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Medicare's prospective payment system (PPS) for hospital cases is based on diagnosis-related groups (DRGs). A wide variety of other third-party payers for hospital care have adapted elements of this system for their own use. The extent of DRG use varies considerably both by type of payer and by geographical area. Users include: 21 State Medicaid programs, 3 workers' compensation systems, the Civilian Health and Medical Program of the Uniformed Services (CHAMPUS), more than one-half of the Blue Cross and Blue Shield Association (BCBSA) member plans, several self-insured employers, and a few employer coalitions. We describe how each of these payers use DRGs. No single approach is dominant. Some payers negotiate specific prices for so many combinations of DRG and hospital that the paradigm that payment equals rate times weight does not apply. What has emerged appears to be a very flexible payment system in which the only constant is the use of DRGs as a measure of output.

Objectives The authors estimated the associations between transient risk factors and laceration injuries in workers at two meatpacking plants in the Midwest. Methods The case-crossover design was used to collect within-subject transient work task and personal-level exposure information. RRs of laceration injuries were estimated by comparing exposures during the 'hazard' period (just before the laceration injury) with exposures in the 'control' period (the previous workweek). Stratified analyses were utilised to estimate the effects of gender, ethnicity, training and the number of adjacent coworkers on each transient risk factor. Results The authors interviewed 295 meatpacking workers with laceration injuries (mean age 36.6 years, SD 11.2, 75% men, 48% Hispanic). Recent tool sharpening (RR 5.3, 95% CI 3.8 to 7.4) and equipment malfunction (RR 5.3, 95% CI 3.9 to 7.3) were associated with the highest RR for laceration injury, followed by using an unusual work method to accomplish a task (RR 4.1, 95% CI 2.6 to 6.4) and performing an unusual task (RR 2.3, 95% CI 1.8 to 3.0). Rushing and being distracted were not significantly associated with an elevated RR of a laceration injury. In stratified analyses, there were a number of significant differences in laceration risk factors by gender, ethnicity, training, and number of workers on the line. Conclusions Sharpening tools, equipment malfunction, using an unusual work method to accomplish a task and performing an unusual task were all associated with increased risk of lacerations. Expanded training in atypical work circumstances and evaluation of tool sharpening procedures are intervention areas in meatpacking that need examination. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To estimate the effect of a new road traffic law against alcohol-impaired driving in Japan. METHODS: Japan passed a new road traffic law in June 2002 intended to reduce alcohol-impaired driving by decreasing the permissible blood alcohol level and by increasing penalties. Using data collected from police reports, the number of traffic fatalities and injuries were analyzed by time series. RESULTS: Simple comparisons of the average of all severe traffic injuries, traffic fatalities, alcohol-impaired traffic injuries, alcohol-impaired severe traffic injuries, and alcohol-impaired traffic fatalities per billion kilometers driven showed reductions after enactment of the new road traffic law in June 2002. The rate of alcohol-related traffic fatalities per billion kilometers driven decreased by 38% in the post-law period. In segmented regression analyses with adjustment for baseline trends, seasonality, and autocorrelation, all traffic injuries, severe traffic injuries, alcohol-impaired traffic injuries, alcohol-impaired severe traffic injuries, and alcohol-impaired traffic fatalities per billion kilometers driven declined significantly from baseline after the new traffic law. CONCLUSION: Large, immediate public health benefits resulted from the new road traffic law in Japan. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This exploratory study evaluated the feasibility of field exposure assessment methods to characterize the noise sources and levels that farm youths experience during a typical workday. METHODS: Detailed exposure assessments were performed with a sample of 10 farm youths working on Vermont dairy farms to characterize potential noise hazards typical in the farm setting. Personal and area noise measurements were taken using noise dosimeters. Information concerning work- and non-work-related noise exposure histories was collected via questionnaire. RESULTS: The average age was 15.5 years (SD 2.5, range 10-18). Youths started working at an average age of 8.4 years (SD 2.3, range 6-12) and during the summer months worked an average of 41.3 hours per week (SD 32.3, range 2-68). Two youths exceeded the OSHA action level, having eight-hour time-weighted averages of 95 dBA and 92 dBA, or alternatively, doses of 206% and 127%. (The OSHA action level for the hearing conservation amendment is an eight-hour time-weighted average of 85 dBA or a dose of 50%.) Participants exceeding the action level reported working with tractors, skid steers (Bobcats), and all-terrain vehicles and doing general barn work. Additional sources of noise exposure included a mechanical silo elevator, chain saw, and wood splitter. CONCLUSION: Two of the monitored subjects were overexposed to noise in their farm work. Youths may be exposed to noise levels that exceed adult OSHA hearing conservation amendment action level as part of their daily farm activities. [ABSTRACT FROM AUTHOR]

Little information is available concerning the acetabular morphology in adults with a history of bladder exstrophy. We documented the pelvic anatomy in adult patients with bladder exstrophy who never had prior surgery. We retrospectively reviewed 31 patients (62 hips) seen from 1976 to 2003 for urologic problems related to bladder exstrophy without adjunctive pelvic osteotomy. There were 18 males and 13 females with an average age of 30 years at last followup. Radiographs at final followup were analyzed for lateral center-edge angle, acetabular index, head extrusion, hip center of rotation, acetabular version, retroversion index, sacral width, and interteardrop distance. Most hips (60 hips) had no arthritis. The average lateral center-edge angle, ace-tabular index, and head extrusion index were 32 degrees, 5.7 degrees, and 0.266%, respectively. Fifty-eight percent of hips had a retroverted acetabulum and 42% were neutral or anteverted. The interteardrop distance averaged 154 mm. Most patients will not have early arthritis develop, and the majority of patients (58%) have retroverted orientation of the acetabulum. [ABSTRACT FROM AUTHOR]

