Howard Dean Hosgood

Children with severe neutropenia are advised to avoid activities and public spaces where they may be exposed to potential sources of infection, due to the risk of neutropenic fever, an oncologic emergency. The influence of exposure to environmental infectious disease risk factors (IDRFs) on the incidence of bacteremia has been difficult to study. Lockdowns enforced during the COVID-19 pandemic resulted in widespread social distancing and were associated with reduced opportunities for exposure to such environmental risk factors. We performed a retrospective chart review to compare the incidence of fever and bloodstream infection in patients with chemotherapy-induced neutropenia before (March 15, 2019 to March 14, 2020) and during the COVID-19 pandemic (March 15, 2020 to March 14, 2021). Before COVID-19, there were 219 episodes of neutropenia, 79 episodes with fever, and 12 episodes with bacteremia. During COVID-19, there were 236 episodes of neutropenia, 80 episodes with fever, and 13 episodes with bacteremia. In this small retrospective study, we did not observe a statistically significant difference in the incidence of either febrile neutropenia or febrile neutropenic bloodstream infection across 2 years with differing levels of exposure to environmental IDRFs (febrile neutropenia: IRR=0.89, P =0.38; bloodstream infection: IRR=1.01, P =0.99). Further multicenter studies are needed to better define the risks of exposure to potential environmental sources of infection, which may ultimately impact provider guidance for children with severe neutropenia.

Background: Lung cancer remains the leading cause of cancer mortality worldwide, and approximately one quarter of cases occur among individuals who never smoke. Mitochondria are highly susceptible to oxidative damage from environmental stressors, which can alter mitochondrial DNA (mtDNA) copy number (mtDNAcn) and induce mtDNA fragmentation. Although prior studies of mtDNAcn and lung cancer have yielded inconsistent results, the role of mtDNA fragmentation has not been examined. Methods: We conducted a nested case–control study within the prospective Shanghai Women’s Health Study, including 789 incident lung cancer cases among never-smoking women and 789 individually matched controls. Prediagnostic whole-blood samples were analyzed for mtDNA fraction with breaks (mtDNAfb) and mtDNAcn using high-throughput quantitative PCR assays. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for lung cancer risk associated with mtDNAfb and mtDNAcn, adjusting for age, body mass index, and plate. We further assessed an interaction between mtDNAfb and mtDNAcn. Results: Higher mtDNAfb was inversely associated with lung cancer risk, with 34% lower odds among participants with high mtDNAfb compared with those with low mtDNAfb (OR = 0.66; 95% CI, 0.51–0.85). Notably, a significant interaction was observed between mtDNAfb and mtDNAcn (P interaction = 8.3 × 10−6), with a stronger inverse association between mtDNAfb and lung cancer among women with low mtDNAcn. Conclusions: Lower mtDNA fragmentation is associated with increased lung cancer risk among never-smoking women, particularly among those with low mtDNAcn. Impact: mtDNA fragmentation may represent a novel biomarker of impaired mitochondrial response to oxidative stress relevant to lung carcinogenesis.

As most persons spend most of their time indoors (>80% on most days), indoor air quality is potentially an important health concern, particularly in elderly populations at high risk for dementia. It is important to note that until recently, little attention has been given to indoor air quality and related standards; most regulatory thresholds remain limited to outdoor environments. Recognizing that the environments in which we live and work shape health, it is time to place indoor air quality at the center of brain health policy and research agendas, and to take intentional steps towards comprehensive in-home assessment.

Background: Lung adenocarcinoma in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve lung adenocarcinoma risk prediction. Methods: PRSs were developed using genome-wide association study summary statistics from East Asian (8002 cases; 20 782 controls) and European (2058 cases; 5575 controls) populations. Single-ancestry models included a PRS with 25 single nucleotide variants (PRS-25), PRS clumping and thresholding (CT), and LDpred2; multi-ancestry models included LDpred2 plus European PRS-128, PRS-CSx, and clumping and thresholding, super learning, empirical Bayes (CT-SLEB). Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium and externally validated in the Nanjing Lung Cancer Cohort. We assessed predictive accuracy via area under the curve operating procedure (AUC), with 10-year and (ages 30-80 years) absolute risks estimates. Results: The best multi-ancestry PRS, using East Asian and European data via CT-SLEB, outperformed the best East Asian-only (LDpred2; AUC = 0.629, 95% confidence interval [CI] = 0.618 to 0.641), achieving an AUC of 0.640 (95% CI = 0.629 to 0.653) and odds ratio of 1.71 (95% CI = 1.61 to 1.82) per standard deviation increase. Nanjing Lung Cancer Cohort validation confirmed robust performance (AUC = 0.649, 95% CI = 0.623 to 0.676). The top 20% PRS group had a 3.92-fold higher lung adenocarcinoma risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year lung adenocarcinoma risk at age 50 years (0.42%) by age 41 years, 9 years earlier. Conclusions: Multi-ancestry PRS approaches enhance lung adenocarcinoma risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

