OBJECTIVES: This study aimed to gain a better understanding of how resistance determinants in Salmonella and Campylobacter contribute to 14-, 15- and 16-membered ring macrolide resistance phenotypes. METHODS: A total of 126 azithromycin-resistant (AziR) and -susceptible (AziS) [Salmonella (n = 45) and Campylobacter (n = 81)] isolates were selected for antimicrobial susceptibility testing (AST) and WGS. RESULTS: Seven functional macrolide resistance determinants, including erm(42), mef(C), mph(A), mph(E), mph(G), msr(E) and one point mutation (acrB_R717L) were previously identified in AziR  Salmonella. These determinants resulted in an 8- and 16-fold 15-membered ring gamithromycin and azithromycin MIC50 increase, respectively, compared with AziS isolates, with a maximum MIC increase of up to 256. The same isolates also exhibited up to a 32-fold 14-membered ring erythromycin MIC50 increase. Salmonella with erm(42) or acrB_R717L showed up to 128-fold 16-membered ring macrolide tildipirosin MIC increase, compared with isolates that were susceptible or carrying other macrolide resistance genes. In Campylobacter, all AziR isolates had an MIC50 ranging from 32 to 4096 mg/L of the various membered ring macrolides, whereases all susceptible Campylobacter isolates had significantly lower MIC50 values, ranging from 0.25 to 4 mg/L. The MIC50 of the various ring macrolides for AziR  Campylobacter isolates was 16- to 4096-fold higher when compared with AziS  Campylobacter. CONCLUSIONS: Our study has revealed that the function of macrolide resistance genes in Salmonella can be associated with specific macrolide ring structures, whereas the single 23S rRNA mutation in Campylobacter results in significantly elevated MICs of all macrolides. for the various ring macrolides.

The Pacific Island Health Officers' Association, the World Health Organization, and the Pacific Community co-organized the launch of the Pacific Vector Network (PVN) to address challenges posed by mosquito-borne diseases, including dengue fever, Zika virus disease, chikungunya, malaria, and lymphatic filariasis. The PVN was created as a new initiative under the Pacific Public Health Surveillance Network (PPHSN). This launch was a critical step in the build-up to PVN as a full-service network of PPHSN in the coming years. The Pacific Island Countries and areas (PIC)-led network comprises vector management leadership, officers, and technical partners dedicated to supporting information-sharing to promote evidence-based collective action and innovation. The setup of a Technical Working Body to ensure governance and to steer forward the work of the network was a key deliverable. This manuscript describes the proceedings and discussions of PIC representatives and several regional partners at the inaugural PVN meeting held 5-7 June 2023 in Hawai'i, USA.

BACKGROUND: Brain infections pose substantial challenges in diagnosis and management and carry high mortality and morbidity, especially in low-income and middle-income countries. We aimed to improve the diagnosis and early management of patients admitted to hospital (adults aged 16 years and older and children aged >28 days) with suspected acute brain infections at 13 hospitals in Brazil, India, and Malawi. METHODS: With hospital stakeholders, policy makers, and patient and public representatives, we co-designed a multifaceted clinical and laboratory intervention, informed by an evaluation of routine practice. The intervention, tailored for each setting, included a diagnostic and management algorithm, a lumbar puncture pack, a testing panel, and staff training. We used multivariable logistic regression and interrupted time series analysis to compare the coprimary outcomes-the percentage of patients achieving a syndromic diagnosis and the percentage achieving a microbiological diagnosis before and after the intervention. The study was registered at ClinicalTrials.gov (NCT04190303) and is complete. FINDINGS: Between Jan 5, 2021, and Nov 30, 2022, we screened 10 462 patients and enrolled a total of 2233 patients at 13 hospital sites connected to the four study centres in Brazil, India, and Malawi. 1376 (62%) were recruited before the intervention and 857 (38%) were recruited after the intervention. 2154 patients (96%) had assessment of the primary outcome (1330 [62%] patients recruited pre-intervention and 824 [38%] recruited post-intervention). The median age across centres was 23 years (IQR 6-44), with 1276 (59%) being adults aged 16 years or older and 888 (41%) children aged between 29 days and 15 years; 1264 (59%) patients were male and 890 (41%) were female. Data on race and ethnicity were not recorded. 1020 (77%) of 1320 patients received a syndromic diagnosis before the intervention, rising to 701 (86%) of 813 after the intervention (adjusted odds ratio [aOR] 1·81 [95% CI 1·40-2·34]; p<0·0001). A microbiological diagnosis was made in 294 (22%) of 1330 patients pre-intervention, increasing to 250 (30%) of 824 patients post-intervention (aOR 1·46 [95% CI 1·18-1·79]; p=0·00040). Interrupted time series analysis confirmed that these increases exceeded a modest underlying trend of improvement over time. The percentage receiving a lumbar puncture, time to appropriate therapy, and functional outcome also improved. INTERPRETATION: Diagnosis and management of patients with suspected acute brain infections improved following introduction of a simple intervention package across a diverse range of hospitals on three continents. The intervention is now being implemented in other settings as part of the WHO Meningitis Roadmap and encephalitis control initiatives. FUNDING: UK National Institute for Health and Care Research.

