Flood exposure and pregnancy loss in 33 developing countries.

Floods have affected billions worldwide. Yet, the indirect health impacts of floods on vulnerable groups, particularly women in the developing world, remain underexplored. Here, we evaluated the risk of pregnancy loss for women exposed to floods. We analyzed 90,465 individual pregnancy loss records from 33 developing countries, cross-referencing each with spatial-temporal flood databases. We found that gestational flood exposure is associated with increased pregnancy loss with an odds ratio of 1.08 (95% confidence interval: 1.04 - 1.11). This risk is pronounced for women outside the peak reproductive age range (<21 or >35) or during the mid and late-stage of pregnancy. The risk escalated for women dependent on surface water, with lower income or education levels. We estimated that, over the 2010s, gestational flood events might be responsible for approximately 107,888 (CIs: 53,944 - 148,345) excess pregnancy losses annually across 33 developing countries. Notably, there is a consistent upward trend in annual excess pregnancy losses from 2010 to 2020, and was more prominent over Central America, the Caribbean, South America, and South Asia. Our findings underscore the disparities in maternal and child health aggravated by flood events in an evolving climate.

Short-term high temperature may increase the incidence risk of collective conflicts: A case-crossover study in the Greater Middle East.

BACKGROUND: Violent conflict is a formidable global challenge, with long-lasting impacts on individual health and society security. There has been compelling evidence that heat can increase aggression intention on the individual level. However, little is known about the short-term relationship between ambient temperature and collective violent conflicts, especially in less developed regions. METHOD: We conducted a time-stratified case-crossover study combined with the distributed lag nonlinear model (DLNM) among 247,773 violent conflicts from 29 countries or regions in the Greater Middle East, between 1997 and 2021. Potential modification effects of economic status and climate conditions were explored by stratified analyses. Negative control and sensitivity analyses were also performed to test the robustness of our model. RESULTS: We observed significant associations between higher temperature and the onset of five categories of violent conflicts. The effects generally occurred within the first several days after exposure. The incidence risks of battles, violence against civilians, explosions/remote violence, protests and riots were 1.60 [95 % confidence interval (CI): 1.31-1.95], 1.82 (95 % CI: 1.37-2.42), 1.24 (95 % CI: 1.08-1.41), 1.16 (95 % CI: 1.09-1.24) and 1.54 (95 % CI: 1.22-1.95) when comparing extreme high temperatures to minimum-risk temperatures. The associations were generally more prominent in areas with lower economic levels and associations in regions of the continental climate are also stronger. CONCLUSIONS: Our finding reveals novel and concrete evidence that short-term high temperature could increase the risk of multiple forms of violent conflict in the Greater Middle East and provides new insights into the potential short-term mechanisms under the heat-collective violence association.

Associations between fine particulate air pollution with small-airway inflammation: A nationwide analysis in 122 Chinese cities.

Alveolar nitric oxide is a non-invasive indicator of small-airway inflammation, a key pathophysiologic mechanism underlying lower respiratory diseases. However, no epidemiological studies have investigated the impact of fine particulate matter (PM2.5) exposure on the concentration of alveolar nitric oxide (CANO). To explore the associations between PM2.5 exposure in multiple periods and CANO, we conducted a nationwide cross-sectional study in 122 Chinese cities between 2019 and 2021. Utilizing a satellite-based model with a spatial resolution of 1 × 1 km, we matched long-term, mid-term, and short-term PM2.5 exposure for 28,399 individuals based on their home addresses. Multivariable linear regression models were applied to estimate the associations between PM2.5 at multiple exposure windows and CANO. Stratified analyses were also performed to identify potentially vulnerable subgroups. We found that per interquartile range (IQR) unit higher in 1-year average, 1-month average, and 7-day average PM2.5 concentration was significantly associated with increments of 17.78% [95% confidence interval (95%CI): 12.54%, 23.26%], 8.76% (95%CI: 7.35%, 10.19%), and 4.00% (95%CI: 2.81%, 5.20%) increment in CANO, respectively. The exposure-response relationship curves consistently increased with the slope becoming statistically significant beyond 20 µg/m3. Males, children, smokers, individuals with respiratory symptoms or using inhaled corticosteroids, and those living in Southern China were more vulnerable to PM2.5 exposure. In conclusion, our study provided novel evidence that PM2.5 exposure in long-term, mid-term, and short-term periods could significantly elevate small-airway inflammation represented by CANO. Our results highlight the significance of CANO measurement as a non-invasive tool for early screening in the management of PM2.5-related inflammatory respiratory diseases.

