weeks post treatment completion). A cost-effectiveness analysis will be performed., Discussion: The T-SHARP Trial will be the first to our knowledge to test the efficacy of an innovative telehealth intervention with PWID with uncontrolled HIV delivered via an SSP to support HIV viral suppression. Tele-Harm Reduction is further facilitated by a peer to support adherence and bridge the digital divide. This innovative, flipped healthcare model sets aside the traditional healthcare system, reduces multi-level barriers to care, and meets PWID where they are. The T-SHARP trial is a pragmatic clinical trial that seeks to transform the way that PWID access HIV care and improve HIV clinical outcomes., Trial Registration: ClinicalTrials.gov NCT05208697. Trial registry name: Tele-Harm Reduction. Registration date: January 26, 2022., (© 2023. The Author(s).)

Background: Hospitalizations for severe injection drug use-related infections (SIRIs) are characterized by high costs, frequent patient-directed discharge, and high readmission rates. Beyond the health system impacts, these admissions can be traumatizing to people who inject drugs (PWID), who often receive inadequate treatment for their substance use disorders (SUD). The Jackson SIRI team was developed as an integrated infectious disease/SUD treatment intervention for patients hospitalized at a public safety-net hospital in Miami, Florida in 2020. We conducted a qualitative study to identify patient- and clinician-level perceived implementation barriers and facilitators to the SIRI team intervention., Methods: Participants were patients with history of SIRIs (n = 7) and healthcare clinicians (n = 8) at one implementing hospital (Jackson Memorial Hospital). Semi-structured qualitative interviews were performed with a guide created using the Consolidated Framework for Implementation Research (CFIR). Interviews were transcribed, double coded, and categorized by study team members using CFIR constructs., Results: Implementation barriers to the SIRI team intervention identified by participants included: (1) complexity of the SIRI team intervention; (2) lack of resources for PWID experiencing homelessness, financial insecurity, and uninsured status; (3) clinician-level stigma and lack of knowledge around addiction and medications for opioid use disorder (OUD); and (4) concerns about underinvestment in the intervention. Implementation facilitators of the intervention included: (1) a non-judgmental, harm reduction-oriented approach; (2) the team's advocacy for PWID as a means of institutional culture change; (3) provision of close post-hospital follow-up that is often inaccessible for PWID; (4) strong communication with patients and their hospital physicians; and (5) addressing diverse needs such as housing, insurance, and psychological wellbeing., Conclusion: Integration of infectious disease and SUD treatment is a promising approach to managing patients with SIRIs. Implementation success depends on institutional buy-in, holistic care beyond the medical domain, and an ethos rooted in harm reduction across multilevel (inner and outer) implementation contexts., (© 2023. The Author(s).)

Macroalgae are a promising feedstock for several industries due to their large content of proteins and carbohydrates and the high biomass productivities. A novel extraction and fractionation concept based on ionic liquids (ILs) using Ulva lactuca as model organism is presented. Biomolecules are first extracted by means of IL-assisted mechanical shear, followed by two-phase partitioning or ultrafiltration in order to fractionate proteins and carbohydrates and to recover the IL. Ethyl methyl imidazolium dibutyl phosphate ([Emim][DBP]) is strongly selective to proteins, leading to extraction yields up to 80.4% for proteins and 30.7% for carbohydrates. The complete process, including extraction and ultrafiltration, allowed protein recovery of up to 64.6 and 15.4% of the carbohydrates in the retentate phase, while a maximum of 85.7% of the IL was recovered in the permeate phase. The native structure of the extracted proteins was preserved during extraction and fractionation as shown by gel electrophoresis. Selective extraction of proteins from macroalgae under non-denaturing conditions using ILs followed by the recovery of IL using ultrafiltration is for the first time reported. The proposed extraction-fractionation approach is simple and can be potentially applied for the biorefinery of macroalgae at the commercial scale., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background: To address the infectious disease (ID) and substance use disorder (SUD) syndemic, we developed an integrated ID/SUD clinical team rooted in harm reduction at a county hospital in Miami, Florida. The Severe Injection-Related