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Studies across multiple soils find increasing pH decreases water repellency. In this study, water repellency and a range of other soil physical properties of bulk soils, aggregates and intact specimens were measured on a long-term pH field experiment on a single sandy loam soil under a ley-arable crop rotation, with soil pH adjustments occurring annually by adding FeSO4 or CaCO3, to lower or raise the pH, respectively. Crop impacts were investigated by comparing 3rd year grass-white clover to spring oats, at the beginning (May) and end (September) of the growing season to allow soil structure comparisons. As in previous research, increased CO2 microbial respiration (p 55 years of chemical additions to amend soil pH.

Background: Zaire Ebolavirus disease (EVD) outbreaks can be controlled using rVSV-ZEBOV vaccination and other public health measures. People in high-risk areas may have pre-existing antibodies from asymptomatic Ebolavirus exposure that might affect response to rVSV-ZEBOV. Therefore, we assessed the impact pre-existing immunity had on post-vaccination IgG titre, virus neutralisation, and reactogenicity following vaccination., Methods: In this prospective cohort study, 2115 consenting close contacts ("proches") of EVD survivors were recruited. Proches were vaccinated with rVSV-ZEBOV and followed up for 28 days for safety and immunogenicity. Anti-GP IgG titre at baseline and day 28 was assessed by ELISA. Samples from a representative subset were evaluated using live virus neutralisation., Results: Ten percent were seropositive at baseline. At day 28, IgG in baseline seronegative (GMT 0.106 IU/ml, 95% CI: 0.100 to 0.113) and seropositive (GMT 0.237 IU/ml, 0.210 to 0.267) participants significantly increased from baseline (both p < 0.0001). There was strong correlation between antibody titres and virus neutralisation in day 28 samples (Spearman's rho 0.75). Vaccinees with baseline IgG antibodies against Zaire Ebolavirus had similar safety profiles to those without detectable antibodies (63.6% vs 66.1% adults experienced any adverse event; 49.1% vs 60.9% in children), with almost all adverse events graded as mild. No serious adverse events were attributed to vaccination. No EVD survivors tested positive for Ebolavirus by RT-PCR., Conclusions: These data add further evidence of rVSV-ZEBOV safety and immunogenicity, including in people with pre-existing antibodies from suspected natural ZEBOV infection whose state does not blunt rVSV-ZEBOV immune response. Pre-vaccination serological screening is not required., (© 2024. The Author(s).)

Purpose: Unanticipated health care resource utilization, in the form of either emergency department utilization (EDU) or hospital admission (HA), may be an indicator of lower-quality cancer care. The objective of this study was to develop a predictive model for EDU and HAs within 14 days of receipt of systemic therapy for patients with solid tumors., Methods: We abstracted electronic health data on oncology encounters from all patients receiving systemic therapy for solid tumors from March 1, 2015, to August 21, 2020, in the Duke University Health System. We defined a primary composite outcome of an EDU or HA within 14 days after the encounter and then developed a predictive model for the primary outcome using least absolute shrinkage and selection operator regression. To evaluate the model, we calculated the area under the receiver operator curve and the calibration slope., Results: Twelve thousand eight hundred ninety unique patients with 134,641 oncology encounters were included. Five thousand one hundred fifty of these patients (40.0%) had at least one EDU or HA within 14 days of at least one treatment. Forty-six variables were incorporated into the final model. The top predictors, in order of absolute value of the predictive coefficients, were temperature, systolic blood pressure, cancer group, and marital status. The model's AUC was 0.73 (95% CI, 0.722 to 0.732), indicating good sensitivity and specificity to outcome., Conclusion: The model developed in this study demonstrated good sensitivity in identifying patients with solid tumors who are at highest risk for EDU or HA and could be implemented in clinical practice to allow for preventive outpatient interventions.

Since November 2023, the absolute number of attendances at emergency departments for pneumonia among children aged 5-14 years in England have been above expected levels for the time of year. This increased signal peaked during March 2024 but then persisted into early summer 2024 despite decreases in prevalence of seasonal respiratory pathogens. Record linkage between emergency department and laboratory databases points to this unusual activity being driven largely by Mycoplasma pneumoniae .

Significance: Characterisation of tobacco product emissions is an important step in assessing their impact on public health. Accurate and repeatable emissions data require that a leak-tight seal be made between the smoking or vaping machine and the mouth-end of the tobacco product being tested. This requirement is challenging because of the variety of tobacco product mouth-end geometries being puffed on by consumers today. We developed and tested a prototype universal smoking machine adaptor (USMA) that interfaces with existing machines and reliably seals with a variety of tobacco product masses and geometries., Methods: Emissions were machine-generated using the USMA and other available adaptors for a variety of electronic cigarettes (n=7 brands), cigars (n=4), cigarillos (n=2), a heated tobacco product, and a reference cigarette (1R6F), and mainstream total particulate matter (TPM) and nicotine were quantified. Data variability (precision, n≥10 replicates/brand) for all products and error (accuracy) from certified values (1R6F) were compared across adaptors., Results: TPM and nicotine emissions generated using the USMA were accurate, precise and agreed with certified values for the 1R6F reference cigarette. Replicate data indicate that USMA repeatability across all tobacco products tested generally meets or exceeds that from the comparison adaptors and extant data., Conclusion: The USMA seals well with a variety of combustible tobacco products, e-cigarettes with differing geometries and plastic-tipped cigarillos. Variability for all measures was similar or smaller for the USMA compared with other adaptors., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Significance: Historically, tobacco product emissions testing using smoking machines has largely focused on combustible products, such as cigarettes and cigars. However, the popularity of newer products, such as electronic cigarettes (e-cigarettes), has complicated emissions testing because the products' mouth-end geometries do not readily seal with existing smoking and vaping machines. The demand for emissions data on popularly used products has led to inefficient and non-standardised solutions, such as laboratories making their geometry-specific custom adaptors and/or employing flexible tubing, for each unique mouth-end geometry tested. A user-friendly, validated, universal smoking machine adaptor (USMA) is needed for testing the variety of tobacco products reflecting consumer use, including e-cigarettes, heated tobacco products, cigarettes, plastic-tipped cigarillos and cigars., Methods: A prototype USMA that is compatible with existing smoking/vaping machines was designed and fabricated. The quality of the seal between the USMA and different tobacco products, including e-cigarettes, cigars and cigarillos, was evaluated by examining the leak rate., Results: Unlike commercial, product-specific adaptors, the USMA seals well with a wide range of tobacco product mouth-end geometries and masses. This includes e-cigarettes with non-cylindrical mouth ends and cigarillos with cuboid-like plastic tips. USMA leak rates were lower than or equivalent to commercial, product-specific adaptors., Conclusion: This report provides initial evidence that the USMA seals reliably with a variety of tobacco product mouth-end geometries and can be used with existing linear smoking/vaping machines to potentially improve the precision, repeatability and reproducibility of machine smoke yield data. Accurate and reproducible emissions testing is critical for regulating tobacco products., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The 2022/23 influenza season in the United Kingdom saw the return of influenza to prepandemic levels following two seasons with low influenza activity. The early season was dominated by A(H3N2), with cocirculation of A(H1N1), reaching a peak late December 2022, while influenza B circulated at low levels during the latter part of the season. From September to March 2022/23, influenza vaccines were offered, free of charge, to all aged 2-13 (and 14-15 in Scotland and Wales), adults up to 49 years of age with clinical risk conditions and adults aged 50 and above across the mainland United Kingdom., Methods: End-of-season adjusted vaccine effectiveness (VE) estimates against sentinel primary-care attendance for influenza-like illness, where influenza infection was laboratory confirmed, were calculated using the test negative design, adjusting for potential confounders., Methods: Results In the mainland United Kingdom, end-of-season VE against all laboratory-confirmed influenza for all those > 65 years of age, most of whom received adjuvanted quadrivalent vaccines, was 30% (95% CI: -6% to 54%). VE for those aged 18-64, who largely received cell-based vaccines, was 47% (95% CI: 37%-56%). Overall VE for 2-17 year olds, predominantly receiving live attenuated vaccines, was 66% (95% CI: 53%-76%)., Conclusion: The paper provides evidence of moderate influenza VE in 2022/23., (© 2024 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

The designs and liquid formulations of Electronic Nicotine Delivery System (ENDS) devices continue to rapidly evolve. Thus, it is important to monitor and characterize ENDS aerosols for changes in toxic constituents. Many ENDS liquid formulations now include the addition of organic acids in a 1 to 1 molar ratio with nicotine. Metal concentrations in aerosols produced by ENDS devices with different nicotine salt formulations were analyzed. Aerosols from devices containing lactic acid had higher nickel, zinc, copper, and chromium concentrations than aerosols produced by devices containing benzoic acid or levulinic acid. Our scanning electron microscope with energy dispersive X-ray analytical findings showed that the metals determined in the inductively coupled plasma-mass spectrometry analytical results were consistent with the metal compositions of the ENDS device components that were exposed to the liquids and that nickel is a major constituent in many ENDS internal components. As a result of the exposure of the nickel-containing components to the ENDS liquids, resulting aerosol nickel concentrations per puff were higher from devices that contained lactic acid in comparison to devices with benzoic or levulinic acid. The aerosol nickel concentrations in 10 puffs from ENDS-containing lactic acid were, in some cases, hundreds of times higher than cigarette mainstream smoke nickel deliveries. Thus, the design of an ENDS device in terms of both physical construction components and the liquid chemical formulations could directly impact potential exposures to toxic constituents such as metals.

