An age- and sex-specific biokinetic model for radon.

Publication 137 of the International Commission on Radiological Protection (ICRP) describes a biokinetic model for radon used to derive dose coefficients for occupational intake of radon isotopes. The model depicts transfer of inhaled or ingested radon to blood, exchange of radon between blood and tissues, and gradual loss of radon from the body based on physical laws governing transfer of a non-reactive and soluble gas between materials. This paper describes an age- and sex-specific variation of that model developed for use in an upcoming ICRP series of reports on environmental intake of radionuclides by members of the public titled 'Dose Coefficients for Intakes of Radionuclides by Members of the Public'. The proposed model modifies the model structure and transfer coefficients presented in Publication 137 to allow more realistic dosimetric treatment of bone marrow and breast and expands the model to address pre-adult ages, based on the physical principles used in the development of the model of Publication 137 together with anatomical and physiological changes occurring during human development.

Toward Microbiome Engineering: Expanding the Repertoire of Genetically Tractable Members of the Human Gut Microbiome.

Genetic manipulation is necessary to interrogate the functions of microbes in their environments, such as the human gut microbiome. Yet, the vast majority of human gut microbiome species are not genetically tractable. Here, we review the hurdles to seizing genetic control of more species. We address the barriers preventing the application of genetic techniques to gut microbes and report on genetic systems currently under development. While methods aimed at genetically transforming many species simultaneously in situ show promise, they are unable to overcome many of the same challenges that exist for individual microbes. Unless a major conceptual breakthrough emerges, the genetic tractability of the microbiome will remain an arduous task. Increasing the list of genetically tractable organisms from the human gut remains one of the highest priorities for microbiome research and will provide the foundation for microbiome engineering.

Media coverage and speculation about the impact of the COVID-19 pandemic on suicide: a content analysis of UK news.

OBJECTIVES: Since the start of the COVID-19 pandemic, there has been much concern and speculation about rises in suicide rates, despite evidence that suicides did not in fact increase in the first year of the pandemic in most countries with real-time suicide data. This public narrative is potentially harmful, as well as misleading, and is likely to be perpetuated by sensational news coverage. METHOD: Using a bespoke database, we analysed the quality and content of print and online UK news (including opinion pieces) on the impact of COVID-19 on suicidality, based on adherence to international recommendations. χ2 tests were conducted to examine variability in relation to key characteristics (eg, type of publication) and to four 'restriction phases' (based on UK government official lockdown measures) over the first 14 months of the pandemic. RESULTS: We identified 372 stories about COVID-19 and suicidality in online and print news between the first UK lockdown (March 2020) and May 2021 (when restrictions were significantly eased in the UK). Throughout this period, over a third of articles (39.2%) and headlines (41.4%) claimed or predicted a rise in suicide, often attributed to feelings of entrapment and poor mental health (especially among young people) and fueled by expert commentary and speculation. Almost a third of reports were rated as being of negative quality (116, 31.2%), and at least half included no signposting to help and support. However, reporting improved in phases of less stringent COVID-19 restrictions and over time, with later articles and headlines including fewer negative statements and predictions about rises in suicides, and greater reliance on academic evidence. CONCLUSIONS: As the longer-term consequences of the pandemic develop, and other national and global events unfold, it is increasingly important that the media, and the wider community of experts shaping its narratives, strive for a positive and evidence-informed approach to news coverage of suicide.

The burden of chlamydia, gonorrhea, and syphilis in older adults in the United States: A systematic review.

BACKGROUND: Increases in life expectancy, the availability of sexual performance enhancing medication, and changes in sexual partnering suggest that sexually transmitted infections (STIs) among older persons could be on the rise, yet there have been relatively few studies examining STIs in this demographic. Our systematic review aimed to further characterize the incidence and prevalence of chlamydia, gonorrhea, and syphilis, along with associated risk factors among older adults (45 years or older) in the United States. METHODS: We searched five electronic databases (PubMed, Embase, Cinahl, Web of Science, and Global Health) for data published from inception to January 2021. The retrieved articles were screened based on eligibility criteria, and subsequent review of relevant article bibliographies was conducted. RESULTS: Of 4748 articles identified, 23 studies met our inclusion criteria and one additional article was identified through bibliography review. Of the 23 included articles, only 3 (11.5%) were focused exclusively on evaluating STIs in an older population. We found prevalence to be the following ranges: syphilis (0-18%), chlamydia (0-14.2%) and gonorrhea (0-15%). Few studies specifically investigated risk factors in this demographic. CONCLUSIONS: The understudied burden of STIs in the older adult population substantiates the need to recognize issues surrounding sexuality in this demographic.

