Oxford University Clinical Research Unit Nepal

Abstract Background Antimicrobial resistance (AMR) is an increasing threat to global health. There are > 14 million cases of enteric fever every year and > 135,000 deaths. The disease is primarily controlled by antimicrobial treatment, but this is becoming increasingly difficult due to AMR. Our objectives were to assess the prevalence and geographic distribution of AMR in Salmonella enterica serovars Typhi and Paratyphi A infections globally, to evaluate the extent of the problem, and to facilitate the creation of geospatial maps of AMR prevalence to help targeted public health intervention. Methods We performed a systematic review of the literature by searching seven databases for studies published between 1990 and 2018. We recategorised isolates to allow the analysis of fluoroquinolone resistance trends over the study period. The prevalence of multidrug resistance (MDR) and fluoroquinolone non-susceptibility (FQNS) in individual studies was illustrated by forest plots, and a random effects meta-analysis was performed, stratified by Global Burden of Disease (GBD) region and 5-year time period. Heterogeneity was assessed using the I 2 statistics. We present a descriptive analysis of ceftriaxone and azithromycin resistance. Findings We identified 4557 articles, of which 384, comprising 124,347 isolates (94,616 S . Typhi and 29,731 S . Paratyphi A) met the pre-specified inclusion criteria. The majority (276/384; 72%) of studies were from South Asia; 40 (10%) articles were identified from Sub-Saharan Africa. With the exception of MDR S . Typhi in South Asia, which declined between 1990 and 2018, and MDR S . Paratyphi A, which remained at low levels, resistance trends worsened for all antimicrobials in all regions. We identified several data gaps in Africa and the Middle East. Incomplete reporting of antimicrobial susceptibility testing (AST) and lack of quality assurance were identified. Interpretation Drug-resistant enteric fever is widespread in low- and middle-income countries, and the situation is worsening. It is essential that public health and clinical measures, which include improvements in water quality and sanitation, the deployment of S . Typhi vaccination, and an informed choice of treatment are implemented. However, there is no licenced vaccine for S . Paratyphi A. The standardised reporting of AST data and rollout of external quality control assessment are urgently needed to facilitate evidence-based policy and practice. Trial registration PROSPERO CRD42018029432 .

BACKGROUND: Low-dose corticosteroids have been shown to reduce mortality for patients with COVID-19 requiring oxygen or ventilatory support (non-invasive mechanical ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation). We evaluated the use of a higher dose of corticosteroids in this patient group. METHODS: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients with clinical evidence of hypoxia (ie, receiving oxygen or with oxygen saturation <92% on room air) were randomly allocated (1:1) to either usual care with higher dose corticosteroids (dexamethasone 20 mg once daily for 5 days followed by 10 mg dexamethasone once daily for 5 days or until discharge if sooner) or usual standard of care alone (which included dexamethasone 6 mg once daily for 10 days or until discharge if sooner). The primary outcome was 28-day mortality among all randomised participants. On May 11, 2022, the independent data monitoring committee recommended stopping recruitment of patients receiving no oxygen or simple oxygen only due to safety concerns. We report the results for these participants only. Recruitment of patients receiving ventilatory support is ongoing. The RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS: Between May 25, 2021, and May 13, 2022, 1272 patients with COVID-19 and hypoxia receiving no oxygen (eight [1%]) or simple oxygen only (1264 [99%]) were randomly allocated to receive usual care plus higher dose corticosteroids (659 patients) versus usual care alone (613 patients, of whom 87% received low-dose corticosteroids during the follow-up period). Of those randomly assigned, 745 (59%) were in Asia, 512 (40%) in the UK, and 15 (1%) in Africa. 248 (19%) had diabetes and 769 (60%) were male. Overall, 123 (19%) of 659 patients allocated to higher dose corticosteroids versus 75 (12%) of 613 patients allocated to usual care died within 28 days (rate ratio 1·59 [95% CI 1·20-2·10]; p=0·0012). There was also an excess of pneumonia reported to be due to non-COVID infection (64 cases [10%] vs 37 cases [6%]; absolute difference 3·7% [95% CI 0·7-6·6]) and an increase in hyperglycaemia requiring increased insulin dose (142 [22%] vs 87 [14%]; absolute difference 7·4% [95% CI 3·2-11·5]). INTERPRETATION: In patients hospitalised for COVID-19 with clinical hypoxia who required either no oxygen or simple oxygen only, higher dose corticosteroids significantly increased the risk of death compared with usual care, which included low-dose corticosteroids. The RECOVERY trial continues to assess the effects of higher dose corticosteroids in patients hospitalised with COVID-19 who require non-invasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. FUNDING: UK Research and Innovation (Medical Research Council), National Institute of Health and Care Research, and Wellcome Trust.