BACKGROUND: Prenatally transmitted viruses can cause severe damage to the developing brain. There is unexplained variability in prenatal brain injury and postnatal neurodevelopmental outcomes, suggesting disease modifiers. Of note, prenatal Zika infection can cause a spectrum of neurodevelopmental disorders, including congenital Zika syndrome. Currently, there is no preventative treatment or cure. The Prenatal Infection and Neurodevelopmental Genetics (PING) Consortium aims to identify modulators of brain injury and adverse neurodevelopmental outcomes for Zika and other prenatal viral infections. METHODS: The Consortium pools information from eight multi-site studies conducted at 23 research centers in six countries to build a growing clinical and genomic repository, which is being mined for modifiers of virally induced brain injury. Partners include Children's National Hospital (USA), Instituto Nacional de Salud (Colombia), the Natural History of Zika Virus Infection in Gestation program (Brazil), Zika Instituto Fernandes Figueira (Brazil), the Centers for Disease Control and Prevention, and the National Institutes of Health. RESULTS: We have enrolled 4102 mothers and 3877 infants with 3063 biological samples and clinical data covering over 80 phenotypic fields and 5000 variables. Thus far, we have performed whole exome sequencing on 1226 participants. CONCLUSION: Here, we present the Consortium's formation and overarching study design. IMPACT: The PING Consortium brings together investigators and institutions to determine the causes of virally induced brain injury and neurological deficits. The clinical and genomic repository, with data from over 8000 patients, will serve as a foundation for a variety of basic and clinical studies.

OBJECTIVES: World Health Organization issued Joint Statement on Data Protection and Privacy in the COVID-19 Response stating that collection of vast amounts of personal data may potentially lead to the infringement of fundamental human rights and freedoms. The Organization for Economic Cooperation and Development called on national governments to adhere to the international principles for data security and confidentiality. This paper describes the methods used to assist the Ministry of Health in bringing awareness of the data ownership, confidentiality and security principles to COVID-19 responders. METHODS: The Sierra Leone Epidemiological Data (SLED) Team data managers conducted training for groups of COVID-19 responders. Training included presentations on data confidentiality, information disclosure, physical and electronic data security, and cyber-security; and interactive discussion of real-life scenarios. A game of Jeopardy was created to test the participant's knowledge. RESULTS: This paper describes the methods used by the SLED Team to bring awareness of the DOCS principles to more than 2,500 COVID-19 responders. CONCLUSION: Similar efforts may benefit other countries where the knowledge, resources, and governing rules for protection of personal data are limited.

Nearly a decade after the National Academy of Medicine released the "Improving Diagnosis in Health Care" report, diagnostic errors remain common, often leading to physical, psychological, emotional, and financial harm. Despite a robust body of research on potential solutions and next steps, the translation of these efforts to patient care has been limited. Improvement initiatives are still narrowly focused on selective themes such as diagnostic stewardship, preventing overdiagnosis, and enhancing clinical reasoning without comprehensively addressing vulnerable systems and processes surrounding diagnosis. To close this implementation gap, the US Centers for Disease Control and Prevention (CDC) released the Core Elements of Hospital Diagnostic Excellence programs on September 17, 2024. This initiative aligns with the World Health Organization's (WHO) 2024 World Patient Safety Day focus on improving diagnosis. These Core Elements provide guidance for the formation of hospital programs to improve diagnosis and aim to integrate various disparate efforts in hospitals. By creating a shared mental model of diagnostic excellence, the Core Elements of Diagnostic Excellence supports actions to break down silos, guide hospitals toward multidisciplinary diagnostic excellence teams, and provide a foundation for building diagnostic excellence programs in hospitals.

The first Ebola Virus Disease (EVD) cases in the 2021 Ebola outbreak were reported by the Democratic Republic of the Congo (DRC) Ministry of Health in February. However, 1 week later, the Guinea Ministry of Health reported its first EVD outbreak since April 2016. U.S. Centers for Disease Control (CDC) in-country operational and workforce capacity were built during the 2014-2016 Ebola outbreak response in West Africa and leveraged during the 2021 EVD outbreaks. During the 2014-2016 West Africa response and the 2021 EVD outbreaks, capacity and capability improvements in laboratory systems, risk communication, surveillance, epidemiology, infection prevention, and control were needed for a successful response. The overarching goal of CDC's operational and workforce capacity improvements was to strengthen countries' abilities to prevent, detect, and respond to outbreaks quickly. The Ebola outbreaks are examples of enhanced public health interventions where CDC has contributed as a partner with in-country ministries of health to save lives and control disease outbreaks. Lessons learned from the recent Ebola outbreaks indicate that a capacity-building approach has the potential application to other public health emergencies and contributes to strengthening global health security.