Short-term exposure to ozone may trigger the onset of Kawasaki disease: An individual-level, case-crossover study in East China.

Kawasaki disease (KD) is an acute, systemic vasculitis that primarily affects children aged under the age of 5. While environmental factors have been linked to the development of KD, the specific role of ozone (O3) pollution in triggering the disease onset remains uncertain. This study aimed to examine the associations between short-term O3 exposure and KD onset in children. Utilizing a satellite-based model with a spatial resolution of 1 × 1 km, we matched 1808 KD patients (out of a total of 6115 eligible individuals) to pre-onset ozone exposures based on their home addresses in East China between 2013 and 2020. Our findings revealed a significant association of O3 exposure with KD onset on the day of onset (lag 0 day). However, this association attenuated and became statistically insignificant on lag 1 and lag 2 days. Each interquartile range (52.32 µg/m3) increase in O3 concentration at lag 0 day was associated with a 16.2% (95% CI: 3.6%, 30.3%) increased risk of KD onset. The E-R curve for O3 exhibited a plateau at low concentrations and then increased rapidly at concentrations ≥75 µg/m3. Notably, these associations were stronger in male children, younger children (<2 years of age) and patients experiencing KD onset during the warm season. This study provides novel epidemiological evidence indicating that short-term O3 exposure is associated with an increased risk of childhood KD onset. These findings emphasized the importance of considering this environmental risk factor in KD prevention strategies.

Global warming may significantly increase childhood anemia burden in sub-Saharan Africa.

Childhood anemia constitutes a global public health problem, especially in low- and middle-income countries (LMICs). However, it remains unknown whether global warming has an impact on childhood anemia. Here, we examined the association between annual temperatures and childhood anemia prevalence in sub-Saharan Africa and then projected childhood anemia burden attributable to climate change. Each 1°C increment in annual temperature was associated with increased odds of childhood anemia (odd ratio = 1.138, 95% confidence interval: 1.134-1.142). Compared with the baseline period (1985-2014), the attributable childhood anemia cases would increase by 7,597 per 100,000 person-years under a high-emission scenario in the 2090s, which would be almost 2-fold and over 3-fold more than those projected in moderate- and low-emission scenarios. Our results reveal the vulnerabilities and inequalities of children for the excess burden of anemia due to climate warming and highlight the importance of climate mitigation and adaptation strategies in LMICs.

Pathogenic variants in the NLRP3 LRR domain at position 861 are responsible for a boost-dependent atypical CAPS phenotype.

BACKGROUND: Cryopyrin-associated periodic syndrome (CAPS) is associated with NLRP3 pathogenic variants, mostly located in the NACHT (neuronal apoptosis inhibitor protein, MHC class 2 transcription activator, incompatibility locus protein from Podospora anserina, telomerase-associated protein) domain. Cold-induced urticarial rash is among the main clinical features. However, this study identified a series of 14 patients with pathogenic variants of the Y861 residue (p.Tyr861) of the LRR domain of NLRP3 and minimal prevalence of cold-induced urticarial rash. OBJECTIVES: This study aimed to address a possible genotype/phenotype correlation for patients with CAPS and to investigate at the cellular levels the impact of the Y861C substitution (p.Tyr861Cys) on NLRP3 activation. METHODS: Clinical features of 14 patients with CAPS and heterozygous substitution at position 861 in the LRR domain of NLRP3 were compared to clinical features of 48 patients with CAPS and pathogenic variants outside the LRR domain of NLRP3. IL-1ß secretion by PBMCs and purified monocytes from patients and healthy donors was evaluated following LPS and monosodium urate crystal stimulation. RESULTS: Patients with substitution at position 861 of NLRP3 demonstrated a higher prevalence of sensorineural hearing loss while being less prone to skin urticarial. In contrast to patients with classical CAPS, cells from patients with a pathogenic variant at position 861 required an activation signal to secrete IL-1ß but produced more IL-1ß during the early and late phase of secretion than cells from healthy donors. CONCLUSIONS: Pathogenic variants of Y861 of NLRP3 drive a boost-dependent oversecretion of IL-1ß associated with an atypical CAPS phenotype.

