The potential for the double risk of rabies and antimicrobial resistance in a high rabies endemic setting:Detection of antibiotic resistance in bacterial isolates from infected dog bite wounds in Uganda

BACKGROUND: Post-exposure treatment for dog bites in humans aims at alleviating the risk of rabies and promoting wound healing. Wound healing may be complicated by bacteria. This study identified the different bacteria and their antibiotic susceptibilities in infected dog bite wounds (DBWs) in Uganda. METHODS: A cross-sectional study was conducted among 376 dog bite patients. Wound swabs from patients with infected DBWs were collected and inoculated into recommended media. They were cultured for both aerobic and anaerobic bacteria. All isolated bacteria were identified based on colony characteristics, gram stain, and standard biochemical tests. Molecular identification was performed for strains that were resistant to three or more antibiotics. Antibiotic susceptibility testing was conducted using the disc diffusion method following the modified Kirby-Bauer method. The data were analysed using Stata version 15 software. RESULTS: Approximately half of the patients (52.9%, 199/376) presented with infected wounds. Majority of the swabs (84.4%, 168/199) were culture positive, and yielded a total of 768 isolates where about half (52.9%, 406/768) were gram positive bacteria, and about two-thirds (64.6%, 496/768) were recovered from category II wounds. Among the gram positive bacteria, 339 (83.5%) were aerobes where Staphylococcus aureus (103, 30.4%), Coagulase-negative staphylococci (68, 20.1%), and Corynebacterium spp (33, 9.7%) had the highest prevalence. For the 362 Gram negative isolates, 217 (59.9%) were aerobes and the commonest isolates were P. maltocida (64, 29.5%), Capnocytophaga canimorsus (36, 16.6%) and P. canis (26, 12.0%). Gram-positive isolates were resistant to metronidazole (93.6%), oxacillin (68.5%), ceftriaxone (14.6%) and amoxicillin/clavulanic acid (14.0%). Gram negative isolates were resistant to metronidazole (100%), ampicillin (30.7%), oxacillin (29.3%), and doxycycline (22.9%). Multidrug resistance was in 105 (29.0%) and 121/406 (29.8%) of the gram-negative and gram-positive isolates, respectively. All gram-positive isolates were susceptible to vancomycin and ciprofloxacin. CONCLUSIONS: Infection rates of DBWs in Uganda are high and the dominant bacterial isolates are Staphylococcus aureus, Pasteurella spps, and Capnocytophaga canimorsus. Multidrug resistance to commonly used antibiotics is high. The recommendation in the Uganda Clinical Guidelines to use metronidazole in the management of DBWs should be reviewed. DBWs should be enlisted for routine antimicrobial resistance surveillance and rational use of antimicrobial agents should be promoted. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13756-022-01181-0

Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid

\ua9 2024 National Academy of Sciences. All rights reserved.α-,β-,and γ-Synuclein are intrinsically disordered proteins implicated in physiological processes in the nervous system of vertebrates. α-synuclein (αSyn) is the amyloidogenic protein associated with Parkinson\u27s disease and certain other neurodegenerative disorders. Intensive research has focused on the mechanisms that cause αSyn to form amyloid structures, identifying its NAC region as being necessary and sufficient for amyloid assembly. Recent work has shown that a 7-residue sequence (P1) is necessary for αSyn amyloid formation. Although γ-synuclein (γSyn) is 55% identical in sequence to αSyn and its pathological deposits are also observed in association with neurodegenerative conditions, γSyn is resilient to amyloid formation in vitro. Here, we report a rare single nucleotide polymorphism (SNP) in the SNCG gene encoding γSyn, found in two patients with amyotrophic lateral sclerosis (ALS). The SNP results in the substitution of Met38 with Ile in the P1 region of the protein. These individuals also had a second, common and nonpathological, SNP in SNCG resulting in the substitution of Glu110 with Val. In vitro studies demonstrate that the Ile38 variant accelerates amyloid fibril assembly. Contrastingly, Val110 retards fibril assembly and mitigates the effect of Ile38. Substitution of residue 38 with Leu had little effect, while Val retards, and Ala increases the rate of amyloid formation. Ile38 γSyn also results in the formation of γSyn-containing inclusions in cells. The results show how a single point substitution can enhance amyloid formation of γSyn and highlight the P1 region in driving amyloid formation in another synuclein family member

The outcome of a training programme (RESPECT) on staff’s attitudes towards causes and management of aggression in a Regional Referral Hospital of Northern Uganda

