Background: The first licensed malaria vaccine, RTS,S/AS01<inf>E</inf>, confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy. Method(s): Between Sept 28, 2017, and Sept 25, 2018, 1500 children aged 5-17 months were randomly assigned (1:1:1:1:1) to receive four different RTS,S/AS01<inf>E</inf> regimens or a rabies control vaccine in a phase 2b open-label clinical trial in Ghana and Kenya. Participants in the four RTS,S groups received two full doses at month 0 and month 1 and either full doses at month 2 and month 20 (group R012-20); full doses at month 2, month 14, month 26, and month 38 (group R012-14); fractional doses at month 2, month 14, month 26, and month 38 (group Fx012-14; early fourth dose); or fractional doses at month 7, month 20, and month 32 (group Fx017-20; delayed third dose). We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods (12 months and 20 months) in more than 36 000 dried blood spot specimens from 1500 participants. To study vaccine effects on time to the first new infection, we defined vaccine efficacy as one minus the hazard ratio (HR; RTS,S vs control) of the first new infection. We performed a post-hoc analysis of vaccine efficacy based on malaria infection status at first vaccination and force of infection by month 2. This trial (MAL-095) is registered with ClinicalTrials.gov, NCT03281291. Finding(s): We observed significant and similar vaccine efficacy (25-43%; 95% CI union 9-53) against first new infection for all four RTS,S/AS01<inf>E</inf> regimens across both follow-up periods (12 months and 20 months). Each RTS,S/AS01<inf>E</inf> regimen significantly reduced the mean number of new infections in the 20-month follow-up period by 1.1-1.6 infections (95% CI union 0.6-2.1). Vaccine efficacy against first new infection was significantly higher in participants who were infected with malaria (68%; 95% CI 50-80) than in those who were uninfected (37%; 23-48) at the first vaccination (p=0.0053). Interpretation(s): All tested dosing regimens blocked some infections to a similar degree. Improved vaccine efficacy in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation. Funding(s): GlaxoSmithKline Biologicals SA, PATH, Bill & Melinda Gates Foundation, and the German Federal Ministry of Education and Research. Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

BACKGROUND: The first licensed malaria vaccine, RTS,S/AS01(E), confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy. METHODS: Between Sept 28, 2017, and Sept 25, 2018, 1500 children aged 5-17 months were randomly assigned (1:1:1:1:1) to receive four different RTS,S/AS01(E) regimens or a rabies control vaccine in a phase 2b open-label clinical trial in Ghana and Kenya. Participants in the four RTS,S groups received two full doses at month 0 and month 1 and either full doses at month 2 and month 20 (group R012-20); full doses at month 2, month 14, month 26, and month 38 (group R012-14); fractional doses at month 2, month 14, month 26, and month 38 (group Fx012-14; early fourth dose); or fractional doses at month 7, month 20, and month 32 (group Fx017-20; delayed third dose). We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods (12 months and 20 months) in more than 36 000 dried blood spot specimens from 1500 participants. To study vaccine effects on time to the first new infection, we defined vaccine efficacy as one minus the hazard ratio (HR; RTS,S vs control) of the first new infection. We performed a post-hoc analysis of vaccine efficacy based on malaria infection status at first vaccination and force of infection by month 2. This trial (MAL-095) is registered with ClinicalTrials.gov, NCT03281291. FINDINGS: We observed significant and similar vaccine efficacy (25-43%; 95% CI union 9-53) against first new infection for all four RTS,S/AS01(E) regimens across both follow-up periods (12 months and 20 months). Each RTS,S/AS01(E) regimen significantly reduced the mean number of new infections in the 20-month follow-up period by 1·1-1·6 infections (95% CI union 0·6-2·1). Vaccine efficacy against first new infection was significantly higher in participants who were infected with malaria (68%; 95% CI 50-80) than in those who were uninfected (37%; 23-48) at the first vaccination (p=0·0053). INTERPRETATION: All tested dosing regimens blocked some infections to a similar degree. Improved vaccine efficacy in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation. FUNDING: GlaxoSmithKline Biologicals SA, PATH, Bill & Melinda Gates Foundation, and the German Federal Ministry of Education and Research.

BACKGROUND: The RTS, S/AS01E malaria vaccine (RTS, S) is recommended for children in moderate-to-high Plasmodium falciparum malaria transmission areas. This phase 2b trial (NCT03276962) evaluates RTS, S fractional- and full-dose regimens in Ghana and Kenya. METHODS: 1500 children aged 5-17 months were randomised (1:1:1:1:1) to receive RTS, S or rabies control vaccine. RTS, S groups received two full RTS, S doses at month (M)0/M1 followed by either full (groups R012-20, R012-14-26) or fractional (1/5) doses (groups Fx012-14-26, Fx017-20-32). RESULTS: At M32 post-first dose, vaccine efficacy (VE) against clinical malaria (all episodes) ranged from 38% (R012-20; 95%CI: 24-49) to 53% (R012-14-26; 95%CI: 42-62). Vaccine impact estimates (cumulative number of malaria cases averted/1000 children vaccinated) were 1344 (R012-20), 2450 (R012-14-26), 2273 (Fx012-14-26), 2112 (Fx017-20-32). To account for differences in vaccine volume (fractional- versus full-dose), in a post-hoc analysis, we also estimated cases averted/1000 RTS, S full-dose equivalents: 336 (R012-20), 490 (R012-14-26), 874 (Fx012-14-26), 880 (Fx017-20-32). CONCLUSIONS: VE against clinical malaria was similar in all RTS, S groups. Vaccine impact accounting for full-dose equivalence suggests that using fractional-dose regimens could be a viable dose-sparing strategy. If borne out through trial end (M50), these observations underscore the means to reduce cost per regimen with a goal of maximising impact and optimising supply.