Background: Two new products for preventing Respiratory Syncytial Virus (RSV) in young children have been licensed: a single-dose long-acting monoclonal antibody (la-mAB) and a maternal vaccine (MV). To facilitate the selection of new RSV intervention programmes for large-scale implementation, this study provides an assessment to compare the costs of potential programmes with the health benefits accrued., Methods: Using an existing dynamic transmission model, we compared maternal vaccination to la-mAB therapy against RSV in England and Wales by calculating the impact and cost-effectiveness. We calibrated a statistical model to the efficacy trial data to accurately capture their immune waning and estimated the impact of seasonal and year-round programmes for la-mAB and MV programmes. Using these impact estimates, we identified the most cost-effective programme across pricing and delivery cost assumptions., Findings: For infants under six months old in England and Wales, a year-round MV programme with 60% coverage would avert 32% (95% CrI 22-41%) of RSV hospital admissions and a year-round la-mAB programme with 90% coverage would avert 57% (95% CrI 41-69%). The MV programme has additional health benefits for pregnant women, which account for 20% of the population-level health burden averted. A seasonal la-mAB programme could be cost-effective for up to £84 for purchasing and administration (CCPA) and a seasonal MV could be cost-effective for up to £80 CCPA., Interpretation: This modelling and cost-effectiveness analysis has shown that both the long-acting monoclonal antibodies and the maternal vaccine could substantially reduce the burden of RSV disease in the infant population. Our analysis has informed JCVI's recommendations for an RSV immunisation programme to protect newborns and infants., Funding: National Institute for Health Research., Competing Interests: All authors declare no conflict of interest., (© 2023 Published by Elsevier Ltd.)

Under International Health Regulations from 2005, a human infection caused by a novel influenza A virus variant is considered an event that has potential for high public health impact and is immediately notifiable to the World Health Organisation. We here describe the clinical, epidemiological and virological features of a confirmed human case of swine influenza A(H1N2)v in England detected through community respiratory virus surveillance. Swabbing and contact tracing helped refine public health risk assessment, following this unusual and unexpected finding.

Opinion Statement: Sentinel lymph node mapping (SLNM) and dissection (SLND) should be used as an alternative to full inguinofemoral lymph node dissection (IFLND) in select patients with early-stage vulvar cancer. IFLND is associated with high postoperative complications such as wound breakdown, lymphedema, lymphocyst formation, and infection. SLND in select patients offers a safe, effective, and less morbid alternative. Candidates for SLND include patients with a unifocal vulvar tumor less than four centimeters, clinically negative lymph nodes, and no prior inguinofemoral surgeries. SLND should ideally be performed by a high-volume SLN surgeon. Most commonly, SLND is performed using both radiocolloid lymphoscintigraphy (e.g., Technetium-99) and a visual tracer such as blue dye; however, near infrared imaging with indocyanine green injection is becoming more widely adopted. Further prospective studies are needed to examine the safety and efficacy of various techniques for SLND. SLND has been demonstrated to be cost-effective, especially when including perioperative complications. Further studies are needed to demonstrate quality of life differences between IFLND and SLND., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: An increase in acute severe hepatitis of unknown aetiology in previously healthy children in the UK in March, 2022, triggered global case-finding. We aimed to describe UK epidemiological investigations of cases and their possible causes., Methods: We actively surveilled unexplained paediatric acute hepatitis (transaminase >500 international units per litre) in children younger than 16 years presenting since Jan 1, 2022, through notifications from paediatricians, microbiologists, and paediatric liver units; we collected demographic, clinical, and exposure information. Then, we did a case-control study to investigate the association between adenoviraemia and other viruses and case-status using multivariable Firth penalised logistic regression. Cases aged 1-10 years and tested for adenovirus were included and compared with controls (ie, children admitted to hospital with an acute non-hepatitis illness who had residual blood samples collected between Jan 1 and May 28, 2022, and without known laboratory-confirmed diagnosis or previous adenovirus testing). Controls were frequency-matched on sex, age band, sample months, and nation or supra-region with randomised selection. We explored temporal associations between frequency of circulating viruses identified through routine laboratory pathogen surveillance and occurrence of cases by linear regression. SARS-CoV-2 seropositivity of cases was examined against residual serum from age-matched clinical comparison groups., Findings: Between Jan 1 and July 4, 2022, 274 cases were identified (median age 3 years [IQR 2-5]). 131 (48%) participants were male, 142 (52%) were female, and one (<1%) participant had sex data unknown. Jaundice (195 [83%] of 235) and gastrointestinal symptoms (202 [91%] of 222) were common. 15 (5%) children required liver transplantation and none died. Adenovirus was detected in 172 (68%) of 252 participants tested, regardless of sample type; 137 (63%) of 218 samples were positive for adenovirus in the blood. For cases that were successfully genotyped, 58 (81%) of 72 had Ad41F, and 57 were identified as positive via blood samples (six of these were among participants who had undergone a transplant). In the case-control analysis, adenoviraemia was associated with hepatitis case-status (adjusted OR 37·4 [95% CI 15·5-90·3]). Increases in the detection of adenovirus from faecal samples, but not other infectious agents, in routine laboratory pathogen surveillance correlated with hepatitis cases 4 weeks later, which independently suggested an association (β 0·06 [95% CI 0·02-0·11]). No association was identified for SARS-CoV-2 antibody seropositivity., Interpretation: We observed an association between adenovirus 41F viraemia and paediatric acute hepatitis. These results can inform diagnostic testing recommendations, clinical management, and exploratory in vitro or clinical studies of paediatric acute hepatitis of unknown aetiology. The role of potential co-factors, including other viruses and host susceptibility, requires further investigation., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Tobacco use is a major cause of preventable morbidity and mortality globally. Tobacco products, including smokeless tobacco (ST), generally contain tobacco-specific N -nitrosamines (TSNAs), such as N '-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-butanone (NNK), which are potent carcinogens that cause mutations in critical genes in human DNA. This review covers the series of biochemical and chemical transformations, related to TSNAs, leading from tobacco cultivation to cancer initiation. A key aim of this review is to provide a greater understanding of TSNAs: their precursors, the microbial and chemical mechanisms that contribute to their formation in ST, their mutagenicity leading to cancer due to ST use, and potential means of lowering TSNA levels in tobacco products. TSNAs are not present in harvested tobacco but can form due to nitrosating agents reacting with tobacco alkaloids present in tobacco during certain types of curing. TSNAs can also form during or following ST production when certain microorganisms perform nitrate metabolism, with dissimilatory nitrate reductases converting nitrate to nitrite that is then released into tobacco and reacts chemically with tobacco alkaloids. When ST usage occurs, TSNAs are absorbed and metabolized to reactive compounds that form DNA adducts leading to mutations in critical target genes, including the RAS oncogenes and the p53 tumor suppressor gene. DNA repair mechanisms remove most adducts induced by carcinogens, thus preventing many but not all mutations. Lastly, because TSNAs and other agents cause cancer, previously documented strategies for lowering their levels in ST products are discussed, including using tobacco with lower nornicotine levels, pasteurization and other means of eliminating microorganisms, omitting fermentation and fire-curing, refrigerating ST products, and including nitrite scavenging chemicals as ST ingredients.

