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Objectives Anaemia represents a common toxicity with amphotericin B-based induction therapy in HIV-infected persons with cryptococcal meningitis. We sought to examine the impact of amphotericin-related anaemia on survival. Methods We used data from Ugandan and South African trial participants to characterize the variation of haemoglobin concentrations from diagnosis to 12 weeks post-diagnosis. Anaemia severity was classified based on the haemoglobin concentration at cryptococcal meningitis diagnosis, and nadir haemoglobin values during amphotericin induction. Cox proportional hazard models were used to estimate 2- and 10-week mortality risk. We also estimated 10-week mortality risk among participants with nadir haemoglobin < 8.5 g/ dL during amphotericin induction and who survived ≥ 2 weeks post-enrolment. Results The median haemoglobin concentration at meningitis diagnosis was 11.5 g/ dL [interquartile range ( IQR) 9.7-13 g/ dL; n = 311] with a mean decline of 4.2 g/ dL [95% confidence interval ( CI) −4.6 to −3.8; P < 0.001; n = 148] from diagnosis to nadir value among participants with baseline haemoglobin ≥ 8.5 g/ dL. The median haemoglobin concentration was 8.1 g/ dL ( IQR 6.5-9.5 g/ dL) at 2 weeks, increasing to 9.4 g/ dL ( IQR 8.2-10.9 g/ dL) by 4 weeks and continuing to increase to 12 weeks. Among participants with haemoglobin < 8.5 g/ dL at diagnosis, mortality risk was elevated at 2 weeks [hazard ratio ( HR) 2.7; 95% CI 1.5-4.9; P < 0.01] and 10 weeks ( HR 1.8; 95% CI 1.1-2.2; P = 0.03), relative to those with haemoglobin ≥ 8.5 g/ dL. New-onset anaemia occurring with amphotericin therapy did not have a statistically significant association with 10-week mortality ( HR 2.0; 95% CI 0.5-9.1; P = 0.4). Conclusions Amphotericin induced significant haemoglobin declines, which were mostly transient and did not impact 10-week mortality. Individuals with moderate to life-threatening anaemia at baseline had a higher mortality risk at 2 and 10 weeks post-enrolment. [ABSTRACT FROM AUTHOR]

Background: The Oncotype DX Genomic Prostate Score (ODX-GPS) is a gene expression assay that predicts disease aggressiveness. The objective of this study was to identify sociodemographic and regional factors associated with ODX-GPS uptake., Methods: Data from Surveillance Epidemiology and End Results registries on men with localized prostate cancer with a Gleason score of 3 + 3 or 3 + 4, PSA ≤20 ng/mL, and stage T1c to T2c disease from 2013 through 2017 were linked with ODX-GPS data. Census-tract level neighborhood socioeconomic status (nSES) quintiles were constructed using a composite socioeconomic score. Multivariable logistic regression was used to estimate the associations of ODX-GPS uptake with age at diagnosis, race and ethnicity, nSES, geographic region, insurance type, and marital status, accounting for National Comprehensive Cancer Network risk group, year of diagnosis, and clustering by census tract., Results: Among 111,434 eligible men, 5.5% had ODX-GPS test uptake. Of these, 78.3% were non-Hispanic White, 9.6% were Black, 6.7% were Hispanic, and 3.6% were Asian American. Black men had the lowest odds of ODX-GPS uptake (odds ratio, 0.70; 95% confidence interval [CI], 0.63-0.76). Those in the highest versus lowest quintile of nSES were 1.64 times more likely (95% CI, 1.38-2.94) to have ODX-GPS uptake. The odds of ODX-GPS uptake were statistically significantly higher among men residing in the Northeast, West, and Midwest compared to the South., Conclusions: Disparities in ODX-GPS uptake by race, ethnicity, nSES, and geographical region were identified. Concerted efforts should be made to ensure that this clinical test is equitably available., (© 2024 American Cancer Society.)

Background: Immunosuppressed individuals have elevated risk of virus-related cancers. Identifying cancers with elevated risk in people with HIV and solid organ transplant recipients, 2 immunosuppressed populations, may help identify novel etiologic relationships with infectious agents., Methods: We used 2 linkages of population-based cancer registries with HIV and transplant registries in the United States. Cancer entities were systematically classified according to site and histology codes. Standardized incidence ratios were used to compare risk in people with HIV and solid organ transplant recipients with the general population. For selected cancer entities, incidence rate ratios were calculated for indicators of immunosuppression within each population., Results: We identified 38 047 cancer cases in solid organ transplant recipients and 53 592 in people with HIV, yielding overall standardized incidence ratios of 1.66 (95% confidence interval [CI] = 1.65 to 1.68) and 1.49 (95% CI = 1.47 to 1.50), respectively. A total of 43 cancer entities met selection criteria, including conjunctival squamous cell carcinoma (people with HIV standardized incidence ratio = 7.1, 95% CI = 5.5 to 9.2; solid organ transplant recipients standardized incidence ratio = 9.4, 95% CI = 6.8 to 12.6). Sebaceous adenocarcinoma was elevated in solid organ transplant recipients (standardized incidence ratio = 16.2, 95% CI = 14.0 to 18.6) and, among solid organ transplant recipients, associated with greater risk in lung and heart transplant recipients compared with recipients of other organs (incidence rate ratio = 2.3, 95% CI = 1.7 to 3.2). Salivary gland tumors, malignant fibrous histiocytoma, and intrahepatic cholangiocarcinoma showed elevated risk in solid organ transplant recipients (standardized incidence ratio = 3.9,  4.7, and  3.2, respectively) but not in people with HIV. However, risks for these cancers were elevated following an AIDS diagnosis among people with HIV (incidence rate ratio = 2.4, 4.3, and  2.0, respectively)., Conclusions: Elevated standardized incidence ratios among solid organ transplant recipients and people with HIV, and associations with immunosuppression within these populations, suggest novel infectious causes for several cancers including conjunctival squamous cell carcinoma, sebaceous adenocarcinoma, salivary gland tumors, malignant fibrous histiocytoma, and intrahepatic cholangiocarcinoma., (Published by Oxford University Press 2024.)