Infection (SIRI) team treats people who inject drugs (PWID) and provides medical care, SUD treatment, and patient navigation during hospitalization and after hospital discharge. We assessed the impact of the SIRI team on ID and SUD treatment and healthcare utilization outcomes., Methods: We prospectively collected data on patients seen by the SIRI team. A diagnostic code algorithm confirmed by chart review was used to identify a historical control group of patients with SIRI hospitalizations in the year preceding implementation of the SIRI team. The primary outcome was death or readmission within 90 days post-hospital discharge. Secondary outcomes included initiation of medications for opioid use disorder (MOUD) and antibiotic course completion., Results: There were 129 patients included in the study: 59 in the SIRI team intervention and 70 in the pre-SIRI team control group. SIRI team patients had a 45% risk reduction (aRR, 0.55 [95% confidence interval CI, .32-.95]; 24% vs 44%) of being readmitted in 90 days or dying compared to pre-SIRI historical controls. SIRI team patients were more likely to initiate MOUD in the hospital (93% vs 33%, P < .01), complete antibiotic treatment (90% vs 60%, P < .01), and less likely to have patient-directed discharge (17% vs 37%, P = .02)., Conclusions: An integrated ID/SUD team was associated with improvements in healthcare utilization, MOUD initiation, and antibiotic completion for PWID with infections., Competing Interests: Potential conflicts of interest. The authors declare no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: A recent surge in HIV outbreaks, driven by the opioid and stimulant use crises, has destabilized our progress toward targets set forth by Ending the HIV Epidemic: A Plan for America for the high-priority community of people who inject drugs (PWID), particularly Black PWID., Methods: In order to ascertain the acceptability and feasibility of using a mobile syringe services program (SSP) for comprehensive HIV prevention via PrEP and medications for opioid use disorder (MOUD), our mixed methods approach included a quantitative assessment and semi-structured qualitative interviews with Black PWID (n = 30) in Miami-Dade County who were actively engaged in mobile syringe services., Results: Participants felt that delivery of MOUD and PrEP at a mobile SSP would be both feasible and acceptable, helping to address transportation, cost, and stigma barriers common within traditional healthcare settings. Participants preferred staff who are compassionate and nonjudgmental and have lived experience., Conclusions: A mobile harm reduction setting could be an effective venue for delivering comprehensive HIV prevention services to Black PWID, a community that experiences significant barriers to care via marginalization and racism in a fragmented healthcare system., (© 2022. The Author(s).)

Introduction: Total neoadjuvant therapy (TNT) is a new therapeutic strategy in patients with rectal cancer. We examined the role of TNT, in addition to other pre-operative factors, as a predictor for pathologic complete response (pCR)., Methods: A retrospective analysis of all rectal cancer patients who underwent surgery between 2016 and 2021 was conducted. Patients were classified into two groups-pCR group and residual tumor group. Patient data were reviewed and entered into univariate and multivariate analyses to determine predictors of pCR., Results: A total of 172 patients were treated with neoadjuvant therapy and underwent surgery during the study period. Sixty patients (34.9%) were treated with TNT while 112 (65.1%) were treated with traditional neoadjuvant chemoradiation. The overall pCR rate was 25.6% (44 patients), with 31.6% (19 patients) in patients who received TNT compared to 22.3% (25 patients) in patients who received neoadjuvant chemoradiation (NCRT). Univariate analysis of clinical and radiological factors correlated with pCR demonstrated no significant differences between the two groups in cT stage (p = 0.46), cN stage (p = 0.52), positive circumferential resection margin (CRM) (p = 0.72), tumor location (p = 0.35), symptomatic presentation (p = 0.09), and anal sphincter involvement (p = 0.68). Multivariate logistic analysis demonstrated that only pre-operative TNT (OR:2.35; 95% CI 1.06-5.25; p = 0.03) was predictive of pCR, while extramural vascular invasion (EMVI) was a predictor for lower rates of pCR (OR: 0.28; 95% CI 0.09-0.9; p = 0.03)., Conclusion: Rectal cancer patients undergoing TNT prior to surgery have a higher chance of developing a complete pathologic response. Evaluation of this therapy should be continued and extended to larger numbers of patients to see if the differences we observed are real., (© 2022. The Society for Surgery of the Alimentary Tract.)