BACKGROUND: With the increased availability of licensed vaccines for respiratory viruses such as severe acute respiratory syndrome coronavirus 2, respiratory syncytial virus (RSV), and influenza virus, a better understanding of the viral aetiology of severe acute respiratory infections (SARI) among children could help in optimising the use of these vaccines. We conducted a study among children aged <5 years hospitalised with SARI at a tertiary care children's hospital in north India and tested for common respiratory pathogens. METHODS: We randomly enrolled eligible SARI cases aged <5 years from August 2013 to July 2015. SARI cases were defined as either <7-day history of fever with cough or in children aged eight days to three months, a physician diagnosis of acute lower respiratory infection requiring hospitalisation. We also enrolled an age-group matched control without any acute illness in a 2:1 ratio from the outpatient clinic within 24 hours of case enrolment. Nasopharyngeal and/or oropharyngeal swabs were collected and tested using TaqMan Array Cards, a real-time reverse transcription polymerase chain reaction-based multi-pathogen testing platform for selected respiratory viruses among the enrolled cases and controls. We compared the prevalence of each pathogen among cases and controls using the χ(2) (χ(2)) or Fisher exact test (P < 0.05). We used logistic regression to estimate adjusted odds ratios (aORs) which were then used to calculate aetiologic fractions (EFs). RESULTS: We enrolled 840 cases and 419 outpatient controls. Almost half of the individuals in the whole sample were aged <6 months (n = 521, 41.4%). Females made up 33.7% of cases and 37.2% of controls. Viral detections were more common among cases (69%, 95% confidence interval (CI) = 66, 73) compared to controls (33%; 95% CI = 29, 38) (P < 0.01). RSV (n = 257, 31%; 95% CI = 28, 34%) was the most common virus detected among cases. Influenza A was detected among 24 (3%; 95% CI = 2, 4%), and influenza B among 5 (1%; 95% CI = 0, 1%) cases. The association between the virus and SARI was strongest for RSV (aOR = 23; 95% CI = 12, 47; EF = 96%). Antivirals were administered to 1% of SARI cases while 78% received antibiotics. CONCLUSIONS: Using a multi-pathogen molecular detection method, we detected respiratory viruses among more than two-thirds of children aged <5 years admitted with SARI in the Delhi tertiary care children's hospital. The guidelines for preventing and managing SARI cases among children could be optimised further with the improved availability of antivirals and vaccines.

BACKGROUND: Of the 43 mpox cases reported by the WHO in South East Asia between January 2022 and March 2023, 24 (56%) were from India. OBJECTIVES: We describe the clinical and epidemiological profile of cases identified through India's hospital case-based surveillance. MATERIALS AND METHODS: We identified mpox cases as a positive result for mpox virus polymerase-chain-reaction assay, reported through surveillance from July 1, 2022 to January 7, 2023. Cases and clinicians were interviewed, and data were abstracted from the medical records. We conducted contact tracing among family, close social networks, and healthcare personnel staff for the first 17 cases. We collected the data on sociodemographics, clinical findings, and behavior, and described data using summary statistics. RESULTS: We identified 24 laboratory-confirmed cases (42% females, median age 30 years, range 22-38), including one death (case fatality rate 4.2%). We collected clinical and behavioural data from 21 of 24 cases. All had rashes with vesicles and genital lesions; 7 (33%) reported genital lesions as the first symptom; and 3 (13%) reported complications. Among the 21 cases, all were sexually active, none self-identified as men having sex with men (MSM), and 6 (29%) reported multiple sex partners. We identified 51 contacts of the first 17 reported cases, none reported symptoms suggestive of mpox. CONCLUSION: The clinical and behavioral characteristics of mpox cases in India are consistent with the global 2022 outbreak, with the exception that no cases in India reported MSM. Most were sexually active young adult economic migrants and developed genital lesions.

Wisdom is the hallmark of social judgment, but how people across cultures recognize wisdom remains unclear-distinct philosophical traditions suggest different views of wisdom's cardinal features. We explore perception of wise minds across 16 socio-economically and culturally diverse convenience samples from 12 countries. Participants assessed wisdom exemplars, non-exemplars, and themselves on 19 socio-cognitive characteristics, subsequently rating targets' wisdom, knowledge, and understanding. Analyses reveal two positively related dimensions-Reflective Orientation and Socio-Emotional Awareness. These dimensions are consistent across the studied cultural regions and interact when informing wisdom ratings: wisest targets-as perceived by participants-score high on both dimensions, whereas the least wise are not reflective but moderately socio-emotional. Additionally, individuals view themselves as less reflective but more socio-emotionally aware than most wisdom exemplars. Our findings expand folk psychology and social judgment research beyond the Global North, showing how individuals perceive desirable cognitive and socio-emotional qualities, and contribute to an understanding of mind perception.