Background: Precision medicine has become a mainstay of cancer care in recent years. The National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program has been an authoritative source of cancer statistics and data since 1973. However, tumor genomic information has not been adequately captured in the cancer surveillance data, which impedes population-based research on molecular subtypes. To address this, the SEER Program has developed and implemented a centralized process to link SEER registries' tumor cases with genomic test results that are provided by molecular laboratories to the registries., Methods: Data linkages were carried out following operating procedures for centralized linkages established by the SEER Program. The linkages used Match*Pro, a probabilistic linkage software, and were facilitated by the registries' trusted third party (an honest broker). The SEER registries provide to NCI limited datasets that undergo preliminary evaluation prior to their release to the research community., Results: Recently conducted genomic linkages included OncotypeDX Breast Recurrence Score, OncotypeDX Breast Ductal Carcinoma in Situ, OncotypeDX Genomic Prostate Score, Decipher Prostate Genomic Classifier, DecisionDX Uveal Melanoma, DecisionDX Preferentially Expressed Antigen in Melanoma, DecisionDX Melanoma, and germline tests results in Georgia and California SEER registries., Conclusions: The linkages of cancer cases from SEER registries with genomic test results obtained from molecular laboratories offer an effective approach for data collection in cancer surveillance. By providing de-identified data to the research community, the NCI's SEER Program enables scientists to investigate numerous research inquiries., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Certain workers are at increased risk for acquiring Legionnaires' disease compared with other workers. This study aims to identify occupations at increased risk for acquiring Legionnaires' disease., Methods: Using data from the US Centers for Disease Control and Prevention's Supplemental Legionnaires' Disease Surveillance System, this study identified Legionnaires' disease confirmed patients ≥16 years of age in 39 states with reported symptom onset during 2014-2016. Age-adjusted and sex-adjusted incidence rate ratios (IRR) stratified by occupation group were calculated by comparing Legionnaires' disease patients in an occupation group (eg, transportation) to those in all other occupation groups (eg, non-transportation)., Results: A total of 2553 patients had a known occupation group. The two occupations with the highest burden were transportation (N=287; IRR=2.11) and construction (N=269; IRR=1.82). Truck drivers comprised the majority (69.7%) of the transportation occupation group and construction labourers comprised almost half (49%) of the construction occupation group. The healthcare support occupation had the highest IRR (N=75; IRR=2.16)., Conclusion: Transportation and construction workers, who are generally not covered by guidance related to building water systems, have increased risk of Legionnaires' disease compared with other workers. One hypothesised risk factor for truck drivers is the use of non-genuine windshield cleaner in their vehicles. A simple intervention is to use genuine windshield cleaner with bactericidal properties (ie, includes isopropanol/methanol) which can reduce the risk of Legionella growth and transmission. To improve surveillance of Legionnaires' disease and identification of similar exposures, the authors encourage the collection of occupation and industry information for all patients with Legionnaires' disease., Competing Interests: Competing interests: The primary author reports 2023 travel support in the form of a registration fee scholarship from the Council of State and Territorial Epidemiologists (CSTE) to attend their annual conference., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Adults with HIV-associated cryptococcal meningitis have overlapping burdens of cytomegalovirus (CMV) and tuberculosis (TB) coinfections. CMV infection/reactivation is strongly associated with CMV-specific memory T-cell activation and upregulation of type 1 interferons, which may lead to increased risk of TB disease and poor outcomes., Methods: We conducted a cohort study of 2-week survivors of cryptococcal meningitis during 2010-2021 to determine TB incidence and all-cause mortality over time stratified by baseline CMV status., Results: We followed 497 Ugandans with HIV-associated cryptococcal meningitis for a median (interquartile range) of 4.6 (2.6-53.9) months. Overall, 42% (210/497) developed incident TB disease or died. One-fifth (98/497, 19.7%) developed incident TB disease, and 29% (142/497) of participants died during follow-up. Of 259 participants with CMV viral load measured at baseline, 37% (96/259) had concurrent CMV viremia (defined as anyone with detectable CMV DNA in plasma/serum by qualitative polymerase chain reaction [PCR] detection). Of 59 with measured CMV immunoglobulin G (IgG), 100% had positive CMV IgG antibody serology (≥10 enzyme-linked immunosorbent assay units/mL). CMV viremia was positively associated with higher HIV viral load (196 667 vs 73 295 copies/mL; P = .002) and higher cerebrospinal fluid fungal burden (68 500 vs 14 000 cfu/mL; P = .002) compared with those without. Participants with high-level CMV viremia (defined as CMV viral load ≥1000 IU/mL) had twice the risk of incident TB (subdistribution adjusted hazard ratio [aHR], 2.18; 95% CI, 1.11-4.27) and death (aHR, 1.99; 95% CI, 1.14-3.49) compared with participants with no or low-level CMV viremia. There was no association between the CMV IgG index and the incidence of TB/death ( P = .75)., Conclusions: CMV viremia >1000 IU/mL at meningitis diagnosis was associated with increased incident TB disease and mortality during long-term follow-up. Future studies to determine the causal relationship and potential for therapeutic intervention are warranted., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Management of localized or recurrent prostate cancer since the 1990s has been based on risk stratification using clinicopathological variables, including Gleason score, T stage (based on digital rectal exam), and prostate-specific antigen (PSA). In this study a novel prognostic test, the Decipher Prostate Genomic Classifier (GC), was used to stratify risk of prostate cancer progression in a US national database of men with prostate cancer., Methods: Records of prostate cancer cases from participating SEER (Surveillance, Epidemiology, and End Results) program registries, diagnosed during the period from 2010 through 2018, were linked to records of testing with the GC prognostic test. Multivariable analysis was used to quantify the association between GC scores or risk groups and use of definitive local therapy after diagnosis in the GC biopsy-tested cohort and postoperative radiotherapy in the GC-tested cohort as well as adverse pathological findings after prostatectomy., Results: A total of 572 545 patients were included in the analysis, of whom 8927 patients underwent GC testing. GC biopsy-tested patients were more likely to undergo active active surveillance or watchful waiting than untested patients (odds ratio [OR] =2.21, 95% confidence interval [CI] = 2.04 to 2.38, P < .001). The highest use of active surveillance or watchful waiting was for patients with a low-risk GC classification (41%) compared with those with an intermediate- (27%) or high-risk (11%) GC classification (P < .001). Among National Comprehensive Cancer Network patients with low and favorable-intermediate risk, higher GC risk class was associated with greater use of local therapy (OR = 4.79, 95% CI = 3.51 to 6.55, P < .001). Within this subset of patients who were subsequently treated with prostatectomy, high GC risk was associated with harboring adverse pathological findings (OR = 2.94, 95% CI = 1.38 to 6.27, P = .005). Use of radiation after prostatectomy was statistically significantly associated with higher GC risk groups (OR = 2.69, 95% CI = 1.89 to 3.84)., Conclusions: There is a strong association between use of the biopsy GC test and likelihood of conservative management. Higher genomic classifier scores are associated with higher rates of adverse pathology at time of surgery and greater use of postoperative radiotherapy.In this study the Decipher Prostate Genomic Classifier (GC) was used to analyze a US national database of men with prostate cancer. Use of the GC was associated with conservative management (ie, active surveillance). Among men who had high-risk GC scores and then had surgery, there was a 3-fold higher chance of having worrisome findings in surgical specimens., (© The Author(s) 2023. Published by Oxford University Press.)

Introduction: Pancreatic cancer (PC) in solid organ transplant (SOT) recipients is not well studied. Some PC cases may be incidentally detected during hepatobiliary imaging., Methods: We evaluated PC among 374,106 SOT recipients during 1995-2017 in the United States using linked data from the national transplant registry and multiple state/regional cancer registries. Standardized incidence ratios (SIRs) were used to compare PC risk in recipients to the general population. We used multivariate Poisson regression to identify independent risk factors for PC. We assessed survival after PC diagnosis using Kaplan-Meier curves and log-rank tests., Results: SOT recipients had elevated incidence for PC compared with the general population (SIR 1.40, 95% CI 1.29-1.52), and this increase was strongest in liver recipients (1.65, 1.41-1.92). Among all recipients, PC incidence was especially increased for cases arising in the head of the pancreas (SIR 1.50, 95% CI 1.34-1.68) and for cases diagnosed at localized stage (1.85, 1.37-2.44). Among SOT recipients, factors independently associated with increased incidence were consistent with those in general population including male sex, older age, non-O blood type, and history of diabetes. Additionally, compared to other organ recipients, liver transplant recipients had higher PC incidence (adjusted incidence rate ratio 1.28; 95% CI 1.06-1.54). Overall survival after PC diagnosis was poor (median 4 months) and similar between liver and other organ transplant recipients (p = 0.08)., Conclusions: PC incidence is elevated among SOT recipients, and more commonly diagnosed in liver transplant recipients perhaps related to incidental detection. However, survival is poor even in liver recipients, arguing against routine PC screening., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The DecisionDx-Melanoma 31-gene expression profile (31-GEP) test is validated to classify cutaneous malignant melanoma (CM) patient risk of recurrence, metastasis, or death as low (class 1A), intermediate (class 1B/2A), or high (class 2B). This study aimed to examine the effect of 31-GEP testing on survival outcomes and confirm the prognostic ability of the 31-GEP at the population level., Methods: Patients with stage I-III CM with a clinical 31-GEP result between 2016 and 2018 were linked to data from 17 SEER registries (n = 4,687) following registries' operation procedures for linkages. Melanoma-specific survival (MSS) and overall survival (OS) differences by 31-GEP risk category were examined using Kaplan-Meier analysis and the log-rank test. Crude and adjusted hazard ratios (HRs) were calculated using Cox regression model to evaluate variables associated with survival. 31-GEP tested patients were propensity score-matched to a cohort of non-31-GEP tested patients from the SEER database. Robustness of the effect of 31-GEP testing was assessed using resampling., Results: Patients with a 31-GEP class 1A result had higher 3-year MSS and OS than patients with a class 1B/2A or class 2B result (MSS: 99.7% v 97.1% v 89.6%, P < .001; OS: 96.6% v 90.2% v 79.4%, P < .001). A class 2B result was an independent predictor of MSS (HR, 7.00; 95% CI, 2.70 to 18.00) and OS (HR, 2.39; 95% CI, 1.54 to 3.70). 31-GEP testing was associated with a 29% lower MSS mortality (HR, 0.71; 95% CI, 0.53 to 0.94) and 17% lower overall mortality (HR, 0.83; 95% CI, 0.70 to 0.99) relative to untested patients., Conclusion: In a population-based, clinically tested melanoma cohort, the 31-GEP stratified patients by their risk of dying from melanoma.