OBJECTIVE: A pilot epidemiologic study was conducted in the People's Republic of China to assess the feasibility of applying the study protocol from a US case-crossover study on transient work-related exposures and the risk of an acute occupational hand injury. DESIGN: Injured workers were recruited from a hand surgery center in Ningbo, Zhejiang, People's Republic of China. A structured face-to-face interview questionnaire was administered. RESULTS: 156 workers with hand injury completed the study (73% men). The enrollment rate was 91%. Of those who refused participation, most indicated their reluctance was due to the requirement to sign the written consent form. Considerable variability was found among interviewers in ascertaining responses from participants to important exposure questions (21.3% v 97%). CONCLUSIONS: Recommendations include the following: (1) exploring effective oral-consent protocols that reduce participant concern and still meet human participant protection requirements; (2) using non-physician interviewers; and (3) increasing the intensity and standardization of interviewer training. [ABSTRACT FROM AUTHOR]

Farm youth face multiple risks for injury and illness in agriculture. Reviewed here is evidence from current literature illustrating the noise and chemical exposure hearing risks that farm youth potentially face. Sources of noise (e.g., machinery) and potentially toxic chemical exposures (e.g. solvents and pesticides) common in the farm environment are reviewed, illustrating the need for heightened research attention to a problem that may affect up to 2 million children in the United States alone and that requires both public and occupational health solutions. As existing studies have not sufficiently explored potential ototoxic effects of these exposures on children and adolescents, recommendations are outlined for research characterizing both chemical and noise exposures to farm youth and their combined effects on hearing. [ABSTRACT FROM AUTHOR]

Context: Farming is one of the most hazardous occupational industries in the USA, and farms pose numerous health risks for youth visiting, living in, or working in the farm environment. Purpose: This review discusses both potential traumatic injuries and hazardous inorganic exposures that are common in agricultural settings. Findings: An estimated 2 million youth under the age of 20 currently live or work on US farms. Approximately 103 farm fatalities occur in this age group each year; over 32 000 nonfatal youth injuries occurred on farms in 1998. Children working in US agriculture make up only 8% of the population of working minors overall, yet they account for 40% of work-related fatalities among minors. Farm children and youth are also exposed to potentially harmful chemicals, such as pesticides and solvents, and many of these exposures go undetected. The long-term health effects of exposure to pesticides or solvents are not known, but the developmental vulnerabilities of children and youth are of particular concern. Conclusions: Clinical and epidemiologic research in pediatric populations is needed to expand the empirical data, particularly for inorganic and organic exposures, musculoskeletal trauma, skin disorders, occupation-induced hearing loss, and psychosocial stress. Rural health professionals can work to reduce these risks to farm youth by becoming more aware of the problem, by conducting clinical and epidemiologic research, and by engaging in advocacy at state and local levels. [ABSTRACT FROM AUTHOR]

Although a number of health hazards associated with pesticide exposure have been well documented, relatively little is known about the knowledge and health beliefs that may influence pesticide handling. This study measured knowledge levels concerning pesticide safety and precautionary handling among applicators and examined relationships between knowledge scores and intentions to use handling precautions, perceptions of pesticide safety peer norms, and perceived self-efficacy to prevent personal exposure. Telephone interviews were conducted with a randomly selected sample of 164 dairy farmers who were pesticide applicators residing in Wisconsin (response rate = 77.4%). The percentage of correct responses to 18 knowledge items ranged from 100% to 45.7%. Knowledge levels were positively related to intentions, beliefs, and self-efficacy regarding use of personal protective gear but were not significantly related to risk perceptions and peer norms concerning pesticide safety. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Women in impoverished inner-city neighborhoods are at high risk for contracting HIV. A randomized, multisite community-level HIV prevention trial was undertaken with women living in 18 low-income housing developments in 5 US cities. METHODS: Baseline and 12-month follow-up population risk characteristics were assessed by surveying 690 women at both time points. In the 9 intervention condition housing developments, a community-level intervention was undertaken that included HIV risk reduction workshops and community HIV prevention events implemented by women who were popular opinion leaders among their peers. RESULTS: The proportion of women in the intervention developments who had any unprotected intercourse in the past 2 months declined from 50% to 37.6%, and the percentage of women's acts of intercourse protected by condoms increased from 30.2% to 47.2%. Among women exposed to intervention activities, the mean frequency of unprotected acts of intercourse in the past 2 months tended to be lower at follow-up (mean = 4.0) than at baseline (mean = 6.0). These changes were corroborated by changes in other risk indicators. CONCLUSIONS: Community-level interventions that involve and engage women in neighborhood-based HIV prevention activities can bring about reductions in high-risk sexual behaviors. [ABSTRACT FROM AUTHOR]

