Layered Screening and Contact-Limiting Interventions Are Necessary to Reduce SARS-Cov-2 Outbreak Risks in Large Urban Jails.

Highly transmissible infections with short serial intervals, such as SARS-Cov-2 and influenza, can quickly overwhelm healthcare resources in institutional settings such as jails. We assessed the impact of intake screening measures on the risk of SARS-CoV-2 outbreaks in this setting. We identified which elements of the intake process created the largest reductions in caseload. We implemented an individual-based simulation representative of SARS-Cov-2 transmission in a large urban jail utilizing testing at entry, quarantine, and post-quarantine testing to protect its general population from mass infection. We tracked the caseload under each scenario and quantified the impact of screening steps by varying quarantine duration, removing testing, and using a range of test sensitivities. We repeated the simulations under a range of transmissibility and community prevalence levels to evaluate the sensitivity of our results. We found that brief quarantine of newly incarcerated individuals separate from the existing population of the jail to permit pre-quarantine and end-of-quarantine tests reduced SARS-CoV-2 caseload 30-70% depending on test sensitivity. These results were robust to variation in the transmissibility. Further quarantine (up to 14 days) on average created only a 5% further reduction in caseload. A multilayered intake process is necessary to limit the spread of highly transmissible pathogens with short serial intervals. The pre-symptomatic phase means that no single strategy can be effective. We also show that shorter durations of quarantine combined with testing can be nearly as effective at preventing spread as longer-duration quarantine up to 14 days.

Burkitt lymphoma risk shows geographic and temporal associations with Plasmodium falciparum infections in Uganda, Tanzania, and Kenya.

Endemic Burkitt lymphoma (eBL) is a pediatric cancer coendemic with malaria in sub-Saharan Africa, suggesting an etiological link between them. However, previous cross-sectional studies of limited geographic areas have not found a convincing association. We used spatially detailed data from the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) study to assess this relationship. EMBLEM is a case-control study of eBL from 2010 through 2016 in six regions of Kenya, Uganda, and Tanzania. To measure the intensity of exposure to the malaria parasite, Plasmodium falciparum, among children in these regions, we used high-resolution spatial data from the Malaria Atlas Project to estimate the annual number of P. falciparum infections from 2000 through 2016 for each of 49 districts within the study region. Cumulative P. falciparum exposure, calculated as the sum of annual infections by birth cohort, varied widely, with a median of 47 estimated infections per child by age 10, ranging from 4 to 315 infections. eBL incidence increased 39% for each 100 additional lifetime P. falciparum infections (95% CI: 6.10 to 81.04%) with the risk peaking among children aged 5 to 11 and declining thereafter. Alternative models using estimated annual P. falciparum infections 0 to 10 y before eBL onset were inconclusive, suggesting that eBL risk is a function of cumulative rather than recent cross-sectional exposure. Our findings provide population-level evidence that eBL is a phenotype related to heavy lifetime exposure to P. falciparum malaria and support emphasizing the link between malaria and eBL.

A guide to backward paper writing for the data sciences.

In this perspective, we outline a set of best practices for the planning, writing, and revision of scientific papers and other forms of professional communication in the data sciences. We propose a backward approach that begins with clearly identifying the scientific and professional goals motivating the work, followed by a purposeful mapping from those goals to each section of a paper. This approach is motivated by the conviction that manuscript writing can be more effective, efficient, creative, and even enjoyable-particularly for early-career researchers-when the overarching goals of the paper and its individual components are clearly mapped out.

Cytotoxic T cells are able to efficiently eliminate cancer cells by additive cytotoxicity.