Burden of trichomoniasis among older adults in the United States: a systematic review.

Despite being one of the most common sexually transmitted infections (STIs) in the United States, the epidemiology of trichomoniasis remains understudied. One population that has been historically overlooked regarding STIs is that of older adults, despite many individuals remaining sexually active well into their older years. We investigated the reported prevalence and incidence of trichomoniasis in adults aged ≥45years in the United States using a systematic literature review. Twelve articles were included in the review, all assessing prevalence of trichomoniasis in this age group. Notably, no included articles assessed trichomoniasis incidence. Data collected encompassed several decades, from 1993 to 2016. Estimates of infection prevalence varied widely and ranged from 0.2% to 21.4% in included populations, with the highest prevalence typically seen among individuals seeking diagnostic testing for STIs. Several studies found increased risk for trichomoniasis in older patients compared to younger age groups. This is the first review to examine the risk of trichomoniasis in older adults, and the surprisingly high prevalence suggests that older adults may merit increased screening for trichomoniasis and sexual health education.

Comparison of Hepatic Arterial Infusion Pump Chemotherapy vs Resection for Patients With Multifocal Intrahepatic Cholangiocarcinoma.

Importance: Intrahepatic cholangiocarcinoma (iCCA) is often multifocal (ie, satellites or intrahepatic metastases) at presentation. Objective: To compare the overall survival (OS) of patients with multifocal iCCA after hepatic arterial infusion pump (HAIP) floxuridine chemotherapy vs resection. Design, Setting, and Participants: In this cohort study, patients with histologically confirmed, multifocal iCCA were eligible. The HAIP group consisted of consecutive patients from a single center who underwent HAIP floxuridine chemotherapy for unresectable multifocal iCCA between January 1, 2001, and December 31, 2018. The resection group consisted of consecutive patients from 12 centers who underwent a curative-intent resection for multifocal iCCA between January 1, 1990, and December 31, 2017. Resectable metastatic disease to regional lymph nodes and previous systemic therapy were permitted. Patients with distant metastatic disease (ie, stage IV), those who underwent resection before starting HAIP floxuridine chemotherapy, and those who received a liver transplant were excluded. Data were analyzed on September 1, 2021. Main Outcomes and Measures: Overall survival in the 2 treatment groups was compared using the Kaplan-Meier method and log-rank test. Results: A total of 319 patients with multifocal iCCA were included: 141 in the HAIP group (median [IQR] age, 62 [53-70] years; 79 [56.0%] women) and 178 in the resection group (median [IQR] age, 60 [50-69] years; 91 [51.1%] men). The HAIP group was characterized by a higher percentage of bilobar disease (88.0% [n = 124] vs 34.3% [n = 61]), larger tumors (median, 8.4 cm vs 7.0 cm), and a higher proportion of patients with 4 or more lesions (66.7% [94] vs 24.2% [43]). Postoperative mortality after 30 days was 0.8% (95% CI, 0.0%-2.1%) in the HAIP group vs 6.2% (95% CI, 2.3%-9.7%) in the resection group (P = .01). The median OS for HAIP was 20.3 months vs 18.9 months for resection (P = .32). Five-year OS in patients with 2 or 3 lesions was 23.7% (95% CI, 12.3%-45.7%) in the HAIP group vs 25.7% (95% CI, 17.9%-37.0%) in the resection group. Five-year OS in patients with 4 or more lesions was 5.0% (95% CI, 1.7%-14.3%) in the HAIP group vs 6.8% (95% CI, 1.8%-25.3%) in the resection group. After adjustment for tumor diameter, number of tumors, and lymph node metastases, the hazard ratio of HAIP vs resection was 0.75 (95% CI, 0.55-1.03; P = .07). Conclusions and Relevance: This cohort study found that patients with multifocal iCCA had similar OS after HAIP floxuridine chemotherapy vs resection. Resection of multifocal intrahepatic cholangiocarcinoma needs to be considered carefully given the complication rate of major liver resection; HAIP floxuridine chemotherapy may be an effective alternative option.

Microbiome engineering: Taming the untractable.

In this issue of Cell, Jin et al. describe several innovative tools for microbiome engineering to enable in situ editing of complex communities. However, challenges remain to overcome the widespread genetic intractability of microbiome constituents.

Musculoskeletal Injuries and Conditions Among Homeless Patients.