Association of Ambient Temperature With the Prevalence of Intimate Partner Violence Among Partnered Women in Low- and Middle-Income South Asian Countries.

Importance: Intimate partner violence (IPV), including physical, sexual, and emotional violence, constitutes a critical public health problem, particularly in low- and middle-income countries. While climate change could escalate violent events, data quantifying its possible association with IPV are scant. Objective: To evaluate the association of ambient temperature with the prevalence of IPV among partnered women in low- and middle-income countries in South Asia, and to estimate the association of future climate warming with IPV. Design, Setting, and Participants: This cross-sectional study used data from the Demographic and Health Survey and included 194 871 ever-partnered women aged 15 to 49 years from 3 South Asian countries (India, Nepal, and Pakistan). The study applied the mixed-effect multivariable logistic regression model to investigate the association of ambient temperature with IPV prevalence. The study further modeled the change in IPV prevalence under various future climate change scenarios. The data included in the analyses were collected from October 1, 2010, to April 30, 2018, and the current analyses were performed from January 2, 2022, to July 11, 2022. Exposure: Annual ambient temperature exposure for each woman, estimated based on an atmospheric reanalysis model of the global climate. Main Outcomes and Measures: The prevalence of IPV and its types (physical, sexual, and emotional violence) were assessed based on self-reported questionnaires from October 1, 2010, to April 30, 2018, and the changes in the prevalence with climate changes were estimated through the 2090s. Results: The study included 194 871 ever-partnered women aged 15 to 49 years (mean [SD] age, 35.4 [7.6] years; overall IPV prevalence, 27.0%) from 3 South Asian countries. The prevalence of physical violence was highest (23.0%), followed by emotional (12.5%), and sexual violence (9.5%). The annual temperature ranges were mostly between 20 °C and 30 °C. A significant association was found between high ambient temperature and the prevalence of IPV against women, with each 1 °C increase in the annual mean temperature associated with a mean increase in IPV prevalence of 4.49% (95% CI, 4.20%-4.78%). According to the study's projections under the unlimited emissions scenarios (SSPs [shared socioeconomic pathways], as defined by the Intergovernmental Panel on Climate Change] 5-8.5), IPV prevalence would increase by 21.0% by the end of the 21st century, while it would only moderately increase under increasingly stricter scenarios (SSP2-4.5 [9.8%] and SSP1-2.6 [5.8%]). In addition, the projected increases in the prevalence of physical (28.3%) and sexual (26.1%) violence were greater than that of emotional violence (8.9%). In the 2090s, India was estimated to experience the highest IPV prevalence increase (23.5%) among the 3 countries, compared with Nepal (14.8%) and Pakistan (5.9%). Conclusions and Relevance: This cross-sectional, multicountry study provides ample epidemiological evidence to support that high ambient temperature may be associated with the risk of IPV against women. These findings highlight the vulnerabilities and inequalities of women experiencing IPV in low- and middle-income countries in the context of global climate warming.

Successful treatment of JAK1-associated inflammatory disease.

BACKGROUND: Gain-of-function variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy, and eosinophilia. OBJECTIVES: This study sought to describe the clinical and immunological characteristics associated with a new gain-of-function variant of JAK1 and report the therapeutic efficacy of Janus kinase (JAK) inhibition. METHODS: The investigators identified a family affected by JAK1-associated autoinflammatory disease and performed clinical assessment and immunological monitoring on 9 patients. JAK1 signaling was studied by flow and mass cytometry in patients' cells at basal state or after immune stimulation. A molecular disease signature in the blood was studied at the transcriptomic level. Patients were treated with 1 of 2 JAK inhibitors: either baricitinib or upadacitinib. Clinical, cellular, and molecular response were evaluated over a 2-year period. RESULTS: Affected individuals displayed a syndromic disease with prominent allergy including atopic dermatitis, ichthyosis, arthralgia, chronic diarrhea, disseminated calcifying fibrous tumors, and elevated whole blood histamine levels. A variant of JAK1 localized in the pseudokinase domain was identified in all 9 affected, tested patients. Hyper-phosphorylation of STAT3 was found in 5 of 6 patients tested. Treatment of patients' cells with baricitinib controlled most of the atypical hyper-phosphorylation of STAT3. Administration of baricitinib to patients led to rapid improvement of the disease in all adults and was associated with reduction of systemic inflammation. CONCLUSIONS: Patients with this new JAK1 gain-of-function pathogenic variant displayed very high levels of blood histamine and showed a variable combination of atopy with articular and gastrointestinal manifestations as well as calcifying fibrous tumors. The disease, which appears to be linked to STAT3 hyperactivation, was well controlled under treatment by JAK inhibitors in adult patients.