INTRODUCTION: HPTN 083 demonstrated the superiority of long-acting cabotegravir (CAB-LA) versus daily oral emtricitabine/tenofovir disoproxil fumarate (TDF/FTC) as pre-exposure prophylaxis (PrEP) among cisgender men and transgender women who have sex with men (MSM/TGW). HPTN 083 provided the first opportunity to understand experiences with injectable PrEP in a clinical trial. METHODS: Participants from two US sites (Chicago, IL and Atlanta, GA) and one international site (Rio de Janeiro, Brazil) were purposively sampled for individual qualitative interviews (N = 40), between November 2019 and March 2020, to explore trial experiences, barriers to adherence and other factors that may have impacted study implementation or outcomes. The blinded phase ended early due to efficacy; this analysis includes interviews conducted prior to unblinding with three groups defined by adherence (i.e. injection visit attendance): adherent (n = 27), non-adherent (n = 12) and early discontinuers (n = 1). Data were organized using NVivo software and analysed using content analysis. RESULTS: Participants (mean age: 27) were primarily cisgender MSM (90%) and Black/African American (60%). Reasons for trial enrolment and PrEP use included a preference for using HIV prevention medication versus treatment in the event of HIV acquisition; the ability to enhance health via study-related education and services; access to a novel, convenient HIV prevention product at no cost; and contributing to MSM/TGW communities through research. Participants contrasted positive experiences with study staff with their routine clinical care, and emphasized increased scheduling flexibility, thorough communication, non-judgemental counselling and open, affirming environments (e.g. compassion, less stigma) as adherence facilitators. Injection experiences were positive overall; some described early injection-related anxiety, which abated with time and when given some measure of control (e.g. pre-injection countdown), and minimal injection site discomfort. Some concerns and misperceptions about injectable PrEP were reported. Barriers to adherence, across all adherence categories, included structural factors (e.g. financial constraints, travel) and competing demands (e.g. work schedules). CONCLUSIONS: Respondents viewed injectable PrEP trial participation as a positive experience and a means of enhancing wellbeing. Study site flexibility and affirming clinic environments, inclusive of non-judgemental counselling, were key facilitators of adherence. To support injection persistence, interventions that address structural barriers and promote flexible means of injection delivery may be most effective.

Background: Cancer-associated venous thromboembolism (CA-VTE) represents a major cause of morbidity and mortality in patients with cancer. Despite poor outcomes, there is an ongoing knowledge gap in epidemiologic data related to this association. Objectives: To compare venous thromboembolism (VTE) characteristics, risk factors, and outcomes between patients with and without active cancer in a racially diverse population. Methods: Our surveillance project occurred at the 3 hospitals in Durham County, North Carolina, from April 2012 through March 2014. Electronic and manual methods were used to identify unique Durham County residents with VTE. Results: We identified 987 patients with VTE during the surveillance period. Of these, 189 patients had active cancer at the time of their VTE event. Patients with CA-VTE were older (median age: 69 years vs 60 years, P < .0001) and had a lower body mass index (median body mass index: 26.0 kg/m2 vs 28.4 kg/m2, P = .0001) than noncancer patients. The most common cancers in our cohort were gastrointestinal, breast, genitourinary, and lung. The proportion of VTE cases with pulmonary embolism (PE) was greater in the cancer cohort compared with that in the noncancer cohort (58.2% vs 44.0%, P = .0004). Overall survival was lower in the CA-VTE group than in patients without cancer (P < .0001). Black patients with CA-VTE had lower proportion of PE (52.3% vs 67.1%, P = .05) but had decreased survival (P < .0003) in comparison with White patients. Conclusion: Future studies may be needed to continue to evaluate local and national VTE data to improve VTE prevention strategies and CA-VTE outcomes. © 2024 The Authors

BACKGROUND: The prevalence of Alzheimer's disease and related disorders (ADRD) is rising. Primary care providers (PCPs) will increasingly be required to play a role in its detection but lack the training to do so. OBJECTIVE: To develop a model for cognitive evaluation which is feasible in primary care and evaluate its implementation in a large health system. METHODS: The Cognition in Primary Care Program consists of web-based training together with integrated tools built into the electronic record. We implemented the program among PCPs at 14 clinics in a large health system. We (1) surveyed PCPs to assess the impact of training on their confidence to evaluate cognition, (2) measured the number of cognitive assessments they performed, and (3) tracked the number of patients diagnosed with mild cognitive impairment (MCI). RESULTS: Thirty-nine PCPs completed the training which covered how to evaluate cognition. Survey response rate from those PCPs was 74%. Six months after the end of the training, they reported confidence in assessing cognition (mean 4.6 on 5-point scale). Cognitive assessments documented in the health record increased from 0.8 per month before the training to 2.5 in the six months after the training. Patients who were newly diagnosed with MCI increased from 4.2 per month before the training to 6.0 per month in the six months after the training. CONCLUSIONS: This model for cognitive evaluation in a large health system was shown to increase cognitive testing and increase diagnoses of MCI. Such improvements are essential for the timely detection of ADRD.

BACKGROUND: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter ACTT-1 clinical trial that randomized patients to remdesivir or placebo. METHODS: Longitudinal specimens collected during hospitalization from a substudy of 642 COVID-19 patients were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed. RESULTS: Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95%CI 1.40-2.71) for levels >245 pg/ml vs 1.04 (95%CI 0.76-1.42) for levels < 245 pg/ml. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive. CONCLUSIONS: Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy.

