Scottish Index of Multiple Deprivation (SIMD) indicators as predictors of mortality among patients hospitalised with COVID-19 disease in the Lothian Region, Scotland during the first wave: a cohort study.

BACKGROUND: Sars-CoV-2, the causative agent of COVID-19, has led to more than 226,000 deaths in the UK and multiple risk factors for mortality including age, sex and deprivation have been identified. This study aimed to identify which individual indicators of the Scottish Index of Multiple Deprivation (SIMD), an area-based deprivation index, were predictive of mortality. METHODS: This was a prospective cohort study of anonymised electronic health records of 710 consecutive patients hospitalised with Covid-19 disease between March and June 2020 in the Lothian Region of Southeast Scotland. Data sources included automatically extracted data from national electronic platforms and manually extracted data from individual admission records. Exposure variables of interest were SIMD quintiles and 12 indicators of deprivation deemed clinically relevant selected from the SIMD. Our primary outcome was mortality. Age and sex adjusted univariable and multivariable analyses were used to determine measures of association between exposures of interest and the primary outcome. RESULTS: After adjusting for age and sex, we found an increased risk of mortality in the more deprived SIMD quintiles 1 and 3 (OR 1.75, CI 0.99-3.08, p = 0.053 and OR 2.17, CI 1.22-3.86, p = 0.009, respectively), but this association was not upheld in our multivariable model containing age, sex, Performance Status and clinical parameters of severity at admission. Of the 12 pre-selected indicators of deprivation, two were associated with greater mortality in our multivariable analysis: income deprivation rate categorised by quartile (Q4 (most deprived): 2.11 (1.20-3.77) p = 0.011)) and greater than expected hospitalisations due to alcohol per SIMD data zone (1.96 (1.28-3.00) p = 0.002)). CONCLUSIONS: SIMD as an aggregate measure of deprivation was not predictive of mortality in our cohort when other exposure measures were accounted for. However, we identified a two-fold increased risk of mortality in patients residing in areas with greater income-deprivation and/or number of hospitalisations due to alcohol. In areas where aggregate measures fail to capture pockets of deprivation, exploring the impact of specific SIMD indicators may be helpful in targeting resources to residents at risk of poorer outcomes from Covid-19.

Distinctive hospital and community resistomes in Scottish urban wastewater: Metagenomics of a paired wastewater sampling design.

The wastewater microbiome contains a multitude of resistant bacteria of human origin, presenting an opportunity for surveillance of resistance in the general population. However, wastewater microbial communities are also influenced by clinical sources, such as hospitals. Identifying signatures of the community and hospital resistome in wastewater is needed for interpretation and risk analysis. In this study, we compare the resistome and microbiome of hospital, community, and mixed municipal wastewater to investigate how and why the composition of these different sites differ. We conducted shotgun metagenomic analysis on wastewater samples from eight wastewater treatment plants (WWTPs), four hospitals, and four community sites in Scotland, using a paired sampling design. Cluster analysis and source attribution random forest models demonstrated that the hospital resistome was distinct from community and WWTP resistomes. Hospital wastewater had a higher abundance and diversity of resistance genes, in keeping with evidence that hospitals act as a reservoir and enricher of resistance. However, this distinctive 'hospital' signature appeared to be weak in the resistome of downstream WWTPs, likely due to dilution. We conclude that hospital and community wastewater resistomes differ, with the hospital wastewater representing a reservoir of patient- and hospital environment-associated bacteria. However, this 'hospital' signature is transient and does not overwhelm the community signature in the resistome of the downstream WWTP influent.

Performance status: A key factor in predicting mortality in the first wave of COVID-19 in South-East Scotland.