Objectives. Women who have sex with women are a relatively hidden group that has been overlooked in most AIDS research and prevention efforts, primarily because the efficiency of HIV transmission between female partners is believed to be low. Although data are scant, it is commonly assumed that members of this population are not at high risk for HIV infection. However, a recent study of lesbian and bisexual women living in the San Francisco Bay area reported a relatively high seroprevalence rate and has raised additional questions about this group's HIV risk. The present study, the first to focus on lesbian and bisexual women living outside major AIDS epicenters, provides additional evidence. It describes risk factors for HIV transmission among lesbian and bisexual women living in small cities in four geographic regions of the United States. Methods. On three consecutive evenings in 1992, members of the research team distributed anonymous structured written surveys to women patrons as they entered gay bars in each of 16 small cities. Results. Almost 17% of bisexual respondents and 0.5% of lesbians reported having had unprotected vaginal or anal sex with a male during the two months prior to the survey. Almost 10 percent of bisexual women and 8.8% of lesbians in the sample reported a history of injection drug use. Among those women surveyed who said they had been tested, 1.4% reported they were infected with HIV. Conclusions. Self-identified sexual orientation was highly consistent with recent sexual behavior. HIV risk related to sexual behavior was concentrated among self identified bisexual women. The prevalence of injection drug use was substantial among both bisexual and lesbians. Developers of HIV risk behavior programs should take the prevalence of these risk behaviors into consideration in the design of effective HIV prevention interventions tailored to the needs of this hidden population. [ABSTRACT FROM AUTHOR]

Research investigating HIV-risk sexual behaviors of men who have sex with men usually combines gay and bisexual men, treating them as a single, homogeneous group. However, gay and bisexual men may differ in their HIV risk behavior and in psychological characteristics indicative of risk. Exclusively gay (N = 1,180) and bisexual men (N = 136) completed anonymous surveys at gay bars. The surveys assessed demographic, psychological, and behavioral data related to sexual behavior and HIV risk. Relative to exclusively gay men, bisexual men had lower intentions to use condoms in their next intercourse occasion, reported a greater frequency of oral sex with men and more oral-sex partners, knew fewer people who were HIV positive, and perceived weaker peer norms favoring safer sex and risk avoidance. One-third of bisexual men reported engaging in unprotected anal intercourse, and 17% of bisexual men had multiple unprotected anal sex partners in the past two months. Interventions tailored to the needs of bisexual men are urgently needed and should focus on increasing intentions to use condoms, increasing HIV-risk sensitization, and fostering norms favoring safer sex and risk avoidance. [ABSTRACT FROM AUTHOR]

High rates of sexually transmitted diseases (STDs), including HIV, and unplanned pregnancies persist in the United States. Women are more likely than men to be infected with an STD and to bear the burdens associated with unplanned pregnancies and with STD-associated complications. Condom use is advocated for sexually active individuals. However, for some persons condom use remains infrequent and inconsistent; this is particularly true for women, who may face substantial barriers (e.g., partner aggression) to enacting consistent condom use. The female condom is the only female-controlled barrier method currently available to protect women from STDs and unplanned pregnancies. In this paper, we review and summarize the literature on the female condom with regard to efficacy, use-effectiveness, and acceptability among potential and current users. In addition, we identify gaps in the literature and suggest paths for future research. [ABSTRACT FROM AUTHOR]

OBJECTIVES. This study describes the prevalence and predictors of human immunodeficiency virus (HIV) risk behaviors among women living in low-income, inner-city housing developments. METHODS. Anonymous questionnaires were administered to 671 women living in 10 inner-city, low-income housing developments in five US cities to determine their levels of HIV risk behavior and predictors of HIV risk practices. RESULTS. Approximately one third of women were at high risk for HIV because of the risk behavior of their sexual partners. HIV risk was highest among women who accurately perceived themselves to be at increased HIV risk, held strong beliefs about barriers to condom use, and reported weak behavioral intentions to reduce risk. Women at higher risk were also younger and reported higher rates of alcohol and substance use. CONCLUSIONS. HIV prevention efforts are needed for inner-city women. Interventions should focus on overcoming women's barriers to condom use, strengthening their intentions to change behaviors, and managing the risk related to their use of substances. [ABSTRACT FROM AUTHOR]

In the years ahead, end-user instruction will expand from the current models of curriculum- and institution-based programs for teaching MEDLINE to include outreach programs to unaffiliated users for teaching specialized database searching. The Southeast Florida AIDS Information Network (SEFAIN), a community-based information system targeting health care providers in a tri-county area, is an example of this new model. The components of SEFAIN and the results of the outreach and educational programs are presented. The advantages of these programs to both providers and librarians are highlighted. Comparisons are drawn between end users who take specialized information courses and those who take MEDLINE courses or no courses. These data will assist librarians in the justification and development of specialized information systems. [ABSTRACT FROM AUTHOR]