Hospitalizations involving fungal infections increased 8.5% each year in the United States during 2019-2021. During 2020-2021, patients hospitalized with COVID-19-associated fungal infections had higher (48.5%) in-hospital mortality rates than those with non-COVID-19-associated fungal infections (12.3%). Improved fungal disease surveillance is needed, particularly during respiratory virus pandemics.

The emergence of a novel coronavirus, namely, SARS-CoV-2, necessitated the use of rapid, accurate diagnostics to quickly diagnose COVID-19. This need has increased with the emergence of new variants and continued waves of COVID-19 cases. The ID NOW COVID-19 assay is a rapid nucleic acid amplification test (NAAT) that is used by hospitals, urgent care facilities, medical clinics, and public health laboratories for rapid molecular SARS-CoV-2 testing at the point of care. The District of Columbia Department of Forensic Sciences Public Health Laboratory Division (DC DFS PHL) implemented ID NOW COVID-19 testing in nontraditional laboratory settings, including a mobile testing unit, health clinic, and emergency department, to assist with rapid identification and isolation for populations at high risk of SARS-CoV-2 transmission in the District of Columbia. The DC DFS PHL provided these nontraditional laboratories with safety risk assessment, assay training, competency assessment, and quality control monitoring as parts of a comprehensive quality management system (QMS). We assessed the accuracy of the ID NOW COVID-19 assay when operated in the context of these trainings and systems. This was done by comparing results from 9,518 paired tests, and strong agreement (κ = 0.88, OPA = 98.3%) was found between the ID NOW COVID-19 assay and laboratory-based NAATs. These findings indicate that the ID NOW COVID-19 assay can be used to detect SARS-CoV-2 in nontraditional laboratory settings when used within the context of a comprehensive QMS.

The association between thromboembolic events (TE) and COVID-19 infection is not completely understood at the population level in the United States. We examined their association using a large US healthcare database. We analyzed data from the Premier Healthcare Database Special COVID-19 Release and conducted a case-control study. Thestudy population consisted of men and non-pregnant women aged18years with (cases) or without (controls) an inpatient ICD-10-CM diagnosis of TE between 3/1/2020 and 6/30/2021. Using multivariable logistic regression, we assessed the association between TE occurrence and COVID-19 diagnosis, adjusting for demographic factors and comorbidities. Among 227,343 cases, 15.2% had a concurrent or prior COVID-19 diagnosis within 30days of their index TE. Multivariable regression analysis showed a statistically significant association between a COVID-19 diagnosis and TE among cases when compared to controls (adjusted odds ratio [aOR]1.75, 95% CI 1.72-1.78). The association was more substantial if a COVID-19 diagnosis occurred 1-30days prior to index hospitalization (aOR3.00, 95% CI 2.88-3.13) compared to the same encounter as the index hospitalization. Our findings suggest an increased risk of TE among persons within 30days of beingdiagnosed COVID-19, highlighting the need for careful consideration of the thrombotic risk among COVID-19 patients, particularly during the first month following diagnosis.

The risk for COVID-19-associated mortality increases with age, disability, and underlying medical conditions (1). Early in the emergence of the Omicron variant of SARS-CoV-2, the virus that causes COVID-19, mortality among hospitalized COVID-19 patients was lower than that during previous pandemic peaks (2-5), and some health authorities reported that a substantial proportion of COVID-19 hospitalizations were not primarily for COVID-19-related illness,* which might account for the lower mortality among hospitalized patients. Using a large hospital administrative database, CDC assessed in-hospital mortality risk overall and by demographic and clinical characteristics during the Delta (July-October 2021), early Omicron (January-March 2022), and later Omicron (April-June 2022) variant periods(†) among patients hospitalized primarily for COVID-19. Model-estimated adjusted mortality risk differences (aMRDs) (measures of absolute risk) and adjusted mortality risk ratios (aMRRs) (measures of relative risk) for in-hospital death were calculated comparing the early and later Omicron periods with the Delta period. Crude mortality risk (cMR) (deaths per 100 patients hospitalized primarily for COVID-19) was lower during the early Omicron (13.1) and later Omicron (4.9) periods than during the Delta (15.1) period (p<0.001). Adjusted mortality risk was lower during the Omicron periods than during the Delta period for patients aged ≥18 years, males and females, all racial and ethnic groups, persons with and without disabilities, and those with one or more underlying medical conditions, as indicated by significant aMRDs and aMRRs (p<0.05). During the later Omicron period, 81.9% of in-hospital deaths occurred among adults aged ≥65 years and 73.4% occurred among persons with three or more underlying medical conditions. Vaccination, early treatment, and appropriate nonpharmaceutical interventions remain important public health priorities for preventing COVID-19 deaths, especially among persons most at risk.

Newly resettled refugee populations often have significant health care needs including pregnancy complications; yet research is lacking on pregnancy complications among refugees in Illinois. This was a retrospective analysis of the 2016-2017 hospital discharge data of refugee women of childbearing age (15-44 years) in Illinois. There were 3,355 hospital encounters by refugee women in our analysis, and 19.1% (n = 640) were associated with complications mainly related to pregnancy. The majority of hospital encounters associated with complications mainly related to pregnancy occurred after the first 8 months of US arrival (85.2%) and were among women who had Medicaid insurance (90.3%), ≥ 5 hospital encounters (60.2%), and who were most commonly from Iraq (23.3%) or Burma (19.4%). Refugee women may benefit from increased awareness and education about prenatal care, support in access, and prompt referrals.