BACKGROUND: COVID-19 mortality risk factors have been established in large cohort studies; long-term mortality outcomes are less documented. METHODS: We performed multivariable logistic regression to identify factors associated with in-patient mortality and intensive care unit (ICU) admission in symptomatic COVID-19 patients admitted to hospitals in South-East Scotland from 1st March to 30th June 2020. One-year mortality was reviewed. RESULTS: Of 726 patients (median age 72; interquartile range: 58-83 years, 55% male), 104 (14%) required ICU admission and 199 (27%) died in hospital. A further 64 died between discharge and 30th June 2021 (36% overall 1-year mortality). Stepwise logistic regression identified age >79 (odds ratio (OR), 4.77 (95% confidence interval (CI), 1.96-12.75)), male sex (OR, 1.83 (95% CI, 1.21-2.80)) and higher European Cooperative Oncology Group/World Health Organization performance status as associated with higher mortality risk. DISCUSSION: Poor functional baseline was the predominant independent risk factor for mortality in COVID-19. More than one-third of individuals had died by 1 year following admission.

Secrets of the Hospital Underbelly: Patterns of Abundance of Antimicrobial Resistance Genes in Hospital Wastewater Vary by Specific Antimicrobial and Bacterial Family.

Background: Hospital wastewater is a major source of antimicrobial resistance (AMR) outflow into the environment. This study uses metagenomics to study how hospital clinical activity impacts antimicrobial resistance genes (ARGs) abundances in hospital wastewater. Methods: Sewage was collected over a 24-h period from multiple wastewater collection points (CPs) representing different specialties within a tertiary hospital site and simultaneously from community sewage works. High throughput shotgun sequencing was performed using Illumina HiSeq4000. ARG abundances were correlated to hospital antimicrobial usage (AMU), data on clinical activity and resistance prevalence in clinical isolates. Results: Microbiota and ARG composition varied between CPs and overall ARG abundance was higher in hospital wastewater than in community influent. ARG and microbiota compositions were correlated (Procrustes analysis, p=0.014). Total antimicrobial usage was not associated with higher ARG abundance in wastewater. However, there was a small positive association between resistance genes and antimicrobial usage matched to ARG phenotype (IRR 1.11, CI 1.06-1.16, p<0.001). Furthermore, analyzing carbapenem and vancomycin resistance separately indicated that counts of ARGs to these antimicrobials were positively associated with their increased usage [carbapenem rate ratio (RR) 1.91, 95% CI 1.01-3.72, p=0.07, and vancomycin RR 10.25, CI 2.32-49.10, p<0.01]. Overall, ARG abundance within hospital wastewater did not reflect resistance patterns in clinical isolates from concurrent hospital inpatients. However, for clinical isolates of the family Enterococcaceae and Staphylococcaceae, there was a positive relationship with wastewater ARG abundance [odds ratio (OR) 1.62, CI 1.33-2.00, p<0.001, and OR 1.65, CI 1.21-2.30, p=0.006 respectively]. Conclusion: We found that the relationship between hospital wastewater ARGs and antimicrobial usage or clinical isolate resistance varies by specific antimicrobial and bacterial family studied. One explanation, we consider is that relationships observed from multiple departments within a single hospital site will be detectable only for ARGs against parenteral antimicrobials uniquely used in the hospital setting. Our work highlights that using metagenomics to identify the full range of ARGs in hospital wastewater is a useful surveillance tool to monitor hospital ARG carriage and outflow and guide environmental policy on AMR.

Segmentation and shielding of the most vulnerable members of the population as elements of an exit strategy from COVID-19 lockdown.

This study demonstrates that an adoption of a segmenting and shielding strategy could increase the scope to partially exit COVID-19 lockdown while limiting the risk of an overwhelming second wave of infection. We illustrate this using a mathematical model that segments the vulnerable population and their closest contacts, the 'shielders'. Effects of extending the duration of lockdown and faster or slower transition to post-lockdown conditions and, most importantly, the trade-off between increased protection of the vulnerable segment and fewer restrictions on the general population are explored. Our study shows that the most important determinants of outcome are: (i) post-lockdown transmission rates within the general and between the general and vulnerable segments; (ii) fractions of the population in the vulnerable and shielder segments; (iii) adherence to protective measures; and (iv) build-up of population immunity. Additionally, we found that effective measures in the shielder segment, e.g. intensive routine screening, allow further relaxations in the general population. We find that the outcome of any future policy is strongly influenced by the contact matrix between segments and the relationships between physical distancing measures and transmission rates. This strategy has potential applications for any infectious disease for which there are defined proportions of the population who cannot be treated or who are at risk of severe outcomes. This article is part of the theme issue 'Modelling that shaped the early COVID-19 pandemic response in the UK'.