IMPORTANCE: Infections due to multidrug-resistant organisms (MDROs) are associated with increased morbidity, mortality, length of hospitalization, and health care costs. Regional interventions may be advantageous in mitigating MDROs and associated infections. OBJECTIVE: To evaluate whether implementation of a decolonization collaborative is associated with reduced regional MDRO prevalence, incident clinical cultures, infection-related hospitalizations, costs, and deaths. DESIGN, SETTING, AND PARTICIPANTS: This quality improvement study was conducted from July 1, 2017, to July 31, 2019, across 35 health care facilities in Orange County, California. EXPOSURES: Chlorhexidine bathing and nasal iodophor antisepsis for residents in long-term care and hospitalized patients in contact precautions (CP). MAIN OUTCOMES AND MEASURES: Baseline and end of intervention MDRO point prevalence among participating facilities; incident MDRO (nonscreening) clinical cultures among participating and nonparticipating facilities; and infection-related hospitalizations and associated costs and deaths among residents in participating and nonparticipating nursing homes (NHs). RESULTS: Thirty-five facilities (16 hospitals, 16 NHs, 3 long-term acute care hospitals [LTACHs]) adopted the intervention. Comparing decolonization with baseline periods among participating facilities, the mean (SD) MDRO prevalence decreased from 63.9% (12.2%) to 49.9% (11.3%) among NHs, from 80.0% (7.2%) to 53.3% (13.3%) among LTACHs (odds ratio [OR] for NHs and LTACHs, 0.48; 95% CI, 0.40-0.57), and from 64.1% (8.5%) to 55.4% (13.8%) (OR, 0.75; 95% CI, 0.60-0.93) among hospitalized patients in CP. When comparing decolonization with baseline among NHs, the mean (SD) monthly incident MDRO clinical cultures changed from 2.7 (1.9) to 1.7 (1.1) among participating NHs, from 1.7 (1.4) to 1.5 (1.1) among nonparticipating NHs (group × period interaction reduction, 30.4%; 95% CI, 16.4%-42.1%), from 25.5 (18.6) to 25.0 (15.9) among participating hospitals, from 12.5 (10.1) to 14.3 (10.2) among nonparticipating hospitals (group × period interaction reduction, 12.9%; 95% CI, 3.3%-21.5%), and from 14.8 (8.6) to 8.2 (6.1) among LTACHs (all facilities participating; 22.5% reduction; 95% CI, 4.4%-37.1%). For NHs, the rate of infection-related hospitalizations per 1000 resident-days changed from 2.31 during baseline to 1.94 during intervention among participating NHs, and from 1.90 to 2.03 among nonparticipating NHs (group × period interaction reduction, 26.7%; 95% CI, 19.0%-34.5%). Associated hospitalization costs per 1000 resident-days changed from $64 651 to $55 149 among participating NHs and from $55 151 to $59 327 among nonparticipating NHs (group × period interaction reduction, 26.8%; 95% CI, 26.7%-26.9%). Associated hospitalization deaths per 1000 resident-days changed from 0.29 to 0.25 among participating NHs and from 0.23 to 0.24 among nonparticipating NHs (group × period interaction reduction, 23.7%; 95% CI, 4.5%-43.0%). CONCLUSIONS AND RELEVANCE: A regional collaborative involving universal decolonization in long-term care facilities and targeted decolonization among hospital patients in CP was associated with lower MDRO carriage, infections, hospitalizations, costs, and deaths.

Sickle cell disease (SCD) remains a public health priority in the United States because of its association with complex health needs, reduced life expectancy, lifelong disabilities, and high cost of care. A cross-sectional analysis was conducted to calculate the crude and race-specific birth prevalence for SCD using state newborn screening program records during 2016-2020 from 11 Sickle Cell Data Collection program states. The percentage distribution of birth mother residence within Social Vulnerability Index quartiles was derived. Among 3,305 newborns with confirmed SCD (including 57% with homozygous hemoglobin S or sickle β-null thalassemia across 11 states, 90% of whom were Black or African American [Black], and 4% of whom were Hispanic or Latino), the crude SCD birth prevalence was 4.83 per 10,000 (one in every 2,070) live births and 28.54 per 10,000 (one in every 350) non-Hispanic Black newborns. Approximately two thirds (67%) of mothers of newborns with SCD lived in counties with high or very high levels of social vulnerability; most mothers lived in counties with high or very high levels of vulnerability for racial and ethnic minority status (89%) and housing type and transportation (64%) themes. These findings can guide public health, health care systems, and community program planning and implementation that address social determinants of health for infants with SCD. Implementation of tailored interventions, including increasing access to transportation, improving housing, and advancing equity in high vulnerability areas, could facilitate care and improve health outcomes for children with SCD.