Objective: Malignancy-associated bowel obstruction (MBO) is a potential sequela of advanced gynecologic cancers, adversely impacting both quality of life and prognosis. The Henry score (HS) was developed in a gastrointestinal cancer-predominant population to predict 30-day mortality. We aim to characterize MBO in gynecologic cancers and assess the utility of the HS in this population., Methods: This is a retrospective review of patients with gynecologic cancer and MBO admitted to a single academic institution from 2016 to 2021. The primary outcome is to characterize malignant small and large bowel obstructions in primary and recurrent gynecologic cancer using readmission and mortality rates. Secondary outcomes are to assess the Henry score and inpatient MBO management., Results: 179 patients totaling 269 were admissions identified, most commonly affecting patients with ovarian cancer. The majority (89.4%) were managed non-operatively while 10.6% were managed surgically. No significant differences were observed in survival for medical versus surgical management. Thirty-day mortality increased with increasing HS (0%, 0-1; 14.3%, 2-3; 40.9%, 4-5). Over 1/3 (34.1%) of patients were readmitted for recurrent or persistent MBO. Goals of care conversations were documented for 56.8% of patients with HS 4-5. Mortality rates across the entire cohort were high-20.1% and 60.9% had died by 1 and 6 months, respectively., Conclusions: Survival rates following an initial MBO admission are poor. The HS has utility in gynecologic cancers for assessing 30-day mortality and may be a useful tool to aid in the management and counseling of patients with gynecologic cancer and MBO., Competing Interests: Declaration of Competing Interest A.A.S. discloses that she has received clinical trial grant funding from AbbVie, Aravive, Astra Zeneca, Clovis, Eisai, GSK, Merck, Oncoquest, Roche/Genentech, Seagen Inc., VBL Therapeutics, and National Cancer Trial Network paid to her institution; funding for educational programs from Point of Care, Clinical Care Options, Curio Science, Peerview, Bio ASCEND, Research to Practice, GOG Foundation, and Duke University; materials (Ipatasertib and bevacizumab) for preclinical research from Genentech; travel support to attend meetings for GOG Foundation, NRG Oncology, Society of Gynecologic Oncology, American Association of Obstetrics and Gynecology, AbbVie Advisory Board, and Tesaro Advisory Board; she has participated in Advisory Boards (uncompensated) for AstraZeneca, Clovis, Immunogen, Merck, Mersana, and Onconova; Clinical Trial Steering Committees (uncompensated) for the AxXelerate trial (Aravive), AtTEnd trial (Hoffman-LaRoche), the Oval Trial (VBL Therapeutics), and the FLORA-5 trial (Oncoquest); and has leadership roles in GOG Foundation, NRG Oncology (paid), Society of Gynecologic Oncology, American Association of Obstetrics and Gynecology within the past 36 months. B.A.D. discloses that she has received honoraria for GSK advisory board participation and OncLive panel discussion within the last 24 months., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Human papillomavirus (HPV)-related squamous intraepithelial lesion (SIL) or malignancy is associated with a significantly increased risk of second-site SIL or malignancy. The primary objective of this study was to determine the feasibility and acceptability of concurrent anal, cervical, and vulvovaginal screening in patients with a history of HPV-related gynecologic high-grade SIL or malignancy. The secondary objective was to assess subjects' knowledge regarding HPV screening and risks., Methods: Women with high-grade cervical, vulvar, or vaginal SIL or malignancy were enrolled during a 1-year pilot period. Subjects with cervical SIL or malignancy underwent vulvar examination and anoscopy. Subjects with vulvovaginal SIL or malignancy underwent Pap test if indicated and anoscopy. Appropriate referrals were made for abnormal findings. Feasibility was assessed by compliance using study acceptance rate, screening procedure adherence, and referral adherence. Acceptability was assessed using a Likert-scaled question after completion of screening procedures., Results: One hundred three women with a diagnosis of high-grade vulvovaginal or cervical SIL or carcinoma were approached regarding study enrollment; of these, 74 (71.8%) enrolled. The median score on the HPV knowledge assessment was 8.1 ± 1.6 (max score 10). Seventy-three (98.6%) of 74 patients rated the screening procedures as acceptable (score of 5/5). On examination, 14 (18.9%) subjects had abnormalities noted; 7 (9.5%) were referred for colorectal surgical evaluation, and 6/7 (85.7%) were compliant with their referral appointments., Conclusions: Screening examinations for other HPV-related SILs and malignancies, including Pap tests, vulvovaginal inspection, and anoscopy, are acceptable to patients, with abnormal findings in almost 1 in 5 women., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2023, ASCCP.)

The transition to a new electronic health record (EHR) system requires an understanding of how the new system addresses the needs, business processes, and current activities of a healthcare system. To address such requirements, a multidisciplinary team conducted a current state workflow assessment (CSWFA) of clinical and administrative functions to elicit and document business processes (via process diagrams), requirements, workarounds, and process issues (i.e., user interface issues, training gaps) at one healthcare facility. We provided a novel method of evaluating the implementation process to ensure that a CSWFA was documented with key stakeholders. In this analysis, we describe the CSWFA approach and expected outcomes with a specific emphasis on how a qualitative approach can be integrated to explore underlying patterns and relationships in the data. Overall, this methodology enables practitioners to deliver data-driven support initiatives that optimize EHR implementation while considering user experience, productivity, and patient safety., (Copyright © 2023 by the American Health Information Management Association.)

Transmission trees can be established through detailed contact histories, statistical or phylogenetic inference, or a combination of methods. Each approach has its limitations, and the extent to which they succeed in revealing a 'true' transmission history remains unclear. In this study, we compared the transmission trees obtained through contact tracing investigations and various inference methods to identify the contribution and value of each approach. We studied eighty-six sequenced cases reported in Guinea between March and November 2015. Contact tracing investigations classified these cases into eight independent transmission chains. We inferred the transmission history from the genetic sequences of the cases (phylogenetic approach), their onset date (epidemiological approach), and a combination of both (combined approach). The inferred transmission trees were then compared to those from the contact tracing investigations. Inference methods using individual data sources (i.e. the phylogenetic analysis and the epidemiological approach) were insufficiently informative to accurately reconstruct the transmission trees and the direction of transmission. The combined approach was able to identify a reduced pool of infectors for each case and highlight likely connections among chains classified as independent by the contact tracing investigations. Overall, the transmissions identified by the contact tracing investigations agreed with the evolutionary history of the viral genomes, even though some cases appeared to be misclassified. Therefore, collecting genetic sequences during outbreak is key to supplement the information contained in contact tracing investigations. Although none of the methods we used could identify one unique infector per case, the combined approach highlighted the added value of mixing epidemiological and genetic information to reconstruct who infected whom., (© The Author(s) 2023. Published by Oxford University Press.)

Objective: The majority of tumor sequencing currently performed on cancer patients does not include a matched normal control, and in cases where germline testing is performed, it is usually run independently of tumor testing. The rates of concordance between variants identified via germline and tumor testing in this context are poorly understood. We compared tumor and germline sequencing results in patients with breast, ovarian, pancreatic, and prostate cancer who were found to harbor alterations in genes associated with homologous recombination deficiency (HRD) and increased hereditary cancer risk. We then evaluated the potential for a computational somatic-germline-zygosity (SGZ) modeling algorithm to predict germline status based on tumor-only comprehensive genomic profiling (CGP) results., Methods: A retrospective chart review was performed using an academic cancer center's databases of somatic and germline sequencing tests, and concordance between tumor and germline results was assessed. SGZ modeling from tumor-only CGP was compared to germline results to assess this method's accuracy in determining germline mutation status., Results: A total of 115 patients with 146 total alterations were identified. Concordance rates between somatic and germline alterations ranged from 0% to 85.7% depending on the gene and variant classification. After correcting for differences in variant classification and filtering practices, SGZ modeling was found to have 97.2% sensitivity and 90.3% specificity for the prediction of somatic versus germline origin., Conclusions: Mutations in HRD genes identified by tumor-only sequencing are frequently germline. Providers should be aware that technical differences related to assay design, variant filtering, and variant classification can contribute to discordance between tumor-only and germline sequencing test results. In addition, SGZ modeling had high predictive power to distinguish between mutations of somatic and germline origin without the need for a matched normal control, and could potentially be considered to inform clinical decision-making., (© The Author(s) 2022. Published by Oxford University Press.)

Little filtered cigars are tobacco products with many cigarette-like characteristics. However, despite cigars falling under the U.S. Food and Drug Administration regulatory authority, characterizing flavors, which are still allowed in little filtered cigars, and filter design may influence how people use the products and the resulting exposure to harmful and potentially harmful constituents. We estimated nicotine mouth level intake (MLI) from analyses of little cigar filter butt solanesol levels, brand characteristics, carbon monoxide boost, and puff volume in 48 dual cigarette/cigar users during two repeat bouts of ad lib smoking of three little filtered cigar brands. Mean nicotine MLI for the three brands was significantly different with Swisher Sweets (0.1% ventilation) Cherry at 1.20 mg nicotine, Cheyenne Menthol (1.5%) at 0.63 mg, and Santa Fe unflavored (49%) at 0.94 mg. The association between nicotine MLI and puff volume was the same between Cheyenne Menthol and Santa Fe unflavored. However, these were different from Swisher Sweets Cherry. At least five main factors─flavor, ventilation, filter design, nicotine delivery related to tar, and user puff volume─may directly or indirectly impact MLI and its association with other measures. We found that users of little filtered cigars that have different filter ventilation and flavor draw dissimilar amounts of nicotine from the product, which may be accompanied by differences in exposure to other harmful smoke constituents.

