Synthesis and antibacterial action of 3',6'-disubstituted spectinomycins.

Spectinomycin is an aminocyclitol antibiotic with a unique ribosomal binding site. Prior synthetic modifications of spectinomycin have enhanced potency and antibacterial spectrum through addition at the 6'-position to produce trospectomycin and to the 3'-position to produce spectinamides and aminomethyl spectinomycins. This study focused on the design, synthesis, and evaluation of three 3',6'-disubstituted spectinomycin analogs: trospectinamide, N-benzyl linked aminomethyl, and N-ethylene linked aminomethyl trospectomycins. Computational experiments predicted that these disubstituted analogs would be capable of binding within the SPC ribosomal binding site. The new analogs were synthesized from trospectomycin, adapting the previously established routes for the spectinamide and aminomethyl spectinomycin series. In a cell-free translation assay, the disubstituted analogs showed ribosomal inhibition similar to spectinomycin or trospectomycin. These disubstituted analogs demonstrated inhibitory MIC activity against various bacterial species with the 3'-modification dictating spectrum of activity, leading to improved activity against mycobacterium species. Notably, N-ethylene linked aminomethyl trospectomycins exhibited increased potency against Mycobacterium abscessus and trospectinamide displayed robust activity against M. tuberculosis, aligning with the selective efficacy of spectinamides. The study also found that trospectomycin is susceptible to efflux in M. tuberculosis and M. abscessus. These findings contribute to the understanding of the structure-activity relationship of spectinomycin analogs and can guide the design and synthesis of more effective spectinomycin compounds.

Inpatient Hepatitis C Treatment Coordination and Initiation for Patients Who Inject Drugs.

BACKGROUND: With hepatitis C (HCV) incidence rising due to injection drug use, people who inject drugs (PWID) are a priority population for direct-acting antivirals (DAA). However, significant barriers exist. At our institution, hospitalized PWID were screened for HCV but not effectively linked to care. AIM: To improve retention in HCV care among hospitalized PWID. SETTING: Quaternary academic center in the Southeast US from August 2021 through August 2022. PARTICIPANTS: Hospitalized PWID with HCV. PROGRAM DESCRIPTION: E-consultation-prompted care coordination and HCV treatment with outpatient telehealth. PROGRAM EVALUATION: Care cascades were constructed to assess retention and HCV treatment, with the primary outcome defined as DAA completion or sustained virologic response after week 4. Of 28 patients, 11 started DAAs inpatient, 8 initiated outpatient, and 9 were lost to follow-up or transferred care. Overall, 82% were linked to care and 52% completed treatment. For inpatient initiators, 73% achieved the outcome. Of non-inpatient initiators, 71% were linked to care, 53% started treatment, and 36% achieved the outcome. DISCUSSION: Inpatient HCV treatment coordination, including DAA initiation, and telehealth follow-up, was feasible and highly effective for hospitalized PWID. Future steps should address barriers to inpatient DAA treatment and expand this model to other similar patient populations.

Pharmacy Services Reboot Roadmap: Resiliency During the COVID-19 Pandemic.

Description Planning for resumption of patient care services during and following the impact of novel coronavirus disease-2019 (COVID-19) while controlling costs are essential for pharmacy services resiliency. Implementation of a pharmacy services reboot roadmap across a 179 hospital health-system is described. The roadmap encompassed eight key areas: pharmacy leadership, staffing and scheduling, clinical pharmacy services, medication safety, medication supply, regulatory and compliance, team support opportunities, and financial stewardship. A supporting checklist and volume-based staffing plan are included as examples to assist pharmacy leaders in planning optimal pharmacy services support as patient volumes increase, particularly in the emergency department, surgical services and critical care areas. Resiliency strategies are provided as tangible planning considerations to assess the current status of, and prepare for, future operational and clinical pharmacy practice needs to support optimal patient care.

Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy.