Background: serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). Methods: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. Results: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal 'sentinel' surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. Conclusions: The consortium's aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. Funding: No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210]).

OBJECTIVE: This study investigated the impact that motor vehicle travel along a newly constructed road has on altitude illness (including acute mountain sickness, high-altitude cerebral edema, and high-altitude pulmonary edema). The new road from Besisahar (760 m) to Manang (3540 m) in Nepal was completed in December 2014. METHODS: We enrolled all patients diagnosed with altitude illness at the Himalayan Rescue Association Manang clinic in fall 2016. Phi coefficients were calculated to test for an association between Nepali ethnicity and rapid ascent by motor vehicle. A retrospective review looked at all patients with altitude illness from fall (September-November) 2010 to spring (February-May) 2016. RESULTS: In fall 2016, more than half (54%) of patients with altitude illness traveled to Manang by motor vehicle, and one-third (33%) reached Manang from low altitude (Besisahar) in less than 48 hours. Nepali nationality had a significant association with motor vehicle travel (phi +0.69, P < .0001) as well as with rapid ascent to Manang (phi +0.72, P < .0001). Compared to previous seasons, fall 2016 saw the most patients diagnosed with altitude illness. The proportion of people with altitude illness who traveled by vehicle and reached Manang in less than 48 hours was significantly greater than the proportion prior to completion of the road (P < .0001 for both). CONCLUSIONS: Rapid ascent by the newly constructed road from Besisahar to Manang appears to be related to a significant increase in the number of patients with all forms of altitude illness, especially among Nepalis. The authors believe that educational interventions emphasizing prevention are urgently needed.