Diagnostic performance of the combined nasal and throat swab in patients admitted to hospital with suspected COVID-19.

BACKGROUND: Accurate diagnosis in patients with suspected coronavirus disease 2019 (COVID-19) is essential to guide treatment and limit spread of the virus. The combined nasal and throat swab is used widely, but its diagnostic performance is uncertain. METHODS: In a prospective, multi-centre, cohort study conducted in secondary and tertiary care hospitals in Scotland, we evaluated the combined nasal and throat swab with reverse transcriptase-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in consecutive patients admitted to hospital with suspected COVID-19. Diagnostic performance of the index and serial tests was evaluated for a primary outcome of confirmed or probable COVID-19, and a secondary outcome of confirmed COVID-19 on serial testing. The diagnosis was adjudicated by a panel, who recorded clinical, laboratory and radiological features blinded to the test results. RESULTS: We enrolled 1368 consecutive patients (median age 68 [interquartile range, IQR 53-80] years, 47% women) who underwent a total of 3822 tests (median 2 [IQR 1-3] tests per patient). The primary outcome occurred in 36% (496/1368), of whom 65% (323/496) and 35% (173/496) had confirmed and probable COVID-19, respectively. The index test was positive in 255/496 (51%) patients with the primary outcome, giving a sensitivity and specificity of 51.4% (95% confidence interval [CI] 48.8 to 54.1%) and 99.5% (95% CI 99.0 to 99.8%). Sensitivity increased in those undergoing 2, 3 or 4 tests to 60.1% (95% CI 56.7 to 63.4%), 68.3% (95% CI 64.0 to 72.3%) and 77.6% (95% CI 72.7 to 81.9%), respectively. The sensitivity of the index test was 78.9% (95% CI 74.4 to 83.2%) for the secondary outcome of confirmed COVID-19 on serial testing. CONCLUSIONS: In patients admitted to hospital, a single combined nasal and throat swab with RT-PCR for SARS-CoV-2 has excellent specificity, but limited diagnostic sensitivity for COVID-19. Diagnostic performance is significantly improved by repeated testing.

Risk factors for carbapenemase-producing organisms among inpatients in Scotland: A national matched case-control study.

OBJECTIVE: To determine risk factors for carbapenemase-producing organisms (CPOs) and to determine the prognostic impact of CPOs. DESIGN: A retrospective matched case-control study. PATIENTS: Inpatients across Scotland in 2010-2016 were included. Patients with a CPO were matched with 2 control groups by hospital, admission date, specimen type, and bacteria. One group comprised patients either infected or colonized with a non-CPO and the other group were general inpatients. METHODS: Conditional logistic regression models were used to identify risk factors for CPO infection and colonization, respectively. Mortality rates and length of postisolation hospitalization were compared between CPO and non-CPO patients. RESULTS: In total, 70 CPO infection cases (with 210 general inpatient controls and 121 non-CPO controls) and 34 CPO colonization cases (with 102 general inpatient controls and 60 non-CPO controls) were identified. Risk factors for CPO infection versus general inpatients were prior hospital stay (adjusted odds ratio [aOR], 4.05; 95% confidence interval [CI], 1.52-10.78; P = .005), longer hospitalization (aOR, 1.07; 95% CI, 1.04-1.10; P < .001), longer intensive care unit (ICU) stay (aOR, 1.41; 95% CI, 1.01-1.98; P = .045), and immunodeficiency (aOR, 3.68; 95% CI, 1.16-11.66; P = .027). Risk factors for CPO colonization were prior high-dependency unit (HDU) stay (aOR, 11.46; 95% CI, 1.27-103.09; P = .030) and endocrine, nutritional, and metabolic (ENM) diseases (aOR, 3.41; 95% CI, 1.02-11.33; P = .046). Risk factors for CPO infection versus non-CPO infection were prolonged hospitalization (aOR, 1.02; 95% CI, 1.00-1.03; P = .038) and HDU stay (aOR, 1.13; 95% CI, 1.02-1.26; P = .024). No differences in mortality rates were detected between CPO and non-CPO patients. CPO infection was associated with longer hospital stay than non-CPO infection (P = .041). CONCLUSIONS: A history of (prolonged) hospitalization, prolonged ICU or HDU stay; ENM diseases; and being immunocompromised increased risk for CPO. CPO infection was not associated with increased mortality but was associated with prolonged hospital stay.