Background: In recent years, cleaning has been identified as an occupational risk because of an increased incidence of reported respiratory effects, such as asthma and asthma-like symptoms among cleaning workers. Due to the lack of systematic occupational hygiene analyses and workplace exposure data, it is not clear which cleaning-related exposures induce or aggravate asthma and other respiratory effects. Currently, there is a need for systematic evaluation of cleaning products ingredients and their exposures in the workplace. The objectives of this work were to: a) identify cleaning products' ingredients of concern with respect to respiratory and skin irritation and sensitization; and b) assess the potential for inhalation and dermal exposures to these ingredients during common cleaning tasks.Methods: We prioritized ingredients of concern in cleaning products commonly used in several hospitals in Massachusetts. Methods included workplace interviews, reviews of product Materials Safety Data Sheets and the scientific literature on adverse health effects to humans, reviews of physico-chemical properties of cleaning ingredients, and occupational hygiene observational analyses. Furthermore, the potential for exposure in the workplace was assessed by conducting qualitative assessment of airborne exposures and semi-quantitative assessment of dermal exposures.Results: Cleaning products used for common cleaning tasks were mixtures of many chemicals, including respiratory and dermal irritants and sensitizers. Examples of ingredients of concern include quaternary ammonium compounds, 2-butoxyethanol, and ethanolamines. Cleaning workers are at risk of acute and chronic inhalation exposures to volatile organic compounds (VOC) vapors and aerosols generated from product spraying, and dermal exposures mostly through hands.Conclusion: Cleaning products are mixtures of many chemical ingredients that may impact workers' health through air and dermal exposures. Because cleaning exposures are a function of product formulations and product application procedures, a combination of product evaluation with workplace exposure assessment is critical in developing strategies for protecting workers from cleaning hazards. Our task based assessment methods allowed classification of tasks in different exposure categories, a strategy that can be employed by epidemiological investigations related to cleaning. The methods presented here can be used by occupational and environmental health practitioners to identify intervention strategies. [ABSTRACT FROM AUTHOR]

Objectives: Understanding immune response dynamics during the COVID-19 pandemic is crucial for optimizing future vaccine strategies. This study investigated the infection- and vaccine-induced SARS-CoV-2 antibody responses in the Albanian population from August 2021 to August 2022., Methods: This used a cross-sectional approach, analyzing two independent, randomly selected population samples over 1 year. Participants' demographic, health, vaccination, and COVID-19 data were collected, with blood samples assessed via enzyme linked immunosorbent assay for immunoglobulin G class anti-spike and anti-nucleocapsid antibodies., Results: By August 2022, all individuals receiving one vaccine dose achieved antibody levels comparable to those receiving two doses (median 7.71 index ratio [IR] vs 7.00 IR). In August 2021, those with previous COVID-19 infection receiving one vaccine dose showed median anti-spike immunoglobulin G levels of 7.22 IR compared with 4.84 IR in those without previous infection receiving two doses. However, individuals aged ≥61 years required two vaccine doses to achieve similar immune responses as younger individuals with one dose., Conclusions: These findings underscore the importance of hybrid immunity, suggesting one vaccine dose may suffice for individuals with previous COVID-19 infection, whereas older adults require additional doses for optimal protection. This study provides insights into humoral immune response dynamics, which is crucial for refining COVID-19 vaccination strategies in middle-income countries with low vaccination coverage and high infection rates., Competing Interests: The authors have no competing interests to declare., (© 2024 The Author(s).)

Recent studies have shown that seagrasses could possess potential applications in the treatment of inflammatory disorders. Five seagrass species ( Zostera muelleri , Halodule uninervis , Cymodocea rotundata , Syringodium isoetifolium , and Thalassia hemprichii ) from the Great Barrier Reef (QLD, Australia) were thus collected, and their preliminary antioxidant and anti-inflammatory activities were evaluated. From the acetone extracts of five seagrass species subjected to 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging antioxidant assay, the extract of Z. muelleri had the highest activity (half minimal concentration of inhibition (IC 50 ) = 138 µg/mL), with the aerial parts (IC 50 = 119 µg/mL) possessing significantly higher antioxidant activity than the roots (IC 50 ≥ 500 µg/mL). A human peripheral blood mononuclear cells (PBMCs) assay with bacterial lipopolysaccharide (LPS) activation and LEGENDplex cytokine analysis showed that the aerial extract of Z. muelleri significantly reduced the levels of inflammatory cytokines tumour necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 by 29%, 74%, and 90%, respectively, relative to the LPS treatment group. The aerial extract was thus fractionated with methanol (MeOH) and hexane fraction, and purification of the MeOH fraction by HPLC led to the isolation of 4-hydroxybenzoic acid ( 1 ), luteolin ( 2 ), and apigenin ( 3 ) as its major constituents. These compounds have been previously shown to reduce levels of TNF-α, IL-1β, and IL-6 and represent some of the major bioactive components of Z. muelleri aerial parts. This investigation represents the first study of the antioxidant and anti-inflammatory properties of Z. muelleri and the first isolation of small molecules from this species. These results highlight the potential for using seagrasses in treating inflammation and the need for further investigation.

Inducing necroptosis in cancer cells has emerged as an effective strategy to overcome drug resistance. However, while organic small molecules have been extensively studied for this purpose, metal-based compounds have received relatively little attention as triggers of necroptosis. The development of ruthenium (II) hybrid compounds, particularly those containing triazene (Ru-TRZ), highlights a novel avenue for modulating necroptotic cell death. Here we show that incorporating a methyltriazene moiety, a known alkylating warhead, confers superior mitochondrial-targeting properties and enhances cell death compared to amide-containing counterparts. Ru-hybrid TRZ2 exhibits also antitumor efficacy against in vivo drug-resistant cancer cells. Mechanistically, we demonstrate that Ru-TRZ hybrids induce apoptosis. In addition, by activating downstream RIPK3-driven cell death, TRZ2 proficiently restrains normal mitochondrial function and activity, leading to cancer cell necroptosis. Finally, TRZ2 synergizes anti-proliferative activity and cell death effects induced by conventional drugs. In conclusion, Ru-TRZ2 stands as a promising ruthenium-based chemotherapeutic agent inducing necroptosis in drug resistant cancer cells., (© 2024. The Author(s).)