Rabab Batool and colleagues1Batool R Qamar ZH Salam RA Yousafzai MT Ashorn P Qamar FN Efficacy of typhoid vaccines against culture-confirmed Salmonella Typhi in typhoid endemic countries: a systematic review and meta-analysis.Lancet Glob Health. 2024; 12: e589-e598Google Scholar report the efficacy and safety of typhoid vaccines in preventing culture-confirmed Salmonella Typhi infections using a systematic review and meta-analysis. The authors find a pooled vaccine efficacy of 83% for the new WHO-approved typhoid conjugate vaccine (TCV) at 1–2 years after vaccination in individuals aged 6 months to 16 years who received a single dose, the highest efficacy among WHO-prequalified typhoid vaccines. Despite the disease being eliminated from high-income countries, typhoid still causes a huge burden of enteric fever globally, disrupting the lives of children in settings with inadequate quality water and poor sanitation. Increasing antimicrobial resistance and challenging access to medical care in the most resource poor and isolated communities means that typhoid remains a killer. Climate change has been connected to heightened risk of typhoid, and, during the 2022 floods in Pakistan, these new TCVs emerged as potent tools in alleviating the burden of typhoid fever and combating the emergence and spread of drug-resistant S Typhi. There are currently two WHO-prequalified TCVs, which means that WHO considers them appropriate for distribution through international agencies. The first TCV, which is reported in Batool and colleagues’ meta-analysis, is a tetanus toxoid conjugate vaccine manufactured by the Indian company Bharat Biotech. The vaccine was recommended by WHO Strategic Advisory Group of Experts on Immunization in October, 2017, for use in endemic countries or in countries with a high burden of antimicrobial resistant S Typhi; this was followed closely by the Gavi funding for its introduction in Gavi-eligible countries and WHO-prequalification in January, 2018.2WHOTyphoid vaccine: WHO position paper—March 2018.Wkly Epidemiol Rec. 2018; 13: 153-172Google Scholar The second TCV, a Vi-CRM197 conjugate, manufactured by Biological E (also based in India), was WHO-prequalified in December, 2020, on the basis of a comparable immune response to the previous TCV.3WHOComparison table of WHO prequalified typhoid conjugate vaccines (TCV).https://iris.who.int/bitstream/handle/10665/345367/WHO-IVB-2021.04-eng.pdfDate: 2021Date accessed: February 4, 2024Google Scholar Both vaccines are administered as a single dose and can be given to children aged 6 months and older. At the time of writing, six countries with endemic typhoid have already introduced TCV into their routine immunisation schedule, with catch-up to age 16 years in most countries, and more than 56 million children immunised. More countries are expected to introduce TCV in the coming years. Although the data are encouraging, the meta-analysis found that vaccine efficacy among children younger than 5 years was lower (but still substantial) than that among children aged 5 years and older (73% vs 87%). Furthermore, the highest burden of disease is among school-aged children (highest in children aged 5–9 years, followed by children aged 10–14 years) in most studies, and therefore the robust protection across all ages over the first 2 years is very encouraging.4Meiring JE Shakya M Khanam F et al.Burden of enteric fever at three urban sites in Africa and Asia: a multicentre population-based study.Lancet Glob Health. 2021; 9: e1688-e1696Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar Although these differences in efficacy might not be clinically important given the large burden of disease, a key question is whether these findings also affect the duration of protection with a single dose, especially since most future cohorts of children, after the initial campaigns, will be vaccinated following routine immunisation schedules in which the vaccine is given at age 6–15 months. We have shown, in a controlled human infection model of typhoid, that TCV-induced IgA antibodies correlate with protection against deliberate infection of volunteers in Oxford, UK.5Dahora LC Jin C Spreng RL et al.IgA and IgG1 specific to vi polysaccharide of Salmonella Typhi correlate with protection status in a typhoid fever controlled human infection model.Front Immunol. 2019; 102582Crossref Scopus (26) Google Scholar In field trials in Nepal and Bangladesh, we found that children in the youngest age group (younger than 2 years) had lower IgA responses to TCV than older children (aged 2–16 years).6Shakya M Voysey M Theiss-Nyland K et al.Efficacy of typhoid conjugate vaccine in Nepal: final results of a phase 3, randomised, controlled trial.Lancet Glob Health. 2021; 9: e1561-e1568Summary Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 7Khanam F Babu G Rahman N et al.Immune responses in children after vaccination with a typhoid Vi-tetanus toxoid conjugate vaccine in Bangladesh.Vaccine. 2023; 41: 3137-3140Crossref Scopus (1) Google Scholar Furthermore, some analyses presented at the international invasive Salmonella conference held in Kigali, Uganda indicate that waning over 4–5 years for anti-TCV IgG and IgA antibodies might be more pronounced in the youngest age group.8Shakya M, Bijukchhe SM, Pant D, et al. TyVAC Nepal: two dose and extended immunogenicity. 13th International Conference on Typhoid and Other Invasive Salmonelloses; Dec 5, 2023.Google Scholar, 9Khanam F, Qadri F, Rahman N, et al. Trend of anti-Vi-IgG and anti-Vi-IgA antibody responses induced in Vi-TT recipients over the period of five years among Bangladeshi children. 13th International Conference on Typhoid & Other Invasive Salmonelloses; Dec 6, 2023.Google Scholar While these studies continue with the goal of establishing the duration of immunity and protection following TCVs in South Asia, results from Africa provide some reassurance that longer term protection was observed. Investigators in Malawi conducted an extended TCV trial follow-up and found an overall high efficacy of 78·3% (95% CI 66·3–86·1%) up to 4 years post-vaccination in children aged 9 months to 12 years.10Patel PD Liang Y Meiring JE et al.Efficacy of typhoid conjugate vaccine: final analysis of a 4-year, phase 3, randomised controlled trial in Malawian children.Lancet. 2024; 6736: 1-10Google Scholar If there are differences between study sites in duration of protection, it will be important to understand whether this relates to differences in the force of infection, environmental factors, or genetic differences in immunity. As more data emerge, there must be a debate about whether booster doses could improve the level and duration of protection; however, for now, the availability and integration of TCV into an increasing number of immunisation programmes over the past 2 years is an immensely important moment for typhoid control. The technology for TCVs has been available for approximately 40 years, and yet millions of people have continued to become infected and die from the disease. To effectively achieve the goal of typhoid elimination, vaccination efforts must be complemented with ongoing initiatives aimed at improving water and sanitation practices, ensuring accurate diagnosis and treatment of typhoid fever, tackling antimicrobial resistance, and identifying and treating asymptomatic carriers. Indeed, when water is clean, we will not need vaccines for typhoid or many other enteric pathogens. AJP is chair of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation and was a member of WHO's Strategic Advisory Group of Experts on Immunization until 2022. AJP has led research at Oxford University on typhoid and paratyphoid vaccines funded by the Bill & Melinda Gates Foundation, the Wellcome Trust, the European Commission, the Medical Research Council, and the Serum Institute of India. Efficacy of typhoid vaccines against culture-confirmed Salmonella Typhi in typhoid endemic countries: a systematic review and meta-analysisThe existing data from included trials provide promising results regarding the efficacy and safety of the four recommended typhoid vaccines. TCV and Vi-rEPA were found to have the highest efficacy at 2 years post-immunisation. However, follow-up data for Vi-rEPA are scarce and only TCV is pre-qualified by WHO. Therefore, roll-out of TCV into routine immunisation programmes in typhoid endemic settings is highly recommended. Full-Text PDF Open Access