As part of public health preparedness for infectious disease threats, CDC collaborates with other U.S. public health officials to ensure that the Laboratory Response Network (LRN) has diagnostic tools to detect Orthopoxviruses, the genus that includes Variola virus, the causative agent of smallpox. LRN is a network of state and local public health, federal, U.S. Department of Defense (DOD), veterinary, food, and environmental testing laboratories. CDC developed, and the Food and Drug Administration (FDA) granted 510(k) clearance* for the Non-variola Orthopoxvirus Real-time PCR Primer and Probe Set (non-variola Orthopoxvirus [NVO] assay), a polymerase chain reaction (PCR) diagnostic test to detect NVO. On May 17, 2022, CDC was contacted by the Massachusetts Department of Public Health (DPH) regarding a suspected case of monkeypox, a disease caused by the Orthopoxvirus Monkeypox virus. Specimens were collected and tested by the Massachusetts DPH public health laboratory with LRN testing capability using the NVO assay. Nationwide, 68 LRN laboratories had capacity to test approximately 8,000 NVO tests per week during June. During May 17-June 30, LRN laboratories tested 2,009 specimens from suspected monkeypox cases. Among those, 730 (36.3%) specimens from 395 patients were positive for NVO. NVO-positive specimens from 159 persons were confirmed by CDC to be monkeypox; final characterization is pending for 236. Prompt identification of persons with infection allowed rapid response to the outbreak, including isolation and treatment of patients, administration of vaccines, and other public health action. To further facilitate access to testing and increase convenience for providers and patients by using existing provider-laboratory relationships, CDC and LRN are supporting five large commercial laboratories with a national footprint (Aegis Science, LabCorp, Mayo Clinic Laboratories, Quest Diagnostics, and Sonic Healthcare) to establish NVO testing capacity of 10,000 specimens per week per laboratory. On July 6, 2022, the first commercial laboratory began accepting specimens for NVO testing based on clinician orders.

BACKGROUND: Controlled infection studies in malaria-naive adults suggest increased vaccine efficacy for fractional-dose versus full-dose regimens of RTS,S/AS01. We report first results of an ongoing trial assessing different fractional-dose regimens in children, in natural exposure settings. METHODS: This open-label, phase 2b, randomised controlled trial is conducted at the Malaria Research Center, Agogo, Ashanti Region (Ghana), and the Kenya Medical Research Institute and the US Centers for Disease Control and Prevention site in Siaya County (Kenya). We enrolled children aged 5-17 months without serious acute or chronic illness who had previously received three doses of diphtheria, tetanus, pertussis, and hepatitis B vaccine and at least three doses of oral polio vaccine. Children were randomly assigned (1:1:1:1:1) using a web-based randomisation system with a minimisation procedure accounting for centre to receive rabies control vaccine (M012 schedule) or two full doses of RTS,S/AS01(E) at month 0 and month 1, followed by either full doses at months 2 and 20 (group R012-20 [standard regimen]), full doses at months 2, 14, 26, and 38 (R012-14), fractional doses at months 2, 14, 26, and 38 (Fx012-14), or fractional doses at months 7, 20, and 32 (Fx017-20). The fractional doses were administered as one fifth (0·1 mL) of the full RTS,S dose (0·5 mL) after reconstitution. All vaccines were administered by intramuscular injection in the left deltoid. The primary outcome was occurrence of clinical malaria cases from month 2·5 until month 14 for the Fx012-14 group versus the pooled R012-14 and R012-20 groups in the per-protocol set. We assessed incremental vaccine efficacy of the Fx012-14 group versus the pooled R012-14 and R012-20 group over 12 months after dose three. Safety was assessed in all children who received at least one vaccine dose. This trial is registered with ClinicalTrials.gov, NCT03276962. FINDINGS: Between Sept 28, 2017, and Sept 25, 2018, 2157 children were enrolled, of whom 1609 were randomly assigned to a treatment group (322 to each RTS,S/AS01(E) group and 321 to the rabies vaccine control group). 1500 children received at least one study vaccine dose and the per-protocol set comprised 1332 children. Over 12 months after dose three, the incremental vaccine efficacy in the Fx012-14 group versus the pooled R012-14 and R12-20 groups was -21% (95% CI -57 to 7; p=0·15). Up to month 21, serious adverse events occurred in 48 (16%) of 298 children in the R012-20 group, 45 (15%) of 294 in the R012-14 group, 47 (15%) of 304 in the Fx012-14 group, 62 (20%) of 311 in the Fx017-20 group, and 71 (24%) of 293 in the control group, with no safety signals observed. INTERPRETATION: The Fx012-14 regimen was not superior to the standard regimen over 12 months after dose three. All RTS,S/AS01(E) regimens provided substantial, similar protection against clinical malaria, suggesting potential flexibility in the recommended dosing regimen and schedule. This, and the effect of annual boosters, will be further evaluated through 50 months of follow-up. FUNDING: GlaxoSmithKline Biologicals; PATH's Malaria Vaccine Initiative.

