Toll-like receptor and pro-inflammatory cytokine expression during prolonged hyperinsulinaemia in horses: Implications for laminitis

Equine laminitis, a disease of the lamellar structure of the horse’s hoof, can be incited by numerous factors that include inflammatory and metabolic aetiologies. However, the role of inflammation in hyperinsulinaemic laminitis has not been adequately defined. Tolllike receptor (TLR) activation results in up-regulation of inflammatory pathways and the release of pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-�), and may be a pathogenic factor in laminitis. The aim of this study was to determine whether TLR4 expression and subsequent pro-inflammatory cytokine production is increased in lamellae and skeletal muscle during equine hyperinsulinaemia. Standardbred horses were treated with either a prolonged, euglycaemic hyperinsulinaemic clamp (p-EHC) or a prolonged, glucose infusion (p-GI), which induced marked and moderate hyperinsulinaemia, respectively. Age-matched control horses were treated simultaneously with a balanced electrolyte solution. Treated horses developed clinical (p-EHC) or subclinical (p-GI) laminitis, whereas controls did not. Skeletal muscle and lamellar protein extracts were analysed by Western blotting for TLR4, IL-6, TNF-� and suppressor of cytokine signalling 3 (SOCS3) expression. Lamellar protein expression of TLR4 and TNF-�, but not IL-6, was increased by the p-EHC, compared to control horses. A significant positive correlation was found between lamellar TLR4 and SOCS3. Skeletal muscle protein expression of TLR4 signalling parameters did not differ between control and p-EHC-treated horses. Similarly, the p-GI did not result in up-regulation of lamellar protein expression of any parameter. The results suggest that insulin-sensitive tissues may not accurately reflect lamellar pathology during hyperinsulinaemia. While TLR4 is present in the lamellae, its activation appears unlikely to contribute significantly to the developmental pathogenesis of hyperinsulinaemic laminitis. However, inflammation may have a role to play in the later stages (e.g., repair or remodelling) of the disease

Testing for Network and Spatial Autocorrelation

Testing for dependence has been a well-established component of spatial statistical analyses for decades. In particular, several popular test statistics have desirable properties for testing for the presence of spatial autocorrelation in continuous variables. In this paper we propose two contributions to the literature on tests for autocorrelation. First, we propose a new test for autocorrelation in categorical variables. While some methods currently exist for assessing spatial autocorrelation in categorical variables, the most popular method is unwieldy, somewhat ad hoc, and fails to provide grounds for a single omnibus test. Second, we discuss the importance of testing for autocorrelation in network, rather than spatial, data, motivated by applications in social network data. We demonstrate that existing tests for autocorrelation in spatial data for continuous variables and our new test for categorical variables can both be used in the network setting

Virologic, Immunologic and Clinical Responses in Foreign-Born versus US-Born HIV-1 Infected Adults Initiating Antiretroviral Therapy: An Observational Cohort Study

Introduction: Mortality rates within the first year of combination antiretroviral therapy (cART) initiation are several-fold higher in resource-limited countries than in resource-replete settings. However studies in western countries examining virologic, immunologic and clinical responses after cART initiation in indigenous versus non-indigenous populations have shown mixed results. This study aimed to determine whether there is a difference in these outcomes in a United States setting between foreign-born and US-born patients. Methods: This retrospective observational cohort study of HIV-1 infected adults in one urban clinic in the United States compared virologic suppression, immune recovery and rates of AIDS defining events (ADEs) within the first year of cART using linear mixed effect models, log rank tests and Cox proportional hazard models. Data were analyzed for 94 foreign-born and 1242 US-born patients. Results: Foreign-born patients were younger (31.7 years versus 38.5 years), more often female (38.3% versus 27.1%), less often injection drug users (3.2% versus 9.5%) or men who have sex with men (19.0% versus 54.5%), and had higher loss to follow-up rates (14.9% versus 6.2%). No significant differences were detected between the groups in suppression of plasma HIV-1 RNA, CD4+ cell recovery or development of ADEs. Conclusions: During the first year on cART, virologic suppression, immune recovery and development of ADEs were comparable between foreign-born and US-born patients in care in a US clinic. Differential rates of loss to follow-up warrant further investigation in the foreign-born population

Development of a new, combined rapid method using phage and PCR for detection and identification of viable Mycobacterium paratuberculosis bacteria within 48 hours