The devastating sequelae of diabetes mellitus include microvascular permeability, which results in retinopathy. Despite clinical and scientific advances, there remains a need for new approaches to treat retinopathy. Here, we have presented a possible treatment strategy, whereby targeting the small GTPase ARF6 alters VEGFR2 trafficking and reverses signs of pathology in 4 animal models that represent features of diabetic retinopathy and in a fifth model of ocular pathological angiogenesis. Specifically, we determined that the same signaling pathway utilizes distinct GEFs to sequentially activate ARF6, and these GEFs exert distinct but complementary effects on VEGFR2 trafficking and signal transduction. ARF6 activation was independently regulated by 2 different ARF GEFs - ARNO and GEP100. Interaction between VEGFR2 and ARNO activated ARF6 and stimulated VEGFR2 internalization, whereas a VEGFR2 interaction with GEP100 activated ARF6 to promote VEGFR2 recycling via coreceptor binding. Intervening in either pathway inhibited VEGFR2 signal output. Finally, using a combination of in vitro, cellular, genetic, and pharmacologic techniques, we demonstrated that ARF6 is pivotal in VEGFR2 trafficking and that targeting ARF6-mediated VEGFR2 trafficking has potential as a therapeutic approach for retinal vascular diseases such as diabetic retinopathy.

ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma.

Activating mutations in Gαq proteins, which form the α subunit of certain heterotrimeric G proteins, drive uveal melanoma oncogenesis by triggering multiple downstream signaling pathways, including PLC/PKC, Rho/Rac, and YAP. Here we show that the small GTPase ARF6 acts as a proximal node of oncogenic Gαq signaling to induce all of these downstream pathways as well as ß-catenin signaling. ARF6 activates these diverse pathways through a common mechanism: the trafficking of GNAQ and ß-catenin from the plasma membrane to cytoplasmic vesicles and the nucleus, respectively. Blocking ARF6 with a small-molecule inhibitor reduces uveal melanoma cell proliferation and tumorigenesis in a mouse model, confirming the functional relevance of this pathway and suggesting a therapeutic strategy for Gα-mediated diseases.

Clustered randomised controlled trial of two education interventions designed to increase physical activity and well-being of secondary school students: the MOVE Project.

OBJECTIVE: To assess the effectiveness of 2 interventions in improving the physical activity and well-being of secondary school children. DESIGN: A clustered randomised controlled trial; classes, 1 per school, were assigned to 1 of 3 intervention arms or a control group based on a 2×2 factorial design. The interventions were peer-mentoring and participative learning. Year 7 children (aged 11-12) in the peer-mentoring intervention were paired with year 9 children for 6 weekly mentoring meetings. Year 7 children in the participative learning arm took part in 6 weekly geography lessons using personalised physical activity and Global Positioning System (GPS) data. Year 7 children in the combined intervention received both interventions, with the year 9 children only participating in the mentoring sessions. PARTICIPANTS: 1494 year 7 students from 60 schools in the North of England took part in the trial. Of these, 43 students opted out of taking part in the evaluation measurements, 2 moved teaching group and 58 changed school. Valid accelerometry outcome data were collected for 892 students from 53 schools; and well-being outcome data were available for 927 students from 52 schools. MAIN OUTCOME MEASURES: The primary outcomes were mean minutes of accelerometer-measured moderate-to-vigorous intensity physical activity per day, and well-being as evaluated by the KIDSCREEN-27 questionnaire. These data were collected 6 weeks after the intervention; a 12-month follow-up is planned. RESULTS: No significant effects (main or interaction) were observed for the outcomes. However, small positive differences were found for both outcomes for the participative learning intervention. CONCLUSIONS: These findings suggest that the 2 school-based interventions did not modify levels of physical activity or well-being within the period monitored. Change in physical activity may require more comprehensive individual behavioural intervention, and/or more system-based efforts to address wider environmental influences such as family, peers, physical environment, transport and educational policy. TRIAL REGISTRATION NUMBER: ISRCTN82956355.