Long-term cardiometabolic effects of ambient ozone pollution in a large Chinese population.

Limited studies investigated the effects of long-term ozone exposure on cardiometabolic health. We aimed to examine the association of long-term ozone exposure with a range of cardiometabolic diseases, as well as the subclinical indicators in Eastern China. The study included 202,042 adults living in 11 prefecture-level areas in Zhejiang Province between 2014 and 2021. Using a satellite-based model with a 1 × 1 km spatial resolution, we estimated residential 5-year average ozone exposures for each subject. Mixed-effects logistic and linear regression models were applied to explore the associations of ozone exposure with cardiometabolic diseases and subclinical indicators, respectively. We found that a 9% [95% confidence interval (95% CI): 7-12%] higher in odds of cardiometabolic disease per 10 µg/m3 increase in ozone exposure. Specifically, we also found higher prevalence of cardiovascular diseases (15%), stroke (19%), hypertension (7%), dyslipidemia (15%), and hypertriglyceridemia (9%) associated with ozone exposure. However, we did not find significant associations between ozone exposure and coronary heart disease, myocardial infarction, or diabetes mellitus. Long-term ozone exposures were also significantly associated with adverse changes in systolic blood pressure, diastolic blood pressure, total serum cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, glucose concentration, and body mass index. Our results showed that people with lower education levels, those over 50 years old, and those who were overweight or obese were more susceptible to the effects of ozone on cardiometabolic diseases. Our findings demonstrated the detrimental effects of long-term ozone exposure on cardiometabolic health, emphasizing the need for ozone control strategies to reduce the burden of cardiometabolic diseases.

Fine and coarse particulate air pollution and hospital admissions for a wide range of respiratory diseases: a nationwide case-crossover study.

BACKGROUND: The associations between fine and coarse particulate matter (PM2.5 and PM2.5-10) air pollution and hospital admissions for full-spectrum respiratory diseases were rarely investigated, especially for age-specific associations. We aim to estimate the age-specific associations of short-term exposures to PM2.5 and PM2.5-10 with hospital admissions for full-spectrum respiratory diseases in China. METHODS: We conducted an individual-level case-crossover study based on a nationwide hospital-based registry including 153 hospitals across 20 provincial regions in China in 2013-20. We applied conditional logistic regression models and distributed lag models to estimate the exposure- and lag-response associations. RESULTS: A total of 1 399 955 hospital admission records for various respiratory diseases were identified. The associations of PM2.5 and PM2.5-10 with total respiratory hospitalizations lasted for 4 days, and an interquartile range increase in PM2.5 (34.5 µg/m3) and PM2.5-10 (26.0 µg/m3) was associated with 1.73% [95% confidence interval (95% CI): 1.34%, 2.12%)] and 1.70% (95% CI: 1.31%, 2.10%) increases, respectively, in total respiratory hospitalizations over lag 0-4 days. Acute respiratory infections (i.e. pneumonia, bronchitis and bronchiolitis) were consistently associated with PM2.5 or PM2.5-10 exposure across different age groups. We found the disease spectrum varied by age, including rarely reported findings (i.e. acute laryngitis and tracheitis, and influenza) among children and well-established associations (i.e. chronic obstructive pulmonary disease, asthma, acute bronchitis and emphysema) among older populations. Besides, the associations were stronger in females, children and older populations. CONCLUSIONS: This nationwide case-crossover study provides robust evidence that short-term exposure to both PM2.5 and PM2.5-10 was associated with increased hospital admissions for a wide range of respiratory diseases, and the spectra of respiratory diseases varied by age. Females, children and older populations were more susceptible.