Background: Cryptococcal meningitis is a common cause of AIDS-related mortality. Although symptom recurrence after initial treatment is common, the etiology is often difficult to decipher. We sought to summarize characteristics, etiologies, and outcomes among persons with second-episode symptomatic recurrence., Methods: We prospectively enrolled Ugandans with cryptococcal meningitis and obtained patient characteristics, antiretroviral therapy (ART) and cryptococcosis histories, clinical outcomes, and cerebrospinal fluid (CSF) analysis results. We independently adjudicated cases of second-episode meningitis to categorize patients as (1) microbiological relapse, (2) paradoxical immune reconstitution inflammatory syndrome (IRIS), (3) persistent elevated intracranial pressure (ICP) only, or (4) persistent symptoms only, along with controls of primary cryptococcal meningitis. We compared groups with chi-square or Kruskal-Wallis tests as appropriate., Results: 724 participants were included (n = 607 primary episode, 81 relapse, 28 paradoxical IRIS, 2 persistently elevated ICP, 6 persistent symptoms). Participants with culture-positive relapse had lower CD4 (25 cells/μL; IQR: 9-76) and lower CSF white blood cell (WBC; 4 cells/μL; IQR: 4-85) counts than paradoxical IRIS (CD4: 78 cells/μL; IQR: 47-142; WBC: 45 cells/μL; IQR: 8-128). Among those with CSF WBC <5 cells/μL, 86% (43/50) had relapse. Among those with CD4 counts <50 cells/μL, 91% (39/43) had relapse. Eighteen-week mortality (from current symptom onset) was 47% among first episodes of cryptococcal meningitis, 31% in culture-positive relapses, and 14% in paradoxical IRIS., Conclusions: Poor immune reconstitution was noted more often in relapse than IRIS as evidenced by lower CSF WBC and blood CD4 counts. These easily obtained laboratory values should prompt initiation of antifungal treatment while awaiting culture results., Clinical Trials Registration: NCT01802385., Competing Interests: Potential conflicts of interest. N. C. B. reports Data and Safety Monitoring Board (DSMB) participation for an investigator-initiated trial of losartan safety in coronavirus disease 2019 (COVID-19) [Bengston CD, Montgomery RN, Nazir U et al. Front Med (Lausanne). 2021], doi: 10.3389/fmed.2021.630209 and grants or contracts from NIH NINDS (K23 NS110470). D. R. B. and C. P. S. report grants or contracts from NIH NIAID (T32 AI055433). C. P. S. also reports grants or contracts from NIH NIAID (T32AI055433). J. R. reports grants or contracts from NIH-FIC (K01TW010268). M. A. reports grants or contracts from NINDS/FIC (D43TW009345), NIH-NINDS (K23 NS122601), and NIH NIAID (T32 AI055433). S. M. L. reports grants or contracts from NINDS/FIC (D43TW009345) and NIH National Institute of Mental Health (NIMH) (K23 MH121220). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Different survival metrics have different applicability to clinical practice and research. We evaluated how choice of survival metric influences assessment of cancer survival among American Indian and Alaska Native (AIAN) people relative to non-Hispanic Whites (NHW). A secondary objective was to present variations in survival among AIAN people by age, sex, stage, and Indian Health Service (IHS) region., Methods: Five-year survival was calculated using the North American Association of Central Cancer Registries Cancer in North America dataset. We calculated survival among AIAN people, compared with NHW using four approaches: (i) observed (crude) survival, (ii) cause-specific survival, (iii) relative survival using age- and sex-adjusted lifetables, and (iv) relative survival using lifetables additionally adjusted for race, geography, and socioeconomic status. For AIAN people, we evaluated how survival varied by age, stage at diagnosis, and IHS region., Results: Observed survival methods produced the lowest estimates, and-excepting prostate cancer-cause-specific methods produced the highest survival estimates. Survival was lower among AIAN people than NHW for all methods. Among AIAN people, survival was higher among those 20-64 years, females, and tumors diagnosed at local stage. Survival varied by IHS region and cancer sites., Conclusions: These results support the assertion that using the same methodology to compare survival estimates between racial and ethnic groups is of paramount importance, but that the choice of metric requires careful consideration of study objectives., Impact: These findings have the potential to impact choice of survival metric to explore disparities among AIAN people., (©2023 American Association for Cancer Research.)

Little is known about the outcomes among solid organ transplant recipients with a pretransplant cancer diagnosis. We used linked data from the Scientific Registry of Transplant Recipients with 33 US cancer registries. Cox proportional hazards models assessed associations of pretransplant cancer with overall mortality, cancer-specific mortality, and development of a new posttransplant cancer. Among 311 677 recipients, the presence of a single pretransplant cancer was associated with increased overall mortality (adjusted hazard ratio [aHR], 1.19; 95% CI, 1.15-1.23) and cancer-specific mortality (aHR, 1.93; 95% CI, 1.76-2.12); results for 2+ pretransplant cancers were similar. Cancer-specific mortality was not significantly increased for uterine, prostate, or thyroid cancers (aHRs were 0.83, 1.22, and 1.54, respectively) but strongly elevated for lung cancer and myeloma (aHRs were 3.72 and 4.42, respectively). A pretransplant cancer diagnosis was also associated with increased risk of developing posttransplant cancer (aHR, 1.32; 95% CI, 1.23-1.40). Among 306 recipients whose cancer death was confirmed by cancer registry data, 158 deaths (51.6%) were from a de novo posttransplant cancer and 105 (34.3%) from the pretransplant cancer. Pretransplant cancer diagnoses are associated with increased mortality after transplantation, but some deaths are related to posttransplant cancers and other causes. Improved candidate selection and cancer screening and prevention may reduce mortality in this population., (Copyright © 2022 American Society of Transplantation & American Society of Transplant Surgeons. All rights reserved.)