Health impacts of pedestrian head-loading: a review of the evidence with particular reference to women and children in sub-Saharan Africa.

Across sub-Saharan Africa, women and children play major roles as pedestrian load-transporters, in the widespread absence of basic sanitation services, electricity and affordable/reliable motorised transport. The majority of loads, including water and firewood for domestic purposes, are carried on the head. Load-carrying has implications not only for school attendance and performance, women's time budgets and gender relations, but arguably also for health and well-being. We report findings from a comprehensive review of relevant literature, undertaken June-September 2012, focussing particularly on biomechanics, maternal health, and the psycho-social impacts of load-carrying; we also draw from our own research. Key knowledge gaps and areas for future research are highlighted.

Malaria risk behaviours, socio-cultural practices and rural livelihoods in southern Tanzania: implications for bednet usage.

Most malaria risk reduction strategies are firmly embedded in biomedical practices and public health perspectives. National and international programmes to 'control' malaria are particularly characterised by the promotion of public health interventions which converge on the disease vector, the malaria mosquito, notably through the use of indoor household spraying with insecticides, and the deployment of insecticide-treated bednets (ITNs). With convincing evidence for the effectiveness of ITNs in reducing the incidence of malaria, control programmes have emphasised the notion of 'scaling-up' bednet coverage. Much previous research on people's 'compliance' with bednet programmes has tended to focus on the quantification of bednet usage and on deriving explanations for 'non-compliance' based on household or individual indicators such as wealth, age, gender or educational level, or on climatic factors such as season and temperature. However, malaria risk behaviours are also rooted in wider aspects of local livelihoods, and socio-cultural beliefs and practices which interplay with the use and, crucially, non-use, of bednets. This paper draws on empirical data derived from in-depth, one-to-one semi-structured interviews, focus groups and participatory methods (mapping and diagramming) with participants in two villages in rural Tanzania to explore the nature of these practices and vulnerabilities, and their potential impact on malaria exposure risk. Participants included farmers and pastoralists, both men and women, as well as village 'officials'. By eliciting local understandings of malaria-related behaviours we explore how malaria risks are played out in people's everyday lives, and the circumstances and decision-making which underpin non-usage of bednets. Our findings reveal the importance of shifting sleeping patterns in response to livelihood needs and socio-cultural practices and events. These arrangements militate against the consistent and sustained use of the bednet which are called for by public health policies. In particular we demonstrate the importance of the spatial and temporal dimensions of farming practices and the role of conflict over access to shared land; the impact of livelihood activities on malaria risks for school-aged children; risk behaviours during 'special' socio-cultural events such as funeral ceremonies; and routine, outdoor activities around dawn and dusk and the gendered nature of these practices.

Predicting time to readmission in patients with recent histories of recurrent psychiatric hospitalization: a matched-control survival analysis.

The most robust predictor of future psychiatric hospitalization is the number of previous admissions. About half of psychiatric inpatients with histories of repeated hospitalizations are readmitted within 12 months. This study sought to determine which patient characteristics predicted time-to-readmission within 12 months after controlling for the number of previous hospitalizations in 75 adults with recent histories of recurrent admissions and 75 matched controls. Results revealed multiple clinical and demographic between-group differences at index hospitalization. However, the only predictors of shorter time-to-readmission in multivariate Cox proportional hazards were unemployment (hazards ratio = 9.26) and residential living status (hazards ratio = 2.05) after controlling for prior hospitalizations (hazard ratio = 1.24). Unemployment and residential living status were not proxies of psychosis or moderated by illness severity or comorbid substance use. Results suggest that early psychiatric readmission may be more influenced by residential and employment status than by severe mental illness.

Characteristics of inpatients with a history of recurrent psychiatric hospitalizations: a matched-control study.