INTRODUCTION: The purpose of this study was to analyze existing literature on musculoskeletal diseases that homeless populations face and provide recommendations on improving musculoskeletal outcomes for homeless individuals. METHODS: A comprehensive search of the literature was performed in March 2020 using the PubMed/MEDLINE (1966 to March 2020), Embase (1975 to April 2020), and CINHAL (1982 to 2020) databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used for accuracy of reporting, and the Newcastle-Ottawa Scale was used for quality assessment. RESULTS: Twenty-nine articles met inclusion criteria. Seven studies observed an increased prevalence of musculoskeletal injuries among the homeless population, four observed increased susceptibility to bacterial soft-tissue infection, four observed increased fractures/traumatic injuries, three described increased chronic pain, and six focused on conditions specific to the foot and ankle region. DISCUSSION: Homeless individuals often have inadequate access to care and rely on the emergency department for traumatic injuries. These findings have important implications for surgeons and public health officials and highlight the need for evidence-based interventions and increased follow-up. Targeted efforts and better tracking of follow-up and emergency department usage could improve health outcomes for homeless individuals and reduce the need costly late-stage interventions by providing early and more consistent care.

Development of a Senior Medical Student Robotic Surgery Training Elective.

As robotic surgery has become more widespread, early exposure to the robotic platform is becoming increasingly important, not only to graduate medical education, but also for medical students pursuing surgical residency. In an effort to orient students to robotic technology and decrease the learning curve for what is likely to become an integral part of residency training, we created a formal, elective robotic surgery curriculum for senior medical students. Throughout this 2-week fourth year rotation, students completed online training modules and assessment; mastered exercises on the simulator system related to the console, camera, energy, dexterity, and suturing skills; attended didactics; utilized the dual console during one-on-one simulation lab sessions with attending robotic surgery experts; and translated new skills to biotissue anastomoses as well as bedside-assisting in the operating room. During cases, students were able to have more meaningful observation experiences, recognizing the significance of various robotic approaches employed and utilization of specific instruments. Future aims of this rotation will assess student experience as it impacts readiness for surgical residency.

EFFECTIVE DOSE COEFFICIENTS FOR RADON AND PROGENY: A REVIEW OF ICRP AND UNSCEAR VALUES.

The International Commission on Radiological Protection (ICRP) publishes guidance on protection against radon exposure in homes and workplaces. ICRP Publication 137 recommends a dose coefficient of 3 mSv per mJ h m-3 (~10 mSv WLM-1) to be used in most circumstances of radon exposure, for workers in buildings and in underground mines. Recently, United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) reviewed radon epidemiology and dosimetry and concluded that its established dose coefficient of 1.6 mSv per mJ h m-3 (5.7 mSv WLM-1) should be retained for use in its comparisons of radiation exposures from different sources in a population. This paper explains and compares the reviews of the scientific evidence from UNSCEAR and ICRP. It is shown that the UNSCEAR and ICRP reviews are consistent and support the use of the ICRP reference dose coefficients for radiation protection purposes. It is concluded that the ICRP dose coefficient should be used to calculate doses to workers.

Implicit and Explicit Attitudes Toward Antihypertensive Medications Explain Variation in Pharmacy Refill and Self-Reported Adherence Beyond Traditional Risk Factors: Potential Novel Mechanism Underlying Adherence.

Background In pursuit of novel mechanisms underlying persistent low medication adherence rates, we assessed contributions of implicit and explicit attitudes, beyond traditional risk factors, in explaining variation in objective and subjective antihypertensive medication adherence. Methods and Results Implicit and explicit attitudes were assessed using the difference scores from the computer-based Single Category Implicit Association Test and the Necessity and Concerns subscales of the Beliefs about Medicines Questionnaire, respectively. Antihypertensive medication adherence was measured using pharmacy refill proportion of days covered (PDC: mean PDC, low PDC <0.8) and the self-report 4-item Krousel-Wood Medication Adherence Scale (K-Wood-MAS-4: mean K-Wood-MAS-4, low adherence via K-Wood-MAS-4 ≥1). Hierarchical logistic and linear regression models controlled for traditional risk factors including social determinants of health, explicit, and implicit attitudes in a stepwise fashion. Community-dwelling insured participants (n=85: 44.7% female; 20.0% Black; mean age, 62.3 years; 43.5% low PDC, and 31.8% low adherence via K-Wood-MAS-4) had mean (SD) explicit and implicit attitude scores of 7.188 (5.683) and 0.035 (0.334), respectively. Low PDC was inversely associated with more positive explicit (adjusted odds ratio [aOR], 0.87; 95% CI, 0.78-0.98; P=0.022) and implicit (aOR, 0.12; 95% CI, 0.02-0.80; P=0.029) attitudes, which accounted for an additional 8.6% (P=0.016) and 6.5% (P=0.029) of variation in low PDC, respectively. Lower mean K-Wood-MAS-4 scores (better adherence) were associated only with more positive explicit attitudes (adjusted ß, -0.04; 95% CI, -0.07 to -0.01; P=0.026); explicit attitudes explained an additional 5.6% (P=0.023) of K-Wood-MAS-4 variance. Conclusions Implicit and explicit attitudes explained significantly more variation in medication adherence beyond traditional risk factors, including social determinants of health, and should be explored as potential mechanisms underlying adherence behavior.