Background: Net and crude cancer survival statistics can be calculated using cause of death or expected survival from life tables. In some instances, using cause of death information may be advantageous. The Surveillance, Epidemiology, and End Results (SEER) Program cause-specific cause of death variable (North American Association of Central Cancer Registries [NAACCR] item #1914) designates that a patient died of their cancer. We evaluated how miss-ingness in NAACCR item #1914 impacted survival estimates to determine fitness for use in NAACCR Cancer in North America (CiNA) products., Methods: We used CiNA survival and prevalence data (November 2020 submission) to calculate 60-month cause-specific survival among persons aged 15-99 years at time of diagnosis using NAACCR item #1914. We treated missing/unknown causes of death in 3 ways: excluded from analysis, included as dead from this cancer, or included as censored at time of last follow-up. Autopsy/death-certificate-only cases were excluded from survival analyses. We calculated the proportion of deaths with unknown/missing cause of death by registry and demographic variables., Results: Generally, 60-month cause-specific survival estimates differed by <1% between the 3 approaches when NAACCR item #1914 was missing/unknown for <3% of deaths. When applying a <3% fit-for-use standard to SEER cause-specific cause of death, data from 34 registries were included in cause-specific survival analyses. The proportion of deaths with missing/unknown cause of death varied by primary site, age at diagnosis, race/ethnicity, year of diagnosis, and registry., Conclusion: We have identified missingness cut points for NAACCR item #1914, which strike a balance between scientific integrity and registry inclusiveness, to designate data in NAACCR CiNA data products as fit for use in cause-specific survival analyses., (© 2022 National Cancer Registrars Association.)

Background: Disparities in cancer burden and outcomes according to socioeconomic characteristics have been extensively characterized for US populations. The cancer experience of refugees, who may share characteristics of other socioeconomically disadvantaged populations and also experience distinct barriers to care, has not been described previously. We conducted a proof-of-concept study evaluating our ability to characterize cancer incidence in refugees resettled to Idaho via a novel linkage of cancer data and administrative data characterizing refugee arrivals to Idaho., Methods: In July 2021, the Cancer Data Registry of Idaho probabilistically linked cancer surveillance data and refugee arrival data (2008- 2019 diagnosis and arrival years) collected through the Centers for Disease Control and Prevention's Electronic Disease Notification (EDN) System. We used SEER*Stat to calculate standardized incidence ratios (SIR) for malignant tumors and benign/borderline malignant brain and other nervous system (ONS) tumors using Idaho-specific and Surveillance, Epidemiology, and End Results (SEER) Program referent incidence rates., Results: 60 malignant and 7 benign brain and ONS tumors were diagnosed among 9,499 refugees resettled to Idaho. Refugees had fewer than expected malignant tumors overall (57 observed vs 96.0 expected; SIR, 0.60; 95% CI, 0.45-0.77). An excess of tumors of the esophagus were diagnosed among Southeast Asian refugees (4 observed vs 0.64 expected; SIR, 6.3; 95% CI, 1.7-16.0). We also used EDN data to update country of birth for linked persons., Conclusions: Linking EDN refugee data to cancer surveillance data presented unique challenges. However, we used a novel data source to augment cancer data and characterize incidence in refugees, potentially improving our ability to serve this vulnerable population.

Purpose: Idaho's Women's Health Check (WHC) Program provides breast and cervical cancer screening to under- and uninsured women via funding from the National Breast and Cervical Cancer Early Detection Program (NBCCEDP). Because WHC serves populations with less access to health care, this study evaluated time from breast cancer diagnosis to treatment for women enrolled in the WHC program and linked to Cancer Data Registry of Idaho (CDRI) case data (WHC-linked) and the remainder of female Idaho resident breast cases., Methods: Among Idaho residents aged 50-64 years diagnosed during 2011-2017 with ductal carcinoma in situ or invasive breast cancer, we assessed differences in the median time from definitive diagnosis to treatment initiation overall and by demographic and tumor characteristics, and differences in the distribution of demographic and tumor-related variables between 231 WHC-linked and 3,040 non-linked breast cancer cases., Results: WHC-linked cases were significantly less likely to be non-Hispanic white, and more likely to live in poorer census tracts, be diagnosed at a later stage, and be treated with mastectomy. Most WHC-linked (92%) and non-linked women (94%) began treatment within 60 days of diagnosis; no differences in time to treatment were observed., Conclusion: Disparities in the interval from definitive diagnosis to breast cancer treatment initiation were not observed for women enrolled in the WHC program relative to other Idaho women.

Background: Many antimicrobial-resistant infections are community-acquired, yet community carriage of microorganisms by healthy individuals is poorly characterized. We assessed microorganism carriage on the hands of Minnesota State Fair attendees and explored associated factors. Methods: Minnesota State Fair attendees (in 2014) from households with ≥2 members (≥1 member being <19 years old [a child]) were eligible to participate. Participants provided biological samples via a hand plating technique and completed a questionnaire on factors potentially related to microorganism carriage. Using presumptive taxonomic identifications and disk-diffusion-determined resistance phenotypes, hand-culture isolates were classified by microbial type; types were grouped into four broad categories based on inferred pathogenicity and consistency with the skin microbiota. Descriptive statistics, X 2 tests, and generalized linear mixed-effects models were used to explore associations between survey and culture data. Results: We enrolled 206 participants from 82 households during 2 days; 50% of subjects were children. Overall, 99.5% (205/206) of hand samples yielded microorganisms. Most were non-pathogenic, whether skin microbiota (98.5% of participants) or non-skin microbiota (93.2% of participants). Only 2.4% (5/206) of samples yielded antibiotic-resistant bacteria. Children were more likely than adults to carry potentially pathogenic (OR = 3.63, 95% CI: 1.66-7.93) and presumably non-pathogenic (OR = 6.61, 95% CI: 1.67-26.15) non-skin microorganisms. Conclusions: Large community gatherings can serve as efficient sites for estimating the prevalence of microorganism carriage. A small proportion of participants carried antimicrobial-resistant pathogens on their hands; most carried non-pathogenic microorganisms, and no exposures specific to the state fair were associated with microorganism carriage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Mason, Morawski, Bayliss, Noor, Jama, Clabots and Johnson.)

Background: Produce-associated outbreaks of Shiga toxin-producing Escherichia coli (STEC) were first identified in 1991. In April 2018, New Jersey and Pennsylvania officials reported a cluster of STEC O157 infections associated with multiple locations of a restaurant chain. The Centers for Disease Control and Prevention (CDC) queried PulseNet, the national laboratory network for foodborne disease surveillance, for additional cases and began a national investigation., Methods: A case was defined as an infection between 13 March and 22 August 2018 with 1 of the 22 identified outbreak-associated E. coli O157:H7 or E. coli O61 pulsed-field gel electrophoresis pattern combinations, or with a strain STEC O157 that was closely related to the main outbreak strain by whole-genome sequencing. We conducted epidemiologic and traceback investigations to identify illness subclusters and common sources. A US Food and Drug Administration-led environmental assessment, which tested water, soil, manure, compost, and scat samples, was conducted to evaluate potential sources of STEC contamination., Results: We identified 240 case-patients from 37 states; 104 were hospitalized, 28 developed hemolytic uremic syndrome, and 5 died. Of 179 people who were interviewed, 152 (85%) reported consuming romaine lettuce in the week before illness onset. Twenty subclusters were identified. Product traceback from subcluster restaurants identified numerous romaine lettuce distributors and growers; all lettuce originated from the Yuma growing region. Water samples collected from an irrigation canal in the region yielded the outbreak strain of STEC O157., Conclusions: We report on the largest multistate leafy greens-linked STEC O157 outbreak in several decades. The investigation highlights the complexities associated with investigating outbreaks involving widespread environmental contamination., (Published by Oxford University Press for the Infectious Diseases Society of America 2019.)