What is already known about this topic As more persons are exposed to and infected by SARS-CoV-2, reports of patients who experience persistent symptoms or organ dysfunction after acute COVID-19 and develop post-COVID conditions have increased. | What is added by this report COVID-19 survivors have twice the risk for developing pulmonary embolism or respiratory conditions; one in five COVID-19 survivors aged 1864 years and one in four survivors aged 65 years experienced at least one incident condition that might be attributable to previous COVID-19. | What are the implications for public health practice Implementation of COVID-19 prevention strategies, as well as routine assessment for post-COVID conditions among persons who survive COVID-19, is critical to reducing the incidence and impact of post-COVID conditions, particularly among adults aged 65 years. | A growing number of persons previously infected with SARS-CoV-2, the virus that causes COVID-19, have reported persistent symptoms, or the onset of long-term symptoms, 4 weeks after acute COVID-19; these symptoms are commonly referred to as post-COVID conditions, or long COVID (1). Electronic health record (EHR) data during March 2020November 2021, for persons in the United States aged 18 years were used to assess the incidence of 26 conditions often attributable to post-COVID (hereafter also referred to as incident conditions) among patients who had received a previous COVID-19 diagnosis (case-patients) compared with the incidence among matched patients without evidence of COVID-19 in the EHR (control patients). The analysis was stratified by two age groups (persons aged 1864 and 65 years). Patients were followed for 30365 days after the index encounter until one or more incident conditions were observed or through October 31, 2021 (whichever occurred first). Among all patients aged 18 years, 38% of case-patients experienced an incident condition compared with 16% of controls; conditions affected multiple systems, and included cardiovascular, pulmonary, hematologic, renal, endocrine, gastrointestinal, musculoskeletal, neurologic, and psychiatric signs and symptoms. By age group, the highest risk ratios (RRs) were for acute pulmonary embolism (RR = 2.1 and 2.2 among persons aged 1864 and 65 years, respectively) and respiratory signs and symptoms (RR = 2.1 in both age groups). Among those aged 1864 years, 35.4% of case-patients experienced an incident condition compared with 14.6% of controls. Among those aged 65 years, 45.4% of case-patients experienced an incident condition compared with 18.5% of controls. These findings translate to one in five COVID-19 survivors aged 1864 years, and one in four survivors aged 65 years experiencing an incident condition that might be attributable to previous COVID-19. Implementation of COVID-19 prevention strategies, as well as routine assessment for post-COVID conditions among persons who survive COVID-19, is critical to reducing the incidence and impact of post-COVID, particularly among adults aged 65 years (2). | Suggested citation for this article: Bull-Otterson L, Baca S, Saydah S, et al. PostCOVID Conditions Among Adult COVID-19 Survivors Aged 1864 and 65 Years United States, March 2020November 2021. MMWR Morb Mortal Wkly Rep. ePub: 24 May 2022. | mm7121e1.htms_cid=mm7121e1_w | mm7121e1-H.pdf

What is already known about this topic? As more persons are exposed to and infected by SARS-CoV-2, reports of patients who experience persistent symptoms or organ dysfunction after acute COVID-19 and develop post-COVID conditions have increased. | What is added by this report? COVID-19 survivors have twice the risk for developing pulmonary embolism or respiratory conditions; one in five COVID-19 survivors aged 18–64 years and one in four survivors aged ≥65 years experienced at least one incident condition that might be attributable to previous COVID-19. | What are the implications for public health practice? Implementation of COVID-19 prevention strategies, as well as routine assessment for post-COVID conditions among persons who survive COVID-19, is critical to reducing the incidence and impact of post-COVID conditions, particularly among adults aged ≥65 years. | A growing number of persons previously infected with SARS-CoV-2, the virus that causes COVID-19, have reported persistent symptoms, or the onset of long-term symptoms, ≥4 weeks after acute COVID-19; these symptoms are commonly referred to as post-COVID conditions, or long COVID (1). Electronic health record (EHR) data during March 2020–November 2021, for persons in the United States aged ≥18 years were used to assess the incidence of 26 conditions often attributable to post-COVID (hereafter also referred to as incident conditions) among patients who had received a previous COVID-19 diagnosis (case-patients) compared with the incidence among matched patients without evidence of COVID-19 in the EHR (control patients). The analysis was stratified by two age groups (persons aged 18–64 and ≥65 years). Patients were followed for 30–365 days after the index encounter until one or more incident conditions were observed or through October 31, 2021 (whichever occurred first). Among all patients aged ≥18 years, 38% of case-patients experienced an incident condition compared with 16% of controls; conditions affected multiple systems, and included cardiovascular, pulmonary, hematologic, renal, endocrine, gastrointestinal, musculoskeletal, neurologic, and psychiatric signs and symptoms. By age group, the highest risk ratios (RRs) were for acute pulmonary embolism (RR = 2.1 and 2.2 among persons aged 18–64 and ≥65 years, respectively) and respiratory signs and symptoms (RR = 2.1 in both age groups). Among those aged 18–64 years, 35.4% of case-patients experienced an incident condition compared with 14.6% of controls. Among those aged ≥65 years, 45.4% of case-patients experienced an incident condition compared with 18.5% of controls. These findings translate to one in five COVID-19 survivors aged 18–64 years, and one in four survivors aged ≥65 years experiencing an incident condition that might be attributable to previous COVID-19. Implementation of COVID-19 prevention strategies, as well as routine assessment for post-COVID conditions among persons who survive COVID-19, is critical to reducing the incidence and impact of post-COVID, particularly among adults aged ≥65 years (2). | Suggested citation for this article: Bull-Otterson L, Baca S, Saydah S, et al. Post–COVID Conditions Among Adult COVID-19 Survivors Aged 18–64 and ≥65 Years — United States, March 2020–November 2021. MMWR Morb Mortal Wkly Rep. ePub: 24 May 2022. | mm7121e1.htm?s_cid=mm7121e1_w | mm7121e1-H.pdf

Summary | What is already known about this topic | | As more persons are exposed to and infected by SARS-CoV-2, reports of patients who experience persistent symptoms or organ dysfunction after acute COVID-19 and develop post-COVID conditions have increased. | | What is added by this report | | COVID-19 survivors have twice the risk for developing pulmonary embolism or respiratory conditions; one in five COVID-19 survivors aged 1864 years and one in four survivors aged 65 years experienced at least one incident condition that might be attributable to previous COVID-19. | | What are the implications for public health practice | | Implementation of COVID-19 prevention strategies, as well as routine assessment for post-COVID conditions among persons who survive COVID-19, is critical to reducing the incidence and impact of post-COVID conditions, particularly among adults aged 65 years.