Background: Seasonal epidemics of respiratory syncytial virus (RSV) cause a clinically significant burden of disease among young children. Non-pharmaceutical interventions targeted at SARS-CoV-2 have affected the activity of other respiratory pathogens. We describe changes in the epidemiology of RSV among children younger than 5 years in England since 2020., Methods: Surveillance data on RSV infections, comprising laboratory-confirmed cases, proportion of positive tests, hospital admissions for RSV-attributable illness, and syndromic indicators for RSV-associated disease (emergency department attendances for acute bronchitis or bronchiolitis, non-emergency health advice telephone service [NHS 111] calls for cough, general practitioner [GP] in-hours consultations for respiratory tract infections, and GP out-of-hours contacts for acute bronchitis or bronchiolitis) were analysed from Dec 29, 2014 to March 13, 2022, for children younger than 5 years. Data were extracted from national laboratory, clinical, and syndromic surveillance systems. Time-series analyses using generalised linear models were used to estimate the effect of non-pharmaceutical interventions targeting SARS-CoV-2 on RSV indicators, with absolute and relative changes calculated by comparing observed and predicted values., Findings: RSV-associated activity was reduced for all RSV indicators during winter 2020-21 in England, with 10 280 (relative change -99·5% [95% prediction interval -100·0 to -99·1]) fewer laboratory-confirmed cases, 22·2 (-99·6%) percentage points lower test positivity, 92 530 (-80·8% [-80·9 to -80·8]) fewer hospital admissions, 96 672 (-73·7% [-73·7 to -73·7]) fewer NHS 111 calls, 2924 (-88·8% [-90·4 to -87·2]) fewer out-of-hours GP contacts, 91 304 (-89·9% [-90·0 to -89·9]) in-hours GP consultations, and 27 486 (-85·3% [-85·4 to -85·2]) fewer emergency department attendances for children younger than 5 years compared with predicted values based on winter seasons before the COVID-19 pandemic. An unprecedented summer surge of RSV activity occurred in 2021, including 11 255 (1258·3% [1178·3 to 1345·8]) extra laboratory-confirmed cases, 11·6 percentage points (527·3%) higher test positivity, 7604 (10·7% [10·7 to 10·8]) additional hospital admissions, 84 425 (124·8% [124·7 to 124·9]) more calls to NHS 111, 409 (39·0% [36·6 to 41·8]) more out-of-hours GP contacts, and 9789 (84·9% [84·5 to 85·4]) more emergency department attendances compared with the predicted values, although there were 21 805 (-34·1% [-34·1 to -34·0]) fewer in-hours GP consultations than expected. Most indicators were also lower than expected in winter 2021-22, although to a lesser extent than in winter 2020-21., Interpretation: The extraordinary absence of RSV during winter 2020-21 probably resulted in a cohort of young children without natural immunity to RSV, thereby raising the potential for increased RSV incidence, out-of-season activity, and health-service pressures when measures to restrict SARS-CoV-2 transmission were relaxed., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Mainstream smoke yields of hydrogen cyanide (HCN) and three aromatic amines, 1-aminonaphthalene, 2-aminonaphthalene, and 4-aminobiphenyl, from 60 little cigar brands currently on the US market were measured for both International Organization for Standardization (ISO) and Canadian Intense (CI) smoking regimens. The smoke yields are compared with those from 50 cigarette products measured by Counts et al. of Philip Morris USA (PMUSA) in 2005 [Counts et al. Regul. Toxicol. Pharmacol. 2005 41, 185-227] and 50 cigarette products measured by the Centers for Disease Control and Prevention (CDC) in cooperation with the Food and Drug Administration (FDA) in 2012 [Tynan et al. Consumption of Cigarettes and Combustible Tobacco: United States, 2000-2011. In Morbidity and Mortality Weekly Report ; Centers for Disease Control and Prevention, 2012; 565-580]. For the little cigars, the average HCN yield with the ISO smoking regimen is 335 μg/cigar (range: 77-809 μg/cigar), which is 332% higher than the average of 50 PMUSA 2005 cigarettes and 243% higher than the average of 50 CDC/FDA 2012 cigarettes. For the CI smoking regimen, the average HCN yield is 619 μg/cigar (range: 464-1045 μg/cigar), which is 70.5% higher than the average of 50 PMUSA 2005 cigarettes and 69% higher than the average of the 50 CDC/FDA 2012 cigarettes. For aromatic amines, the average ISO smoking regimen smoke yields are 36.6 ng/cigar (range: 15.9-70.6 ng/cigar) for 1-aminonaphthalene, 24.6 ng/cigar (range: 12.3-36.7 ng/cigar) for 2-aminonaphthalene, and 5.6 ng/cigar (range: 2.3-17.2 ng/cigar) for 4-aminobiphenyl. The average ISO yields of aromatic amines from little cigars are 141% to 210% higher compared to the average yields of 50 PMUSA cigarettes. The average CI smoke regimen yields are 73.0 ng/cigar (range: 32.1-112.2 ng/cigar) for 1-aminonaphthalene, 45.2 ng/cigar (range: 24.6-74.8 ng/cigar) for 2-aminonaphthalene, and 12.7 ng/cigar (range: 5.5-37.5 ng/cigar) for 4-aminobiphenyl. The average CI aromatic amine yields are 143% to 220% higher compared to the average yields of 50 PMUSA cigarettes, almost identical to the relative yields under the ISO smoking regimen. Both HCN and aromatic amine yields are 1.5× to 3× higher for the tested little cigars than for the conventional cigarettes; however, there are notable differences in the relationships of these yields to certain product characteristics, such as weight, ventilation, and tobacco type. The higher smoke yields of these compounds from little cigars indicates that cigar smokers may be at risk of a higher exposure to HCN and aromatic amines on a per stick basis and thus increased health concerns.

Background: Smokeless tobacco (ST) products are widely used throughout the world and contribute to morbidity and mortality in users through an increased risk of cancers and oral diseases. Bacterial populations in ST contribute to taste, but their presence can also create carcinogenic, Tobacco-Specific N-nitrosamines (TSNAs). Previous studies of microbial communities in tobacco products lacked chemistry data (e.g. nicotine, TSNAs) to characterize the products and identify associations between carcinogen levels and taxonomic groups. This study uses statistical analysis to identify potential associations between microbial and chemical constituents in moist snuff products., Methods: We quantitatively analyzed 38 smokeless tobacco products for TSNAs using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and nicotine using gas chromatography with mass spectrometry (GC-MS). Moisture content determinations (by weight loss on drying), and pH measurements were also performed. We used 16S rRNA gene sequencing to characterize the microbial composition, and additionally measured total 16S bacterial counts using a quantitative PCR assay., Results: Our findings link chemical constituents to their associated bacterial populations. We found core taxonomic groups often varied between manufacturers. When manufacturer and flavor were controlled for as confounding variables, the genus Lactobacillus was found to be positively associated with TSNAs. while the genera Enteractinococcus and Brevibacterium were negatively associated. Three genera (Corynebacterium, Brachybacterium, and Xanthomonas) were found to be negatively associated with nicotine concentrations. Associations were also investigated separately for products from each manufacturer. Products from one manufacturer had a positive association between TSNAs and bacteria in the genus Marinilactibacillus. Additionally, we found that TSNA levels in many products were lower compared with previously published chemical surveys. Finally, we observed consistent results when either relative or absolute abundance data were analyzed, while results from analyses of log-ratio-transformed abundances were divergent., Competing Interests: The commercial affiliation of authors (LMK) does not alter their adherence to PLOS ONE policies on sharing data and materials.

Chemicals of unknown inhalational toxicity are present in electronic cigarette and vaping products. E-cigarettes typically contain nicotine and other relatively hydrophilic chemicals while vaping products typically contain cannabinoids and other hydrophobic chemicals. For example, vaping products can include hydrophobic terpenes such as squalane (SQA) and squalene (SQE). However, little is known about the SQA and SQE transmission from liquid to aerosol. SQA and SQE are used in commercial products that are applied dermally and ingested orally, but limited information is available on their inhalational exposure and toxicity. We developed and validated a quantitative method to measure SQE and SQA in bronchoalveolar lavage fluid to assess if these chemicals accumulate in lung epithelial lining fluid after inhalation. Calibration curves spanned a range of 0.50-30.0 µg analyte per mL bronchoalveolar lavage fluid. Recoveries were found to be 97-105% for SQE and 81-106% for SQA. Limits of detection were 0.50 μg/ml for both SQE and SQA. The method was applied to bronchoalveolar lavage fluid samples of patients from the 2019 outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI) and a comparison group. Neither SQA nor SQE was detected above the method LOD for any samples analyzed; conversely, SQA or SQE were reproducibly measured in spiked quality control BAL fluids (relative standards deviations <15% for both analytes). Further applications of this method may help to evaluate the potential toxicity of SQA and SQE chronically inhaled from EVPs., 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 © 2022 Cowan, Tran, Watson, Blount and Valentín-Blasini.)