Background: In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks., Methods: We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010-2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days., Results: Mortality through 18 weeks was 37% for EFA > = 0.60 (n = 170), 36% for 0.40-0.59 (n = 182), 39% for 0.30-0.39 (n = 112), 35% for 0.20-0.29 (n = 87), and 50% for those with EFA < 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA < 0.20 to those with EFA > = 0.20, was 1.60 (95% confidence interval, 1.25, 2.04; P = .002). The lowest EFA group had lower median CD4 T-cell counts (P < .01) and lower proportion of patients with CSF pleocytosis (P < .001)., Conclusions: EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of > = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA < 0.20. This EFA threshold may be considered a target for a surrogate endpoint. This builds upon existing studies to validate EFA as a surrogate endpoint., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: This review describes the geographic and temporal distribution of, detection methods for, and other epidemiological features of published leptospirosis outbreaks, with the aim of informing efforts to standardize outbreak-reporting practices., Methods: We conducted a systematic review of leptospirosis outbreaks reported in the scientific literature and ProMED during 1970-2012. Predefined criteria were used to identify and classify outbreaks and a standard form was used to extract information., Results: During 1970-2012, we identified 318 outbreaks (average: 7 outbreaks/year; range: 1-19). Most outbreaks were reported in the Latin America and the Caribbean region (36%), followed by Southern Asia (13%), and North America (11%). Most outbreaks were located in tropical and subtropical ecoregions (55%). Quality classification showed that there was clear description of laboratory-confirmed cases in 40% of outbreaks. Among those, the average outbreak size was 82 cases overall (range: 2-2 259) but reached 253 cases in tropical/subtropical ecoregions. Common risk factors included outdoor work activities (25%), exposure to floodwaters (23%), and recreational exposure to water (22%). Epidemiologic investigation was conducted in 80% of outbreaks, mainly as case interviews. Case fatality was 5% overall (range: 0%-60%)., Conclusions: Outbreak reporting increased over the study period with outbreaks covering tropical and non-tropical regions. Outbreaks varied by size, setting, and risk factors; however, data reviewed often had limited information regarding diagnosis and epidemiology. Guidelines are recommended to develop standardized procedures for diagnostic and epidemiological investigations during an outbreak and for reporting., Competing Interests: Conflicts of interest. The authors declare no conflict of interest.

Background: The Social Security Administration Service to Epidemiological Researchers (SSA-SER) can help central cancer registries meet the contractual follow-up requirements of the Surveillance, Epidemiology, and End Results (SEER) Program and improve survival estimate accuracy. We evaluated the impact of first-time SSA-SER linkage on follow-up rates and survival estimates for 2 SEER registries. Methods: In May 2019, cancer registries in Idaho (Cancer Data Registry of Idaho [CDRI]) and New York (New York State Cancer Registry [NYSCR]) used results from an SSA-SER linkage to update date of last contact and vital status for patients with a SEER-reportable tumor diagnosed during 2000-2016. We compared follow-up completeness through 2017 between pre-SSA-SER linkage and post-SSA-SER linkage data. Among individuals with a first primary tumor diagnosed during 2009-2015, we calculated 60-month age-standardized all sites and site-specific relative survival ratio (RSR) estimates via the presumed alive method using pre-SSA linkage data, and survival time calculated from last known date of contact using post-SSA linkage data. Results: SSA-SER linkage improved overall followup completeness from 79.0% to 97.4% and 55.7% to 92.6% for CDRI and NYSCR, respectively. Follow-up completeness improved most for laboratory-only reported tumors, in situ tumors, melanomas of the skin, prostate cancers, and benign and borderline brain and other central nervous system tumors. Post-SSA linkage RSRs were lower than pre-SSA presumed alive RSRs by an average -0.47% and -2.16% for Idaho and New York, respectively. Conclusions: SSA-SER linkage greatly and efficiently improved follow-up completeness for the 2 participating registries and revealed small difference in survival estimates by method. Use of the SSA-SER by all US registries would standardize and improve US survival estimates.

Background: In 2016, after 8 years of twice-annual nationwide preventive chemotherapy (PC) administration to school-age children (SAC), the Bangladesh Ministry of Health & Family Welfare (MOHFW) sought improved impact and intervention monitoring data to assess progress toward the newly adopted goal of eliminating soil-transmitted helminthiasis (STH) as a public health problem., Methods: We surveyed four Bangladeshi districts between August and October 2017. We conducted a multi-stage, cluster-sample, household survey which produced equal-probability samples for preschool-age children (PSAC; 1-4 years), SAC (5-14 years), and adults (≥ 15 years). Standardized questionnaires were administered, using Android-based smart phones running an Open Data Kit application. Stool samples were collected and testing for STH prevalence and infection intensity used the Kato-Katz technique., Results: In all, 4318 stool samples were collected from 7164 participants. Estimates of STH prevalence by risk group in three of the four surveyed districts ranged from 3.4 to 5.0%, all with upper, 1-sided 95% confidence limits < 10%. However, STH prevalence estimates in Sirajganj District ranged from 23.4 to 29.1%. Infections in that district were spatially focal; four of the 30 survey clusters had > 50% prevalence in at least one risk group. Among all tested specimens, Ascaris lumbricoides was the most common STH parasite [8.2% (n = 352)], followed by Trichuris trichiura [0.9% (n = 37)], and hookworm [0.6% (n = 27)]. In each district, PC coverage among SAC was above the 75% program target but did not exceed 45% among PSAC in any district. Improved sanitation at home, school, or work was over 90% in all districts., Conclusions: In the three low-prevalence districts, the MOHFW is considering decreasing the frequency of mass drug administration, per World Health Organization (WHO) guidelines. Also, the MOHFW will focus programmatic resources and supervisory efforts on Sirajganj District. Despite considering WHO guidance, the MOHFW will not expand PC administration to women of reproductive age partly due to the low prevalence of hookworm and T. trichiura, the STH parasites that contribute most to morbidity in that risk group. Data collected from surveys such as ours would help effectively guide future STH control efforts in Bangladesh and elsewhere.

Introduction: Progress in U.S. 5-year survival trends for all cancers combined was assessed using the North American Cancer Survival Index, a sum of age-, sex-, and cancer site-standardized relative survival ratios., Methods: In January 2019, authors calculated 5-year cancer survival indices and 95% CIs by race and sex for 2005-2011, 2006-2012, 2007-2013, and 2008-2014 diagnosis cohorts with data from 42 cancer registries., Results: Overall 5-year survival increased from 63.5% (95% CI=63.4, 63.5) in 2005-2011 to 64.1% (95% CI=64.1, 64.2) in 2008-2014. Survival increased 0.9 and 0.5 percentage points in female and male patients, respectively; the survival disparity among blacks versus whites decreased by 0.5%. In 2008-2014, the Cancer Survival Index was 7.7% higher for whites (64.6%; 95% CI=64.6, 64.7) than for blacks (56.9%; 95% CI=56.7, 57.1)., Conclusions: Cancer Survival Index survival estimates increased among all race and sex subpopulations during 2005-2014. A substantial but decreasing survival gap persisted between blacks and whites. The Cancer Survival Index can assist decision makers and others in comparing cancer survival among populations and over time and in monitoring progress toward national cancer surveillance objectives., (Published by Elsevier Inc.)