Chromatin accessibility dynamics of Chlamydia-infected epithelial cells.

Chlamydia are Gram-negative, obligate intracellular bacterial pathogens responsible for a broad spectrum of human and animal diseases. In humans, Chlamydia trachomatis is the most prevalent bacterial sexually transmitted infection worldwide and is the causative agent of trachoma (infectious blindness) in disadvantaged populations. Over the course of its developmental cycle, Chlamydia extensively remodels its intracellular niche and parasitises the host cell for nutrients, with substantial resulting changes to the host cell transcriptome and proteome. However, little information is available on the impact of chlamydial infection on the host cell epigenome and global gene regulation. Regions of open eukaryotic chromatin correspond to nucleosome-depleted regions, which in turn are associated with regulatory functions and transcription factor binding. We applied formaldehyde-assisted isolation of regulatory elements enrichment followed by sequencing (FAIRE-Seq) to generate temporal chromatin maps of C. trachomatis-infected human epithelial cells in vitro over the chlamydial developmental cycle. We detected both conserved and distinct temporal changes to genome-wide chromatin accessibility associated with C. trachomatis infection. The observed differentially accessible chromatin regions include temporally-enriched sets of transcription factors, which may help shape the host cell response to infection. These regions and motifs were linked to genomic features and genes associated with immune responses, re-direction of host cell nutrients, intracellular signalling, cell-cell adhesion, extracellular matrix, metabolism and apoptosis. This work provides another perspective to the complex response to chlamydial infection, and will inform further studies of transcriptional regulation and the epigenome in Chlamydia-infected human cells and tissues.

Risk of SARS-CoV-2 Transmission During Flexible Laryngoscopy: A Systematic Review.

IMPORTANCE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reportedly infected otolaryngologists disproportionately in the early parts of the coronavirus disease 2019 pandemic. Recommendations from national and international health organizations suggest minimizing the use of flexible laryngoscopy as a result. OBJECTIVE: To review evidence on the risks of aerosolization and transmission of SARS-CoV-2 from patients to health care personnel during endoscopy of the upper aerodigestive tract. EVIDENCE REVIEW: A comprehensive review of literature was performed on April 19, 2020, using the PubMed/MEDLINE (1966-April 2020), Embase (1975-April 2020), and Web of Science (1900-April 2020) databases. All English-language primary research studies were included if they assessed the transmission of SARS-CoV-2 or SARS-CoV-1 during procedures in the upper aerodigestive tract. The primary outcome measure was disease transmission among health care workers. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for accuracy of reporting. FINDINGS: The queries for SARS-CoV-2 and SARS-CoV-1 identified 6 articles for systematic review. No studies included in this review provided data for SARS-CoV-2 transmission during flexible laryngoscopy. A total of 204 of 1264 health care workers (16.1%) had procedure-specific infections of SARS-CoV-1 or SARS-CoV-2. Among those, 53 of 221 (24.0%) were exposed during intubation, 1 of 15 (6.7%) during bronchoscopy, and 1 of 1 (100%) during endoscopy-assisted intubation. CONCLUSIONS AND RELEVANCE: A substantial lack of research precludes formal conclusions about the safety of flexible laryngoscopy and transmission of SARS-CoV-2 from patients to health care workers. The use of appropriate precautionary measures and personal protective equipment appears to reduce the risk of transmission. Given the uncertainty in transmission and the known benefits of safety precautions, upper airway endoscopy may be reasonable to perform if precautionary steps are taken.

Innovative recruitment and clinical orientation programme to manage NHS junior doctor shortfall: A district hospital experience.

BACKGROUND: International medical graduates (IMGs) contribute significantly towards the NHS care provision. No standardised clinical orientation programme (COP) for IMGs new to the NHS exists. OBJECTIVE: Our objective was to describe recruitment and retention strategies for junior doctors (JDs) in general medicine and develop a framework to anticipate outcomes of these interventions using the realist evaluation methodology. METHODS: We performed quality improvement interventions of recruitment and COP for new entrant IMGs in our organisation employed between December 2017 and April 2019. RESULTS: Twenty-three IMGs were recruited, 96% successfully completed the COP with a mean contract duration of 13±5 months. From the academic year 2017/18 to 2018/19, mean JD post occupancy increased from 54±3 to 73±4 JDs (p<0.001) and JD locum spend fell by £1.9 million. CONCLUSION: Our structured COP provides a stable, trained and financially sustainable JD workforce. Application in broader NHS settings is recommended.