BACKGROUND: The World Health Organization (WHO) recommends routine surveillance of pretreatment human immunodeficiency virus (HIV) drug resistance (HIVDR) in children <18 months of age diagnosed with HIV through early infant diagnosis (EID). In 2016, 262 children <18 months of age were diagnosed with HIV in Namibia through EID. Levels of HIVDR in this population are unknown. METHODS: In 2016, Namibia surveyed pretreatment HIVDR among children aged <18 months following WHO guidance. Reverse transcriptase, protease, and integrase regions of HIV-1 were genotyped from remnant dried blood spot specimens from all infants diagnosed with HIV in Namibia in 2016. HIVDR was predicted using the Stanford HIVdb algorithm. RESULTS: Of 262 specimens genotyped, 198 HIV-1 protease and reverse transcriptase sequences and 118 HIV-1 integrase sequences were successfully amplified and analyzed. The prevalence of efavirenz/nevirapine (EFV/NVP), abacavir (ABC), zidovudine, lamivudine/emtricitabine (3TC/FTC), and tenofovir (TDF) resistance was 62.6%, 17.7%, 5.6%, 15.7%, and 10.1%, respectively. No integrase inhibitor resistance was detected. CONCLUSIONS: The high level of EFV/NVP resistance is unsurprising; however, levels of ABC and TDF resistance are among the highest observed to date in infants in sub-Saharan Africa. The absence of resistance to dolutegravir (DTG) is reassuring but underscores the need to further study the impact of ABC and 3TC/FTC resistance on pediatric protease inhibitor- and DTG-based regimens and accelerate access to other antiretroviral drugs. Results underscore the need for antiretroviral therapy optimization and prompt management of high viral loads in infants and pregnant and breastfeeding women.

The B.1.1.529 (Omicron) variant of SARS-CoV-2, the virus that causes COVID-19, was first clinically identified in the United States on December 1, 2021, and spread rapidly. By late December, it became the predominant strain, and by January 15, 2022, it represented 99.5% of sequenced specimens in the United States* (1). The Omicron variant has been shown to be more transmissible and less virulent than previously circulating variants (2,3). To better understand the severity of disease and health care utilization associated with the emergence of the Omicron variant in the United States, CDC examined data from three surveillance systems and a large health care database to assess multiple indicators across three high-COVID-19 transmission periods: December 1, 2020-February 28, 2021 (winter 2020-21); July 15-October 31, 2021 (SARS-CoV-2 B.1.617.2 [Delta] predominance); and December 19, 2021-January 15, 2022 (Omicron predominance). The highest daily 7-day moving average to date of cases (798,976 daily cases during January 9-15, 2022), emergency department (ED) visits (48,238), and admissions (21,586) were reported during the Omicron period, however, the highest daily 7-day moving average of deaths (1,854) was lower than during previous periods. During the Omicron period, a maximum of 20.6% of staffed inpatient beds were in use for COVID-19 patients, 3.4 and 7.2 percentage points higher than during the winter 2020-21 and Delta periods, respectively. However, intensive care unit (ICU) bed use did not increase to the same degree: 30.4% of staffed ICU beds were in use for COVID-19 patients during the Omicron period, 0.5 percentage points lower than during the winter 2020-21 period and 1.2 percentage points higher than during the Delta period. The ratio of peak ED visits to cases (event-to-case ratios) (87 per 1,000 cases), hospital admissions (27 per 1,000 cases), and deaths (nine per 1,000 cases [lagged by 3 weeks]) during the Omicron period were lower than those observed during the winter 2020-21 (92, 68, and 16 respectively) and Delta (167, 78, and 13, respectively) periods. Further, among hospitalized COVID-19 patients from 199 U.S. hospitals, the mean length of stay and percentages who were admitted to an ICU, received invasive mechanical ventilation (IMV), and died while in the hospital were lower during the Omicron period than during previous periods. COVID-19 disease severity appears to be lower during the Omicron period than during previous periods of high transmission, likely related to higher vaccination coverage,(†) which reduces disease severity (4), lower virulence of the Omicron variant (3,5,6), and infection-acquired immunity (3,7). Although disease severity appears lower with the Omicron variant, the high volume of ED visits and hospitalizations can strain local health care systems in the United States, and the average daily number of deaths remains substantial.(§) This underscores the importance of national emergency preparedness, specifically, hospital surge capacity and the ability to adequately staff local health care systems. In addition, being up to date on vaccination and following other recommended prevention strategies are critical to preventing infections, severe illness, or death from COVID-19.