OBJECTIVE: This study examined the association between patient characteristics and inpatient hospitalization among patients with a history of recurrent psychiatric hospitalizations (two or more hospitalizations in the 18 months before the index hospitalization) (N=75) and patients without such a history (N=75). METHODS: Characteristics at the time of the index hospitalization and 48-month inpatient utilization rates (24 months before and 24 months after the index hospitalization) were extracted from medical records. Backwards stepwise regression models were used to identify characteristics independently associated with inpatient utilization. RESULTS: Psychotic disorder and unemployment at the time of index hospitalization were independently associated with higher inpatient utilization over the 48 months. Only the number of hospitalizations in the prior 24 months predicted the number of readmissions after the index hospitalization. CONCLUSIONS: Psychosis and unemployment seem to have an independent effect on the number of hospitalizations.

Advancing insights into methods for studying environment-health relationships: a multidisciplinary approach to understanding Legionnaires' disease.

Recent years have witnessed important advances in the analysis of spatially referenced health data. This paper uses GIS and point pattern modelling to address previously unanswered questions regarding the spatial epidemiology of Legionnaires' disease. We demonstrate a distance effect for proximity of residence to cooling towers; mixed support for a directional effect; and some evidence relating to multiple sources. In uncovering complex conceptual and technical problems in the spatial modelling of infection risk we also extended the limits of existing point pattern techniques. We advocate further multidisciplinary research to advance methodological developments for understanding spatial environment-health relationships.

Social implications of arsenic poisoning in Bangladesh.

Besides its toxicity, groundwater arsenic contamination creates widespread social problems for its victims and their families in Bangladesh. There is, for instance, a tendency to ostracise arsenic-affected people, arsenicosis being thought of as a contagious disease. Within the community, arsenic-affected people are barred from social activities and often face rejection, even by their immediate family members. Women with visible arsenicosis symptoms are unable to get married and some affected housewives are divorced by their husbands. Children with symptoms are not sent to school in an effort to hide the problem. This paper employs mainly qualitative methods to interpret people's understandings about the toxic impact of groundwater arsenic poisoning on their social lives. Arsenic-affected patients in southwest Bangladesh were asked to determine their 'own priorities' in measuring arsenic toxicity on their social activities and to explore their perceptions about their own survival strategies. We found that patients' experiences reveal severe negative social impacts, and a sharp difference of perceptions about arsenic and social issues between arsenicosis patients and unaffected people.

Users' perspectives on epidemiological, GIS and point pattern approaches to analysing environment and health data.

Despite examples showing the usefulness of geographical information systems (GIS) and spatial point pattern analysis in health research, there remain barriers to their widespread use within health service settings. This paper explores potential users' views on the relative usefulness of such approaches for analysing spatially referenced environmental health data. Our findings indicate that researchers and practitioners do not always prefer the approach with which they are most familiar. In addition, there is a need for higher levels of understanding of, and confidence in, GIS and point pattern analysis techniques amongst health service professionals. The greatest need is for multi-disciplinary research which uses the most appropriate approach for each investigation, rather than that with which researchers are most familiar.

The spatial pattern of risk from arsenic poisoning: a Bangladesh case study.

Arsenic poisoning in Bangladesh has been one of the biggest environmental health and social disasters of recent times. About seventy million people in Bangladesh are exposed to toxic levels of arsenic (0.05 mg/L) in drinking water. It is ironic that so many tubewells have been installed in recent times to provide drinking water that is safe from water-borne diseases but that the water pumped is contaminated with toxic levels of arsenic. Along with the clinical manifestations, some social problems have also emerged due to arsenic toxicity. Analysing the spatial risk pattern of arsenic in groundwater is the main objective of this paper. Establishing the extent of arsenic exposure to the people will facilitate an understanding of the health effects and estimating the population risk over the area. This paper seeks to explore the spatial pattern of arsenic concentrations in groundwater for analyzing and mapping 'problem regions' or 'risk zones' for composite arsenic hazard information by using GIS-based data processing and spatial analysis along with state-of-the-art decision-making techniques. Quantitative data along with spatial information were employed and analyzed for this paper.