Background: Sepsis is a severe systemic inflammatory response to infections that is accompanied by organ dysfunction and has a high mortality rate in adult intensive care units. Most genetic studies have identified gene variants associated with development and outcomes of sepsis focusing on biological candidates. We conducted the first genome-wide association study (GWAS) of 28-day survival in adult patients with sepsis., Methods: This study was conducted in two stages. The first stage was performed on 687 European sepsis patients from the GEN-SEP network and 7.5 million imputed variants. Association testing was conducted with Cox regression models, adjusting by sex, age, and the main principal components of genetic variation. A second stage focusing on the prioritized genetic variants was performed on 2,063 ICU sepsis patients (1362 European Americans and 701 African-Americans) from the MESSI study. A meta-analysis of results from the two stages was conducted and significance was established at p < 5.0 × 10 -8 . Whole-blood transcriptomic, functional annotations, and sensitivity analyses were evaluated on the identified genes and variants., Findings: We identified three independent low-frequency variants associated with reduced 28-day sepsis survival, including a missense variant in SAMD9 (hazard ratio [95% confidence interval] = 1.64 [1.37-6.78], p = 4.92 × 10 -8 ). SAMD9 encodes a possible mediator of the inflammatory response to tissue injury., Interpretation: We performed the first GWAS of 28-day sepsis survival and identified novel variants associated with reduced survival. Larger sample size studies are needed to better assess the genetic effects in sepsis survival and to validate the findings., (© 2022. The Author(s).)

We report on the effect of naked CaS nanostructures on the proliferation of carcinoma cancer cells and normal fibroblasts in vitro. The CaS nanostructures were prepared via the microwave-mediated decomposition of dimethyl sulfoxide (DMSO) in the presence of calcium acetate Ca ( CH 3 CO 2 ) 2 . Light scattering measurements revealed that dispersions contain CaS nanostructures in the size range of a few Å to about 1 nanometer, and are formed when DMSO is decomposed in the presence of Ca ( CH 3 CO 2 ) 2 . Theoretical calculations at the DFT/B3LYP/DGDZVP level of theory on ( C a S ) n clusters ( n = 1 , 2 , 3 , and 4) are consistent with clusters in this size range. The absorption spectra of the CaS nanostructures are dominated by strong bands in the UV, as well as weaker absorption bands in the visible. We found that a single dose of CaS nanoclusters smaller than 0.8 nm in diameter does not affect the survival and growth rate of normal fibroblasts and inhibits the proliferation rate of carcinoma cells in vitro. Larger CaS nanostructures, approximately (1.1 ± 0.2) nm in diameter, have a similar effect on carcinoma cell proliferation and survival rate. The CaS nanoclusters have little effect on the normal fibroblast cell cycle. Human carcinoma cells treated with CaS nanocluster dispersion exhibited a decreased ability to properly enter the cell cycle, marked by a decrease in cell concentration in the G0/G1 phase in the first 24 h and an increase in cells held in the SubG1 and G0/G1 phases up to 72 h post-treatment. Apoptosis and necrotic channels were found to play significant roles in the death of human carcinoma exposed to the CaS nanoclusters. In contrast, any effect on normal fibroblasts appeared to be short-lived and non-detrimental. The interaction of CaS with several functional groups was further investigated using theoretical calculations. CaS is predicted to interact with thiol ( R-SH ), hydroxide ( R - OH ), amino ( R - NH 2 ), carboxylic acid ( R - COOH ), ammonium ( R-NH 3 + ), and carboxylate ( R-COO - ) functional groups. None of these interactions are predicted to result in the dissociation of CaS. Thermodynamic considerations, on the other hand, are consistent with the dissociation of CaS into Ca 2 + ions and H 2 S in acidic media, both of which are known to cause apoptosis or cell death. Passive uptake and extracellular pH values of carcinoma cells are proposed to result in the observed selectivity of CaS to inhibit cancer cell proliferation with no significant effect on normal fibroblast cells. The results encourage further research with other cell lines in vitro as well as in vivo to translate this nanotechnology into clinical use., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

Background: Natural disasters are typically associated with the emergence of infectious diseases. On 15 June 2010, severe storms caused flooding in the Var department (France). A rumour about increased risk of Staphylococcusaureus skin infections after bathing in the sea began to circulate on Internet a few days after the floods. The aim of this study was to compare the rumour with the true incidence of cases of infection., Methods: Since 1999, we have been conducting a prospective survey of S. aureus skin infections in our hospital to study their clinical, laboratory and epidemiologic features. We compared data on cases of Staphylococcus skin infection recorded in our institution from 2008 to 2012., Results: We found that there was no increase in S. aureus skin infections after the floods compared to the previous and subsequent years., Conclusion: We had a unique