Vaccination against SARS-CoV-2, the virus that causes COVID-19, is highly effective at preventing COVID-19-associated hospitalization and death; however, some vaccinated persons might develop COVID-19 with severe outcomes(†) (1,2). Using data from 465 facilities in a large U.S. health care database, this study assessed the frequency of and risk factors for developing a severe COVID-19 outcome after completing a primary COVID-19 vaccination series (primary vaccination), defined as receipt of 2 doses of an mRNA vaccine (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) or a single dose of JNJ-78436735 [Janssen (Johnson & Johnson)] ≥14 days before illness onset. Severe COVID-19 outcomes were defined as hospitalization with a diagnosis of acute respiratory failure, need for noninvasive ventilation (NIV), admission to an intensive care unit (ICU) including all persons requiring invasive mechanical ventilation, or death (including discharge to hospice). Among 1,228,664 persons who completed primary vaccination during December 2020-October 2021, a total of 2,246 (18.0 per 10,000 vaccinated persons) developed COVID-19 and 189 (1.5 per 10,000) had a severe outcome, including 36 who died (0.3 deaths per 10,000). Risk for severe outcomes was higher among persons who were aged ≥65 years, were immunosuppressed, or had at least one of six other underlying conditions. All persons with severe outcomes had at least one of these risk factors, and 77.8% of those who died had four or more risk factors. Severe COVID-19 outcomes after primary vaccination are rare; however, vaccinated persons who are aged ≥65 years, are immunosuppressed, or have other underlying conditions might be at increased risk. These persons should receive targeted interventions including chronic disease management, precautions to reduce exposure, additional primary and booster vaccine doses, and effective pharmaceutical therapy as indicated to reduce risk for severe COVID-19 outcomes. Increasing COVID-19 vaccination coverage is a public health priority.

Persons from racial and ethnic minority groups are disproportionately affected by COVID-19, including experiencing increased risk for infection (1), hospitalization (2,3), and death (4,5). Using administrative discharge data, CDC assessed monthly trends in the proportion of hospitalized patients with COVID-19 among racial and ethnic groups in the United States during March-December 2020 by U.S. Census region. Cumulative and monthly age-adjusted COVID-19 proportionate hospitalization ratios (aPHRs) were calculated for racial and ethnic minority patients relative to non-Hispanic White patients. Within each of the four U.S. Census regions, the cumulative aPHR was highest for Hispanic or Latino patients (range = 2.7-3.9). Racial and ethnic disparities in COVID-19 hospitalization were largest during May-July 2020; the peak monthly aPHR among Hispanic or Latino patients was >9.0 in the West and Midwest, >6.0 in the South, and >3.0 in the Northeast. The aPHRs declined for most racial and ethnic groups during July-November 2020 but increased for some racial and ethnic groups in some regions during December. Disparities in COVID-19 hospitalization by race/ethnicity varied by region and became less pronounced over the course of the pandemic, as COVID-19 hospitalizations increased among non-Hispanic White persons. Identification of specific social determinants of health that contribute to geographic and temporal differences in racial and ethnic disparities at the local level can help guide tailored public health prevention strategies and equitable allocation of resources, including COVID-19 vaccination, to address COVID-19-related health disparities and can inform approaches to achieve greater health equity during future public health threats.

BACKGROUND: We assessed the safety and immunogenicity of the RTS,S/AS01 malaria vaccine in a subset of children identified as HIV-infected during a large phase III randomized controlled trial conducted in seven sub-Saharan African countries. METHODS: Infants 6-12 weeks and children 5-17 months old were randomized to receive 4 RTS,S/AS01 doses (R3R group), 3 RTS,S/AS01 doses plus 1 comparator vaccine dose (R3C group), or 4 comparator vaccine doses (C3C group) at study months 0, 1, 2 and 20. Infants and children with WHO stage III/IV HIV disease were excluded but HIV testing was not routinely performed on all participants; our analyses included children identified as HIV-infected based on medical history or clinical suspicion and confirmed by polymerase chain reaction or antibody testing. Serious adverse events (SAEs) and anti-circumsporozoite (CS) antibodies were assessed. RESULTS: Of 15459 children enrolled in the trial, at least 1953 were tested for HIV and 153 were confirmed as HIV-infected (R3R: 51; R3C: 54; C3C: 48). Among these children, SAEs were reported for 92.2% (95% CI: 81.1-97.8) in the R3R, 85.2% (72.9-93.4) in the R3C and 87.5% (74.8-95.3) in the C3C group over a median follow-up of 39.3, 39.4 and 38.3 months, respectively. Fifteen HIV-infected participants in each group (R3R: 29.4%, R3C: 27.8%, C3C: 31.3%) died during the study. No deaths were considered vaccination-related. In a matched case-control analysis, 1 month post dose 3 anti-CS geometric mean antibody concentrations were 193.3 EU/mL in RTS,S/AS01-vaccinated HIV-infected children and 491.5 EU/mL in RTS,S/AS01-vaccinated immunogenicity controls with unknown or negative HIV status (p=0.0001). CONCLUSIONS: The safety profile of RTS,S/AS01 in HIV-infected children was comparable to that of the comparator (meningococcal or rabies) vaccines. RTS,S/AS01 was immunogenic in HIV-infected children but antibody concentrations were lower than in children with an unknown or negative HIV status. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT00866619.

A phase III, double-blind, randomized, controlled trial (NCT00866619) in sub-Saharan Africa showed RTS,S/AS01 vaccine efficacy against malaria. We now present in-depth safety results from this study. 8922 children (enrolled at 5-17 months) and 6537 infants (enrolled at 6-12 weeks) were 1:1:1-randomized to receive 4 doses of RTS,S/AS01 (R3R) or non-malaria control vaccine (C3C), or 3 RTS,S/AS01 doses plus control (R3C). Aggregate safety data were reviewed by a multi-functional team. Severe malaria with Blantyre Coma Score </=2 (cerebral malaria [CM]) and gender-specific mortality were assessed post-hoc. Serious adverse event (SAE) and fatal SAE incidences throughout the study were 24.2%-28.4% and 1.5%-2.5%, respectively across groups; 0.0%-0.3% of participants reported vaccination-related SAEs. The incidence of febrile convulsions in children was higher during the first 2-3 days post-vaccination with RTS,S/AS01 than with control vaccine, consistent with the time window of post-vaccination febrile reactions in this study (mostly the day after vaccination). A statistically significant numerical imbalance was observed for meningitis cases in children (R3R: 11, R3C: 10, C3C: 1) but not in infants. CM cases were more frequent in RTS,S/AS01-vaccinated children (R3R: 19, R3C: 24, C3C: 10) but not in infants. All-cause mortality was higher in RTS,S/AS01-vaccinated versus control girls (2.4% vs 1.3%, all ages) in our setting with low overall mortality. The observed meningitis and CM signals are considered likely chance findings, that - given their severity - warrant further evaluation in phase IV studies and WHO-led pilot implementation programs to establish the RTS,S/AS01 benefit-risk profile in real-life settings.