Lethal hit delivery by cytotoxic T lymphocytes (CTL) towards B lymphoma cells occurs as a binary, "yes/no" process. In non-hematologic solid tumors, however, CTL often fail to kill target cells during 1:1 conjugation. Here we describe a mechanism of "additive cytotoxicity" by which time-dependent integration of sublethal damage events, delivered by multiple CTL transiting between individual tumor cells, mediates effective elimination. Reversible sublethal damage includes perforin-dependent membrane pore formation, nuclear envelope rupture and DNA damage. Statistical modeling reveals that 3 serial hits delivered with decay intervals below 50 min discriminate between tumor cell death or survival after recovery. In live melanoma lesions in vivo, sublethal multi-hit delivery is most effective in interstitial tissue where high CTL densities and swarming support frequent serial CTL-tumor cell encounters. This identifies CTL-mediated cytotoxicity by multi-hit delivery as an incremental and tunable process, whereby accelerating damage magnitude and frequency may improve immune efficacy.

Coccidioidomycosis and COVID-19 Co-Infection, United States, 2020.

We review the interaction between coronavirus disease (COVID-19) and coccidioidomycosis, a respiratory infection caused by inhalation of Coccidioides fungal spores in dust. We examine risk for co-infection among construction and agricultural workers, incarcerated persons, Black and Latino populations, and persons living in high dust areas. We further identify common risk factors for co-infection, including older age, diabetes, immunosuppression, racial or ethnic minority status, and smoking. Because these diseases cause similar symptoms, the COVID-19 pandemic might exacerbate delays in coccidioidomycosis diagnosis, potentially interfering with prompt administration of antifungal therapies. Finally, we examine the clinical implications of co-infection, including severe COVID-19 and reactivation of latent coccidioidomycosis. Physicians should consider coccidioidomycosis as a possible diagnosis when treating patients with respiratory symptoms. Preventive measures such as wearing face masks might mitigate exposure to dust and severe acute respiratory syndrome coronavirus 2, thereby protecting against both infections.

Measuring the impact of spatial perturbations on the relationship between data privacy and validity of descriptive statistics.

BACKGROUND: Like many scientific fields, epidemiology is addressing issues of research reproducibility. Spatial epidemiology, which often uses the inherently identifiable variable of participant address, must balance reproducibility with participant privacy. In this study, we assess the impact of several different data perturbation methods on key spatial statistics and patient privacy. METHODS: We analyzed the impact of perturbation on spatial patterns in the full set of address-level mortality data from Lawrence, MA during the period from 1911 to 1913. The original death locations were perturbed using seven different published approaches to stochastic and deterministic spatial data anonymization. Key spatial descriptive statistics were calculated for each perturbation, including changes in spatial pattern center, Global Moran's I, Local Moran's I, distance to the k-th nearest neighbors, and the L-function (a normalized form of Ripley's K). A spatially adapted form of k-anonymity was used to measure the privacy protection conferred by each method, and its compliance with HIPAA and GDPR privacy standards. RESULTS: Random perturbation at 50 m, donut masking between 5 and 50 m, and Voronoi masking maintain the validity of descriptive spatial statistics better than other perturbations. Grid center masking with both 100 × 100 and 250 × 250 m cells led to large changes in descriptive spatial statistics. None of the perturbation methods adhered to the HIPAA standard that all points have a k-anonymity > 10. All other perturbation methods employed had at least 265 points, or over 6%, not adhering to the HIPAA standard. CONCLUSIONS: Using the set of published perturbation methods applied in this analysis, HIPAA and GDPR compliant de-identification was not compatible with maintaining key spatial patterns as measured by our chosen summary statistics. Further research should investigate alternate methods to balancing tradeoffs between spatial data privacy and preservation of key patterns in public health data that are of scientific and medical importance.

Racial Disparities in Coronavirus Disease 2019 (COVID-19) Mortality Are Driven by Unequal Infection Risks.