The FASTPlaqueTB assay is an established diagnostic aid for the rapid detection of Mycobacterium tuberculosis from human sputum samples. Using the FASTPlaqueTB assay reagents, viable Mycobacterium avium subsp. paratuberculosis cells were detected as phage plaques in just 24 h. The bacteriophage used does not infect M. avium subsp. paratuberculosis alone, so to add specificity to this assay, a PCR-based identification method was introduced to amplify M. avium subsp. paratuberculosis-specific sequences from the DNA of the mycobacterial cell detected by the phage. To give further diagnostic information, a multiplex PCR method was developed to allow simultaneous amplification of either M. avium subsp. paratuberculosis or M. tuberculosis complex-specific sequences from plaque samples. Combining the plaque PCR technique with the phage-based detection assay allowed the rapid and specific detection of viable M. avium subsp. paratuberculosis in milk samples in just 48 h

Environmental surveillance identifies multiple introductions of MRSA CC398 in an Equine Veterinary Hospital in the UK, 2011-2016

Bacterial environmental and surgical site infection (SSI) surveillance was implemented from 2011-2016 in a UK Equine Referral Veterinary Hospital and identified 81 methicillin-resistant Staphylococcus aureus (MRSA) isolates. A cluster of MRSA SSIs occurred in early 2016 with the isolates confirmed as ST398 by multilocus sequence typing (MLST), which prompted retrospective analysis of all MRSA isolates obtained from the environment (n = 62), SSIs (n = 13) and hand plates (n = 6) in the past five years. Sixty five of these isolates were typed to CC398 and a selection of these (n = 38) were further characterised for resistance and virulence genes, SCCmec and spa typing. Overall, MRSA was identified in 62/540 (11.5%) of environmental samples, 6/81 of the hand-plates (7.4%) and 13/208 of the SSIs (6.3%). spa t011 was the most frequent (24/38) and Based Upon Repeat Pattern (BURP) analysis identified spa t011 as one of the two group founders of the main spa CC identified across the five years (spa CC011/3423). However, 3 singletons (t073, t786, t064) were also identified suggesting separate introductions into the hospital environment. This long-term MRSA surveillance study revealed multiple introductions of MRSA CC398 in a UK Equine Hospital, identifying an emerging zoonotic pathogen so far only sporadically recorded in the UK

Drug Use and Receipt of Highly Active Antiretroviral Therapy among HIV-Infected Persons in Two U.S. Clinic Cohorts

Drug use and receipt of highly active antiretroviral therapy (HAART) were assessed in HIV-infected persons from the Comprehensive Care Center (CCC; Nashville, TN) and Johns Hopkins University HIV Clinic (JHU; Baltimore, MD) between 1999 and 2005.Participants with and without injection drug use (IDU) history in the CCC and JHU cohorts were evaluated. Additional analysis of persons with history of IDU, non-injection drug use (NIDU), and no drug use from CCC were performed. Activity of IDU and NIDU also was assessed for the CCC cohort. HAART use and time on HAART were analyzed according to drug use category and site of care.1745 persons were included from CCC: 268 (15%) with IDU history and 796 (46%) with NIDU history. 1977 persons were included from JHU: 731 (35%) with IDU history. Overall, the cohorts differed in IDU risk factor rates, age, race, sex, and time in follow-up. In multivariate analyses, IDU was associated with decreased HAART receipt overall (OR = 0.61, 95% CI: [0.45-0.84] and OR = 0.58, 95% CI: [0.46-0.73], respectively for CCC and JHU) and less time on HAART at JHU (0.70, [0.55-0.88]), but not statistically associated with time on HAART at CCC (0.78, [0.56-1.09]). NIDU was independently associated with decreased HAART receipt (0.62, [0.47-0.81]) and less time on HAART (0.66, [0.52-0.85]) at CCC. These associations were not altered significantly whether patients at CCC were categorized according to historical drug use or drug use during the study period.Persons with IDU history from both clinic populations were less likely to receive HAART and tended to have less cumulative time on HAART. Effects of NIDU were similar to IDU at CCC. NIDU without IDU is an important contributor to HAART utilization

The relationship between adverse neighborhood socioeconomic context and HIV continuum of care outcomes in a diverse HIV clinic cohort in the Southern United States