Host immunity exerts strong selective pressure on pathogens. Population-level genetic analysis can identify signatures of this selection, but these signatures reflect the net selective effect of all hosts and vectors in a population. In contrast, analysis of pathogen diversity within hosts provides information on individual, host-specific selection pressures. Here, we combine these complementary approaches in an analysis of the malaria parasite Plasmodium falciparum using haplotype sequences from thousands of natural infections in sub-Saharan Africa. We find that parasite genotypes show preferential clustering within multi-strain infections in young children, and identify individual amino acid positions that may contribute to strain-specific immunity. Our results demonstrate that natural host defenses to P. falciparum act in an allele-specific manner to block specific parasite haplotypes from establishing blood-stage infections. This selection partially explains the extreme amino acid diversity of many parasite antigens and suggests that vaccines targeting such proteins should account for allele-specific immunity.

Background: We performed a systematic review of foodborne botulism outbreaks to describe their clinical aspects and descriptive epidemiology in order to inform public health response strategies. Methods: We searched seven databases for reports of foodborne botulism outbreaks published in English from database inception to May 2015. We summarized descriptive characteristics and analyzed differences in exposure and toxin types by geographic region. We performed logistic regression to assess correlations between exposure source, implicated food, and outbreak size. Results: There were 197 outbreaks reported between 1920 and 2014. The median number of cases per outbreak was 3 (range 2-97). The majority of reported outbreaks (109; 55%) occurred in the United States. Toxin types A, B, E, and F were identified as the causative agent in 34%, 16%, 17%, and 1% of outbreaks, respectively. The median duration between exposure and symptom onset was approximately 1 day. The mean percentage of cases requiring mechanical ventilation per outbreak was 34%. Seventy percent of all outbreaks and 77% of small outbreaks (</=11 cases) originated from point source exposures, while commercial foods were significantly (odds ratio, 6.9; 95% confidence interval, 2.2-21.1) associated with large outbreaks (>/=12 cases). Conclusions: Toxin type A accounted for half of outbreaks, and these outbreaks had a higher proportion of patient ventilatory failure. Most outbreaks were due to point source exposures, while outbreaks due to commercial food were larger. For effective responses to foodborne botulism outbreaks, these findings demonstrate the need for timely outbreak investigation and hospital surge capacity.

On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the group's efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos-like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/NOA-exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin-3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM.

BACKGROUND: Crimean-Congo Haemorrhagic Fever Virus (CCHFV) is a zoonotic virus transmitted by Ixodid ticks and causes Crimean-Congo hemorrhagic fever (CCHF) disease in humans with up to 50 % mortality rate. METHODS: Freshly slaughtered livestock at the Kumasi abattoir in the Ashanti Region of Ghana were examined for the presence of ticks once a month over a 6-month period from May to November 2011. The ticks were grouped into pools by species, sex, and animal source. CCHFV was detected in the ticks using reverse transcription PCR. Blood samples were collected from enrolled abattoir workers at initiation, and from those who reported fever in a preceding 30-day period during monthly visits 2-5 months after initiation. Six months after initiation, all participants who provided baseline samples were invited to provide blood samples. Serology was performed using enzyme linked immunosorbent assay (ELISA). Demographic and epidemiological data was also obtained from enrolled participants using a structured questionnaire. RESULTS: Of 428 freshly slaughtered animals comprising 130 sheep, 149 cattle, and 149 goats examined, 144 ticks belonging to the genera Ambylomma, Hyalomma and Boophilus were identified from 57 (13.3 %): 52 (34.9 %), 4 (3.1 %) and 1 (0.7 %) cattle, sheep and goat respectively. Of 97 tick pools tested, 5 pools comprising 1 pool of Hyalomma excavatum and 4 pools of Ambylomma variegatum, collected from cattle, were positive for CCHFV. Of 188 human serum samples collected from 108 abattoir workers, 7 (3.7 %) samples from 6 persons were anti-CCHF IgG positive with one of them also being CCHF IgM positive. The seroprevalence of CCHFV identified in this study was 5.7 %. CONCLUSIONS: This study detected human exposure to CCHF virus in slaughterhouse workers and also identified the CCHF virus in proven vectors (ticks) of Crimean Congo hemorrhagic fever in Ghana. The CCHFV was detected only in ticks collected from cattle, one of the livestock known to play a role in the amplification of the CCHF virus.

BACKGROUND: The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus. METHODS: We used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. RESULTS: In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P=0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy. CONCLUSIONS: These results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles. (Funded by the National Institutes of Health and others.).