BACKGROUND: As of 1 November 2020, there have been >230 000 deaths and 9 million confirmed and probable cases attributable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the United States. However, this overwhelming toll has not been distributed equally, with geographic, race/ethnic, age, and socioeconomic disparities in exposure and mortality defining features of the US coronavirus disease 2019 (COVID-19) epidemic. METHODS: We used individual-level COVID-19 incidence and mortality data from the state of Michigan to estimate age-specific incidence and mortality rates by race/ethnic group. Data were analyzed using hierarchical Bayesian regression models, and model results were validated using posterior predictive checks. RESULTS: In crude and age-standardized analyses we found rates of incidence and mortality more than twice as high than for Whites for all groups except Native Americans. Blacks experienced the greatest burden of confirmed and probable COVID-19 (age-standardized incidence, 1626/100 000 population) and mortality (age-standardized mortality rate, 244/100 000). These rates reflect large disparities, as Blacks experienced age-standardized incidence and mortality rates 5.5 (95% posterior credible interval [CrI], 5.4-5.6) and 6.7 (95% CrI, 6.4-7.1) times higher than Whites, respectively. We found that the bulk of the disparity in mortality between Blacks and Whites is driven by dramatically higher rates of COVID-19 infection across all age groups, particularly among older adults, rather than age-specific variation in case-fatality rates. CONCLUSIONS: This work suggests that well-documented racial disparities in COVID-19 mortality in hard-hit settings, such as Michigan, are driven primarily by variation in household, community, and workplace exposure rather than case-fatality rates.

No effect of norepinephrine dose on anti-Xa activity in critically ill patients
.

OBJECTIVE: Low-molecular-weight heparins are frequently used to prevent venous thromboembolism. Vasopressor therapy may be associated with inadequate anti-factor Xa activity, thereby increasing the risk of venous thromboembolism. We aimed to assess the association between anti-factor Xa activity and norepinephrine dose in intensive care unit (ICU) patients treated with subcutaneous dalteparin for venous thromboembolism prophylaxis. MATERIALS AND METHODS: This was a prospective observational pilot study in adult ICU patients treated with dalteparin 5,000 IU subcutaneously once daily and norepinephrine > 0.25 µg/kg/min. Peak anti-factor Xa activity was monitored and dalteparin doses were adjusted following a predefined dose algorithm. RESULTS: From November 2016 to April 2018, 32 patients were included. No correlation was found between norepinephrine dose and anti-factor Xa activity (r = -0.01, 95% confidence interval = -0.47 - 0.27, p = 0.57). Furthermore, following dalteparin 5,000 IU once daily, 28% of the patients showed anti-factor Xa activity < 0.10 IU/mL. Higher body mass index (BMI) (p < 0.001) but not patients' norepinephrine dose, age, or serum creatinine were risk factors for anti-factor Xa activity < 0.10 IU/mL. Dose increments to 7,500 IU once daily resulted in anti-factor Xa activity ≥ 0.10 IU/mL in all 5 patients (p = 0.043). CONCLUSION: In this cohort of ICU patients, no association was found between norepinephrine dose and anti-factor Xa activity following subcutaneous dalteparin 5,000-IU administration once daily. Furthermore, nearly one-third of the patients showed anti-factor Xa activity below the target concentration for venous thromboembolism prophylaxis. Higher BMI was an independent risk factor for reduced anti-Xa activity.

Seasonal Influence on the Risk of Relapse at a Rise of Antineutrophil Cytoplasmic Antibodies in Vasculitis Patients with Renal Involvement.

OBJECTIVE: The objective of this study was to identify risk factors for a relapse at the time of an increase in antineutrophil cytoplasmic antibodies (ANCA) in patients with renal ANCA-associated vasculitis (AAV). METHODS: All patients between January 2000 and November 2011 with renal AAV having an ANCA rise during remission were included. Differences in time to relapse since the ANCA rise were assessed using a Cox regression model. The level of 25-hydroxy Vitamin D (25(OH)D) was assessed at the ANCA rise and at a subsequent relapse or time-matched during remission. RESULTS: Sixty patients had an ANCA rise, of whom 36 patients relapsed. Three risk factors were associated with a relapse at the time of the ANCA increase: previous disease activity not treated with cyclophosphamide or rituximab (HR 3.48, 95% CI 1.60-7.59), an ANCA rise during the fall season (HR 4.37, 95% CI 1.60-11.90), and an extended ANCA rise (HR 3.57, 95% CI 1.50-8.48). Levels of 25(OH)D significantly decreased during followup in relapsing patients, but not in patients who remained in remission (difference -6.3 ± 14.4, p = 0.017 vs 2.7 ± 16.3, p = 0.430). CONCLUSION: ANCA rises occurring during the fall season are more frequently followed by a relapse than ANCA rises occurring during other seasons. Although it is tempting to speculate that decreasing Vitamin D levels following the ANCA rise can be held responsible for the subsequent relapse, this remains to be determined.