Natural products (NPs) have played a vital role in human survival for millennia, particularly for their medicinal properties. Many traditional medicine practices continue to utilise crude plants and animal products for treating various diseases, including inflammation. In contrast, contemporary medicine focuses more on isolating drug-lead compounds from NPs to develop new and better treatment drugs for treating inflammatory disorders such as inflammatory bowel diseases. There is an ongoing search for new drug leads as there is still no cure for many inflammatory conditions. Various approaches and technologies are used in drug discoveries from NPs. This review comprehensively focuses on anti-inflammatory small molecules and describes the key strategies in identifying, extracting, fractionating and isolating small-molecule drug leads. This review also discusses the (i) most used approaches and recently available techniques, including artificial intelligence (AI), (ii) machine learning, and computational approaches in drug discovery; (iii) provides various animal models and cell lines used in in-vitro and in-vivo assessment of the anti-inflammatory potential of NPs.

Introduction: We evaluated risk factors for biochemical recurrence (BCR) after robot-assisted radical prostatectomy (RARP) based on our department database., Material and Methods: Patients who underwent RARP between 2018 and 2020 were identified and included in our retrospective study. Patients who received neoadjuvant treatment, patients with positive lymph nodes, salvage prostatectomies, and patients with missing data were excluded. BCR was defined as PSA ≥0.2 ng/ml. Parameters that were investigated were the International Society of Urological Pathologists (ISUP) score, stage, and positive surgical margins (PSM) as they were reported in the pathology report. A subgroup analysis based on the tumour stage was performed., Results: A total of 414 patients were included in the analysis. Seventy-seven of them experienced BCR. Based on multivariable analysis, ISUP grade was a strong predictor for BCR with odds ratio (OR): 2.86 (CI: 1.49-5.65; p = 0.002), OR: 5.90 (CI: 1.81-18.6; p = 0.003), OR: 4.63 (CI: 1.79-11.9; p = 0.001) for ISUP grade 3, 4, 5, respectively. Regarding tumour stage, pT2 and pT3a did not show any significant difference in predicting BCR (p = 0.11), whereas pT3b stage was a predictor for BCR with OR: 6.2 (CI: 2.25-17.7; p < 0.001). In the subgroup analysis for 206 patients with pT2 disease, ISUP group and PSM were predictors for BCR. On the other hand, when patients with pT3 disease were inspected, the only parameter that was predictive of BCR was pT3b disease (OR: 4.68, CI: 1.71-13.6; p = 0.003). ISUP grade, the extent of T3 disease, and the extent and ISUP grade of surgical margins were not predictors of BCR., Conclusions: The most important risk factors for BCR after RARP are ISUP grade and tumour stage. In pT2 disease, PSM is a significant predictor of BCR, along with high ISUP grade. The substage pT3b can be considered a predictor of BCR in pT3 cases., Competing Interests: The authors declare no conflicts of interest., (Copyright by Polish Urological Association.)

At the end of gestation, fetal skeleton rapidly accumulates calcium, and bone development continues in offspring postnatally. To accommodate, maternal skeletal physiology is modulated in a serotonin-dependent manner. Selective serotonin reuptake inhibitors (SSRIs) are generally considered safe for treatment of major depressive disorder, postpartum depression, and other psychiatric illnesses during the peripartum period, but because serotonin affects bone remodeling, SSRIs are associated with decreased bone mass across all ages and sexes, and the impact of SSRIs during fetal and postnatal development has not been fully investigated. In the present study, our aim was to examine developmental fluoxetine exposure on offspring skeleton and to assess varying degrees of impact depending on dose and window of exposure in short-term and long-term contexts. We established that a low dose of lactational fluoxetine exposure caused a greater degree of insult to offspring bone than either a low dose during fetal and postpartum development or a high dose during lactation only in mice. We further discovered lasting impacts of developmental fluoxetine exposure, especially during lactation only, on adult bone and body composition. Herein, we provide evidence fluoxetine exposure during early development may have detrimental effects on the skeleton of offspring at weaning and into adulthood., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Monitoring SARS-CoV-2 seroprevalence dynamics during the COVID-19 pandemic is crucial for understanding population immunity and providing insights into public health policies. Limited data exist on this from Albania and other Eastern European countries. This study aimed to investigate SARS-CoV-2 seroprevalence in Albania, comparing August 2021 and August 2022 data from two representative samples of the general population. The objective was to understand the temporal dynamics of SARS-CoV-2 antibodies across age groups and assess the impacts of natural infection and vaccination on population immunity., Methods: This longitudinal study was conducted in two consecutive cross-sectional assessments 12 months apart in Albania's urban all-ages population. IgG anti-Spike-1 and anti-Nucleoprotein SARS-CoV-2 antibodies were measured using ELISA, focusing on seropositivity rates and antibody levels., Methods: The study encompassed 2143 and 2183 individuals in August 2021 and 2022, respectively, with the anti-S1-IgG seropositivity rate escalating from 70.9 ​% to 92.1 ​%. In 2021, seroprevalence ranged from 49.6 ​% (0-15 years) to 82 ​% (>60 years). By August 2022, it surpassed 90 ​% in most age groups, except 0-15 years (73.8 ​%). "Hybrid" immunity (COVID-19+ and Vaccine+) reached 56.6 ​% in 2022, or 2.8 times higher than in 2021, exhibiting the highest antibody levels compared to the only vaccinated or previously COVID-19-infected individuals., Conclusion: This study highlights an overall 94 % seroprevalence in the Albanian population in August 2022 and robust "hybrid" immunity, suggesting substantial protective immunity against SARS-CoV-2. The lower immunity in the 0-15 age group underscores the necessity for youth-targeted vaccine campaigns. These findings provide valuable insights for shaping healthcare measures and vaccination policies., 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., (© 2023 The Authors.)