Objective: To assess the effects of a quality improvement (QI) initiative designed to reduce non-surgical readmissions on a gynecologic oncology service., Methods: A two-phase QI initiative was implemented on an inpatient gynecologic oncology service to reduce non-surgical 30-day readmissions. Phase 1, from July 2018 to June 2020, included trainee education, frequent physical therapy consultation, pharmacy discharge medication review, 72-h post-discharge telephone call, and standardized 10-day clinic follow-up after discharge. Phase 2, from July 2020 to December 2020, incorporated a nurse practitioner to perform discharge navigation and arrange outpatient follow-up. The incidence of non-surgical readmissions during these phases was compared to that of a baseline period (July 2017-June 2018). We also assessed readmissions to identify common indications and evaluate potential demographic and clinical risk factors., Results: Of 390 total non-surgical gynecologic oncology admissions, 100 were readmitted within 30 days (25.6%). Gastrointestinal tract (GI) obstruction, malignancy-associated pain and infection were the most common symptomatic diagnoses at the index admission, and 30% of readmitted patients had an identical indication for readmission. Compared to the baseline period, we observed a reduction in non-surgical readmissions from 34.1% to 22.6% in Phase 1 and to 18.9% in Phase 2 (p < 0.03) based on internal review, and a reduction from 13.9% to 11.9% in Phase 1 and to 4.7% in Phase 2 (p = 0.04) based on healthcare performance tracking data., Conclusions: 30-day hospital readmission among non-surgical gynecologic oncology patients is common. Implementation of a multifaceted readmissions reduction QI initiative significantly improved readmission rates., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The most alarming aspect of the Sudanese toombak smokeless tobacco is that it contains high levels of highly toxic tobacco-specific nitrosamines (TSNAs). Understanding the microbiology of toombak is of relevance because TSNAs are an indirect result of microbial-mediated nitrate reductions. We conducted shotgun metagenomic sequencing on a toombak product for which relevant features are presented here. The microbiota was composed of over 99% Bacteria. The most abundant taxa included Actinobacteria, specifically the genera Enteractinococcus and Corynebacterium, while Firmicutes were represented by the family Bacillaceae and the genus Staphylococcus. Selected gene targets were nitrate reduction and transport, antimicrobial resistance, and other genetic transference mechanisms. Canonical nitrate reduction and transport genes (i.e. nar) were found for Enteractinococcus and Corynebacterium while various species of Staphylococcus exhibited a notable number of antimicrobial resistance and genetic transference genes. The nitrate reduction activity of the microbiota in toombak is suspected to be a contributing factor to its high levels of TSNAs. Additionally, the presence of antimicrobial resistance and transference genes could contribute to deleterious effects on oral and gastrointestinal health of the end user. Overall, the high toxicity and increased incidences of cancer and oral disease of toombak users warrants further investigation into the microbiology of toombak., (© 2021 Society for Applied Microbiology. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

A quantitative method was developed to measure four harmful carbonyls (acetaldehyde, acrolein, crotonaldehyde, and formaldehyde) in aerosol generated from e-cigarette, or vaping, products (EVPs). The method uses a commercially available sorbent bed treated with a derivatization solution to trap and stabilize reactive carbonyls in aerosol emissions from EVPs to reduce reactive analyte losses and improve quantification. Analytes were extracted from the sorbent material using acetonitrile and analyzed via high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The method was applied to aerosols generated from products obtained from case patients with EVP use-associated lung injury (EVALI). The method accuracy ranged from 93.6 to 105% in the solvent and 99.0 to 112% in the matrix. Limits of detection (LODs) were in the low nanogram range at 0.735-2.10 ng for all analytes, except formaldehyde at 14.7 ng. Intermediate precision, as determined from the replicate measurements of quality-control (QC) samples, showed a relative standard deviation (RSD) of less than 20% for all analytes. The EVALI case-related products delivered aerosol containing the following ranges of carbonyls: acetaldehyde (0.0856-5.59 μg), acrolein (0.00646-1.05 μg), crotonaldehyde (0.00168-0.108 μg), and formaldehyde (0.0533-12.6 μg). At least one carbonyl analyte was detected in every product. Carbonyl deliveries from EVALI-associated products of all types are consistent with the previously published results for e-cigarettes, and levels are lower than those observed in smoke from combustible cigarettes. This method is rugged, has high throughput, and is well suited for quantifying four harmful carbonyls in aerosol emissions produced by a broad spectrum of devices/solvents, ranging from e-cigarette containing polar solvents to vaping products containing nonpolar solvents., Competing Interests: The authors declare no competing financial interest., (Not subject to U.S. Copyright. Published 2022 by American Chemical Society.)

Objective: We designed a multi-faceted intervention to increase the rate of outpatient goals of care (GOC) conversations in women with gynecologic cancers who are at high-risk of death., Methods and Materials: A multidisciplinary team developed an educational program around GOC conversations at end-of-life and chose criteria to prospectively identify patients at high-risk of death who might benefit from timely GOC conversations: recurrent or metastatic endometrial, cervical or vulvar cancer or platinum-resistant ovarian cancer. Gynecologic oncology provider consensus was built regarding the need to improve the quality and timing of GOC conversations. Eligible outpatients were prospectively identified and providers alerted pre-encounter; timely GOC documentation within 3 visits of high-risk identification was tracked. Our institution concurrently and subsequently tracked GOC documentation during the last 6 months of life among all established oncology patients., Results: Of 220 pilot period high-risk patients (96 pre- and 124 during pilot period 2017-2018), timely GOC discussion documentation increased from 30.2% to 88.7% (p < 0.001) and this increase was sustained over time. In the post-pilot period (2019-2020), among patients seen by oncologists during last 6 months of life, compared to other cancer types, gynecologic cancer patients had a higher rate of GOC documentation (81% versus 9%; p < 0.001), a lower rate of receiving chemotherapy during the last 14 days of life (2% vs 5%; p = 0.051), and no difference in end-of-life admissions (29% vs 31%; p = NS)., Conclusions: Implementation of systematic outpatient identification of high-risk gynecologic oncology patients is feasible, sustainable, and increases the timely conduct of GOC conversations., Competing Interests: Declaration of Competing Interest No author has a COI pertinent to the work presented., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Typhoid is an endemic in Fiji with increases observed since the early 2000s and frequent outbreaks reported. We assessed the diagnostic accuracy of currently available typhoid rapid diagnostic tests (RDTs) (TUBEX, Typhidot Rapid, and Test-It assay) to establish their performance against blood culture in Fiji and to examine their suitability for rapid typhoid outbreak identification. The performance of RDTs was assessed in the public health reference laboratory in Suva, Fiji, according to the manufacturers' instructions. A simulation was used to examine the potential use of RDTs for attribution of a febrile illness outbreak to typhoid. For the diagnostic evaluation, 179 patients were included; 49 had blood culture-confirmed typhoid, 76 had fever as a result of non-typhoid etiologies, and 54 were age-matched community controls. The median (interquartile range) age was 29 (20-46) years. Of the participants, 92 (51.4%) were male and 131 (73.2%) were indigenous Fijians. The sensitivities of the tests were 77.6% for TUBEX, 75.5% for Typhidot Rapid, and 57.1% for Test-It assay. The Test-It assay had the highest specificity of 93.4%, followed by Typhidot Rapid 85.5% and TUBEX 60.5%. Typhidot Rapid had the best performance in the simulation for attribution of a febrile illness outbreak to typhoid. Typhoid RDTs performed suboptimally for individual patient diagnosis due to low sensitivity and variable specificity. We demonstrate that RDTs could be useful in the field for rapid attribution of febrile illness outbreaks to typhoid. Typhidot Rapid had the best combination of sensitivity, specificity, positive and negative predictive values, cost, and ease of use for this purpose.

A method for determining the fraction of free-base nicotine (α fb ) in electronic cigarette liquids ("e-liquids") based on headspace solid-phase microextraction (h-SPME) is described. The free-base concentration c e,fb = α fb c e,T , where c e,T is the total (free-base + protonated) nicotine in the liquid. For gas/liquid equilibrium of the volatile free-base form, the headspace nicotine concentration is proportional to c e,fb and thus also to α fb . Headspace nicotine is proportionally absorbed with an SPME fiber. The fiber is thermally desorbed in the heated inlet of a gas chromatograph coupled to a mass spectrometer: the desorbed nicotine is measured by gas chromatography-mass spectrometry. For a second h-SPME measurement, an adequate base is added to the sample vial to convert essentially all protonated nicotine to the free-base form (α fb → 1.0). The ratio of the first h-SPME measurement to the second h-SPME measurement gives α fb in the initial sample. Using gaseous ammonia as the added base, the method was (1) verified using lab-prepared e-liquid solutions with known α fb values and (2) used to determine the α fb values for 18 commercial e-liquids. The measured α fb values ranged from 0.0 to 1.0. Increasing measurement error with decreasing α fb caused modestly lower method precision at small α fb . Adding a liquid organic base may be more convenient than adding gaseous ammonia: one of the samples was examined using triethylamine as the added base; the measurements agreed well (with ammonia, 0.27 ± 0.01; with triethylamine, 0.26 ± 0.04). Other workers have proposed examining the nicotine protonation state in e-liquids using three steps: (1) 1:10 dilution with CO 2 -free water; (2) measurement of pH; and (3) calculation of the resulting values for α fb,w,1:10 , the free-base fraction in the diluted mostly aqueous phase. As expected and verified here, because of the generally greater abilities of organic acids to protonate nicotine in water versus in an e-liquid phase, α fb,w,1:10 values can be significantly less than actual e-liquid α fb values when α fb is not close to either 0 or 1.