Background: Seizures commonly occur in patients with cryptococcal meningitis, yet risk factors and outcomes related to seizures are not well described., Methods: We performed post hoc analyses on participants prospectively enrolled in 3 separate human immunodeficiency virus (HIV)-associated cryptococcal meningitis clinical trials during 2010-2017. Documentation of seizures at presentation or during hospitalization and antiseizure medication receipt identified participants with seizures. We summarized participant characteristics by seizure status via Kruskal-Wallis and χ  2 tests. Cox proportional hazards models analyzed the relationship between seizures and mortality. We compared mean quantitative neurocognitive performance Z (QNPZ-8) scores, and individual domain z-scores, at 3-months using independent t tests., Results: Among 821 HIV-infected cryptococcal meningitis participants, 28% (231 of 821) experienced seizures: 15.5% (127 of 821) experienced seizures at presentation, and 12.7% (104 of 821) experienced incident seizures. Participants with seizures at presentation had a significantly lower Glasgow coma scale ([GCS] <15; P < .001), CD4 count (<50 cells/mcL; P = .02), and higher cerebrospinal fluid (CSF) opening pressure (>25 cm H 2 O; P = .004) when compared with participants who never experienced seizures. Cerebrospinal fluid fungal burden was higher among those with seizures at presentation (125 000 Cryptococcus colony-forming units [CFU]/mL CSF) and with seizures during follow-up (92 000 CFU/mL) compared with those who never experienced seizures (36 000 CFU/mL, P < .001). Seizures were associated with increased 10-week mortality (adjusted hazard ratio = 1.45; 95% confidence interval, 1.11-1.89). Participants with seizures had lower neurocognitive function at 3 months (QNPZ-8 = -1.87) compared with those without seizures (QNPZ-8 = -1.36; P < .001)., Conclusions: Seizures were common in this HIV-associated cryptococcal meningitis cohort and were associated with decreased survival and neurocognitive function., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: HIV-infected persons with cryptococcal antigenemia (CrAg) are at high risk for meningitis or death. We evaluated the effect of CrAg screening and preemptive fluconazole therapy, adjunctive to antiretroviral therapy (ART), on 6-month survival among persons with advanced HIV/AIDS., Methods: We enrolled HIV-infected, ART-naive participants with <100 CD4 cells/µL, in a stepped-wedge, cluster-randomized trial from July 2012 to December 2014 at 17 Ugandan clinics. Clinics participated in a prospective observational phase, followed by an interventional phase with laboratory-based, reflexive CrAg screening of residual CD4 count plasma. Asymptomatic CrAg+ participants received preemptive fluconazole therapy. We assessed 6-month survival using Cox-regression, adjusting for nadir CD4, calendar time, and stepped-wedge steps., Results: We included 1280 observational and 2108 interventional participants, of whom 9.3% (195/2108) were CrAg+. CD4-, time-, and stepped-wedge-adjusted analyses demonstrated no difference in survival in the observational vs the interventional arms (hazard ratio = 1.34; 95% confidence interval: 0.86 to 2.10; P = 0.20). Fewer participants initiated ART in the interventional (73%) versus the observational phase (82%, P < 0.001). When ART initiation was modeled as a time-dependent covariate or confounder, survival did not differ. However, 6-month mortality of participants with CrAg titers <1:160 and CrAg-negative patients did not differ. Patients with CrAg titers ≥1:160 had 2.6-fold higher 6-month mortality than patients with titers <1:160., Conclusions: We observed no overall survival benefit of the CrAg screen-and-treat intervention. However, preemptive antifungal therapy for asymptomatic cryptococcosis seemed to be effective in patients with CrAg titer <1:160. A more aggressive approach is required for persons with CrAg titer ≥1:160.

Aim: Tuberculosis meningitis (TBM) diagnosis is difficult, new biomarkers are needed. We evaluated the diagnostic utility of delta-like 1 protein (DLL1), vitamin D binding protein (VDBP) and fetuin., Methods: Biomarker concentrations were measured by ELISA in cryopreserved cerebrospinal fluid from 139 HIV-infected Ugandans with suspected meningitis. TBM was diagnosed by GeneXpert MTB/Rif or culture. Cohort diagnoses included TBM (n = 22), cryptococcal (n = 71), or aseptic meningitis (n = 16) and no meningitis (n = 30)., Results: DLL1 (cut-off value 1150 pg/ml) provided 32% sensitivity and 98% specificity. Adding fetuin, cryptococcal antigen and IFN-γ resulted in sensitivities of 36, 63 and 76% with specificities of 98, 90 and 92%, respectively. VDBP (cut-off value 2.0 μg/ml) provided 81% sensitivity and 68% specificity while fetuin (cut-off value 2 μg/ml) provided a sensitivity of 86% and specificity of 68%., Conclusion: CSF DLL1, VDBP and fetuin exhibited fair diagnostic performance for TBM diagnosis.

Background: HIV-infected persons with detectable cryptococcal antigen (CrAg) in blood have increased morbidity and mortality compared with HIV-infected persons who are CrAg-negative. This study examined neurocognitive function among persons with asymptomatic cryptococcal antigenemia., Methods: Participants from three prospective HIV cohorts underwent neurocognitive testing at the time of antiretroviral therapy (ART) initiation. Cohorts included persons with cryptococcal meningitis (N = 90), asymptomatic CrAg + (N = 87), and HIV-infected persons without central nervous system infection (N = 125). Z-scores for each neurocognitive test were calculated relative to an HIV-negative Ugandan population with a composite quantitative neurocognitive performance Z-score (QNPZ-8) created from eight tested domains. Neurocognitive function was measured pre-ART for all three cohorts and additionally after 4 weeks of ART (and 6 weeks of pre-emptive fluconazole) treatment among asymptomatic CrAg + participants., Results: Cryptococcal meningitis and asymptomatic CrAg + participants had lower median CD4 counts (17 and 26 cells/μL, respectively) than the HIV-infected control cohort (233 cells/μL) as well as lower Karnofsky performance status (60 and 70 vs. 90, respectively). The composite QNPZ-8 for asymptomatic CrAg + (-1.80 Z-score) fell between the cryptococcal meningitis cohort (-2.22 Z-score, P = 0.02) and HIV-infected controls (-1.36, P = 0.003). After four weeks of ART and six weeks of fluconazole, the asymptomatic CrAg + cohort neurocognitive performance improved (-1.0 Z-score, P < 0.001)., Conclusion: Significant deficits in neurocognitive function were identified in asymptomatic CrAg + persons with advanced HIV/AIDS even without signs or sequelae of meningitis. Neurocognitive function in this group improves over time after initiation of pre-emptive fluconazole treatment and ART, but short term adherence support may be necessary.

In the USA, increased cerebrospinal fluid (CSF) inflammatory cytokines have been observed in antiretroviral therapy (ART)-naive, HIV-seropositive individuals with HIV-associated neurocognitive disorder (HAND). We characterized the relationship between HAND and CSF biomarker expression in ART-naive, HIV-seropositive individuals in Rakai, Uganda. We analyzed CSF of 78 HIV-seropositive, ART-naive Ugandan adults for 17 cytokines and 20 neurodegenerative biomarkers via Luminex multiplex assay. These adults underwent neurocognitive assessment to determine their degree of HAND. We compared biomarker concentrations between high and low CD4 groups and across HAND classifications, adjusting for multiple comparisons. Individuals with CD4 <200 cells/μL (N = 38) had elevated levels of CSF Interleukin (IL)-2, IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, matrix metalloproteinase (MMP)-1, MMP-7, and S100 calcium-binding protein B (S100B) and lower levels of amyloid β42. Individuals with CD4 351-500 cells/μL (N = 40) had significantly higher CSF levels of interleukin (IL)-1β, amyloid β42, and soluble receptor for advanced glycation end products (sRAGE). Increasing levels of S100B, platelet-derived growth factor-AA (PDGF-AA), brain-derived neurotrophic factor (BDNF), and sRAGE were associated with decreased odds of mild neurocognitive disorder (n = 22) or HIV-associated dementia (n = 15) compared with normal function (n = 30) or asymptomatic neurocognitive impairment (n = 11). Increased levels of interferon (IFN)-γ were associated with increased odds of mild neurocognitive impairment or HIV-associated dementia relative to normal or asymptomatic neurocognitive impairment. Proinflammatory CSF cytokines, chemokines, and neurodegenerative biomarkers were present in increasing concentrations with advanced immunosuppression and may play a role in the development of HAND. The presence of select CNS biomarkers may also play a protective role in the development of HAND.