Retention in care and viral suppression are critical to delaying HIV progression and reducing transmission. Neighborhood socioeconomic context (NSEC) may affect HIV care receipt. We therefore assessed NSEC's impact on retention and viral suppression in a diverse HIV clinical cohort. HIV-positive adults with ≥1 visit at the Vanderbilt Comprehensive Care Clinic and 5-digit ZIP code tabulation area (ZCTA) information between 2008 and 2012 contributed. NSEC z-score indices used neighborhood-level socioeconomic indicators for poverty, education, labor-force participation, proportion of males, median age, and proportion of residents of black race by ZCTA. Retention was defined as ≥2 HIV care visits per calendar year, >90 days apart. Viral suppression was defined as an HIV-1 RNA <200 copies/mL at last measurement per calendar year. Modified Poisson regression was used to estimate risk ratios (RR) and 95% confidence intervals (CI). Among 2272 and 2541 adults included for retention and viral suppression analyses, respectively, median age and CD4 count at enrollment were approximately 38 (1st and 3rd quartile: 30, 44) years and 351 (176, 540) cells/μL, respectively, while 24% were female, and 39% were black. Across 243 ZCTAs, median NSEC z-score was 0.09 (-0.66, 0.48). Overall, 79% of person-time contributed was retained and 74% was virally suppressed. In adjusted models, NSEC was not associated with retention, though being in the 4th vs. 1st NSEC quartile was associated with lack of viral suppression (RR = 0.88; 95% CI: 0.80-0.97). Residing in the most adverse NSEC was associated with lack of viral suppression. Future studies are needed to confirm this finding

Muscle fibre type distribution of the thoracolumbar and hindlimb regions of horses: relating fibre type and functional role

Peer reviewe

Measuring supply-side service disruption: a systematic review of the methods for measuring disruption in the context of maternal and newborn health services in low and middle-income settings.

OBJECTIVES: During the COVID-19 pandemic, most essential services experienced some level of disruption. Disruption in LMICs was more severe than in HICs. Early reports suggested that services for maternal and newborn health were disproportionately affected, raising concerns about health equity. Most disruption indicators measure demand-side disruption, or they conflate demand-side and supply-side disruption. There is currently no published guidance on measuring supply-side disruption. The primary objective of this review was to identify methods and approaches used to measure supply-side service disruptions to maternal and newborn health services in the context of COVID-19. DESIGN: We carried out a systematic review and have created a typology of measurement methods and approaches using narrative synthesis. DATA SOURCES: We searched MEDLINE, EMBASE and Global Health in January 2023. We also searched the grey literature. ELIGIBILITY CRITERIA: We included empirical studies describing the measurement of supply-side service disruption of maternal and newborn health services in LMICs in the context of COVID-19. DATA EXTRACTION AND SYNTHESIS: We extracted the aim, method(s), setting, and study outcome(s) from included studies. We synthesised findings by type of measure (ie, provision or quality of services) and methodological approach (ie, qualitative or quantitative). RESULTS: We identified 28 studies describing 5 approaches to measuring supply-side disruption: (1) cross-sectional surveys of the nature and experience of supply-side disruption, (2) surveys to measure temporal changes in service provision or quality, (3) surveys to create composite disruption scores, (4) surveys of service users to measure receipt of services, and (5) clinical observation of the provision and quality of services. CONCLUSION: Our review identified methods and approaches for measuring supply-side service disruption of maternal and newborn health services. These indicators provide important information about the causes and extent of supply-side disruption and provide a useful starting point for developing specific guidance on the measurement of service disruption in LMICs

Measuring the Quality of Observational Study Data in an International HIV Research Network

Observational studies of health conditions and outcomes often combine clinical care data from many sites without explicitly assessing the accuracy and completeness of these data. In order to improve the quality of data in an international multi-site observational cohort of HIV-infected patients, the authors conducted on-site, Good Clinical Practice-based audits of the clinical care datasets submitted by participating HIV clinics. Discrepancies between data submitted for research and data in the clinical records were categorized using the audit codes published by the European Organization for the Research and Treatment of Cancer. Five of seven sites had error rates >10% in key study variables, notably laboratory data, weight measurements, and antiretroviral medications. All sites had significant discrepancies in medication start and stop dates. Clinical care data, particularly antiretroviral regimens and associated dates, are prone to substantial error. Verifying data against source documents through audits will improve the quality of databases and research and can be a technique for retraining staff responsible for clinical data collection. The authors recommend that all participants in observational cohorts use data audits to assess and improve the quality of data and to guide future data collection and abstraction efforts at the point of care