Standard machine smoking protocols provide useful information for examining the impact of design parameters, such as filter ventilation, on mainstream smoke delivery. Unfortunately, their results do not accurately reflect human smoke exposure. Clinical research and topography devices in human studies yield insights into how products are used, but a clinical setting or smoking a cigarette attached to such a device may alter smoking behavior. To better understand smokers' use of filtered cigarette products in a more natural environment, we developed a low-cost, high-throughput approach to estimate mainstream cigarette smoke exposure on a per-cigarette basis. This approach uses an inexpensive flatbed scanner to scan smoked cigarette filter butts and custom software to analyze tar-staining patterns. Total luminosity, or optical staining density, of the scanned images provides quantitative information proportional to mainstream smoke-constituent deliveries on a cigarette-by-cigarette basis. Duplicate sample analysis using this new approach and our laboratory's gold-standard liquid chromatography/tandem mass spectrometry (LC/MS/MS) solanesol method yielded comparable results (+7% bias) from the analysis of 20 commercial cigarettes brands (menthol and nonmentholated). The brands varied in design parameters such as length, filter ventilation, and diameter. Plots correlating the luminosity to mainstream smoked-nicotine deliveries on a per-cigarette basis for these cigarette brands were linear (average R 2 > 0.91 for nicotine and R 2 > 0.83 for the tobacco-specific nitrosamine NNK), on a per-brand basis, with linearity ranging from 0.15 to 3.00 mg nicotine/cigarette. Analysis of spent cigarette filters allows exposures to be characterized on a per-cigarette basis or a "daily dose" via summing across results from all filter butts collected over a 24 h period. This scanner method has a 100-fold lower initial capital cost for equipment than the LC/MS/MS solanesol method and provides high-throughput results (~200 samples per day). Thus, this new method is useful for characterizing exposure related to filtered tobacco-product use.

We developed a quantitative method for analyzing nicotine and menthol in e-cigarette, or vaping, products (EVPs). These products may adversely impact health through inhalational exposure to addictive and harmful chemicals. The presence of unknown substances in do-it-yourself e-liquids, counterfeits, or unregulated products may increase exposure to harmful chemicals, as underscored by the 2019 EVP use-associated lung injury (EVALI) outbreak. To minimize these risks, it is important to accurately quantify nicotine and menthol in e-liquids and aerosol emissions to evaluate EVP authenticity, verify product label accuracy, and identify potentially hazardous products. We developed a simple, versatile, high-throughput method using isotope-dilution gas chromatography-mass spectrometry for quantifying nicotine and menthol concentrations in both e-liquid contents and machine-generated aerosol emissions of EVPs. Rigorous validation has demonstrated that the method is specific, precise (CV<2.71%), accurate (percent error ≤7.0%), and robust. Linear calibration ranges from 0.01 to 1.00 mg/ml for both analytes was achieved, corresponding to expected analyte levels in e-liquids and machine-generated EVP aerosols. Limits of detection (LODs) in the final 10-ml sample extract were 0.4 μg/ml for nicotine and 0.2 μg/ml for menthol. The method was used to analyze aerosol emissions of 141 EVPs associated with the 2019 EVALI outbreak; detectable levels of nicotine (2.19-59.5 mg/g of aerosol) and menthol (1.09-10.69 mg/g of aerosol) were observed in 28 and 11%, respectively, of the samples analyzed. Nicotine was not detected in any of the tetrahydrocannabinol (THC), cannabidiol (CBD), or oil-based products, while menthol (2.95 mg/g of aerosol) was only detected in one of these products (THC-labeled). The analytical method can be used to quantify nicotine and menthol concentrations in the e-liquids and aerosols from a range of EVPs, and these findings highlight a difference between e-cigarette and other vaping products., 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 © 2021 Pérez, Watson, Blount and Valentín-Blasini.)

The most commonly observed forms of aluminum, silicon and titanium in tobacco products are aluminum silicates (e.g., kaolin), silica and titanium(IV) oxide. These compounds are neither water soluble nor volatile at cigarette combustion temperatures. Rather, they are transported in mainstream tobacco smoke as particles after being freed by combustion from the tobacco filler and can induce pulmonary inflammation when inhaled. Aluminum silicate particles are the most frequently observed particles in the pulmonary macrophages of smokers and have become known as 'smokers' inclusions'. A relatively new technique, single particle triple quadrupole inductively coupled plasma-mass spectrometry was used to analyze aluminum-, silicon- and titanium-containing particle deliveries in cigarette and little cigar mainstream tobacco smoke, and to collect information on solid inorganic particles. The mass concentration of aluminum-containing particles transmitted in mainstream smoke was low (0.89-0.56 ng/cigarette), which was not surprising because aluminum silicates are not volatile. Although the collective masses (ng/cigarette) of aluminum-, silicon- and titanium-containing particles under 100 nm diameter transported in mainstream smoke were low, an abundance of 'ultrafine' particles (particles < 100 nm or nanoparticles) was observed. Limitations of the particle background equivalent diameter (the smallest detectable particle size (MassHunter 4.5 Software) due to the environmentally ubiquitous silicon background restricted the determination of silica nanoparticles, but silica particles slightly below 200 nm diameter were consistently detected. Aluminum- and titanium-containing nanoparticles were observed in all cigarette and little cigar samples, with titanium(IV) oxide particle deliveries consistently fewer in number and smaller in diameter than the other two types of particles. The highest concentrations of aluminum-containing particles (as kaolin) were in the nanoparticle range with much lower concentrations extending to the larger particle sizes (>100 nm). The number and range of particle sizes determined in mainstream smoke is consistent with pulmonary deposition of aluminum silicates described by other researchers as contributing to the 'smokers' inclusions' observed in pulmonary macrophages., (Published by Oxford University Press. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

The long-term health effects of using e-cigarette, or vaping, products (EVPs; also known as e-cigarettes, electronic nicotine delivery systems, and vape pens) remain largely unknown. The inhalation of excipients, such as propylene glycol (PG) and glycerin (GLY), may have long-term health effects. In addition to the direct health effects of PG and GLY, glycerin-containing products can be contaminated with toxic ethylene glycol (EG) and diethylene glycol (DEG). To assess this issue, we developed a simple, versatile, high-throughput isotope dilution gas chromatography-tandem mass spectrometry method for quantifying these common excipients and contaminants. The method is applicable to both the liquid contents and machine-generated aerosols of EVPs. Our rigorous method validation demonstrates that the new method is specific, precise, accurate, and rugged/robust. The calibration range is linear from 0.1-7 mg for the excipients and 2.5-1,000 µg for the contaminants. These ranges encompass expected excipients levels in EVP e-liquids and their machine-generated aerosols and the relevant maximum residue safety limit of 1 mg/g, or 0.1% (w/w), for the contaminants. The calculated limits of detection for PG, GLY, EG, and DEG were determined as 0.0109 mg, 0.0132 mg, 0.250 µg, and 0.100 µg, respectively. The method was applied to the aerosol emissions analysis of 141 EVPs associated with the 2019 lung injury outbreak, and found typical levels of PG (120.28-689.35 mg/g of aerosol) and GLY (116.83-845.96 mg/g of aerosol) in all nicotine-containing products; PG (81.58-491.92 mg/g of aerosol) and GLY (303.86-823.47 mg/g of aerosol) in 13% of cannabidiol (CBD) products; PG (74.02-220.18 mg/g of aerosol) and GLY (596.43-859.81 mg/g of aerosol) in products with neither nicotine nor CBD; and none detected in tetrahydrocannabinol (THC) products. No products contained glycol contaminants above the recommended maximum residue safety limit., 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 © 2021 Pérez, Watson, Blount and Valentín-Blasini.)

Purpose: To examine the chemical composition of JUUL pods collected from a convenience sample of 16 high schools in California to identify possible consumer modification or counterfeit use., Methods: Using Gas Chromatography-Mass Spectrometry, we quantitatively analyzed the nicotine, propylene glycol (PG), and vegetable glycerin (VG) in JUUL pods (n = 26) collected from California high schools and compared results to commercial 3% (n = 15) and 5% (n = 24) JUUL pods purchased online., Results: Most of the collected JUUL pods (24/26 pods) had a nicotine concentration (43.3 mg/ml, 95% PI: 21.5-65.1) outside the prediction intervals (PI) of the 3% (33.5 mg/ml, 95% PI: 31.8-35.2) and 5% (55.0 mg/ml, 95% PI: 51.5-58.3) commercial JUUL pods. Most (73%) collected JUUL pods had VG concentrations (583.5 mg/ml, PI: 428.9-738.1) lower than the 3% (722.2 mg/ml, PI: 643.0-801.4) and 5% (710.5 mg/ml, PI: 653.1-767.8) commercial JUUL pods., Conclusions: Used JUUL products collected from high school students or found on school grounds were not chemically consistent with the manufacturer's stated formulations., (Published by Elsevier Inc.)