Introduction Occupational violence has been demonstrated to impact negatively on the well‐being of nurses and patients. Staff attitudes towards causes and management of patients’ aggression influence their practice. Training is likely to influence attitudes towards aggression; however, Uganda's health system lacks adequate resources to provide aggression management training for staff. Aim To assess the impact of a training programme (RESPECT) on staff attitudes towards causes and management of patient's aggression in a Ugandan hospital. Methods This study used a mixed‐methods convergent design. A convenience sample of nurses and support staff employed in the psychiatric ward and other services across the hospital (N = 90) completed the Management of Aggression and Violence Attitude Scale (MAVAS) pre‐ and post‐training. The views of a smaller sample (n = 35) were captured via interviews and focus groups and analysed using thematic analysis. Results Participants reported greater agreement with patients’ physical and social environment (external and situational causative models) as factors influencing patient's aggression. Qualitative findings substantiated the results identified in the survey. Attitudes towards seclusion, restraint and medication remained unchanged. Discussion and implications for practice RESPECT has the potential to change staff attitudes towards aggression in the short term. Further research is needed to investigate long‐term effects and impact on incidents of aggression

Cost Effectiveness of a Pharmacy-Only Refill Program in a Large Urban HIV/AIDS Clinic in Uganda

HIV/AIDS clinics in Uganda and other low-income countries face increasing numbers of patients and workforce shortages. We performed a cost-effectiveness analysis comparing a Pharmacy-only Refill Program (PRP), a form of task-shifting, to the Standard of Care (SOC) at a large HIV/AIDS clinic in Uganda, the Infectious Diseases Institute (IDI). The PRP was started to reduce workforce shortages and optimize patient care by substituting pharmacy visits for SOC involving monthly physician visits for accessing antiretroviral medicines.We used a retrospective cohort analysis to compare the effectiveness of the PRP compared to SOC. Effectiveness was defined as Favorable Immune Response (FIR), measured as having a CD4 lymphocyte count of over 500 cells/µl at follow-up. We used multivariate logistic regression to assess the difference in FIR between patients in the PRP and SOC. We incorporated estimates of effectiveness into an incremental cost-effectiveness analysis performed from a limited societal perspective. We estimated costs from previous studies at IDI and conducted univariate and probabilistic sensitivity analyses. We identified 829 patients, 578 in the PRP and 251 in SOC. After 12.8 months (PRP) and 15.1 months (SOC) of follow-up, 18.9% of patients had a FIR, 18.6% in the PRP and 19.6% in SOC. There was a non-significant 9% decrease in the odds of having a FIR for PRP compared to SOC after adjusting for other variables (OR 0.93, 95% CI 0.55-1.58). The PRP was less costly than the SOC (US$520 vs. 655 annually, respectively). The incremental cost-effectiveness ratio comparing PRP to SOC was US$ 13,500 per FIR. PRP remained cost-effective at univariate and probabilistic sensitivity analysis.The PRP is more cost-effective than the standard of care. Similar task-shifting programs might help large HIV/AIDS clinics in Uganda and other low-income countries to cope with increasing numbers of patients seeking care

Mosaic BRAF fusions are a recurrent cause of congenital melanocytic naevi targetable by MEK inhibition

Among children with multiple congenital melanocytic naevi (CMN), 25% have no established genetic cause, of which many develop a hyperproliferative and severely pruritic phenotype resistant to treatment. Gene fusions have been reported in individual cases of CMN. Here, we study 169 CMN patients, 38 of whom were double wild-type for NRAS/BRAF mutations. Nineteen of these 38 patients had sufficient tissue to undergo RNAseq, which revealed mosaic BRAF fusions in 11/19 patients and mosaic RAF1 fusions in 1/19. Recurrently, fusions involved the loss of the 5’ regulatory domain of BRAF or RAF1 but preserved the kinase domain. We validated all cases and detected the fusions in two separate naevi in 5/12 patients, confirming clonality. The absence of the fusion in blood in 8/12 patients indicated mosaicism. Primary culture of BRAF-fusion naevus cells from 3/12 patients demonstrated highly increased MAPK activation, despite only mildly increased BRAF expression, suggesting additional mechanisms of kinase activation. Trametinib quenched MAPK hyperactivation in vitro and treatment of two patients caused rapid improvement in bulk tissue, improving bodily movement, and reducing inflammation and severe pruritus. These findings offer a genetic diagnosis to an additional group of patients and trametinib as a treatment option for the severe associated phenotypes