Postpartum depression affects many individuals after parturition, and selective serotonin reuptake inhibitors (SSRIs) are often used as the first-line treatment; however, both SSRIs and lactation are independently associated with bone loss due to the role of serotonin in bone remodeling. Previously, we have established that administration of the SSRI fluoxetine during the peripartal period results in alterations in long-term skeletal characteristics. In the present study, we treated mice with either a low or high dose of fluoxetine during lactation to determine the consequences of the perturbation of serotonin signaling during this time period on the dam skeleton. We found that lactational fluoxetine exposure affected both cortical and trabecular parameters, altered gene expression and circulating markers of bone turnover, and affected mammary gland characteristics, and that these effects were more pronounced in the dams that were exposed to the low dose of fluoxetine in comparison to the high dose. Fluoxetine treatment during the postpartum period in rodents had short term effects on bone that were largely resolved 3 months post-weaning. Despite the overall lack of long-term insult to bone, the alterations in serotonin-driven lactational bone remodeling raises the question of whether fluoxetine is a safe option for the treatment of postpartum depression., 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 © 2023 Fricke, Krajco, Perry, Brettingen, Wake, Charles and Hernandez.)

Background: Evidence of the negative impacts of contemporary use insecticides on sperm concentration has increased over the last few decades; however, meta-analyses on this topic are rare., Objectives: This investigation assessed the qualitative and quantitative strength of epidemiological evidence regarding adult exposure to two classes of contemporary use insecticides-organophosphates (OPs) and N -methyl carbamates (NMCs)-and sperm concentration using robust and reproducible systematic review and meta-analysis methods., Methods: Three scientific databases (PubMed, Scopus, and Web of Science), two U.S. government databases (NIOSHTIC-2 and Science.gov), and five nongovernmental organization websites were searched for relevant primary epidemiological studies published in any language through 11 August 2022. Risk of bias and strength of evidence were evaluated according to Navigation Guide systematic review methodology. Bias-adjusted standardized mean difference effect sizes were calculated and pooled using a three-level, multivariate random-effect meta-analysis model with cluster-robust variance estimation., Results: Across 20 studies, 21 study populations, 42 effect sizes, and 1,774 adult men, the pooled bias-adjusted standardized mean difference in sperm concentration between adult men more- and less-exposed to OP and NMC insecticides was - 0.30 (95% CI: - 0.49 , - 0.10 ; P Satt < 0.01 ). Sensitivity and subgroup analyses explored statistical heterogeneity and validated the model robustness. Although the pooled effect estimate was modified by risk of bias, insecticide class, exposure setting, and recruitment setting, it remained negative in direction across all meta-analyses. The body of evidence was rated to be of moderate quality, with sufficient evidence of an association between higher adult OP and NMC insecticide exposure and lower sperm concentration., Discussion: This comprehensive investigation found sufficient evidence of an association between higher OP and NMC insecticide exposure and lower sperm concentration in adults. Although additional cohort studies can be beneficial to fill data gaps, the strength of evidence warrants reducing exposure to OP and NMC insecticides now to prevent continued male reproductive harm. https://doi.org/10.1289/EHP12678.

Plants have been vital to human survival for aeons, especially for their unique medicinal properties. Trees of the Eucalyptus genus are well known for their medicinal properties; however, little is known of the ethnopharmacology and bioactivities of their close relatives in the Corymbia genus. Given the current lack of widespread knowledge of the Corymbia genus, this review aims to provide the first summary of the ethnopharmacology, phytochemistry and bioactivities of this genus. The Scopus, Web of Science, PubMed and Google Scholar databases were searched to identify research articles on the biological activities, phytochemistry and ethnomedical uses of Corymbia species. Of the 115 Corymbia species known, 14 species were found to have ethnomedical uses for the leaves, kino and/or bark. Analysis of the references obtained for these 14 Corymbia spp. revealed that the essential oils, crude extracts and compounds isolated from these species possess an array of biological activities including anti-bacterial, anti-fungal, anti-protozoal, anti-viral, larvicidal, insecticidal, acaricidal, anti-inflammatory, anti-oxidant, anti-cancer and anti-diabetic activities, highlighting the potential for this under-studied genus to provide lead compounds and treatments for a host of medical conditions.