Most studies evaluating epidemiologic relationships between helminths and HIV have been conducted in the pre-ART era, and evidence of the impact of helminth infections on HIV disease progression remains conflicting. Less is known about helminth infection and clinical outcomes in HIV-infected adults receiving antiretroviral therapy (ART). We sampled HIV-infected adults for eight gastrointestinal parasites and correlated parasitic infection with demographic predictors, and clinical and immunologic outcomes. Contrasting with previous studies, we measured parasitic infection with a quantitative, highly sensitive and specific polymerase chain reaction (PCR) method. This cohort study enrolled HIV-infected Ugandans from August-September 2013 in Mbale, Uganda and collected stool and blood samples at enrollment. Real-time PCR quantified stool: Ascaris lumbricoides, Ancylostoma duodenale, Necator americanus, Strongyloides stercoralis, Trichuris trichiura, Cryptosporidium spp., Entamoeba histolytica, and Giardia intestinalis infection. Generalized linear models assessed relationships between parasitic infection and clinical or demographic data. 35% of participants (71/202) tested positive for ≥1 helminth, mainly N. americanus (55/199, 28%), and 4.5% (9/202) were infected with ≥2 stool parasites. Participants with hookworm infection had lower average CD4+ cell counts (-94 cells/mcL, 95%CI: -141, -48 cells/mcL; p<0.001) after adjustment for sex, CD4+ nadir at clinic entry, and time on ART. The high prevalence of parasitic infection and correlation with decreased CD4+ concentrations highlight the need to re-examine the effects of invasive helminth co-infection in rural, HIV-infected populations in the era of widely available ART. Elucidating the relationship between hookworm infection and immune recovery could provide opportunities for health optimization, e.g. integrated deworming, in these vulnerable populations.

Background: Because of investments in human immunodeficiency virus (HIV) care in sub-Saharan Africa, the number of people aware of their status and receiving antiretroviral therapy (ART) has increased; however, HIV/acquired immune deficiency syndrome (AIDS) mortality still remains high., Methods: We performed retrospective analysis of 3 sequential prospective cohorts of HIV-infected Ugandan adults presenting with AIDS and meningitis from 2006 to 2009, 2010 to 2012, and 2013 to 2016. Participants were categorized as follows: (1) unknown HIV status; (2) known HIV + without ART; (3) known HIV + with previous ART. We further categorized 2006 and 2013 cohort participants by duration of HIV-status knowledge and of ART receipt., Results: We screened 1353 persons with suspected meningitis. Cryptococcus was the most common pathogen (63%). Over the decade, we observed an absolute increase of 37% in HIV status knowledge and 59% in antecedent ART receipt at screening. The 2006 cohort participants were new/recent HIV diagnoses (65%) or known HIV + but not receiving ART (35%). Many 2013 cohort participants were new/recent HIV diagnoses (34%) and known HIV + with <1 month ART (20%), but a significant proportion were receiving ART 1-4 months (11%) and >4 months (30%). Four percent of participants discontinued ART. From 2010 to 2016, meningitis cases per month increased by 33%., Conclusions: Although improved HIV screening and ART access remain much-needed interventions in resource-limited settings, greater investment in viral suppression and opportunistic infection care among the growing HIV-infected population receiving ART is essential to reducing ongoing AIDS mortality., (© The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Altered mental status in cryptococcal meningitis results in poorer survival, but underlying causes of altered mentation are poorly understood. Within two clinical trials, we assessed risk factors for altered mental status (GCS score<15) considering baseline clinical characteristics, CSF cytokines/chemokines, and antiretroviral therapy. Among 326 enrolled participants, 97 (30%) had GCS<15 and these patients had lower median CSF cryptococcal antigen titers (P = .042) and CCL2 (P = .005) but higher opening pressures (320 vs. 269 mm H2O; P = .016), IL-10 (P = .044), and CCL3 (P = .008) compared with persons with GCS=15. Altered mental status may be associated with host immune response rather than Cryptococcus burden., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and microbiological efficacy of adjunctive sertraline, previously shown to have in-vitro and in-vivo activity against cryptococcus., Methods: In this open-label dose-finding study, we recruited HIV-infected individuals with cryptococcal meningitis who presented to Mulago Hospital in Kampala, Uganda between Aug 14, 2013, and Aug 30, 2014. To assess safety and tolerability, the first 60 participants were given sertraline at escalating doses of 100 mg/day, 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for an additional 8 weeks. From Nov 29, 2013, participants were randomly assigned (1:1) to receive open-label sertraline at predetermined doses of 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for 8 weeks. Dose assignment was made via computer-generated, permuted block randomisation stratified by antiretroviral therapy (ART) status for people with a first episode of meningitis. The primary outcome was 2-week cerebrospinal fluid (CSF) clearance rate of cryptococcus, termed early fungicidal activity, measured in patients with a first episode of culture-positive meningitis and two or more CSF cultures. This study is registered with ClinicalTrials.gov, number NCT01802385., Findings: Of the 330 individuals assessed, 172 HIV-infected adults with cryptococcal meningitis were enrolled. We gave 100 mg/day sertraline to 17 patients, 200 mg/day to 12 patients, 300 mg/day to 14 patients, and 400 mg/day to 17 patients. 112 participants were randomly assigned to receive sertraline at 200 mg (n=48), 300 mg (n=36), or 400 mg (n=28) daily for the first 2 weeks, and 200 mg/day thereafter. The final population consisted of 17 participants in the 100 mg group, 60 in the 200 mg group, 50 in the 300 mg group, and 45 in the 400 mg in group. Participants receiving any sertraline dose averaged a CSF clearance rate of -0·37 colony forming units per mL per day (95% CI -0·41 to -0·33). Incidence of paradoxical immune reconstitution inflammatory syndrome was 5% (two of 43 newly starting ART) and no cases of relapse occurred over the 12-week study period. 38 (22%) of 172 participants had died at 2 weeks, and 69 (40%) had died at 12 weeks. Six grade 4 adverse events occurred in 17 participants receiving 100 mg, 14 events in 60 participants receiving 200 mg, 19 events in 50 participants receiving 300 mg, and eight events in 45 participants receiving 400 mg. Grade 4 or 5 adverse event risk did not differ between current US Food and Drug Administration-approved dosing of 100-200 mg/day and higher doses of 300-400 mg/day (hazard ratio 1·27, 95% CI 0·69-2·32; p=0·45)., Interpretation: Participants receiving sertraline had faster cryptococcal CSF clearance and a lower incidence of immune reconstitution inflammatory syndrome and relapse than that reported in the past. This inexpensive and off-patent oral medication is a promising adjunctive antifungal therapy., Funding: National Institutes of Health, Grand Challenges Canada., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Improving HIV outcomes among severely immunocompromised HIV-infected persons who have increased morbidity and mortality remains an important issue in sub-Saharan Africa. We sought to evaluate the impact of targeted clinic-based nurse care on antiretroviral therapy (ART) initiation and retention among severely immunocompromised HIV-infected persons., Methods: The study included ART-naive patients with CD4 counts <100 cells per microliter registered in seven urban clinics in Kampala, Uganda. Data were retrospectively collected on patients enrolled from July to December 2011 (routine care cohort). Between July 2012 and September 2013, 1 additional nurse per clinic was hired (nurse counselor cohort) to identify new patients, expedite ART initiation, and trace those who were lost to follow-up. We compared time to ART initiation and 6-month retention in care between cohorts and used a generalized linear model to estimate the relative risk of retention., Results: The study included 258 patients in the routine care cohort and 593 in the nurse counselor cohort. The proportion of patients who initiated ART increased from 190 (73.6%) in the routine care cohort to 506 (85.3%) in the nurse counselor cohort (P < 0.001). At 6 months, 62% of the routine care cohort were retained in care versus 76% in the nurse counselor cohort (P = 0.001). A 21% increase in the likelihood of retention in the nurse counselor cohort (relative risk: 1.21, 95% CI: 1.09 to 1.34) compared with the routine care cohort was observed., Conclusions: Implementation of targeted nurse-led care of severely immunocompromised HIV-infected patients in public outpatient health care facilities resulted in decreased time to ART initiation and increased retention.