Public views on the links between air pollution and health in Northeast England.

We investigated how public perceptions of the links between air pollution and health varied with contextual factors describing individuals and their locality. Information was collected via postal surveys on 2744 adults resident in five neighborhoods in Northeast England. Perceptions were compared by individual factors (health status, age, and gender) and locality factors (relative deprivation, proximity to industry and district-Teesside or Sunderland, with different amounts of heavy industry). There was relatively little variation in views about air pollution and health links between neighborhoods. The greatest contrasts were found when comparing those living near or further from industry and between the two districts. Any differences were related more to awareness of illness in the neighborhood thought to be affected by air pollution, rather than belief that a particular disease was linked to air pollution. Chronic illness status and age were sometimes found to be associated with perceptions of disease affected by air pollution, but gender and material deprivation were not central to differences in risk perceptions among the population studied. In understanding public perceptions about the links between air quality and health, research should focus on the characteristics of places as well as of people.

Genetic selection for modulators of a retinoic-acid-responsive reporter in human cells.

We used a genetic screening methodology, a human cell line bearing a retinoic-acid-responsive enhanced GFP reporter, and a flow sorter to recover dominant modulators of reporter expression. Four inducers and three suppressors that were fused to the C terminus of a protein scaffold for stability were isolated and their mechanisms of action studied. Mutagenesis experiments indicated that six of these dominant agents exerted their effects at the protein level. The single cDNA coding fragment that was isolated comprised the central 64-amino-acid section of human cyclophilin B, which contained its peptidyl-prolyl isomerase domain; this cyclophilin fragment repressed expression of the retinoic-acid-responsive reporter. The remaining clones encoded peptides shorter than 30 amino acids unrelated to known gene open reading frames. Genetic epistasis studies between the strongest inducer, R3, and a dominant-negative mutant of RARalpha suggest that the two factors function in the same pathway. Transcript microarray analyses suggest that R3 induced a subset of the retinoid-responsive genes in melanoma cells. Finally, yeast two-hybrid assays and co-immunoprecipitation studies of human cell extracts identified PAT1 as a protein that interacts with R3.

Molecular cloning and characterization of a rat sensory nerve Ca2+-sensing receptor.

A full-length cDNA encoding a Ca2+-sensing receptor (CaSR) expressed in rat dorsal root ganglia (DRG) was identified using rapid amplification of 5'-cDNA ends and primer extension and then cloned into the plasmid vector pCR3.1. The DNA sequence of the DRG CaSR was 99.9% homologous with published rat kidney CaSR in the coding region and 247 bp upstream of the start site but showed little homology 5' to this site, which maps to exonic junction I/II, supporting the hypothesis that CaSR message arises as a splice variant and showing tissue-to-tissue heterogeneity. Western blot revealed a doublet of 140 and 160 kDa in a thyroparathyroid preparation and a single 140-kDa band in DRG. Deglycosylation using N-glycanase increased the mobility of CaSR protein from both DRG and thyroparathyroid, whereas endo-H was without effect, indicating that the DGR CaSR is a mature form of the receptor. A DRG CaSR-pEGFP fusion product was constructed, and when transfected into HEK-293 cells, it was distributed at the cell membrane and resulted in extracellular Ca2+ (0.5-3 mM)-evoked increases in intracellular Ca2+, which in some instances exhibited oscillatory behavior. We conclude that DRG CaSR cDNA arises from tissue-specific alternative splicing of a single gene, that the amino acid sequence of DRG CaSR is homologous to other known CaSRs, and that the DRG CaSR undergoes differential posttranslational processing relative to the thyroparathyroid CaSR and is functionally active when transfected into a human-derived cell line.