We investigated transmission dynamics of a large human immunodeficiency virus (HIV) outbreak among persons who inject drugs (PWID) in KY and OH during 2017-20 by using detailed phylogenetic, network, recombination, and cluster dating analyses. Using polymerase (pol) sequences from 193 people associated with the investigation, we document high HIV-1 diversity, including Subtype B (44.6 per cent); numerous circulating recombinant forms (CRFs) including CRF02_AG (2.5 per cent) and CRF02_AG-like (21.8 per cent); and many unique recombinant forms composed of CRFs with major subtypes and sub-subtypes [CRF02_AG/B (24.3 per cent), B/CRF02_AG/B (0.5 per cent), and A6/D/B (6.4 per cent)]. Cluster analysis of sequences using a 1.5 per cent genetic distance identified thirteen clusters, including a seventy-five-member cluster composed of CRF02_AG-like and CRF02_AG/B, an eighteen-member CRF02_AG/B cluster, Subtype B clusters of sizes ranging from two to twenty-three, and a nine-member A6/D and A6/D/B cluster. Recombination and phylogenetic analyses identified CRF02_AG/B variants with ten unique breakpoints likely originating from Subtype B and CRF02_AG-like viruses in the largest clusters. The addition of contact tracing results from OH to the genetic networks identified linkage between persons with Subtype B, CRF02_AG, and CRF02_AG/B sequences in the clusters supporting de novo recombinant generation. Superinfection prevalence was 13.3 per cent (8/60) in persons with multiple specimens and included infection with B and CRF02_AG; B and CRF02_AG/B; or B and A6/D/B. In addition to the presence of multiple, distinct molecular clusters associated with this outbreak, cluster dating inferred transmission associated with the largest molecular cluster occurred as early as 2006, with high transmission rates during 2017-8 in certain other molecular clusters. This outbreak among PWID in KY and OH was likely driven by rapid transmission of multiple HIV-1 variants including de novo viral recombinants from circulating viruses within the community. Our findings documenting the high HIV-1 transmission rate and clustering through partner services and molecular clusters emphasize the importance of leveraging multiple different data sources and analyses, including those from disease intervention specialist investigations, to better understand outbreak dynamics and interrupt HIV spread.

BACKGROUND: We aimed to determine if pre-existing immunocompromising conditions (ICCs) were associated with the presentation or outcome of patients with acute coronavirus disease 2019 (COVID-19) admitted for pediatric intensive care. METHODS: 55 hospitals in 30 U.S. states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients <21 years admitted March 12, 2020-December 30, 2021 to the pediatric intensive care unit (PICU) or high acuity unit for acute COVID-19 were included. RESULTS: Of 1,274 patients, 105 (8.2%) had an ICC including 33 (31.4%) hematologic malignancies, 24 (22.9%) primary immunodeficiencies and disorders of hematopoietic cells, 19 (18.1%) nonmalignant organ failure with solid organ transplantation, 16 (15.2%) solid tumors and 13 (12.4%) autoimmune disorders. Patients with ICCs were older, had more underlying renal conditions, and had lower white blood cell and platelet counts than those without ICCs, but had similar clinical disease severity upon admission. In-hospital mortality from COVID-19 was higher (11.4% vs. 4.6%, p = 0.005) and hospitalization was longer (p = 0.01) in patients with ICCs. New major morbidities upon discharge were not different between those with and without ICC (10.5% vs 13.9%, p = 0.40). In patients with ICC, bacterial co-infection was more common in those with life-threatening COVID-19. CONCLUSIONS: In this national case series of patients <21 years of age with acute COVID-19 admitted for intensive care, existence of a prior ICCs were associated with worse clinical outcomes. Reassuringly, most patients with ICCs hospitalized in the PICU for severe acute COVID-19 survived and were discharged home without new severe morbidities.

New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.

AIM: The action to control cardiovascular risk in diabetes (ACCORD) trial showed a neutral average treatment effect of intensive blood glucose and blood pressure (BP) controls in preventing major adverse cardiovascular events (MACE) in individuals with type 2 diabetes. Yet, treatment effects across patient subgroups have not been well understood. We aimed to identify patient subgroups that might benefit from intensive glucose or BP controls for preventing MACE. MATERIALS AND METHODS: As a post-hoc analysis of the ACCORD trial, we included 10 251 individuals with type 2 diabetes. We applied causal forest and causal tree models to identify participant characteristics that modify the efficacy of intensive glucose or BP controls from 68 candidate variables (demographics, comorbidities, medications and biomarkers) at the baseline. The exposure was (a) intensive versus standard glucose control [glycated haemoglobin (HbA1c) <6.0% vs. 7.0%-7.9%], and (b) intensive versus standard BP control (systolic BP <120 vs. <140 mmHg). The primary outcome was MACE. RESULTS: Compared with standard glucose control, intensive one reduced MACE in those with baseline HbA1c <8.5% [relative risk (RR): 0.79, 95% confidence interval (CI): 0.67-0.93] and those with estimated glomerular filtration rate ≥106 ml/min/1.73 m(2) (RR: 0.74, 95% CI: 0.55-0.99). Intensive BP control reduced MACE in those with normal high-density lipoprotein levels (women >55 mg/dl, men >45 mg/dl; RR: 0.51, 95% CI: 0.34-0.74). Risk reductions were not significant in other patient subgroups. CONCLUSIONS: Our findings suggest heterogeneous treatment effects of intensive glucose and BP control and could provide biomarkers for future clinical trials to identify more precise HbA1c and BP treatment goals for individualized medicine.

Recent reports of hookworm infection in Alabama, USA, has prompted surveillance in Mississippi, given the states' similar environmental conditions. We collected stool specimens from 277 children in Rankin County, Mississippi. Kato-Katz microscopic smear, agar plate culture, and quantitative PCR indicated no soil-transmitted helminths. Nevertheless, further surveillance in other high-risk Mississippi counties is warranted.