opportunity to check the rumoured increase in incidence of infectious disease with the true incidence. In our study, the fear of S. aureus skin infections following flooding proved to be unfounded., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Removal sampling data are the primary source of monitoring information for many populations (e.g., invasive species, fisheries). Population dynamics, temporary emigration, and imperfect detection are common sources of variation in monitoring data and are key parameters for informing management. We developed two open robust-design removal models for simultaneously modeling population dynamics, temporary emigration, and imperfect detection: a random walk linear trend model (estimable without ancillary information), and a 2-age class informed population model (InfoPM, closely related to integrated population models) that incorporated prior information for age-structured vital rates and relative juvenile availability. We applied both models to multiyear, removal trapping time-series of a large invasive lizard (Argentine black and white tegu, Salvator merianae ) in three management areas of South Florida to evaluate the effectiveness of management programs. Although estimates of the two models were similar, the InfoPMs generally returned more precise estimates, partitioned dynamics into births, deaths, net migration, and provided a decision support tool to predict population dynamics under different effort scenarios while accounting for uncertainty. Trends in tegu superpopulation abundance estimates were increasing in two management areas despite generally high removal rates. However, tegu abundance appeared to decline in the Core management area, where trapping density was the highest and immigration the lowest. Finally, comparing abundance predictions of no-removal scenarios to those estimated in each management area suggested significant population reductions due to management. These results suggest that local tegu population control via systematic trapping may be feasible with high enough trap density and limited immigration; and highlights the value of these trapping programs. We provided the first estimates of tegu abundance, capture probabilities, and population dynamics, which is critical for effective management. Furthermore, our models are applicable to a wide range of monitoring programs (e.g., carcass recovery or removal point-counts)., (© 2022 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Neurodegenerative diseases represent a growing healthcare problem, mainly related to an aging population worldwide and thus their increasing prevalence. In particular, Alzheimer's disease (AD) and Parkinson's disease (PD) are leading neurodegenerative diseases. To aid their diagnosis and optimize treatment, we have developed a classification algorithm for AD to manipulate magnetic resonance images (MRI) stored in a large database of patients, containing 1,200 images. The algorithm can predict whether a patient is healthy, has mild cognitive impairment, or already has AD. We then applied this classification algorithm to therapeutic outcomes in PD after treatment with deep brain stimulation (DBS), to assess which stereotactic variables were the most important to consider when performing surgery in this indication. Here, we describe the stereotactic system used for DBS procedures, and compare different planning methods with the gold standard normally used (i.e., neurophysiological coordinates recorded intraoperatively). We used information collected from database of 72 DBS electrodes implanted in PD patients, and assessed the potentially most beneficial ranges of deviation within planning and neurophysiological coordinates from the operating room, to provide neurosurgeons with additional landmarks that may help to optimize outcomes: we observed that x coordinate deviation within CT scan and gold standard intra-operative neurophysiological coordinates is a robust matric to pre-assess positive therapy outcomes- "good therapy" prediction if deviation is higher than 2.5 mm. When being less than 2.5 mm, adding directly calculated variables deviation (on Y and Z axis) would lead to specific assessment of "very good therapy"., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Physiologically based pharmacokinetic (PBPK) modeling for biopharmaceutics applications holds great promise as modelling and simulation tool in the field of modern oral modified release (MR) products. Understanding of gastro-intestinal absorption related processes is crucial to ensure the successful development of complex oral drug generic products. In the recent years, PBPK approach has been gradually influencing decision making ability of pharmaceutical industry as well as regulatory agencies. However, there is a gap in understanding its contribution in the field of oral modified release products. In this review, we have collected different recent research articles illustrating the significant contribution of PBPK to the research and development process of oral MR products, with special emphasis on generic drug products. Concretely, literature examples on the utility of PBPK formulation development, for in vitro- in vivo correlations (IVIVC) and prediction of oral bioavailability, and for in-silico food effect predictions were included in the review., (Published by Elsevier B.V.)