The peripartal period is marked by alterations in calcium metabolism to accommodate for embryonic skeletal mineralization and support bone development of offspring in early life, and serotonin plays a critical role in modulating peripartal bone remodeling. Selective serotonin reuptake inhibitors (SSRIs) are commonly used as first-line treatment for psychiatric illness during pregnancy and the postpartum period and considered safe for maternal use during this time frame. In order to evaluate the effect of peripartal alterations of the serotonergic system on maternal skeletal physiology, we treated dams with the SSRI fluoxetine during gestation only, lactation only, or during the entire peripartal period. Overall, we found a low dose of fluoxetine during gestation only had minimal impacts on maternal bone at weaning, but there were implications on maternal skeleton at weaning when dams were exposed during lactation only or during the entire peripartal period. We found that these effects were differential between female mice dosed lactationally or peripartally, and there were also impacts on maternal mammary gland at weaning in both of these groups. Though SSRIs are largely considered safe maternally during the peripartal period, this study raises the question whether safety of SSRIs, specifically fluoxetine, during the peripartal period should be reevaluated., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis (TB), a disease that, although preventable and curable, remains a global epidemic due to the emergence of resistance and a latent form responsible for a long period of treatment. Drug discovery in TB is a challenging task due to the heterogeneity of the disease, the emergence of resistance, and uncomplete knowledge of the pathophysiology of the disease. The limited permeability of the cell wall and the presence of multiple efflux pumps remain a major barrier to achieve effective intracellular drug accumulation. While the complete genome sequence of Mtb has been determined and several potential protein targets have been validated, the lack of adequate models for in vitro and in vivo studies is a limiting factor in TB drug discovery programs. In current therapeutic regimens, less than 0.5% of bacterial proteins are targeted during the biosynthesis of the cell wall and the energetic metabolism of two of the most important processes exploited for TB chemotherapeutics. This review provides an overview on the current challenges in TB drug discovery and emerging Mtb druggable proteins, and explains how chemical probes for protein profiling enabled the identification of new targets and biomarkers, paving the way to disruptive therapeutic regimens and diagnostic tools.

Melanoma is the most aggressive form of skin cancer, with increasing incidence and mortality rates. To overcome current treatment limitations, a hybrid molecule (HM) combining a triazene and a sulfur L-tyrosine analogue, was recently synthesized, incorporated in long blood circulating liposomes (LIP HM) and validated in an immunocompetent melanoma model. The present work constitutes a step forward in the therapeutic assessment of HM formulations. Here, human melanoma cells, A375 and MNT-1, were used and dacarbazine (DTIC), a triazene drug clinically available as first-line treatment for melanoma, constituted the positive control. In cell cycle analysis, A375 cells, after 24-h incubation with HM (60 μM) and DTIC (70 μM), resulted in a 1.2 fold increase (related to control) in the percentage of cells in G0/G1 phase. The therapeutic activity was evaluated in a human murine melanoma model (subcutaneously injected with A375 cells) to most closely resemble the human pathology. Animals treated with LIP HM exhibited the highest antimelanoma effect resulting in a 6-, 5- and 4-fold reduction on tumor volume compared to negative control, Free HM and DTIC groups, respectively. No toxic side effects were detected. Overall, these results constitute another step forward in the validation of the antimelanoma activity of LIP HM, using a murine model that more accurately simulates the pathology that occurs in human patients., Competing Interests: Declaration of Competing 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 Author(s). Published by Elsevier B.V. All rights reserved.)

In a continuation of the exploration of indigo cascade reactions, a series of -OMe, -Ph, -Br and -NO 2 substituted indigos 1a-i were synthesised to probe electronic effects upon the outcome of allylation cascade reactions. When indigos 1a-i in the presence of base were reacted with allyl bromide, spiroindolinepyridoindolones 17-25 (36-75%) were obtained as the major products in each case, marking a shift in outcome relative to that previously reported for unsubstituted indigo. In electron-rich derivatives (-OMe, -Ph), C -allylspiroindolinepyridoindolediones 26-29 (3-11%) were also isolated, which are most likely formed via a Claisen rearrangement of the respective spiroindolinepyridoindolones 18-21. Additionally, the isolation of diallylbiindolone 16, oxazinobiindole 30 and N , N' -diallyl-3,3'-bis(allyloxy)biindole 31 each represented novel polyheterocyclic derivatives, providing intriguing new mechanistic insights, reaction pathways and in the case of 30 the first common heterocyclic skeletal outcome shared in both allylation and propargylation cascade reactions of indigo., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The aggressiveness of melanoma and lack of effective therapies incite the discovery of novel strategies. Recently, a new dual acting hybrid molecule (HM), combining a triazene and a ʟ-tyrosine analogue, was synthesized. HM was designed to specifically be activated by tyrosinase, the enzyme involved in melanin biosynthesis and overexpressed in melanoma. HM displayed remarkable superior antiproliferative activity towards various cancer cell lines compared with temozolomide (TMZ), a triazene drug in clinical use, that acts through DNA alkylation. In B16-F10 cells, HM induced a cell cycle arrest at phase G0/G1 with a 2.8-fold decrease in cell proliferation index. Also, compared to control cells, HM led to a concentration-dependent reduction in tyrosinase activity and increase in caspase 3/7 activity. To maximize the therapeutic performance of HM in vivo, its incorporation in long blood circulating liposomes, containing poly(ethylene glycol) (PEG) at their surface, was performed for passively targeting tumour sites. HM liposomes (LIP HM) exhibited high stability in biological fluids. Preclinical studies demonstrated its safety for systemic administration and in a subcutaneous murine melanoma model, significantly reduced tumour progression. In a metastatic murine melanoma model, a superior antitumour effect was also observed for mice receiving LIP HM, with markedly reduction of lung metastases compared to positive control group (TMZ). Biodistribution studies using 111 In-labelled LIP HM demonstrated its ability for passively targeting tumour sites, thus correlating with the high therapeutic effect observed in the two experimental murine melanoma models. Overall, our proposed nanotherapeutic strategy was validated as an effective and safe alternative against melanoma., Competing Interests: Conflict of interest statement The authors report there are no competing interests to declare., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