Two-tail t test statistical analyses of International Organization for Standardization nonintense and Canadian Intense mainstream smoke yields of total particulate matter, tar, nicotine, and carbon monoxide from cigarettes show that mean quantities are generally higher for a linear smoking machine at a 95% confidence level but a rotary smoking machine has better precision. A novel "super pad" analysis concept combines four smaller filter pads from a linear smoking machine, resulting in increased mean constituent yields and reduced variability. Although measurement variability is still greater than that of rotary machines, super padding may be useful to reduce the variance caused by linear smoking machines.

Background: Chemoprophylactics against emerging epidemic and pandemic infectious diseases offer potential for prevention but require efficacy and safety analysis before widespread use can be recommended. Chemoprophylaxis with repurposed drugs enables deployment ahead of development of novel vaccines. It may have particular utility as a stopgap ahead of vaccine deployment or when vaccines become less effective on virus variants, in countries where there may be structural inaccessibility to vaccines or in specific risk-groups. Rapid implementation of robust trial designs is a persistent challenge in epidemics. We systematically reviewed SARS-CoV-2 and COVID-19 chemoprophylaxis trial registrations from the first 21 weeks of the pandemic to critically appraise significant design features and alignment of study populations to clinical and public health uses, and describe candidate chemoprophylactic agents., Methods: We searched online international trial databases from 31 Dec 2019 to 26 May 2020 using keywords "proph*" or "prevention". Trial protocols assessing efficacy of chemoprophylactic agents for COVID-19 were included. Trial components were screened for eligibility and relevant studies extracted. Key trial design features were assessed., Results: We found 76 chemoprophylaxis study registrations, proposing enrolment of 208,367 people with median size of 490 (IQR 262-1710). A randomised design was specified for 63 trials, 61 included a control group and total proposed enrolment size was 197,010, median 600 (IQR 236-1834). Four protocols provided information on effect size sought. We estimate that for a control group attack rate of 10%, 66% of trials would be underpowered to detect a 50% effect size, and 97% of trials would be underpowered to detect a 30% effect size (at the 80% level). We found evidence of adaptive design in one trial registration only. Laboratory-confirmed infection with or without symptoms was the most common primary outcome. Polymerase chain reaction testing alone was used in 46% of trials, serological testing in 6.6% and 14.5% used both testing methods. Healthcare workers were the target population in 52/79 (65.8%) trials: 49 pre-exposure prophylaxis (PrEP) and 3 post-exposure prophylaxis (PEP). Sixteen trials (20.3%) planned PEP in close contacts. Five studies (6.3%) considered chemoprophylaxis in clinical-risk patients. Older adults were the focus of recruitment in only 3 (3.8%) studies (all long-term care facilities). Two (2.5%) studies of PrEP in the general population included older adults. Hydroxychloroquine was the most common candidate agent in 55/79 trials (69.6%), followed by chloroquine (4/79, 5.0%) and lopinavir/ritonavir (3/79, 3.8%)., Conclusion: Many registered COVID-19 chemoprophylaxis efficacy trials were underpowered to detect clinically meaningful protection at epidemiologically informed attack rates. This, compounded with the time that has taken to organise these trials as compared to the rapid development of COVID-19 vaccines, has rendered these trials of marginal importance. International coordination mechanisms and collaboration is required. Supporting the design of feasible chemoprophylaxis trials, large enough to generate strong evidence, early on in an epidemic using adaptive platform trial designs will allow structured entry and exit of candidate agents and rapid stand-up of trial infrastructure., Review Protocol Registration: Our protocol is registered at https://www.osf.io/vp56f on May 20, 2020.

Study Objectives: Consumer sleep-tracking devices are widely used and becoming more technologically advanced, creating strong interest from researchers and clinicians for their possible use as alternatives to standard actigraphy. We, therefore, tested the performance of many of the latest consumer sleep-tracking devices, alongside actigraphy, versus the gold-standard sleep assessment technique, polysomnography (PSG)., Methods: In total, 34 healthy young adults (22 women; 28.1 ± 3.9 years, mean ± SD) were tested on three consecutive nights (including a disrupted sleep condition) in a sleep laboratory with PSG, along with actigraphy (Philips Respironics Actiwatch 2) and a subset of consumer sleep-tracking devices. Altogether, four wearable (Fatigue Science Readiband, Fitbit Alta HR, Garmin Fenix 5S, Garmin Vivosmart 3) and three nonwearable (EarlySense Live, ResMed S+, SleepScore Max) devices were tested. Sleep/wake summary and epoch-by-epoch agreement measures were compared with PSG., Results: Most devices (Fatigue Science Readiband, Fitbit Alta HR, EarlySense Live, ResMed S+, SleepScore Max) performed as well as or better than actigraphy on sleep/wake performance measures, while the Garmin devices performed worse. Overall, epoch-by-epoch sensitivity was high (all ≥0.93), specificity was low-to-medium (0.18-0.54), sleep stage comparisons were mixed, and devices tended to perform worse on nights with poorer/disrupted sleep., Conclusions: Consumer sleep-tracking devices exhibited high performance in detecting sleep, and most performed equivalent to (or better than) actigraphy in detecting wake. Device sleep stage assessments were inconsistent. Findings indicate that many newer sleep-tracking devices demonstrate promising performance for tracking sleep and wake. Devices should be tested in different populations and settings to further examine their wider validity and utility., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society.)

Background: Identifying mutation-carrying relatives of patients with hereditary cancer syndromes via cascade testing is an underused first step in primary cancer prevention. A feasibility study of facilitated genetic testing of at-risk relatives of patients with a known pathogenic mutation demonstrated encouraging uptake of cascade testing., Primary Objective: Our primary objective is to compare the proportion of genetic testing of identified first-degree relatives of probands with a confirmed BRCA1/2 mutation randomized to a facilitated cascade testing strategy versus standard of care, proband-mediated, information sharing., Study Hypothesis: We hypothesize that facilitated cascade testing will drive significantly higher uptake of genetic testing than the standard of care., Trial Design: The FaCT (Facilitated Cascade Testing) trial is a prospective multi-institutional randomized study comparing the efficacy of a multicomponent facilitated cascade testing intervention with the standard of care. Patients with a known BRCA1/2 mutation (probands) cared for at participating sites will be randomized. Probands randomized to the standard of care group will be instructed to share a family letter with their first-degree relatives and encourage them to complete genetic testing. First-degree relatives of probands randomized to the intervention arm will receive engagement strategies with a patient navigator, an educational video, and accessible genetic testing services., Major Inclusion/exclusion Criteria: Adult participants who are first-degree relatives of a patient with a BRCA1/2 mutation and have not had prior genetic testing will be included., Primary Endpoint: Analyses will assess the proportion of first-degree relatives identified by the proband who complete genetic testing by 6 months in the intervention arm versus the control arm., Sample Size: One hundred and fifty probands with a BRCA1/2 mutation will be randomized. Each proband is expected to provide an average of 3 relatives, for an expected 450 participants., Estimated Dates for Completing Accrual and Presenting Results: January 2024., Trial Registration: NCT04613440., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: We sought to categorize the processes by which gynecologic oncology patients stop chemotherapy and to evaluate associations between these processes and end-of-life outcome metrics., Methods: A cohort of patients with metastatic or recurrent gynecologic cancer in an outpatient setting from January 2016 to May 2018 was identified. All deceased patients in this cohort were included for analysis. Processes of discontinuing chemotherapy were categorized as: 1) definitive decision inpatient; 2) definitive decision outpatient; 3) delayed decision (eg: treatment break and never resumed chemotherapy); 4) no decision. Associations between patient characteristics and clinical outcomes of those who made a definitive outpatient decision versus those who made any other type of decision were assessed., Results: 220 patients were identified; 205 patients were deceased at time of analysis. Of these, 36.6% made a definitive decision to stop chemotherapy as an outpatient, while 41.5% never made a decision to discontinue chemotherapy. Making a definitive decision as an outpatient, when compared to all other decision types, was associated with significantly lower incidence of death in the hospital (5.6% vs 21.1%, p < 0.004) and hospitalization within 30 days of death (20.8% vs 56.6%, p < 0.001), and significantly increased median time from last chemotherapy to death (135.5 vs 62 days, p < 0.001)., Conclusion: Only one in three women in this cohort of patients deceased from gynecologic cancer made a definitive decision to discontinue chemotherapy in an outpatient setting, and this process was associated with improved end-of-life outcomes. Future efforts should examine the impact of interventions designed to increase the proportion of patients who transition away from chemotherapy via shared decision making in the outpatient setting., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cigars are among the broad variety of tobacco products that have not been as extensively studied and characterized as cigarettes. Small cigars wrapped in a tobacco-containing sheet, commonly referred to as little cigars, are a subcategory that are similar to conventional cigarettes with respect to dimensions, filters, and overall appearance. Tobacco-specific nitrosamines (TSNAs) are carcinogens in the tobacco used in both little cigars and cigarettes. This study uses a validated high-performance liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS) method to measure the TSNAs 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N '-nitrosonornicotine (NNN) in the tobacco filler and the nonintense International Organization for Standardization smoking regimen, ISO 3308, and the newer ISO 20778 Cigarette Intensive (CI) smoking regimen mainstream smoke of 60 commercial little cigars. Tobacco filler NNK and NNN quantities ranged from 26 to 2950 and 1440 to 12 100 ng/g tobacco, respectively. NNK and NNN by the ISO nonintense smoking regimen ranged from 89 to 879 and 200 to 1540 ng/cigar, respectively; by the CI regimen, NNK and NNN ranged from 138 to 1570 and 445 to 2780 ng/cigar, respectively. The average transfer (%) for NNK and NNN from tobacco filler to mainstream smoke was 24% and 36% by the ISO nonintense and CI smoking regimens, respectively. By the ISO nonintense and CI smoking regimens, mainstream smoke NNK and NNN yields showed a moderate to strong correlation (ISO nonintense, R 2 = 0.60-0.68, p < 0.0001; CI, R 2 = 0.78-0.81, p < 0.0001) with tobacco filler NNK and NNN quantities. In addition, the mainstream smoke NNK and NNN yields of little cigars were determined to be 3- to 5-fold higher compared to previously tested commercial cigarettes. The mainstream smoke NNK and NNN yields have wide variation among commercial little cigars and suggest that, despite design similarities to cigarettes, machine-smoke yields of carcinogenic TSNAs are higher in little cigars.