The feasibilities of the anaerobic co-digestion of two of the most relevant biowastes, food waste and garden and park waste, were evaluated and compared with the hydrothermal treatment of each waste and the anaerobic co-digestion of raw biowastes with the process water generated. The effects on the process stability and energy recovery were also analyzed. Anaerobic digestion was the best option for food waste treatment from an energetic point of view, with 81% recovery of the energy stored in the feedstock, while the highest energy recovery from garden and park waste was obtained for the solid fraction generated from hydrothermal treatment (85.5%). In addition, the anaerobic co-digestion of food waste with 5% of the process water generated from garden and park waste showed a similar energy recovery to that of food waste only (∼80%), thus improving the biological stability of the process., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Fluoroquinolones (FQs) are a critical group of antimicrobials prescribed in urological infections as they have a broad antimicrobial spectrum of activity and a favorable tissue penetration at the site of infection. However, their clinical practice is not problem-free of treatment failure, risk of emergence of resistance, and rare but important adverse effects. Due to their critical role in clinical improvement, understanding the dose-response relation is necessary to optimize the effectiveness of FQs therapy, as it is essential to select the right antibiotic at the right dose for the right duration in urological infections. The aim of this study was to review the published literature about inter-individual variability in pharmacological processes that can be responsible for the clinical response after empiric dose for the most commonly prescribed urological FQs: ciprofloxacin, levofloxacin, and moxifloxacin. Interindividual pharmacokinetic (PK) variability, particularly in elimination, may contribute to treatment failure. Clearance related to creatinine clearance should be specifically considered for ciprofloxacin and levofloxacin. Likewise, today, undesired interregional variability in FQs antimicrobial activity against certain microorganisms exists. FQs pharmacology, patient-specific characteristics, and the identity of the local infecting organism are key factors in determining clinical outcomes in FQs use.

In nature, cells reside in tissues subject to complex cell-cell interactions, signals from extracellular molecules and niche soluble and mechanical signaling. These microenvironment interactions are responsible for cellular phenotypes and functions, especially in normal settings. However, in 2D cultures, where interactions are limited to the horizontal plane, cells are exposed uniformly to factors or drugs; therefore, this model does not reconstitute the interactions of a natural microenvironment. 3D culture systems more closely resemble the architectural and functional properties of in vivo tissues. In these 3D cultures, the cells are exposed to different concentrations of nutrients, growth factors, oxygen or cytotoxic agents depending on their localization and communication. The 3D architecture also differentially alters the physiological, biochemical, and biomechanical properties that can affect cell growth, cell survival, differentiation and morphogenesis, cell migration and EMT properties, mechanical responses and therapy resistance. This latter point may, in part, explain the failure of current therapies and affect drug discovery research. Organoids are a promising 3D culture system between 2D cultures and in vivo models that allow the manipulation of signaling pathways and genome editing of cells in a body-like environment but lack the many disadvantages of a living system. In this review, we will focus on the role of stem cells in the establishment of organoids and the possible therapeutic applications of this model, especially in the field of cancer research., (© 2022. The Author(s).)

CHOICES was an open-label, randomized, comparative effectiveness trial of office-based extended-release naltrexone versus treatment as usual in people with untreated opioid use disorder and HIV. This study explored facilitators to recruitment in Miami, a successful recruiting site in the national trial. The mixed-methods study included quantitative surveys of randomized participants, medical record abstraction, and qualitative interviews with study staff. Miami recruited 47 (40.5%) of 116 randomized participants in the six-site national trial. In-depth interviews of study staff (n = 6) revealed that Miami had a recruitment approach consisting of street level outreach and a close relationship with the local syringe services program (SSP). Partnership with a local SSP provided access to people living with HIV who inject drugs in Miami. SSPs' fundamental trust within the community of people who inject drugs can be leveraged in studies aiming to improve health outcomes in this underserved and high-priority population., (© 2021. National Council for Mental Wellbeing.)