BACKGROUND: Environmental contamination is suspected to play an important role in Candida auris transmission. Understanding speed and risks of contamination after room disinfection could inform environmental cleaning recommendations. METHODS: We conducted a prospective multicenter study of environmental contamination associated with C. auris colonization at six ventilator-capable skilled nursing facilities and one acute-care hospital in Illinois and California. Known C. auris carriers were sampled at five body-sites followed by sampling of nearby room surfaces before disinfection and at 0, 4, 8, and 12-hours post-disinfection. Samples were cultured for C. auris and bacterial multidrug-resistant organisms (MDROs). Odds of surface contamination after disinfection were analyzed using multilevel generalized estimating equations. RESULTS: Among 41 known C. auris carriers, colonization was detected most frequently on palms/fingertips (76%) and nares (71%). C. auris contamination was detected on 32.2% (66/205) of room surfaces pre-disinfection and 20.5% (39/190) of room surfaces by 4-hours post-disinfection. A higher number of C. auris-colonized body sites was associated with higher odds of environmental contamination at every time point following disinfection, adjusting for facility of residence. In the rooms of 38 (93%) C. auris carriers co-colonized with a bacterial MDRO, 2%-24% of surfaces were additionally contaminated with the same MDRO by 4-hours post-disinfection. CONCLUSIONS: C. auris can contaminate the healthcare environment rapidly after disinfection, highlighting the challenges associated with environmental disinfection. Future research should investigate long-acting disinfectants, antimicrobial surfaces, and more effective patient skin antisepsis to reduce the environmental reservoir of C. auris and bacterial MDROs in healthcare settings.

OBJECTIVE: To develop initial American College of Rheumatology (ACR) guidelines on the use of exercise, rehabilitation, diet, and additional interventions in conjunction with disease-modifying antirheumatic drugs (DMARDs) as part of an integrative management approach for people with rheumatoid arthritis (RA). METHODS: An interprofessional guideline development group constructed clinically relevant Population, Intervention, Comparator, and Outcome (PICO) questions. A literature review team then completed a systematic literature review and applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the certainty of evidence. An interprofessional Voting Panel (n = 20 participants) that included 3 individuals with RA achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: The Voting Panel achieved consensus on 28 recommendations for the use of integrative interventions in conjunction with DMARDs for the management of RA. Consistent engagement in exercise received a strong recommendation. Of 27 conditional recommendations, 4 pertained to exercise, 13 to rehabilitation, 3 to diet, and 7 to additional integrative interventions. These recommendations are specific to RA management, recognizing that other medical indications and general health benefits may exist for many of these interventions. CONCLUSION: This guideline provides initial ACR recommendations on integrative interventions for the management of RA to accompany DMARD treatments. The broad range of interventions included in these recommendations illustrates the importance of an interprofessional, team-based approach to RA management. The conditional nature of most recommendations requires clinicians to engage persons with RA in shared decision-making when applying these recommendations.

Integration of genomic technologies into routine antimicrobial resistance (AMR) surveillance in health-care facilities has the potential to generate rapid, actionable information for patient management and inform infection prevention and control measures in near real time. However, substantial challenges limit the implementation of genomics for AMR surveillance in clinical settings. Through a workshop series and online consultation, international experts from across the AMR and pathogen genomics fields convened to review the evidence base underpinning the use of genomics for AMR surveillance in a range of settings. Here, we summarise the identified challenges and potential benefits of genomic AMR surveillance in health-care settings, and outline the recommendations of the working group to realise this potential. These recommendations include the definition of viable and cost-effective use cases for genomic AMR surveillance, strengthening training competencies (particularly in bioinformatics), and building capacity at local, national, and regional levels using hub and spoke models.

Macrolides of different ring sizes are critically important antimicrobials for human medicine and veterinary medicine, though the widely used 15-membered ring azithromycin in humans is not approved for use in veterinary medicine. We document here the emergence of azithromycin-resistant Salmonella among the NARMS culture collections between 2011 and 2021 in food animals and retail meats, some with co-resistance to ceftriaxone or decreased susceptibility to ciprofloxacin. We also provide insights into the underlying genetic mechanisms and genomic contexts, including the first report of a novel combination of azithromycin resistance determinants and the characterization of multidrug-resistant plasmids. Further, we highlight the emergence of a multidrug-resistant Salmonella Newport clone in food animals (mainly cattle) with both azithromycin resistance and decreased susceptibility to ciprofloxacin. These findings contribute to a better understating of azithromycin resistance mechanisms in Salmonella and warrant further investigations on the drivers behind the emergence of resistant clones.