Predicting the need for further thrombosis diagnostics in suspected DVT is increased by using age adjusted D-dimer values.

INTRODUCTION: Negative D-dimer values combined with clinical decision rules by Wells can help in excluding the diagnosis deep vein thrombosis (DVT). However, with increasing age D-dimer levels increase, possibly leading to false positive results. MATERIALS AND METHODS: In this prospective study we compared the specificity and sensitivity of conventional D-dimer levels and age adjusted D-dimer levels in the diagnosis of DVT. We included 528 patients, all over 50years of age, of whom 117 had a DVT confirmed by duplex ultrasound. RESULTS AND CONCLUSION: Age adjusted D-dimer cut-off values had higher specificity compared to conventional D-dimer values (24.6% vs. 8.5%) as well as a higher negative predictive value (91,8% vs. 89,7%). Therefore we conclude that age adjusted D-dimer levels could be used to exclude the diagnosis of DVT. Ultimately this could lead to the performance of less duplex ultrasounds reducing health care costs and discomfort for the patient.

A low vitamin D status at diagnosis is associated with an early conversion to secondary progressive multiple sclerosis.

Low circulating 25-hydroxyvitamin D (25(OH)D) levels have been associated with an increased risk of relapses in relapsing remitting multiple sclerosis (RRMS), but an association with disability progression is uncertain. Lower 25(OH)D levels are found in secondary progressive MS (SPMS) when compared to RRMS. We hypothesized that a poor vitamin D status in RRMS is associated with an increased risk of conversion to SPMS. In a retrospective longitudinal study we measured 25(OH)D levels at the start of a 3-year follow-up, and analyzed whether these levels predict the risk of RRMS to SPMS conversion. In 338 RRMS patients, vitamin D status did not predict the 3-year risk of conversion to SPMS (n=51; OR 0.970; p=0.65). However, in diagnostic blood samples of SPMS patients with a relatively short RRMS duration (n=19) 25(OH)D levels were significantly lower (38nmol/L; Q1-Q3: 24-50) than in diagnostic samples of matched RRMS patients with no progression to SPMS ((n=38; 55nmol/L; Q1-Q3: 40-70) (p<0.01). These data indicate an association between a low vitamin D status at the start of RRMS and the early conversion to SPMS. Therefore, time to SPMS conversion is of interest as clinical measure in (follow-up of) clinical vitamin D supplementation studies.

Association of disparities in known minor histocompatibility antigens with relapse-free survival and graft-versus-host disease after allogeneic stem cell transplantation.

Allogeneic stem cell transplantation (allo-SCT) can induce remission in patients with hematologic malignancies due to graft-versus-tumor (GVT) responses. This immune-mediated antitumor effect is often accompanied by detrimental graft-versus-host disease (GVHD), however. Both GVT and GVHD are mediated by minor histocompatibility antigen (MiHA)-specific T cells recognizing peptide products from polymorphic genes that differ between recipient and donor. In this study, we evaluated whether mismatches in a panel of 17 MiHAs are associated with clinical outcome after partially T cell-depleted allo-SCT. Comprehensive statistical analysis revealed that DNA mismatches for one or more autosomal-encoded MiHAs was associated with increased relapse-free survival in recipients of sibling transplants (P = .04), particularly in those with multiple myeloma (P = .02). Moreover, mismatches for the ubiquitous Y chromosome-derived MiHAs resulted in a higher incidence of acute GVHD grade III-IV (P = .004), whereas autosomal MiHA mismatches, ubiquitous or restricted to hematopoietic cells, were not associated with severe GVHD. Finally, we found considerable differences among MiHAs in their capability of inducing in vivo T cell responses using dual-color tetramer analysis of peripheral blood samples collected after allo-SCT. Importantly, detection of MiHA-specific T cell responses was associated with improved relapse-free survival in recipients of sibling transplants (P = .01). Our findings provide a rationale for further boosting GVT immunity toward autosomal MiHAs with a hematopoietic restriction to improve outcomes after HLA-matched allo-SCT.