Successful reintroduction of tumour necrosis factor-alpha inhibition after treatment of disseminated Lyme borreliosis.

The importance of tumour necrosis factor-alpha (TNF-α) in the human immune response to Borrelia burgdorferi is uncertain. Murine models suggest a critical role, including spirochaete reactivation following TNF-α inhibition. Our case, combined with a review of the clinical and scientific literature, provides reassurance that TNF-α inhibition can be safely reinstituted after treatment of disseminated borreliosis with standard duration antimicrobial chemotherapy.

Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in Bihar, India: a retrospective cohort study.

BACKGROUND: In the late twentieth century, emergence of high rates of treatment failure with antimonial compounds (SSG) for visceral leishmaniasis (VL) caused a public health crisis in Bihar, India. We hypothesize that exposure to arsenic through drinking contaminated groundwater may be associated with SSG treatment failure due to the development of antimony-resistant parasites. METHODS: A retrospective cohort design was employed, as antimony treatment is no longer in routine use. The study was performed on patients treated with SSG between 2006 and 2010. Outcomes of treatment were assessed through a field questionnaire and treatment failure used as a proxy for parasite resistance. Arsenic exposure was quantified through analysis of 5 water samples from within and surrounding the patient's home. A logistic regression model was used to evaluate the association between arsenic exposure and treatment failure. In a secondary analysis survival curves and Cox regression models were applied to assess the risk of mortality in VL patients exposed to arsenic. RESULTS: One hundred and ten VL patients treated with SSG were analysed. The failure rate with SSG was 59%. Patients with high mean local arsenic level had a non-statistically significant higher risk of treatment failure (OR = 1.78, 95% CI: 0.7-4.6, p = 0.23) than patients using wells with arsenic concentration <10 µg/L. Twenty one patients died in our cohort, 16 directly as a result of VL. Arsenic levels ≥ 10 µg/L increased the risk of all-cause (HR 3.27; 95% CI: 1.4-8.1) and VL related (HR 2.65; 95% CI: 0.96-7.65) deaths. This was time dependent: 3 months post VL symptom development, elevated risks of all-cause mortality (HR 8.56; 95% CI: 2.5-29.1) and of VL related mortality (HR 9.27; 95% CI: 1.8-49.0) were detected. DISCUSSION/CONCLUSION: This study indicates a trend towards increased treatment failure in arsenic exposed patients. The limitations of the retrospective study design may have masked a strong association between arsenic exposure and selection for antimonial resistance in the field. The unanticipated strong correlation between arsenic exposure and VL mortality warrants further investigation.

Chronic exposure to arsenic in drinking water can lead to resistance to antimonial drugs in a mouse model of visceral leishmaniasis.