BACKGROUND: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). METHODS: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. RESULTS: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5-64.9) on day 1 to 6.7 % (95 % CI: 4.8-8.7) on day 2 and 0.9 % (95 % CI: 0.5-1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 degreeC) (AOR = 1.50 (95 % CI: 1.06-2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21-3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38-5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14-4.51), P = 0.020, compared to dihydroartemisinin-piperaquine). CONCLUSIONS: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

BACKGROUND: The RTS,S/AS01 malaria vaccine targets the circumsporozoite protein, inducing antibodies associated with the prevention of Plasmodium falciparum infection. We assessed the association between anti-circumsporozoite antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial done between 2009 and 2014. METHODS: Using data from 8922 African children aged 5-17 months and 6537 African infants aged 6-12 weeks at first vaccination, we analysed the determinants of immunogenicity after RTS,S/AS01 vaccination with or without a booster dose. We assessed the association between the incidence of clinical malaria and anti-circumsporozoite antibody titres using a model of anti-circumsporozoite antibody dynamics and the natural acquisition of protective immunity over time. FINDINGS: RTS,S/AS01-induced anti-circumsporozoite antibody titres were greater in children aged 5-17 months than in those aged 6-12 weeks. Pre-vaccination anti-circumsporozoite titres were associated with lower immunogenicity in children aged 6-12 weeks and higher immunogenicity in those aged 5-17 months. The immunogenicity of the booster dose was strongly associated with immunogenicity after primary vaccination. Anti-circumsporozoite titres wane according to a biphasic exponential distribution. In participants aged 5-17 months, the half-life of the short-lived component of the antibody response was 45 days (95% credible interval 42-48) and that of the long-lived component was 591 days (557-632). After primary vaccination 12% (11-13) of the response was estimated to be long-lived, rising to 30% (28-32%) after a booster dose. An anti-circumsporozoite antibody titre of 121 EU/mL (98-153) was estimated to prevent 50% of infections. Waning anti-circumsporozoite antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and efficacy wanes more rapidly at higher transmission intensity. INTERPRETATION: Anti-circumsporozoite antibody titres are a surrogate of protection for the magnitude and duration of RTS,S/AS01 efficacy, with or without a booster dose, providing a valuable surrogate of effectiveness for new RTS,S formulations in the age groups considered. FUNDING: UK Medical Research Council.

BACKGROUND: Mortality from non-communicable diseases (NCDs) is a major global issue, as other categories of mortality have diminished and life expectancy has increased. The World Health Organization's Member States have called for a 25% reduction in premature NCD mortality by 2025, which can only be achieved by substantial reductions in risk factors and improvements in the management of chronic conditions. A high burden of NCD mortality among much older people, who have survived other hazards, is inevitable. The INDEPTH Network collects detailed individual data within defined Health and Demographic Surveillance sites. By registering deaths and carrying out verbal autopsies to determine cause of death across many such sites, using standardised methods, the Network seeks to generate population-based mortality statistics that are not otherwise available. OBJECTIVE: To describe patterns of adult NCD mortality from INDEPTH Network sites across Africa and Asia, according to the WHO 2012 verbal autopsy (VA) cause categories, with separate consideration of premature (15-64 years) and older (65+ years) NCD mortality. DESIGN: All adult deaths at INDEPTH sites are routinely registered and followed up with VA interviews. For this study, VA archives were transformed into the WHO 2012 VA standard format and processed using the InterVA-4 model to assign cause of death. Routine surveillance data also provide person-time denominators for mortality rates. RESULTS: A total of 80,726 adult (over 15 years) deaths were documented over 7,423,497 person-years of observation. NCDs were attributed as the cause for 35.6% of these deaths. Slightly less than half of adult NCD deaths occurred in the 15-64 age group. Detailed results are presented by age and sex for leading causes of NCD mortality. Per-site rates of NCD mortality were significantly correlated with rates of HIV/AIDS-related mortality. CONCLUSIONS: These findings present important evidence on the distribution of NCD mortality across a wide range of African and Asian settings. This comes against a background of global concern about the burden of NCD mortality, especially among adults aged under 70, and provides an important baseline for future work.

Genome-wide association studies (GWAS) have mapped risk alleles for at least ten distinct cancers to a small region of 63,000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (ASSET) across six distinct cancers in 34,248 cases and 45,036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single nucleotide polymorphisms (SNPs): five in the TERT gene (region 1: rs7726159, P=2.10x10-39; region 3: rs2853677, P=3.30x10-36 and PConditional=2.36x10-8; region 4: rs2736098, P=3.87x10-12 and PConditional=5.19x10-6, region 5: rs13172201, P=0.041 and PConditional=2.04x10-6; and region 6: rs10069690, P=7.49x10-15 and PConditional=5.35x10-7) and one in the neighboring CLPTM1L gene (region 2: rs451360; P=1.90x10-18 and PConditional=7.06x10-16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele specific effects on DNA methylation were seen for a subset of risk loci indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

BACKGROUND: The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. METHODS: We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. RESULTS: The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). CONCLUSIONS: The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number: NCT00866619.).

OBJECTIVES: To describe asbestos-related mortality among manufacturing workers who expanded and processed Libby vermiculite that contained amphibole fiber. METHODS: Standardized mortality ratio was calculated for 465 white male workers 31 years after last Libby vermiculite exposure. RESULTS: Two workers died from mesothelioma, resulting in a significantly increased standardized mortality ratio of 10.5 (95% confidence interval, 1.3 to 38.0). These workers were in the upper 10th percentile of cumulative fiber exposure, that is, 43.80 and 47.23 fiber-years/cm, respectively. One additional worker with cumulative fiber exposure of 5.73 fiber-years/cm developed mesothelioma but is not deceased. There were no other significantly increased standardized mortality ratios. CONCLUSIONS: Workers expanding and processing Libby vermiculite in a manufacturing setting demonstrated an increased risk for the development of mesothelioma following exposure to the amphibole fiber contained within this vermiculite ore source.