Background: In the 2016 ISHLT listing criteria guidelines for heart transplantation, recipients were recommended to have a body mass index (BMI) <35 kg/m². However, outcomes data for subgroups of transplant recipients with a BMI >35 kg/m² are limited. We examined the outcomes of heart transplant recipients who had a BMI of 35 to 39.9 kg/m² or ≥40 kg/m² and compared their outcomes with recipients who had a BMI <35 kg/m 2 ., Methods: Using data from the United Network for Organ Sharing database, we performed a retrospective cohort analysis of 23,009 adults who underwent cardiac transplantation between 2009 and 2018. Transplant recipients were stratified by BMI categories (<35 kg/m², 35-39.9 kg/m², and ≥40 kg/m²). Patient survival was depicted by Kaplan-Meier curves. Cox proportional-hazards modeling was used to determine the prognostic factors associated with mortality within 90 days, 1 year, and 5 years after transplantation., Results: Survival at 90 days, 1 year, and 5 years after transplantation was better in recipients who had a BMI <35 kg/m² than in those who had a BMI of 35 to 39.9 kg/m² (P values ranged from 0.01 to < 0.001) or ≥40 kg/m² (P < 0.001). Additionally, survival at 90 days (P < 0.001) and 1 year (P = 0.002) was significantly better in recipients who had a BMI of 35 to 39.9 kg/m² than in those who had a BMI ≥40 kg/m². In multivariate analysis, a BMI of 35 to 39.9 was significantly associated with increased 90-day mortality (HR = 1.53; 95% CI 1.12, 2.08; P = 0.01) but not increased 1-year (HR = 1.28; 95% CI 0.99, 1.66; P = 0.06) or 5-year mortality (HR = 1.11; 95% CI 0.91, 1.36; P = 0.29)., Conclusions: Although heart transplant recipients with class II obesity (BMI 35-39.9 kg/m²) may have suboptimal survival compared with those who have a BMI <35 kg/m², these patients have better outcomes than do those with class III obesity (BMI ≥40 kg/m²). Thus, contrary to current guidelines, selected patients with class II obesity should be considered for transplantation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This study aimed to develop a definition of vasoplegia that reliably predicts clinical outcomes. Vasoplegia was evaluated using data from the electronic health record for each 15-minute interval for 72 hours following cardiopulmonary bypass. Standardized definitions considered clinical features (systemic vascular resistance [SVR], mean arterial pressure [MAP], cardiac index [CI], norepinephrine equivalents [NEE]), threshold strategy (criteria occurring in any versus all measurements in an interval), and duration (criteria occurring over multiple consecutive versus separated intervals). Minor vasoplegia was MAP < 60 mm Hg or SVR < 800 dynes⋅sec⋅cm-5 with CI > 2.2 L/min/m2 and NEE ≥ 0.1 µg/kg/min. Major vasoplegia was MAP < 60 mm Hg or SVR < 700 dynes⋅sec⋅cm-5 with CI > 2.5 L/min/m2 and NEE ≥ 0.2 µg/kg/min. The primary outcome was incidence of vasoplegia for eight definitions developed utilizing combinations of these criteria. Secondary outcomes were associations between vasoplegia definitions and three clinical outcomes: time to extubation, time to intensive care unit discharge, and nonfavorable discharge. Minor vasoplegia detected anytime within a 15-minute period (MINOR&#95;ANY&#95;15) predicted the highest incidence of vasoplegia (61%) and was associated with two of three clinical outcomes: 1 day delay to first extubation (95% CI: 0.2 to 2) and 7 day delay to first intensive care unit discharge (95% CI: 1 to 13). The MINOR&#95;ANY&#95;15 definition should be externally validated as an optimal definition of vasoplegia., Competing Interests: Dr. Swan received research funding from La Jolla Pharmaceutical Company to support fellowship training for Dr. Rizk and Dr. Iso. Dr. Masud is a paid member of the advisory board for the La Jolla Pharmaceutical Company. The authors do not have any conflicts of interest to report., (Copyright © ASAIO 2021.)

Despite asthma has a considerable genetic component, an important proportion of genetic risks remain unknown, especially for non-European populations. Canary Islanders have the largest African genetic ancestry observed among Southwestern Europeans and the highest asthma prevalence in Spain. Here we examined broad chromosomal regions previously associated with an excess of African genetic ancestry in Canary Islanders, with the aim of identifying novel risk variants associated with asthma susceptibility. In a two-stage cases-control study, we revealed a variant within HLA-DQB1 significantly associated with asthma risk (rs1049213, meta-analysis p = 1.30 × 10 -7 , OR [95% CI] = 1.74 [1.41-2.13]) previously associated with asthma and broad allergic phenotype. Subsequent fine-mapping analyses of classical HLA alleles revealed a novel allele significantly associated with asthma protection (HLA-DQA1*01:02, meta-analysis p = 3.98 × 10 -4 , OR [95% CI] = 0.64 [0.50-0.82]) that had been linked to infectious and autoimmune diseases, and peanut allergy. HLA haplotype analyses revealed a novel haplotype DQA1*01:02-DQB1*06:04 conferring asthma protection (meta-analysis p = 4.71 × 10 -4 , OR [95% CI] = 0.47 [0.29- 0.73])., (© 2021. The Author(s).)