BACKGROUND: Undifferentiated febrile illness (UFI) includes typhoid and typhus fevers and generally designates fever without any localizing signs. UFI is a great therapeutic challenge in countries like Nepal because of the lack of available point-of-care, rapid diagnostic tests. Often patients are empirically treated as presumed enteric fever. Due to the development of high-level resistance to traditionally used fluoroquinolones against enteric fever, azithromycin is now commonly used to treat enteric fever/UFI. The re-emergence of susceptibility of Salmonella typhi to co-trimoxazole makes it a promising oral treatment for UFIs in general. We present a protocol of a randomized controlled trial of azithromycin versus co-trimoxazole for the treatment of UFI. METHODS/DESIGN: This is a parallel-group, double-blind, 1:1, randomized controlled trial of co-trimoxazole versus azithromycin for the treatment of UFI in Nepal. Participants will be patients aged 2 to 65 years, presenting with fever without clear focus for at least 4 days, complying with other study criteria and willing to provide written informed consent. Patients will be randomized either to azithromycin 20 mg/kg/day (maximum 1000 mg/day) in a single daily dose and an identical placebo or co-trimoxazole 60 mg/kg/day (maximum 3000 mg/day) in two divided doses for 7 days. Patients will be followed up with twice-daily telephone calls for 7 days or for at least 48 h after they become afebrile, whichever is later; by home visits on days 2 and 4 of treatment; and by hospital visits on days 7, 14, 28 and 63. The endpoints will be fever clearance time, treatment failure, time to treatment failure, and adverse events. The estimated sample size is 330. The primary analysis population will be all the randomized population and subanalysis will be repeated on patients with blood culture-confirmed enteric fever and culture-negative patients. DISCUSSION: Both azithromycin and co-trimoxazole are available in Nepal and are extensively used in the treatment of UFI. Therefore, it is important to know the better orally administered antimicrobial to treat enteric fever and other UFIs especially against the background of fluoroquinolone-resistant enteric fever. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02773407 . Registered on 5 May 2016.

BACKGROUND: Antimicrobial resistance (AMR) is a pressing global health concern driven by inappropriate antibiotic use, which is in turn influenced by various social, systemic, and individual factors. This study, nested within FIND's AMR Diagnostic Use Accelerator clinical trial in Nepal, aimed to (i) explore the perspectives of patients, caregivers, and healthcare workers (HCWs) on antibiotic prescription adherence and (ii) assess the impact of a training and communication (T&C) intervention on adherence to antibiotic prescriptions. METHODS: Using qualitative, semi-structured interviews, pre-intervention and Day 7 follow-up components, and the Behaviour Change Wheel process, we investigated the facilitators of and barriers to the use and misuse of antibiotic prescriptions. RESULTS: Results of the study revealed that adherence to antibiotic prescriptions is influenced by a complex interplay of factors, including knowledge and understanding, forgetfulness, effective communication, expectations, beliefs and habits, attitudes and behaviours, convenience of purchasing, trust in medical effectiveness, and issues of child preferences. The T&C package was also shown to play a role in addressing specific barriers to treatment adherence. CONCLUSIONS: Overall, the results of this study provide a nuanced understanding of the challenges associated with antibiotic use and suggest that tailored interventions, informed by behaviour frameworks, can enhance prescription adherence, may be applicable in diverse settings and can contribute to the global effort to mitigate the rising threat of AMR.