A polymorphism in the splice donor site of ZNF419 results in the novel renal cell carcinoma-associated minor histocompatibility antigen ZAPHIR.

Nonmyeloablative allogeneic stem cell transplantation (SCT) can induce remission in patients with renal cell carcinoma (RCC), but this graft-versus-tumor (GVT) effect is often accompanied by graft-versus-host disease (GVHD). Here, we evaluated minor histocompatibility antigen (MiHA)-specific T cell responses in two patients with metastatic RCC who were treated with reduced-intensity conditioning SCT followed by donor lymphocyte infusion (DLI). One patient had stable disease and emergence of SMCY.A2-specific CD8+ T cells was observed after DLI with the potential of targeting SMCY-expressing RCC tumor cells. The second patient experienced partial regression of lung metastases from whom we isolated a MiHA-specific CTL clone with the capability of targeting RCC cell lines. Whole genome association scanning revealed that this CTL recognizes a novel HLA-B7-restricted MiHA, designated ZAPHIR, resulting from a polymorphism in the splice donor site of the ZNF419 gene. Tetramer analysis showed that emergence of ZAPHIR-specific CD8+ T cells in peripheral blood occurred in the absence of GVHD. Furthermore, the expression of ZAPHIR in solid tumor cell lines indicates the involvement of ZAPHIR-specific CD8+ T cell responses in selective GVT immunity. These findings illustrate that the ZNF419-encoded MiHA ZAPHIR is an attractive target for specific immunotherapy after allogeneic SCT.

Concurrent detection of circulating minor histocompatibility antigen-specific CD8+ T cells in SCT recipients by combinatorial encoding MHC multimers.

Allogeneic stem cell transplantation (SCT) is a potentially curative treatment for patients with hematologic malignancies. Its therapeutic effect is largely dependent on recognition of minor histocompatibility antigens (MiHA) by donor-derived CD8⁺ T cells. Therefore, monitoring of multiple MiHA-specific CD8⁺ T cell responses may prove to be valuable for evaluating the efficacy of allogeneic SCT. In this study, we investigated the use of the combinatorial encoding MHC multimer technique to simultaneously detect MiHA-specific CD8⁺ T cells in peripheral blood of SCT recipients. Feasibility of this approach was demonstrated by applying dual-color encoding MHC multimers for a set of 10 known MiHA. Interestingly, single staining using a fluorochrome- and Qdot-based five-color combination showed comparable results to dual-color staining for most MiHA-specific CD8⁺ T cell responses. In addition, we determined the potential value of combinatorial encoding MHC multimers in MiHA identification. Therefore, a set of 75 candidate MiHA peptides was predicted from polymorphic genes with a hematopoietic expression profile and further selected for high and intermediate binding affinity for HLA-A2. Screening of a large cohort of SCT recipients resulted in the detection of dual-color encoded CD8⁺ T cells following MHC multimer-based T cell enrichment and short ex vivo expansion. Interestingly, candidate MiHA-specific CD8⁺ T cell responses for LAG3 and TLR10 derived polymorphic peptides could be confirmed by genotyping of the respective SNPs. These findings demonstrate the potency of the combinatorial MHC multimer approach in the monitoring of CD8⁺ T cell responses to known and potential MiHA in limited amounts of peripheral blood from allogeneic SCT recipients.

Polymorphisms in CCR6 are associated with chronic graft-versus-host disease and invasive fungal disease in matched-related hematopoietic stem cell transplantation.