The Indian subcontinent is the only region where arsenic contamination of drinking water coexists with widespread resistance to antimonial drugs that are used to treat the parasitic disease visceral leishmaniasis. We have previously proposed that selection for parasite resistance within visceral leishmaniasis patients who have been exposed to trivalent arsenic results in cross-resistance to the related metalloid antimony, present in the pentavalent state as a complex in drugs such as sodium stibogluconate (Pentostam) and meglumine antimonate (Glucantime). To test this hypothesis, Leishmania donovani was serially passaged in mice exposed to arsenic in drinking water at environmentally relevant levels (10 or 100 ppm). Arsenic accumulation in organs and other tissues was proportional to the level of exposure and similar to that previously reported in human liver biopsies. After five monthly passages in mice exposed to arsenic, isolated parasites were found to be completely refractory to 500 µg · mL(-1) Pentostam compared with the control passage group (38.5 µg · mL(-1)) cultured in vitro in mouse peritoneal macrophages. Reassessment of resistant parasites following further passage for 4 mo in mice without arsenic exposure showed that resistance was stable. Treatment of infected mice with Pentostam confirmed that resistance observed in vitro also occurred in vivo. We conclude that arsenic contamination may have played a significant role in the development of Leishmania antimonial resistance in Bihar because inadequate treatment with antimonial drugs is not exclusive to India, whereas widespread antimonial resistance is.

The R enantiomer of the antitubercular drug PA-824 as a potential oral treatment for visceral Leishmaniasis.

The novel nitroimidazopyran agent (S)-PA-824 has potent antibacterial activity against Mycobacterium tuberculosis in vitro and in vivo and is currently in phase II clinical trials for tuberculosis (TB). In contrast to M. tuberculosis, where (R)-PA-824 is inactive, we report here that both enantiomers of PA-824 show potent parasiticidal activity against Leishmania donovani, the causative agent of visceral leishmaniasis (VL). In leishmania-infected macrophages, (R)-PA-824 is 6-fold more active than (S)-PA-824. Both des-nitro analogues are inactive, underlining the importance of the nitro group in the mechanism of action. Although the in vitro and in vivo pharmacological profiles of the two enantiomers are similar, (R)-PA-824 is more efficacious in the murine model of VL, with >99% suppression of parasite burden when administered orally at 100 mg kg of body weight(-1), twice daily for 5 days. In M. tuberculosis, (S)-PA-824 is a prodrug that is activated by a deazaflavin-dependent nitroreductase (Ddn), an enzyme which is absent in Leishmania spp. Unlike the case with nifurtimox and fexinidazole, transgenic parasites overexpressing the leishmania nitroreductase are not hypersensitive to either (R)-PA-824 or (S)-PA-824, indicating that this enzyme is not the primary target of these compounds. Drug combination studies in vitro indicate that fexinidazole and (R)-PA-824 are additive whereas (S)-PA-824 and (R)-PA-824 show mild antagonistic behavior. Thus, (R)-PA-824 is a promising candidate for late lead optimization for VL and may have potential for future use in combination therapy with fexinidazole, currently in phase II clinical trials against VL.

Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412.

Six healthy young male volunteers at a contract research organization were enrolled in the first phase 1 clinical trial of TGN1412, a novel superagonist anti-CD28 monoclonal antibody that directly stimulates T cells. Within 90 minutes after receiving a single intravenous dose of the drug, all six volunteers had a systemic inflammatory response characterized by a rapid induction of proinflammatory cytokines and accompanied by headache, myalgias, nausea, diarrhea, erythema, vasodilatation, and hypotension. Within 12 to 16 hours after infusion, they became critically ill, with pulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation. Severe and unexpected depletion of lymphocytes and monocytes occurred within 24 hours after infusion. All six patients were transferred to the care of the authors at an intensive care unit at a public hospital, where they received intensive cardiopulmonary support (including dialysis), high-dose methylprednisolone, and an anti-interleukin-2 receptor antagonist antibody. Prolonged cardiovascular shock and acute respiratory distress syndrome developed in two patients, who required intensive organ support for 8 and 16 days. Despite evidence of the multiple cytokine-release syndrome, all six patients survived. Documentation of the clinical course occurring over the 30 days after infusion offers insight into the systemic inflammatory response syndrome in the absence of contaminating pathogens, endotoxin, or underlying disease.