A choledochal cyst is a rare congenital anomaly of the biliary system, characterized by bile duct cystic dilatation, typically affecting the common bile duct. Choledochal cysts are generally categorized using the Todani classification system. The typical symptoms are jaundice, abdominal masses, and recurrent abdominal pain. As most cases are diagnosed in children, adult presentations are uncommon and often associated with complications. A 22-year-old female patient complained of severe abdominal pain and vomiting for 5 days, with signs of jaundice. Her abdominal ultrasound revealed fusiform dilation of the extrahepatic common bile duct with multiple calculi in its distal-most part. On CT cholangiogram of the abdomen, Type IV-A Choledochal cyst with non-obstructive choledocholithiasis was found. Although rare, choledochal cysts are a well-known clinical entity. It is essential to diagnose and treat patients because they may develop complications. Cholecystectomy combined with Roux-en-Y hepaticojejunostomy is the preferred treatment for Type IV-A choledochal cysts. Since choledochal cysts in adults are uncommon, early detection and treatment are essential to avoid serious complications. Ultrasonography (USG), Magnetic resonance cholangiopancreatography (MRCP), and Computed tomography (CT) can provide a diagnosis.

Background: Salmonella Typhi and Paratyphi are WHO priority pathogens that cause serious bloodstream infections. Antimicrobial resistance presents a significant public health burden as it negatively impacts our ability to treat and control enteric fever. The aim of this project is to map the spatial distribution of drug resistant S. Typhi and Paratyphi and to incorporate the impact of AMR into the Global Burden of Disease (GBD) study estimates. Methods & Materials: We conducted a systematic review of the global published literature between 1990 and 2017 to analyse the prevalence of drug resistance in S. Typhi and Paratyphi blood culture isolates. Antimicrobial susceptibility data to all tested drugs were extracted. We calculated the median prevalence (percentage) of resistance according to serotype, GBD super-region and five-year time-period. Results: Data from 518 studies (1990-2015) have been analysed to date; heterogeneity was high (I2 > 80%) within most subgroups. Between 1990-1994 and 2010-2015 the median prevalence (MP) of multidrug resistant (MDR; resistance to chloramphenicol, co-trimoxazole and ampicillin) Typhi decreased in South Asia and North Africa/Middle-East from 42% [IQR 23-66] to 6% [0-19] and 43% [34-48] to 7% [0-33], respectively; remained constant in Southeast Asia, East Asia and Oceania; and increased in sub-Saharan Africa from 6% [3-8] to 33% [4-83]. The MP of MDR Paratyphi was less than 11% for all time-periods in South Asia. The MP of nalidixic acid resistant (NAR; an indicator of fluoroquinolone resistance) Typhi increased from < 5% in 1990-1994 to > 80% in 2010-2015 in South Asia and Southeast Asia but remained low in sub-Saharan Africa (2% [1-3] in 1990-1994; 7% [4-28] in 2010-2015). The MP of NAR Paratyphi was > 81% for all time-periods in South Asia. Conclusion: Our results indicate that Salmonella Typhi strains in South Asia and North Africa/Middle East are regaining sensitivity to first-line drugs; fluoroquinolone resistance is now highly prevalent in South and Southeast Asia. High heterogeneity indicates further spatial-temporal variation exists alongside multiple biases. We intend to adjust for biases and develop a spatial-temporal model to produce accurate temporal national and subnational estimates of resistance. These results will be incorporated into the GBD study, providing a vital source of information.

Abstract The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks twenty-one years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000), and provides a detailed overview of global genotype and antimicrobial resistance (AMR) distribution and temporal trends, generated using open analysis platforms (GenoTyphi and Pathogenwatch). Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show potential of travel-associated data to provide informal “sentinel” surveillance for such locations. The data indicate ciprofloxacin non-susceptibility (&gt;1 resistance determinant) is widespread across geographies and genotypes, with high-level resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020), but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. The Consortium’s aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies.