Front-line therapy for brain metastases and non-brain metastases in advanced epidermal growth factor receptor-mutated non-small cell lung cancer: a network meta-analysis.

BACKGROUND: The brain is a common metastatic site in patients with non-small cell lung cancer (NSCLC), resulting in a relatively poor prognosis. Systemic therapy with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is recommended as the first-line treatment for EGFR -mutated, advanced NSCLC patients. However, intracranial activity varies in different drugs. Thus, brain metastasis (BM) should be considered when choosing the treatment regimens. We conducted this network meta-analysis to explore the optimal first-line therapeutic schedule for advanced EGFR -mutated NSCLC patients with different BM statuses. METHODS: Randomized controlled trials focusing on EGFR-TKIs (alone or in combination) in advanced and EGFR -mutant NSCLC patients, who have not received systematic treatment, were systematically searched up to December 2021. We extracted and analyzed progression-free survival (PFS) and overall survival (OS). A network meta-analysis was performed with the Bayesian statistical model to determine the survival outcomes of all included therapy regimens using the R software. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to compare intervention measures, and overall rankings of therapies were estimated under the Bayesian framework. RESULTS: This analysis included 17 RCTs with 5077 patients and 12 therapies, including osimertinib + bevacizumab, aumolertinib, osimertinib, afatinib, dacomitinib, standards of care (SoC, including gefitinib, erlotinib, or icotinib), SoC + apatinib, SoC + bevacizumab, SoC + ramucirumab, SoC + pemetrexed based chemotherapy (PbCT), PbCT, and pemetrexed free chemotherapy (PfCT). For patients with BM, SoC + PbCT improved PFS compared with SoC (HR = 0.40, 95% CI: 0.17-0.95), and osimertinib + bevacizumab was most likely to rank first in PFS, with a cumulative probability of 34.5%, followed by aumolertinib, with a cumulative probability of 28.3%. For patients without BM, osimertinib + bevacizumab, osimertinib, aumolertinib, SoC + PbCT, dacomitinib, SoC + ramucirumab, SoC + bevacizumab, and afatinib showed superior efficacy compared with SoC (HR = 0.43, 95% CI: 0.20-0.90; HR = 0.46, 95% CI: 0.31-0.68; HR = 0.51, 95% CI: 0.34-0.77; HR = 0.50, 95% CI: 0.38-0.66; HR = 0.62, 95% CI: 0.43-0.89; HR = 0.64, 95% CI: 0.44-0.94; HR = 0.61, 95% CI: 0.48-0.76; HR = 0.71, 95% CI: 0.50-1.00), PbCT (HR = 0.29, 95% CI: 0.11-0.74; HR = 0.31, 95% CI: 0.15-0.62; HR = 0.34, 95% CI: 0.17-0.69; HR = 0.34, 95% CI: 0.18-0.64; HR = 0.42, 95% CI: 0.21-0.82; HR = 0.43, 95% CI: 0.22-0.87; HR = 0.41, 95% CI: 0.22-0.74; HR = 0.48, 95% CI: 0.31-0.75), and PfCT (HR = 0.14, 95% CI: 0.06-0.32; HR = 0.15, 95% CI: 0.09-0.26; HR = 0.17, 95% CI: 0.09-0.29; HR = 0.16, 95% CI: 0.10-0.26; HR = 0.20, 95% CI: 0.12-0.35; HR = 0.21, 95% CI: 0.12-0.39; HR = 0.20, 95% CI: 0.12-0.31; HR = 0.23, 95% CI: 0.16-0.34) in terms of PFS. And, SoC + apatinib showed relatively superior PFS when compared with PbCT (HR = 0.44, 95% CI: 0.22-0.92) and PfCT (HR = 0.21, 95% CI: 0.12-0.39), but similar PFS to SoC (HR = 0.65, 95% CI: 0.42-1.03). No statistical differences were observed for PFS in patients without BM between PbCT and SoC (HR = 1.49, 95% CI: 0.84-2.64), but both showed favorable PFS when compared with PfCT (PfCT vs. SoC, HR = 3.09, 95% CI: 2.06-4.55; PbCT vs. PfCT, HR = 0.14, 95% CI: 0.06-0.32). For patients without BM, osimertinib + bevacizumab was most likely to rank the first, with cumulative probabilities of 47.1%. For OS, SoC + PbCT was most likely to rank first in patients with and without BM, with cumulative probabilities of 46.8%, and 37.3%, respectively. CONCLUSION: Osimertinib + bevacizumab is most likely to rank first in PFS in advanced EGFR -mutated NSCLC patients with or without BM, and SoC + PbCT is most likely to rank first in OS.