Authorship confers credit to those responsible for a publication. In 1985, the International Committee of Medical Journal Editors criteria were founded to standardize authorship assignment. We sought to investigate practices and values in authorship assignment in Society of Gynecologic Oncology (SGO) members. An anonymous online survey was distributed to SGO members from 09/2018-10/2018. Three multivariable logistic regression models were fit to predict ICJME authorship acceptance, assignment and denial. Of 1111 members surveyed, 266 responses were received (23.9%); 30.6% reported prior authorship assignment that did not meet ICMJE criteria, and 18.8% (n = 50) reported a history of accepting authorship not meeting ICJME criteria. Reasons for non-adherence included: inclusion of the author's patients in the study (59.3%), resumé building (45.7%), and networking for career advancement (22.2%). The majority responded that ICJME criteria were generalizable (91.3%), helpful (83.8%), and considered non-adherence as scientific misconduct (66.0%). On multivariable analysis, practice duration of 5-20 years (HR 0.40, 95% CI 0.16, 0.99, p < 0.05) or > 20 years (HR 0.22, 95% CI 0.08, 0.59, p < 0.05) were significant predictors for adherence with ICMJE authorship assignment compared to fellows and those in practice < 5 years. Similarly, practice duration of 5-20 years (HR 10.0, 95% CI 2.0, 49.2, p < 0.05) or > 20 years (HR 25.9, 95% CI 1.06, 3.9, p < 0.05) were significant predictors for denial of authorship assignment compared to fellows and those in practice < 5 years. While the majority of respondents report that ICJME criteria are helpful, adherence to these criteria is a concern, especially in fellows and early-career faculty., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Zika virus (ZIKV) has caused large, brief outbreaks in isolated populations, however ZIKV can also persist at low levels over multiple years. The reasons for these diverse transmission dynamics remain poorly understood. In Fiji, which has experienced multiple large single-season dengue epidemics, there was evidence of multi-year transmission of ZIKV between 2013 and 2017. To identify factors that could explain these differences in dynamics between closely related mosquito-borne flaviviruses, we jointly fit a transmission dynamic model to surveillance, serological and molecular data. We estimate that the observed dynamics of ZIKV were the result of two key factors: strong seasonal effects, which created an ecologically optimal time of year for outbreaks; and introduction of ZIKV after this optimal time, which allowed ZIKV transmission to persist over multiple seasons. The ability to jointly fit to multiple data sources could help identify a similar range of possible outbreak dynamics in other settings.

The mainstream smoke yields of five volatile organic compounds (VOCs) were determined from 60 commercial U.S. little cigar products under ISO 3308 and Canadian Intense (CI) smoking regimens on linear smoking machines using a gas sampling bag collection. The five VOCs, 1,3-butadiene, acrylonitrile, benzene, isoprene, and toluene were analyzed using an automated GC/MS analytical method validated for measuring various VOCs in mainstream smoke. The VOCs range in amounts from micrograms to milligrams per little cigar. VOC deliveries vary considerably among the little cigar products under the ISO smoking regimen primarily due to varying filter ventilation. Under the CI smoking regimen where filter ventilation is blocked, the delivery range narrows, although individual and total VOC yields are approximately 2 fold higher than those under the ISO smoking regimen. Correlation analysis reveals strong associations between acrylonitrile and 1,3-butadiene or toluene under the ISO smoking regimen. Compared to cigarettes, little cigars delivered substantially higher VOC mainstream smoke yields under both ISO and CI smoking regimens. Moreover, little cigar smoke also contains higher VOCs than cigarette smoke when adjusted for mass of tobacco.

Nitromethane is a volatile organic compound categorized as a Group 2B carcinogen by the International Agency for Research on Cancer. It has been detected in mainstream cigarette smoke, but few reliable methods have been reported for accurate quantification. We developed, a sensitive, selective, fully validated method for the targeted determination of nitromethane in mainstream tobacco smoke in ten U.S. domestic brands and two quality control materials (3R4F and CM6). The vapor phase portion of machine-generated cigarette mainstream smoke, under modified ISO 3308:2000 regime (ISO) and modified intense regime (HCI), from single cigarettes was collected using airtight polyvinylfluoride sampling bags. The bags' contents were extracted using methanol containing an isotopically labeled internal standard followed by gas chromatography-tandem mass spectrometry. This approach is sufficiently sensitive to measure nitromethane levels in the nanogram range, with a method limit of detection of 72.3 ng/cig. Within-product variability estimated from the replicate analysis of 10 products ranged from 4.6%-16.3% (n = 6) over the two different smoking regimes, and method reproducibility estimated from two products used as quality control materials (3R4F and CM6) yielded intermediate precision values ranging from 16.6 to 20.8% (n = 20). Under HCI, nitromethane yields in machine-generated cigarette smoke from ten different domestic cigarette products ranged from 3.2 to 12 μg/cig; under ISO yields ranged from 1.6 to 4.9 μg/cig under standardized smoking machine conditions. Nitromethane yields are related to both the smoke regime (blocking of vent holes, puff duration and puff volume) and the heterogeneity of tobacco mixtures. This method provides a selective and fully validated technique to accurately quantify nitromethane in mainstream cigarette smoke, with minimal waste generation. It is an improvement over previous methods with regards to specificity, throughput, and simplicity of the sample collection process., Competing Interests: The authors report no declarations of interest.

Background: Recent advances in next-generation sequencing have allowed for an increase in molecular tumor profiling., Objective: We sought to assess the actionability and clinical utilization of molecular tumor profiling results obtained via Foundation Medicine tumor sequencing tests in uterine and ovarian cancers., Patients and Methods: We performed a single-institution retrospective chart review to obtain demographic and clinical information in patients with uterine and ovarian cancer whose tumors were submitted to Foundation Medicine for molecular tumor profiling over a 7-year period. Alterations identified on testing were stratified according to the OncoKB database actionability algorithm. Descriptive statistics were primarily used to analyze the data., Results: Tumors from 185 women with gynecologic cancer were submitted for molecular tumor profiling between 2013 and 2019. The majority of tests (144/185; 78%) were ordered after a diagnosis of recurrence. In 60 (32%), no actionable molecular alteration was identified. Thirteen (7%) identified an alteration that directed to a US Food and Drug Administration-approved therapy in that tumor type, while 112 (61%) had alterations with investigational or hypothetical treatment implications. In patients with any actionable finding, treatment was initiated in 27 (15%) based on these results., Conclusions: The majority of uterine and ovarian cancers (93%) did not have molecular alterations with corresponding Food and Drug Administration-approved treatments. Even in patients with a potentially actionable alteration, gynecologic oncologists were more likely to choose an alternative therapy. Further investigation is warranted to determine which patients with uterine and ovarian cancer are most likely to benefit from molecular tumor profiling and the ideal timing of testing. The potential to identify effective therapeutic options in a minority of patients needs to be balanced with the current limited clinical applicability of these results in most cases.