Mortality of Patients Lost to Follow-Up in Antiretroviral Treatment Programmes in Resource-Limited Settings: Systematic Review and Meta-Analysis

BACKGROUND: The retention of patients in antiretroviral therapy (ART) programmes is an important issue in resource-limited settings. Loss to follow up can be substantial, but it is unclear what the outcomes are in patients who are lost to programmes. METHODS AND FINDINGS: We searched the PubMed, EMBASE, Latin American and Caribbean Health Sciences Literature (LILACS), Indian Medlars Centre (IndMed) and African Index Medicus (AIM) databases and the abstracts of three conferences for studies that traced patients lost to follow up to ascertain their vital status. Main outcomes were the proportion of patients traced, the proportion found to be alive and the proportion that had died. Where available, we also examined the reasons why some patients could not be traced, why patients found to be alive did not return to the clinic, and the causes of death. We combined mortality data from several studies using random-effects meta-analysis. Seventeen studies were eligible. All were from sub-Saharan Africa, except one study from India, and none were conducted in children. A total of 6420 patients (range 44 to 1343 patients) were included. Patients were traced using telephone calls, home visits and through social networks. Overall the vital status of 4021 patients could be ascertained (63%, range across studies: 45% to 86%); 1602 patients had died. The combined mortality was 40% (95% confidence interval 33%-48%), with substantial heterogeneity between studies (P<0.0001). Mortality in African programmes ranged from 12% to 87% of patients lost to follow-up. Mortality was inversely associated with the rate of loss to follow up in the programme: it declined from around 60% to 20% as the percentage of patients lost to the programme increased from 5% to 50%. Among patients not found, telephone numbers and addresses were frequently incorrect or missing. Common reasons for not returning to the clinic were transfer to another programme, financial problems and improving or deteriorating health. Causes of death were available for 47 deaths: 29 (62%) died of an AIDS defining illness. CONCLUSIONS: In ART programmes in resource-limited settings a substantial minority of adults lost to follow up cannot be traced, and among those traced 20% to 60% had died. Our findings have implications both for patient care and the monitoring and evaluation of programmes

Incident Tuberculosis during Antiretroviral Therapy Contributes to Suboptimal Immune Reconstitution in a Large Urban HIV Clinic in Sub-Saharan Africa

Antiretroviral therapy (ART) effectively decreases tuberculosis (TB) incidence long-term, but is associated with high TB incidence rates in the first 6 months. We sought to determine the incidence and the long-term effects of TB during ART on HIV treatment outcome, and the risk factors for incident TB during ART in a large urban HIV clinic in Uganda.Routinely collected longitudinal clinical data from all patients initiated on first-line ART was retrospectively analysed. 5,982 patients were included with a median baseline CD4+ T cell count (CD4 count) of 117 cells/mm(3) (interquartile range [IQR]; 42, 182). In the first 2 years, there were 336 (5.6%) incident TB events in 10,710 person-years (py) of follow-up (3.14 cases/100 pyar [95% CI 2.82-3.49]); incidence rates at 0-3, 3-6, 6-12 and 12-24 months were 11.25 (9.58-13.21), 6.27 (4.99-7.87), 2.47 (1.87-3.36) and 1.02 (0.80-1.31), respectively. Incident TB during ART was independently associated with baseline CD4 count of <50 cells/mm(3) (hazard ratio [HR] 1.84 [1.25-2.70], P = 0.002) and male gender (HR 1.68 [1.34-2.11], P<0.001). After two years on ART, the patients who had developed TB in the first 12 months had a significantly lower median CD4 count increase (184 cells/mm(3) [IQR; 107, 258, n = 118] vs 209 cells/mm(3) [124, 309, n = 2166], P = 0.01), a larger proportion of suboptimal immune reconstitution according to two definitions (increase in CD4 count <200 cells/mm(3): 57.4% vs 46.9%, P = 0.03, and absolute CD4 count <200 cells/mm(3): 30.4 vs 19.9%, P = 0.006), and a higher percentage of immunological failure according to the WHO criteria (13.6% vs 6.5%, P = 0.003). Incident TB during ART was independently associated with poor CD4 count recovery and fulfilling WHO immunological failure definitions.Incident TB during ART occurs most often within 3 months and in patients with CD4 counts less than 50 cells/mm(3). Incident TB during ART is associated with long-term impairment in immune recovery