BACKGROUND: All countries are required to implement International Health Regulations (IHR) through development and implementation of multi-year National Action Plans for Health Security (NAPHS). IHR implementation requires annual operational planning which involves several tools such as NAPHS, State Party Annual Report (SPAR), Joint External Evaluation (JEE) and WHO IHR Benchmarks tool. Sierra Leone has successfully improved IHR capacities across the years through successful annual operational planning using the above tools. We conducted a study to document and share the country's unique approach to implementation of NAPHS. METHODS: This was an observational study where the process of implementing and monitoring NAPHS in Sierra Leone was observed at the national level from 2018 to 2021. Data was obtained through review and analysis of NAPHS annual operational plans, quarterly review reports and annual IHR assessment reports. Available data was supplemented by information from key informants. Qualitative data was captured as notes and analysed for various themes while quantitative data was analyzed mainly for means and proportions. RESULTS: The overall national IHR Joint External Evaluation self-assessment score for human health improved from 44% in 2018 to 51% in 2019 and 57% in 2020. The score for the animal sector improved from 32% in 2018 to 43% in 2019 and 52% in 2020. A new JEE tool with new indicators was used in 2021 and the score for both human and animal sectors declined slightly to 51%. Key enablers of success included strong political commitment, whole-of-government approach, annual assessments using JEE tool, annual operational planning using WHO IHR Benchmarks tool and real time online monitoring of progress. Key challenges included disruption created by COVID-19 response, poor health infrastructure, low funding and inadequate health workforce. CONCLUSION: IHR annual operational planning and implementation using evidence-based data and tools can facilitate strengthening of IHR capacity and should be encouraged.

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs.

Despite the improvements in HIV care outcomes in the United States (US), non-US-born persons continue to be disproportionately affected by HIV. We analyzed National HIV Surveillance System (NHSS) data on HIV diagnoses, stage 3 (AIDS) at diagnosis, linkage to medical care, and viral suppression for non-US-born persons by region of birth (RoB) reported to the (NHSS) in 2020 to determine care outcomes among this population. Overall, a larger proportion of non-US-born persons received a late-stage diagnosis [stage 3 (AIDS)] classification. Among all non-US-born persons, African-born males, Asian-born females, and persons aged 55 + years had the highest proportions of late-stage diagnosis. Despite a late-stage of diagnosis, a higher proportion of non-US-born persons were linked to medical care and were virally suppressed compared to US-born persons. HIV care outcomes varied by RoB and selected characteristics. Knowing the RoB of non-US-born persons is necessary to identify culturally sensitive approaches for prevention planning and increasing testing activities to ultimately increase early diagnosis in this population.

Since May 2022, mpox has been identified in 108 countries without endemic disease; most cases have been in gay, bisexual, or other men who have sex with men. To determine number of missed cases, we conducted 2 studies during June-September 2022: a prospective serologic survey detecting orthopoxvirus antibodies among men who have sex with men in San Francisco, California, and a retrospective monkeypox virus PCR testing of swab specimens submitted for other infectious disease testing among all patients across the United States. The serosurvey of 225 participants (median age 34 years) detected 18 (8.0%) who were orthopoxvirus IgG positive and 3 (1.3%) who were also orthopoxvirus IgM positive. The retrospective PCR study of 1,196 patients (median age 30 years; 54.8% male) detected 67 (5.6%) specimens positive for monkeypox virus. There are likely few undiagnosed cases of mpox in regions where sexual healthcare is accessible and patient and clinician awareness about mpox is increased.

The Lancet Series on Work and Health1, 2, 3 recognises that changes in the world of work are causing new occupational hazards to physical and mental health and increasing health inequalities within and between countries. These changes have profound implications for official workers’ health data and monitoring systems, which have become a global health priority as the world seeks to reach the Sustainable Development Goals (SDGs).4, 5 These monitoring systems are public goods that provide international organisations, governments, and communities the evidence base for policy and practice that ensures health for all workers. We argue that these monitoring systems must respond to changing working environments by expanding capture of workers’ rights, working conditions, and health inequalities. We outline normative data and monitoring products to reach this systemic shift and provide the public health vision for this new direction. | | No worker should die or get ill because of their work, or be left behind in occupational health protection and promotion. All workers are entitled to the human rights to: health;6 a clean, healthy, and sustainable environment; and a safe and healthy working environment.7 However, WHO and the International Labour Organization (ILO) estimate that annually 2 million deaths and 90 million disability-adjusted life-years are attributable to selected occupational risk factors.8 Recognition is growing that improving workers’ health and health equity requires action on the social and environmental determinants of health. Examples include strengthened evidence on the effects of the emerging psychosocial hazard of long working hours on cardiovascular disease,9 and the environmental and climate crises strengthening attention to workers’ environmental and climatic hazards (eg, air pollution and heat exposures). Occupational health policy increasingly comprises health equity analysis and targets. The WHO/ILO joint estimates show geographical and socioeconomic health inequalities—an increased number of deaths is noted among workers in Africa, South-East Asia, and the Western Pacific, and among men and people aged 55 years or older.8 People working in the informal economy, and migrant, outdoor, and front-line workers are often especially disadvantaged. Health-care workers, despite working in a sector that aims to restore, protect, and promote health, often face hazardous working conditions and are exposed to pathogens (eg, SARS-CoV-2), violence, and long working hours, among others. Ongoing changes in working environments (eg, globalisation, automation, digitisation, new pandemics, environmental pollution, and climate change) exacerbate these inequalities. Ultimately, unhealthy working conditions act as barriers for realising workers’ rights to health, population health, and health equity, and threaten the goal of achieving the SDGs globally.