Quantitative cerebrospinal fluid (CSF) cultures provide a measure of disease severity in cryptococcal meningitis. The fungal clearance rate by quantitative cultures has become a primary endpoint for phase II clinical trials. This study determined the inter-assay accuracy of three different quantitative culture methodologies. Among 91 participants with meningitis symptoms in Kampala, Uganda, during August-November 2013, 305 CSF samples were prospectively collected from patients at multiple time points during treatment. Samples were simultaneously cultured by three methods: (1) St. George's 100 mcl input volume of CSF with five 1:10 serial dilutions, (2) AIDS Clinical Trials Group (ACTG) method using 1000, 100, 10 mcl input volumes, and two 1:100 dilutions with 100 and 10 mcl input volume per dilution on seven agar plates; and (3) 10 mcl calibrated loop of undiluted and 1:100 diluted CSF (loop). Quantitative culture values did not statistically differ between St. George-ACTG methods (P= .09) but did for St. George-10 mcl loop (P< .001). Repeated measures pairwise correlation between any of the methods was high (r≥0.88). For detecting sterility, the ACTG-method had the highest negative predictive value of 97% (91% St. George, 60% loop), but the ACTG-method had occasional (∼10%) difficulties in quantification due to colony clumping. For CSF clearance rate, St. George-ACTG methods did not differ overall (mean -0.05 ± 0.07 log10CFU/ml/day;P= .14) on a group level; however, individual-level clearance varied. The St. George and ACTG quantitative CSF culture methods produced comparable but not identical results. Quantitative cultures can inform treatment management strategies., (© The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The effect of tenofovir and amphotericin coadministration on kidney function is poorly characterized. We measured creatinine during induction therapy and at 4 weeks after diagnosis in Ugandans undergoing cryptococcal meningitis therapy and classified as not receiving antiretroviral therapy (ART), receiving nontenofovir ART or receiving tenofovir-based ART. Longitudinal creatinine changes and grade 2-4 creatinine adverse events were evaluated across groups. Creatinine concentrations were similar across ART groups. At 4 weeks after diagnosis, creatinine was 0.25 mg/dL higher than at diagnosis, but similar across groups. Adverse event incidence was also similar across ART groups. Tenofovir and amphotericin coadministration did not increase the risk of kidney dysfunction.

Habitual intake of black tea has been associated with relatively lower serum cholesterol concentrations in observational studies. However, clinical trial results evaluating the effects of black tea on serum cholesterol have been inconsistent. Several factors could explain these mixed results, in particular, uncontrolled confounding caused by lifestyle factors (eg, diet). This diet-controlled clinical trial estimates the effect of black tea flavonoid consumption on cholesterol concentrations in 57 borderline hypercholesterolemic individuals (total cholesterol concentrations between 190 and 260 mg/dL [4.9 and 6.7 mmol/L]). A double-blind, randomized crossover trial was conducted in Minneapolis, MN, from April 2002 through April 2004 in which key conditions were tightly controlled to minimize possible confounding. Participants consumed a controlled low-flavonoid diet plus 5 cups per day of black tea or tea-like placebo during two 4-week treatment periods. The flavonoid-free caffeinated placebo matched the tea in color and taste. Differences in cholesterol concentrations at the end of each treatment period were evaluated via linear mixed models. Differences among those treated with tea vs placebo were 3.43 mg/dL (0.09 mmol/L) (95% CI -7.08 to 13.94) for total cholesterol, -1.02 mg/dL (-0.03 mmol/L) (95% CI -11.34 to 9.30) for low-density lipoprotein cholesterol, 0.58 mg/dL (0.02 mmol/L) (95% CI -2.98 to 4.14) for high-density lipoprotein cholesterol, 15.22 mg/dL (0.17 mmol/L) (95% CI -40.91 to 71.35) for triglycerides, and -0.39 mg/dL (-0.01 mmol/L) (95% CI -11.16 to 10.38) for low-density lipoprotein plus high-density lipoprotein cholesterol fraction. The low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio decreased by -0.1 units (95% CI -0.41 to 0.21). No results were statistically or clinically significant. The intake of 5 cups of black tea per day did not alter the lipid profile of borderline hypercholesterolemic subjects significantly., (Copyright © 2015 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Background: (1→3)-β-d-Glucan (BDG) is a helpful diagnostic marker for many invasive fungal infections. However, BDG is not thought to be useful in diagnosing cryptococcosis. We evaluated the utility of BDG as an adjunct diagnostic tool for patients infected with human immunodeficiency virus (HIV) and presenting with suspected cryptococcal meningitis., Methods: The Fungitell assay was used to measure BDG concentrations in cerebrospinal fluid (CSF) (n = 177) and serum (n = 109) of HIV-infected Ugandans and South Africans with suspected meningitis. Correlations between BDG concentrations and quantitative CSF cryptococcal cultures, CSF cryptococcal antigen (CRAG) titers, and 18 different CSF cytokine concentrations were assessed using non-parametric tests. Mixed models evaluated longitudinal changes in CSF BDG concentrations. Survival analyses were used to evaluate BDG's relationship with mortality., Results: The Fungitell BDG assay provided 89% sensitivity and 85% specificity in CSF for cryptococcal meningitis. Serum sensitivity was suboptimal (79%). Cerebrospinal fluid BDG concentrations at diagnosis were median (interquartile range) 343 (200-597) pg/mL in cryptococcal patients and 37 (23-46) pg/mL in patients without cryptococcosis. Sensitivity in CSF improved to 98% (53 of 54) when initial fungal burdens were ≥10 000 colony-forming units/mL. (1→3)-β-d-Glucan normalized rapidly after initiating antifungal therapy. Baseline BDG concentrations correlated with CSF fungal burden (rho = 0.820; P < .001), CSF CRAG lateral flow assay titers (rho = 0.780, P < .001), and monocyte chemotactic protein-1 levels in CSF (P = .047). In patients with cryptococcal meningitis, BDG ≥500 pg/mL at diagnosis was associated with increased 10-week mortality., Conclusions: (1→3)-β-d-Glucan is detectable in the CSF of HIV-infected patients with Cryptococcus, and it may provide useful prognostic information. Sensitivity is less than CRAG; however, BDG normalizes rapidly, unlike CRAG, making BDG potentially useful in diagnosing recurrent episodes.