Graft-versus-host disease (GVHD) and fungal infections are frequent complications after allogeneic hematopoietic stem cell transplantation (HSCT). Single nucleotide polymorphisms (SNPs) in genes of the immune system can influence the inflammatory cascade and T cell-driven alloimmune reactions after HSCT, and thus increasing the incidence of GVHD and infectious complications. Here, we investigated the effect of SNPs in IL-23R and CCR6 on posttransplantation outcome in 161 recipients of partially T cell-depleted HSCT. Remarkably, IL-23R SNPs were not associated with clinical outcome, but we found that disparities in the CCR6 tagSNP rs2301436 and SNP rs3093023 are independently associated with the occurrence of chronic GVHD (cGVHD) and invasive fungal disease. In multivariate analysis, patients receiving a transplant from a homozygous rs2301436 G allele donor showed less cGVHD (odds ratio [OR]: 0.16; P = .002), as was the case for a homozygous donor rs3093023 G allele (OR: 0.24; P = .005). In parallel, the GG genotype at rs2301436 in donors was associated with a higher incidence of invasive fungal disease at day 100 after HSCT (OR: 3.59; P = .008). This study shows that CCR6 SNPs can be used to predict clinical outcome, and that polymorphisms in the CCR6 gene may influence T cell-mediated immune reactions after HSCT.

Identification of a novel lipopolysaccharide core biosynthesis gene cluster in Bordetella pertussis, and influence of core structure and lipid A glucosamine substitution on endotoxic activity.

Lipopolysaccharide (LPS), also known as endotoxin, is one of the main constituents of the gram-negative bacterial outer membrane. Whereas the lipid A portion of LPS is generally considered the main determinant for endotoxic activity, the oligosaccharide moiety plays an important role in immune evasion and the interaction with professional antigen-presenting cells. Here we describe a novel four-gene cluster involved in the biosynthesis of the Bordetella pertussis core oligosaccharide. By insertionally inactivating these genes and studying the resulting LPS structures, we show that at least two of the genes encode active glycosyltransferases, while a third gene encodes a deacetylase also required for biosynthesis of full-length oligosaccharide. In addition, we demonstrate that mutations in the locus differentially affect LPS and whole-cell endotoxic activities. Furthermore, while analyzing the mutant LPS structures, we confirmed a novel modification of the lipid A phosphate with glucosamine and found that inactivation of the responsible glycosyltransferase reduces the endotoxic activity of the LPS.

Placental Plasmodium falciparum infection: causes and consequences of in utero sensitization to parasite antigens.

Available evidence suggests that, in African populations, systemic blood-dwelling parasitoses of mothers are associated with enhanced susceptibility to infection of their offspring. Thus, children born to mothers with filariasis or schistosomiasis are infected earlier, and offspring of mothers with placental Plasmodium falciparum at delivery, commonly referred to as pregnancy-associated malaria or PAM, are themselves at higher risk of developing parasitaemia during infancy. Since foetal/neonatal antigen-presenting cells (APC) are either immature or provide insufficient costimulatory signals to T cells, thus favouring tolerance induction, it is commonly assumed that soluble parasite components [protein antigens], transferred transplacentally and inducing foetal immune tolerance, are largely, if not exclusively, responsible for these outcomes. Plasmodial asexual blood stage antigen-specific T cells are detectable in as many as two-thirds of all cord blood samples in malaria-endemic countries of sub-Saharan Africa, indicating that in utero sensitization may be a common phenomenon during pregnancy in these populations. Parasite antigen-specific T cell responses of neonates born to helminth-infected mothers display a highly skewed Th2-type cytokine pattern, with a prominent role for the regulatory cytokine interleukin (IL)-10. Similarly, the cord blood immune response of those born to mothers identified with on-going PAM is characterised by inducible parasite antigen-specific IL-10-producing regulatory T cells that can inhibit both APC HLA expression and Th1-type T cell responses. In contrast, plasmodial antigen-specific Th1-type responses, characterised by IFN-gamma production, predominate in cord blood of those born to mothers successfully treated for Pf malaria during gestation, suggesting that the duration and/or the nature of antigen exposure in utero governs the outcome with respect to neonatal immune responses. Aspects of APC function in the context of these differentially modulated responses, whether and how the latter translate into altered susceptibility to Pf infection during infancy, as well as the possible implications for vaccination in early life, are aspects that are discussed in this review.