We investigate the standard and dual Bondi-Metzner-Sachs (BMS) supertranslation generators on a black hole horizon and draw some conclusions about black hole physics. Recently, it has been shown that in addition to conventional BMS supertranslation symmetries, there exists an additional infinite set of magnetic asymptotic symmetries, dual BMS supertranslations, again parametrized by a function on the two-sphere. We show that the Dirac bracket between these generators exhibits an anomalous central term when one parameter function exhibits a singularity in the complex stereographical coordinates on the sphere. In order to preserve general coordinate invariance, we demonstrate that this central term can be removed by postulating a holographic gravitational Chern-Simons theory on the horizon. This indicates that for an anomaly-free theory of quantum gravity in the presence of a black hole, one should include a boundary theory on the horizon.

Introduction: The coronavirus (COVID-19) pandemic has overwhelmed most health services. As a result, many surgeries have been deferred and diagnoses delayed. The aim of this study was to assess the effect of the COVID-19 pandemic at a high-volume pelvic oncology centre., Methods: A retrospective review was performed of clinical activity from 2017 to 2020. We compared caseload for index procedures 2017-2019 (period 1) versus 2020 (period 2) to see the effect of the COVID pandemic. We then compared the activity during the first lockdown (March 23rd) to the rest of the year when we increased our theatre access by utilising a 'clean' site., Results: The average annual number of robotic assisted radical cystectomy (RARC) and robotic assisted radical prostatectomy (RARP) performed during period 1 was 82 and 352 respectively. This reduced to 68 (17.1% reduction) and 262 (25.6% reduction) during period 2. The number of patients who underwent prostate brachytherapy decreased from 308 to 243 (21% reduction). The number of prostate biopsies decreased from 420 to 234 (44.3% reduction). The number of radical orchidectomies decreased from 18 to 11 (39% reduction). The mean number of RARC and RARP per month during period 2 was 5.5 and 22. This decreased to 4 and 9 per month during the first national lockdown but was maintained thereafter despite two further lockdowns., Conclusion: There has been a substantial decrease in urological oncology caseload during the COVID pandemic. The use of alternate pathways such as 'clean' sites can ensure continuity of care for cancer surgery and training needs.

The potential health consequences of glyphosate-induced gut microbiome alterations have become a matter of intense debate. As part of a multifaceted study investigating toxicity, carcinogenicity and multigenerational effects of glyphosate and its commercial herbicide formulations, we assessed changes in bacterial and fungal populations in the caecum microbiota of rats exposed prenatally until adulthood (13 weeks after weaning) to three doses of glyphosate (0.5, 5, 50 mg/kg body weight/day), or to the formulated herbicide products Roundup Bioflow and RangerPro at the same glyphosate-equivalent doses. Caecum bacterial microbiota were evaluated by 16S rRNA sequencing whilst the fungal population was determined by ITS2 amplicon sequencing. Results showed that both fungal and bacterial diversity were affected by the Roundup formulations in a dose-dependent manner, whilst glyphosate alone significantly altered only bacterial diversity. At taxa level, a reduction in Bacteroidota abundance, marked by alterations in the levels of Alloprevotella, Prevotella and Prevotellaceae UCG-003 , was concomitant to increased levels of Firmicutes (e.g., Romboutsia , Dubosiella , Eubacterium brachy group or Christensenellaceae ) and Actinobacteria (e.g., Enterorhabdus, Adlercreutzia , or Asaccharobacter ) . Treponema and Mycoplasma also had their levels reduced by the pesticide treatments. Analysis of fungal composition indicated that the abundance of the rat gut commensal Ascomycota Kazachstania was reduced while the abundance of Gibberella, Penicillium, Claviceps, Cornuvesica, Candida, Trichoderma and Sarocladium were increased by exposure to the Roundup formulations, but not to glyphosate. Altogether, our data suggest that glyphosate and its Roundup RangerPro and Bioflow caused profound changes in caecum microbiome composition by affecting the fitness of major commensals, which in turn reduced competition and allowed opportunistic fungi to grow in the gut, in particular in animals exposed to the herbicide formulations. This further indicates that changes in gut microbiome composition might influence the long-term toxicity, carcinogenicity and multigenerational effects of glyphosate-based herbicides., Competing Interests: RM has served as a consultant on glyphosate risk assessment issues as part of litigation in the US over glyphosate health effects. MP has provided expert consultation in legal proceedings related to occupational and environmental health issues including the health effects of pesticide exposures and exposure to COVID19. 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 Mesnage, Panzacchi, Bourne, Mein, Perry, Hu, Chen, Mandrioli, Belpoggi and Antoniou.)

Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interest.