Low ambient temperature and temperature drop as novel risk factors of acute glaucoma: a case-crossover study.

The prevalence of glaucoma has seasonal variation in population, but the role of ambient temperature and its variation remains unclear in this seasonal trend. So, we conducted a time-stratified case-crossover study to examine the association of ambient temperature and temperature change between neighboring days (TCN) with the risk of acute glaucoma. Data on meteorological parameters and glaucoma outpatient visit between 2015 and 2021 covered all districts of Shanghai. Conditional logistic regression with distributed lag nonlinear model was applied to estimate the association of temperature or TCN with the risk of acute glaucoma. A total of 7,746 patients diagnosed with acute primary angle-closure glaucoma (APACG) were included in this analysis. We observed a significant increase in the risk of acute glaucoma with cold temperature and temperature drop. Compared with the referent temperature (32℃), moderate low (12 °C) and extreme low (4 °C) temperature exposures were associated with higher risk of acute glaucoma outpatient visit, with the highest cumulative OR of 1.46 (95% CI: 1.11, 1.91) and 1.50 (95% CI: 1.09, 2.06) over lag 0-2 days. Temperature drop (TCN = - 4 °C) also increases the risk of acute glaucoma (OR = 1.34, 95% CI: 1.07, 1.67) over lag 0-7 days, comparing with no temperature change. Patients of female and above age 65 were more vulnerable to cold exposure and temperature drop. This case-crossover study provided novel and robust individual-level evidence that low ambient temperature and temperature drop significantly increase the acute glaucoma risk. The findings provide protective strategies for glaucoma patient, especially for female and the old, under cold exposure and sudden temperature decline.

Quantifying Podocyte Number in a Small Sample Size of Glomeruli with CUBIC to Evaluate Podocyte Depletion of db/db Mice.

The loss of podocyte is crucial for diagnosis and prognosis of diabetic kidney disease, whereas commonly two-dimensional methods for quantifying podocyte number existed with issues of low fidelity and accuracy. In this study, clear, unobstructed brain imaging cocktails and computational analysis (CUBIC), one of three-dimensional optical clearing approaches, was used which combines tissue clearing, immunolabeling, and a light-sheet microscope to image and evaluate podocytes in C57BL/6 (C57) and db/db mice. We discovered that 77 podocytes per glomerulus were in C57 mice. On the subject of db/db mice, there were 74 podocytes by the age of 8 w, 72 podocytes by the age of 12 w, and 66 podocytes by the age of 16 w, compared with 76 podocytes in the control group, suggesting that there was a significant decrease in podocyte number in db/db mice with the age of 16 w, showing a trend which positively correlated to the deterioration of kidney function. Sample size estimation using the PASS software revealed that taking 5%, 7.5%, and 10% of the mean podocyte number per glomerulus as the statistical allowable error and 95% as total confidence interval, 33, 15, and 9 glomeruli were independently needed to be sampled in C57 mice to represent the overall glomeruli to calculate podocyte number. Furthermore, in the control group of db/db mice, 36, 18, and 11 glomeruli were needed, compared with 46, 24, and 14 glomeruli in db/db mice by the age of 8 w, 43, 21, and 12 glomeruli by the age of 12 w, and 52, 27, and 16 by the age of 16 w. These findings indicated that precise quantification of podocyte number could judge the progression of diabetic kidney disease. In addition, a small number of glomeruli could be actually representative of the whole sample size, which indicated apparent practicability of CUBIC for clinical use.

Ambient air pollution and hospitalization for type 2 diabetes in China: A nationwide, individual-level case-crossover study.