A remarkable increase in vapor pressure deficit (VPD) has been recorded in the last decades in relation to global warming. Higher VPD generally leads to stomatal closure and limitations to leaf carbon uptake. Assessing tree conductance responses to VPD is a key step for modeling plant performances and productivity under future environmental conditions, especially when trees are cultivated well outside their native range as for hazelnut ( Corylus spp.). Our main aim is to assess the stand-level surface canopy conductance ( G surf ) responses to VPD in hazelnut across different continents to provide a proxy for potential productivity. Tree sap flow ( Fd ) was measured by Thermal dissipation probes (TDP) probes (six per sites) in eight hazelnut orchards in France, Italy, Georgia, Australia, and Chile during three growing seasons since 2016, together with the main meteorological parameters. We extracted diurnal Fd to estimate the canopy conductance G occurred at low values of VPD (on average 0.57 kPa) showing that hazelnut promptly avoids leaf dehydration and that maximum leaf gas exchange is limited at relatively low VPD (i.e., often less than 1 kPa). The sensitivity of the conductance surf. . VPD (i.e., -d G surf occurred at low values of VPD (on average 0.57 kPa) showing that hazelnut promptly avoids leaf dehydration and that maximum leaf gas exchange is limited at relatively low VPD (i.e., often less than 1 kPa). The sensitivity of the conductance vs . VPD (i.e., -d G /dlnVPD) resulted much lower (average m = -0.36) compared to other tree species, with little differences among sites. We identified a range of suboptimal VPD conditions for G surf maximization ( G surf > 80% compared to maximum) in each site, named "VPD 80 ," which multiplied by the mean G surf might be used as a proxy for assessing the maximum gas exchange of the orchard with a specific management and site. Potential gas exchange appeared relatively constant in most of the sites except in France (much higher) and in the driest Australian site (much lower). This study assessed the sensitivity of hazelnut to VPD and proposed a simple proxy for predicting the potential gas exchange in different areas. Our results can be used for defining suitability maps based on average VPD conditions, thus facilitating correct identification of the potentially most productive sites., Competing Interests: This study received funding from Hazelnut Company, Division of Ferrero Group. The funder had the following involvement with this study: the study design and the location of study areas were agreed with the funder, besides the funder partly supported the field data collection. The 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. The handling editor declared a past co-authorship with one of the authors ES., (Copyright © 2021 Pasqualotto, Carraro, Suarez Huerta and Anfodillo.)

Introduction: Hospitalizations for severe injection-related infections (SIRI), such as endocarditis, osteomyelitis, and skin and soft tissue infections (SSTI) are increasingly common. People who inject drugs (PWID) experiencing SIRIs often receive inadequate substance use disorder (SUD) treatment and lack of access to harm reduction services. This translates into lengthy hospitalizations with high rates of patient-directed discharge, readmissions, and post-hospitalization mortality. The purpose of this study was to describe the development of an integrated "SIRI Team" and its initial barriers and facilitators to success., Materials and Methods: The Jackson SIRI Team was developed to improve both hospital and patient-level outcomes for individuals hospitalized with SIRIs at Jackson Memorial Hospital, a 1550-bed public hospital in Miami, Florida, United States. The SIRI Team provides integrated infectious disease and SUD treatment across the healthcare system starting from the inpatient setting and continuing for 90-days post-hospital discharge. The team uses a harm reduction approach, provides care coordination, focuses on access to medications for opioid use disorder (MOUD), and utilizes a variety of infection and addiction treatment modalities to suit each individual patient., Results: Over the initial 8-months of the SIRI Team, 21 patients were treated with 20 surviving until discharge. Infections included osteomyelitis, endocarditis, bacteraemia/fungemia, SSTIs, and septic arthritis. All patients had OUD and 95% used stimulants. All patients were discharged on MOUD and 95% completed their prescribed antibiotic course. At 90-days post-discharge, 25% had been readmitted and 70% reported taking MOUD., Conclusions: A model of integrated infectious disease and SUD care for the treatment of SIRIs has the potential to improve infection and addiction outcomes. Providing attentive, patient-centered care, using a harm reduction approach can facilitate engagement of this marginalized population with the healthcare system.KEY MESSAGESIntegrated infectious disease and addiction treatment is a novel approach to treating severe injection-related infections.Harm reduction should be applied to treating patients with severe injection-related infections with a goal of facilitating antibiotic completion, remission from substance use disorder, and reducing hospital readmissions.