Background and Objective: The lung microbiome was previously thought to be a sterile environment where only gaseous exchange takes place, but recent studies have shown the presence of microbiota in the lung. This review investigates the current literature on the effects of an environmental driven dysbiosis on the healthy oral and respiratory microbiome and its relationship to lung cancer risk in never-smokers. Methods: An online electronic search was performed on PubMed of all English-language literature using combinations of the following keywords: “lung cancer”, “dysbiosis”, “non-smokers”, “oral microbiome”, and “respiratory microbiome”. All population-based studies reporting results on oral and/or respiratory microbiome in adults were considered for our narrative review. Key Content and Findings: Metagenomic analyses have been performed on isolated samples from healthy participants and compared to samples from those with lung cancer. Research shows that a decrease in alpha diversity of microbes in the oral microbiome is associated with increased risk of lung cancer, along with differences in beta diversity in the sputum of lung cancer cases and healthy controls. Further, several studies have observed that significant changes in the abundance of genera such as increased abundance of Lactobacillales, Bacilli, and Firmicutes associated with an increased lung cancer risk among participants with exposure to certain household solid fuels. Conclusions: These findings suggest potential carcinogenic processes such as increased inflammation associated with changes in flora. Additionally, studies showed that increase in certain taxa such as Bacteroides and Spirochetes might have a protective effect on lung cancer risk. The review also provides insight into how understanding the microbial changes can be beneficial for lung cancer treatment and disease-free survival. Larger studies in different populations need to be performed to strengthen the current associations between microbial diversity and lung cancer risk.

The incidence of non-Hodgkin lymphoma (NHL) has been increasing in recent decades in all industrialized countries.¹ Although risk factors such as certain autoimmune conditions and occupational exposures such as benzene, trichloroethylene, and formaldehyde are known to increase the risk of NHL, the etiology of this disease is still not well characterized.^2-6 Previous research⁷ has demonstrated an association between increased mitochondrial DNA copy number (mtDNAcn) and increased risk of NHL. In healthy, nondamaged cells, mitochondria, eukaryotic organelles in the body involved in energy production through the production of adenosine triphosphate, have 2 to 10 copies of their genomes, mtDNA.⁸ Mitochondrial DNA differs from genomic DNA in that it lacks introns and protective histones, leaving it more vulnerable to oxidative damage from reactive oxygen species or other environmental stressors.^8,9 The mtDNAcn increases when mitochondria sense damage, because mitochondria have limited DNA repair capacity with an increased number of mutations in response to damage.^10,11 When exposed to environmental stress, mitochondria shift toward fragmentation (fission) as a prosurvival mechanism, with studies showing linear associations between fragmentation and cytotoxic effects when exposed to cell stress.¹² This study sought to evaluate whether mtDNA fraction with breaks (mtDNAfb) is associated with the risk of developing NHL using prediagnostic blood samples collected prospectively in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.

Background: Adalimumab is the only FDA‐approved biologic for hidradenitis suppurativa (HS). In the setting of increasing obesity rates worldwide, the relationship between adalimumab efficacy for HS and BMI is essential to understand. We assessed this relationship through markers of disease severity and inflammation.Methods: Institutional review board‐approved retrospective chart review of Montefiore/Einstein HS Center (HSC) patients (n = 57) treated with adalimumab. The relationship between BMI and adalimumab efficacy was assessed through disease severity (HS‐Physician Global Assessment [HS‐PGA] 0 and Numerical Rating Scale Pain [NRS‐Pain]) and inflammatory markers (erythrocyte sedimentation rate [ESR], C‐reactive protein [CRP], and interleukin‐6 [IL‐6]). A BMI ≥ 30 is defined as obese; BMI < 30 is defined as non‐obese.Results: The mean age was 35.8 ± 13.0 years. After adalimumab therapy, those with BMI < 30 experienced significant reductions in HS‐PGA (−1.5 ± 0.9; P < 0.0001) and NRS‐Pain (−1.6 ± 2.1; P < 0.0001), as well as mean decreases in inflammatory markers ESR, CRP, and IL‐6 (−17.90 ± 23.6, −0.71 ± 1.4, −5.88 ± 7.9, respectively; P > 0.05). Obese patients (BMI ≥ 30) experienced mean increases in HS‐PGA (+0.22 ± 0.8; P > 0.05) and NRS‐Pain scores (+1.41 ± 3.5; P > 0.05) as well as mean increases in ESR, CRP, and IL‐6 (+2.62 ± 28.3, +0.44 ± 3.0, +2.35 ± 6.9, respectively; P > 0.05). Comparing the cohorts, differences in changes in HS‐PGA, NRS‐Pain, ESR, and IL‐6 after therapy are significantly different (P < 0.05).Conclusions: We identified significantly lower efficacy of adalimumab in HS patients with BMI ≥ 30 compared to those with BMI < 30. Those with BMI ≥ 30 demonstrated signs of both clinical and physiological deterioration while on adalimumab. Future studies are needed to examine adalimumab dosing for HS patients with high BMI, as well as a critical reconsideration of weight‐based therapies.

Occupational exposure to trichloroethylene (TCE) has been associated with alterations in B‐cell activation factors and an increased risk of non‐Hodgkin's lymphoma (NHL). Here, we aimed to examine the biological processes influenced by TCE exposure to understand the underlying molecular mechanisms. This cross‐sectional molecular epidemiology study included data of 1317 targeted proteins in the serum from 42 TCE exposed and 34 unexposed factory workers in Guangdong, China. We used multivariable linear regressions to identify proteins associated with TCE exposure and examined their exposure‐response relationship across categories of TCE exposure (unexposed, low exposed: β = −.08; p‐value = .0003) and kynureninase (KYNU; β = −.10, p‐value = .002). These proteins also showed a significant exposure‐response relation across the unexposed, low exposed, and high exposed workers (all p‐trends < .001, false discovery rate [FDR] < 0.20). Pathway analysis of TCE‐related proteins showed significant enrichment (FDR < 0.05) for several inflammatory and immune pathways. TCE exposure was associated with TNFRSF17, a key B‐cell maturation antigen that mediates B‐cell survival and KYNU, an enzyme that plays a role in T‐cell mediated immune response. Given that altered immunity is an established risk factor for NHL, our findings support the biological plausibility of linking TCE exposure with NHL.