Scarce evidence is available on the short-term association between air pollution and type 2 diabetes (T2D). We aimed to evaluate the associations between short-term exposure to six criteria air pollutants and hospitalization for T2D based on a national registry. We conducted an individual-level, time-stratified case-crossover study among inpatients with a primary diagnosis of T2D from 153 hospitals across 20 provincial regions in China (2013-2021). Daily concentrations of fine particulate matter (PM2.5), inhalable particle (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2) and carbon monoxide (CO), and ozone were collected from the nearest monitoring stations. T2D patients were separated into those admission for T2D with and without complications. Distributed lag non-linear models combined with conditional logistic regressions were used to estimate the associations. A total of 88,904 patients were hospitalized for T2D. Short-term exposures to all six air pollutants above except for ozone were significantly associated with the risk of hospitalization for T2D and both subclasses. An interquartile range increase in the concentrations of PM2.5, PM10, NO2, SO2, and CO at lag 0-2 d was associated with higher hospitalization risk of T2D by 1.71% (95%CI: 0.56%, 2.87%), 2.08% (0.88%, 3.29%), 4.85% (3.29%, 6.44%), 2.44% (1.22%, 3.67%) and 2.55% (1.24%, 3.88%), respectively. The associations of T2D hospitalizations were stronger in cold season than in warm season. Air pollutants had more acute and stronger associations with T2D with complications. The exposure-response relationship curves showed no thresholds, and the slopes were larger for T2D with complications. This nationwide individual-level, case-crossover study provides the first comprehensive evidence that short-term exposure to multiple criteria air pollutants may increase the risk of hospitalizations for T2D, especially for T2D with complications.

Ambient heat stress and urolithiasis attacks in China: Implication for climate change.

BACKGROUND: Although the existing studies have suggested a significant association between high temperatures and urolithiasis, no nationwide studies have quantified the burden attributable to environmental heat stress and explored how the urolithiasis burden would vary in a warming climate. METHODS: We collected data on urolithiasis attacks from 137 hospitals in 59 main cities from 20 provincial regions of China from 2000 to 2020. An individual-level case-crossover analysis was conducted to estimate the effect of daily wet-bulb globe temperature (WBGT), a heat stress index combining temperature and humidity, on urolithiasis attacks. Stratified analyses were performed by region, age, and sex. We further quantified the future WBGT-related burden of urolithiasis from the Coupled Model Intercomparison Project Phase 6 under three Shared Socioeconomic Pathway (SSP) scenarios. RESULTS: In total, 118,180 urolithiasis patients were evaluated. The exposure-response curve for the association between WBGT and urolithiasis attacks was J-shaped, with a significantly increased risk for WBGT higher than 14.8 °C. The middle-aged and elderly group (≥45 years old) had a higher risk of WBGT-related urolithiasis attacks than in the younger group, while no significant sex difference was observed. The attributable fraction (AF) due to high WBGT would increase from 10.1% in the 2010s to 16.1% in the 2090s under the SSP585 scenario. Warm regions were projected to experience disproportionately higher AFs and larger increments in the future. CONCLUSIONS: This nationwide investigation provides novel evidence on the acute effect of high WBGT on urolithiasis attacks and demonstrates the increasing disease burden in a warming climate.

Large scale controlled Fab exchange GMP process to prepare bispecific antibodies.

Objective: Bispecific antibodies (BsAbs) have demonstrated significant therapeutic impacts for the treatment of a broad spectrum of diseases that include oncology, auto-immune, and infectious diseases. However, the large-scale production of clinical batches of bispecific antibodies still has many challenges that include having low yield, poor stability, and laborious downstream purification processes. To address such challenges, we describe the optimization of the controlled Fab arm exchange (cFAE) process for the efficient generation of BsAbs. Methods: The process optimization of a large-scale good manufacturing practice (GMP) cFAE strategy to prepare BsAbs was based on screening the parameters of temperature, reduction, oxidation, and buffer exchange. We include critical quality standards for the reducing agent cysteamine hydrochloride. Results: This large-scale production protocol enabled the generation of bispecific antibodies with >90% exchange yield and at >95% purity. The subsequent downstream processing could use typical mAb procedures. Furthermore, we demonstrated that the bispecific generation protocol can be scaled up to ∼60 L reaction scale using parental monoclonal antibodies that were expressed in a 200 L bioreactor. Conclusion: We presented a robust development strategy for the cFAE process that can be used for a larger scale GMP BsAb production.