Thyroid storm represents a critical and life-threatening complication from hyperthyroidism, with a notable mortality risk. Limited literature reports have explored the correlation between thyroid storm and peri-myocarditis, although the precise pathophysiological underpinnings remain unclear. The pathophysiology of how thyroid storm and peri-myocarditis are associated is not clearly understood; however, unfavorable prognostic factors include atrial fibrillation and recurrent thyrotoxicosis. Here, we present a case concerning recurrent peri-myocarditis concomitant with a thyroid storm.

An analysis of the largest Salmonella Typhi genome collection to date (n=13,000) provides an updated overview of global genome diversity and antimicrobial resistance trends over time to inform public health action.

For those traveling to high altitude, it has been postulated that blood pressure (BP) changes when compared to sea level. Also at altitude, periodic breathing has been well described and is correlated to decreased sleep quality.

Background: Targeting both diagnostic capacity and behaviours has the potential for decreasing unnecessary antibiotic prescriptions in acute febrile patients, thereby improving patient health outcomes, supporting actions against AntiMicrobial Resistance (AMR) and contributing to Universal Health Coverage (UHC). Methods and materials: The clinical study of the ‘AMR Diagnostic Use Accelerator’ based at 9 sites in 6 LMICs comprises a qualitative behavioural component to answer the question: “What are the behavioural determinants of the uptake of diagnostic algorithms, PoC tests and associated prescribing practices, by healthcare workers and adherence to antibiotic prescriptions by patients presenting with acute fever and respiratory tract infections at outpatient clinics in LMICs.” A baseline qualitative study is being conducted to understand the contextual factors and behavioural determinants towards adherence to prescriptions. The findings will form part of the clinical intervention arm consisting of diagnostic algorithms, PoC tests, prescribing decision trees, clinic process flow, training and communication on adherence to prescription. This is compared with a control of current practice. Results: Data collection includes adherence to prescription by study participants, future intentions regarding antibiotics in clinic visits, and the effects of communication intervention on patients. The information we are gathering will inform a training and communication package which will be rolled out during the clinical intervention. Conclusion: Further research will investigate the long-term effects of behavioural determinants for healthcare workers who will use the clinical algorithms, new PoC rapid diagnostic tests and associated prescribing practices. Using the COM-B (Capacity, Opportunity and Motivation) and TDF (Theoretical Domains Framework) models, findings on behavioural determinants will be used to develop recommendations for behaviour change interventions to address the key areas of uptake of PoC diagnostic tests, algorithms, associated prescribing practices, and adherence to prescriptions by patients.

Abstract The COVID-19 pandemic exposed gaps in global emerging infectious disease preparedness, particularly for countries with high levels of economic migration, such as Nepal. The Epidemic Intelligence project analysed SARS-CoV-2 genomic and epidemiological data from 2,046 COVID-19 patients across three Nepali regions to study viral dynamics, phylogeography, and long COVID. Participants were interviewed at diagnosis, and at 3-, 6-, and 12-months post-infection. Long COVID was explored using three standardised definitions from the literature, and logistic regression was used to identify risk factors, stratified by SARS-CoV-2 variant. Over 40% of participants reported long COVID at 3 months defined by symptoms ≥12 weeks and the presence of at least one symptom from the Wellcome Trust Longitudinal Population Study questionnaire. 10.6% (n=211/1992) of participants reported at least two of the symptom clusters from the WHO Delphi consensus definition at 3 months, and 0.7% (n=14/1992) reported all three symptom clusters. The prevalence of long COVID was higher among people infected with the Delta variant than the Omicron variant across all definitions and time points. Among Delta cases, female sex, chronic comorbidity, and full vaccination were associated with long COVID; whereas for people infected with Omicron, only age between 40-54 was a risk factor. Phylogeographic analyses revealed the epidemiological importance of Nepal’s porous border with India and the changing role of migration in viral spread as the pandemic evolved. Our findings also highlight the burden of post-COVID syndrome in low-resource settings and the need for further research to mitigate the financial and clinical impact. Integration of pathogen genomic analysis with clinical and epidemiological data can guide public health responses during the emergence of novel infectious diseases.