Background: People who inject drugs (PWID) have been a marginalized and a stigmatized population since the beginning of the AIDS epidemic and have not experienced the same life-changing benefits of antiretroviral therapy as others. Tele-Harm Reduction (THR) is a telehealth-enhanced, harm reduction intervention, delivered within a trusted SSP venue. It aims to facilitate initiation of care and achieve rapid HIV viral suppression among PWID living with HIV., Methods: In this mixed-methods study, we employed the Practical, Robust, Implementation and Sustainability Model (PRISM) implementation science framework to identify multilevel barriers and facilitators to implementing the THR intervention. Focus groups (n = 2, 16 participants), stakeholder interviews (n = 7) and in-depth interviews were conducted with PWID living with HIV (n = 25). In addition, to assess feasibility and acceptability, we pilot tested the THR intervention and reported viral suppression at 6 months., Results: Focus groups and stakeholder interviews revealed system and organizational level barriers to implementation including requirements for identification and in person visits, waiting times, stigma, case management inexperience, multiple electronic health records, and billing. A potential facilitator was using telehealth for case management and initial provider visit. In the in depth interviews conducted with PWID living with HIV, participants expressed that the SSP creates a convenient, comfortable, confidential environment for delivering multiple, non-stigmatizing PWID-specific services. 35 PWID living with HIV were enrolled in the pilot study, 35 initiated antiretroviral therapy, and 25 (78.1%) were virally suppressed at six months., Conclusion: Rooted in harm reduction, the THR intervention shows promise in being an acceptable and feasible intervention that may facilitate engagement in HIV care and viral suppression among PWID., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The objective of this study was to evaluate bilastine dosing recommendations in older adults and overcome the limitation of insufficient data from phase I studies in this underrepresented population. This was achieved by integrating bilastine physicochemical, in vitro and in vivo data in young adults and the effect of aging in the pharmacology by means of two alternative approaches: a physiologically-based pharmacokinetic (PBPK) model and a semi-mechanistic population pharmacokinetic (Senescence) model. Intestinal apical efflux and basolateral influx transporters were needed in the PBPK model to capture the observations from young adults after single i.v. (10 mg) and p.o. (20 mg) doses, supporting the hypothesis of involvement of gut transporters on secretion. The model was then used to extrapolate the pharmacokinetics (PKs) to elderly subjects considering their specific physiology. Additionally, the Senescence model was develop starting from a published population PK) model, previously applied for pediatrics, and incorporating declining functions on different physiological systems and changes in body composition with aging. Both models were qualified using observed data in a small group of young elderlies (N = 16, mean age = 68.69 years). The PBPK model was further used to evaluate the dose in older subjects (mean age = 80 years) via simulation. The PBPK model supported the hypothesis that basolateral influx and apical efflux transporters are involved in bilastine PK. Both, PBPK and Senescence models indicated that a 20 mg q.d. dose is safe and effective for geriatrics of any age. This approach provides an alternative to generate supplementary data to inform dosing recommendations in under-represented groups in clinical trials., (© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: The risks and benefits of remote corticosteroid weaning in heart transplant recipients more than 2 years post-transplant are unknown. We compared outcomes in patients undergoing early and remote steroid weaning after heart transplantation., Methods: We performed a retrospective study (range 09, 1991-04, 2017). Primary outcomes included short-term and long-term mortality, allograft dysfunction, and burden of rejection. Secondary outcomes included impact on hemoglobin A1c, lipid panel, bone scan T-score, and body mass index., Results: 63 patients underwent corticosteroid weaning between 2012 and 2017. Outcomes of patients weaned early (n = 34; median time from transplant = 1.1 years) were compared with those weaned late (n = 29; median time from transplant = 4.4 years). 52 (82.5%) patients were successfully weaned off corticosteroids. No statistically significant difference in outcomes was found between the early and late weaning groups (p = .20). There were no differences in allograft function (p-value = .16), incidence of rejection (p = .46), or mortality (p = .15). Improvement in metabolic profile was seen in both groups but was not statistically significant., Conclusions: In heart transplant recipients, remote vs early weaning of corticosteroids is not associated with significant differences in graft function or the incidence of rejection after 1-year follow-up. Moreover, there were no significant differences in survival up to 3 years between the two groups., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Admixed populations arise when two or more ancestral populations interbreed. As a result of this admixture, the genome of admixed populations is defined by tracts of variable size inherited from these parental groups and has particular genetic features that provide valuable information about their demographic history. Diverse methods can be used to derive the ancestry apportionment of admixed individuals, and such inferences can be leveraged for the discovery of genetic loci associated with diseases and traits, therefore having important biomedical implications. In this review article, we summarize the most common methods of global and local genetic ancestry estimation and discuss the use of admixture mapping studies in human diseases.