Maximum Somatic Allele Frequency-Adjusted Blood-Based Tumor Mutational Burden Predicts the Efficacy of Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Recent studies exhibited the unstable prediction ability of blood-based tumor mutational burden (bTMB) when predicting the response of immune checkpoint inhibitors (ICIs) therapy in patients with non-small cell lung cancer (NSCLC). Circulating tumor DNA (ctDNA) abundance, usually represented by maximum somatic allele frequency (MSAF), was one possible confounding factor influencing bTMB ability in ICIs response prediction. METHODS: MSAF-adjusted bTMB (Ma-bTMB) was established and validated in patients with advanced NSCLC among Geneplus Cancer Genome Database (GCGD, n = 1679), Zhuo (n = 35), Wang (n = 45), POPLAR (NCT01903993, n = 211) and OAK (NCT02008227, n = 642) cohorts. RESULTS: MSAF demonstrated a modest positive correlation with bTMB and a negative one with survival benefit. Improved survival outcomes of ICIs therapy have been observed among patients with high-Ma-bTMB compared to those with low-Ma-bTMB in Zhuo and Wang cohorts. In addition, compared to low-Ma-bTMB, high-Ma-bTMB was associated with more positive clinical benefits from ICIs therapy than chemotherapy both in POPLAR and OAK cohorts. Further exploration suggested that Ma-bTMB could precisely identify more potential ICIs beneficiaries compared to bTMB and LAF-bTMB, complementary to PD-L1 expression. CONCLUSIONS: We developed Ma-bTMB, a convenient, readily available, non-invasive predictive biomarker effectively differentiates beneficiaries of ICIs therapy in advanced NSCLC, warranting future clinical trials.

Correlations of switch/sucrose nonfermentable complex mutations with clinical outcomes in advanced non-small cell lung cancer.

BACKGROUND: The switch/sucrose nonfermentable complex mutations (SWI/SNF-mut) are common in non-small cell lung cancer (NSCLC). However, the association of SWI/SNF-mut with the clinical outcomes of immune checkpoint inhibitors (ICIs), particularly of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), has not been established. METHODS: We retrospectively collected data of patients at Cancer Hospital Chinese Academy of Medical Sciences. Patients with advanced NSCLC who received programmed cell death protein-1 or programmed cell death ligand 1 (PD-[L]1) inhibitors were included in cohort 1 and those with EGFR mutations (EGFR-mutant) received EGFR-TKIs monotherapy were included in cohort 2. Two reported Memorial Sloan-Kettering Cancer Center (MSKCC) cohorts received immunotherapy alone used as the validation for cohort 1. We analyzed the relationship between SWI/SNF alterations and clinical outcomes in each cohort. RESULTS: In total, 1162 patients were included, of which 230 patients (19.8%) were identified as SWI/SNF-mut with the most common genetic alterations being ARID1A (33.4%) and SMARCA4 (28.3%). In cohort 1 (n = 146), patients with co-mutations of SWI/SNF and Kirsten rat sarcoma oncogene (KRAS) (SWI/SNFmutKRASmut, n = 18) had significantly prolonged progression-free survival (PFS) (8.6 m vs. 1.9 m; hazard ratio [HR],  0.31; 95% confidence intervals [CI], 0.11-0.83; p = 0.032) to PD-(L)1 inhibitors monotherapy, which was consistent with the MSKCC cohorts (not reach [NR] vs. 6.3 m; HR, 0.36, 95% CI, 0.15-0.82; p = 0.016). In cohort 2 (n = 205), ARID1A-mut (n = 16) was associated with improved PFS after EGFR-TKIs (20.6 m vs. 11.2 m; HR, 0.47, 95% CI, 0.27-0.94; p = 0.023). CONCLUSIONS: In advanced NSCLC, patients with SWI/SNFmutKRASmut seem to benefit more from ICIs. Furthermore, ARID1A-mut may provide a protective effect to EGFR-TKIs in EGFR-mutant patients. However, this is a retrospective single-institution analysis that requires further validation by large prospective studies.