Sleep problems in advanced cancer patients and their caregivers: Who is disturbing whom?

Background The aims of the study were to understand sleep problems and their effects in advanced cancer patients and spousal and intimate partner caregivers and to examine the directionality of the link between patients' and caregivers' sleep problems. Methods Fifty-four advanced cancer patients and their spousal and intimate partners were administered a battery of questionnaires that included the Pittsburgh Sleep Quality Index and the Center for Epidemiological Studies at the patients' cancer diagnosis and at 2, 4, and 6 months after diagnosis. Results Patients' and caregivers' sleep duration was significantly related. Using cross-lagged panel analyses, caregivers' sleep quality significantly predicted patients' sleep quality and patients' sleep quality subsequently predicted caregivers' sleep quality. Patients' sleep latency significantly was found to significantly predict caregivers' sleep latency. Conclusion Patients diagnosed with cancer and their intimate partners have poor sleep quality and sleep patterns are related.

Early Transcriptional Landscapes of Chlamydia trachomatis-Infected Epithelial Cells at Single Cell Resolution.

Chlamydia are Gram-negative obligate intracellular bacterial pathogens responsible for a variety of disease in humans and animals worldwide. Chlamydia trachomatis causes trachoma in disadvantaged populations, and is the most common bacterial sexually transmitted infection in humans, causing reproductive tract disease. Antibiotic therapy successfully treats diagnosed chlamydial infections, however asymptomatic infections are common. High-throughput transcriptomic approaches have explored chlamydial gene expression and infected host cell gene expression. However, these were performed on large cell populations, averaging gene expression profiles across all cells sampled and potentially obscuring biologically relevant subsets of cells. We generated a pilot dataset, applying single cell RNA-Seq (scRNA-Seq) to C. trachomatis infected and mock-infected epithelial cells to assess the utility, pitfalls and challenges of single cell approaches applied to chlamydial biology, and to potentially identify early host cell biomarkers of chlamydial infection. Two hundred sixty-four time-matched C. trachomatis-infected and mock-infected HEp-2 cells were collected and subjected to scRNA-Seq. After quality control, 200 cells were retained for analysis. Two distinct clusters distinguished 3-h cells from 6- and 12-h. Pseudotime analysis identified a possible infection-specific cellular trajectory for Chlamydia-infected cells, while differential expression analyses found temporal expression of metallothioneins and genes involved with cell cycle regulation, innate immune responses, cytoskeletal components, lipid biosynthesis and cellular stress. We find that changes to the host cell transcriptome at early times of C. trachomatis infection are readily discernible by scRNA-Seq, supporting the utility of single cell approaches to identify host cell biomarkers of chlamydial infection, and to further deconvolute the complex host response to infection.

Structure-activity analysis of peptidic Chlamydia HtrA inhibitors.

Chlamydia trachomatis high temperature requirement A (CtHtrA) is a serine protease that performs proteolytic and chaperone functions in pathogenic Chlamydiae; and is seen as a prospective drug target. This study details the strategies employed in optimizing the irreversible CtHtrA inhibitor JO146 [Boc-Val-Pro-ValP(OPh)2] for potency and selectivity. A series of adaptations both at the warhead and specificity residues P1 and P3 yielded 23 analogues, which were tested in human neutrophil elastase (HNE) and CtHtrA enzyme assays as well as Chlamydia cell culture assays. Trypsin and chymotrypsin inhibition assays were also conducted to measure off-target selectivity. Replacing the phosphonate moiety with α-ketobenzothiazole produced a reversible analogue with considerable CtHtrA inhibition and cell culture activity. Tertiary leucine at P3 (8a) yielded approximately 33-fold increase in CtHtrA inhibitory activity, with an IC50 = 0.68 ±â€¯0.02 µM against HNE, while valine at P1 retained the best anti-chlamydial activity. This study provides a pathway for obtaining clinically relevant inhibitors.

Dual RNA-Seq of Chlamydia and Host Cells.

During the infection of a host cell by a bacterial pathogen, a cascading series of gene expression changes occurs as each organism manipulates or responds to the other via defense or survival strategies. Unraveling this complex interplay is key for our understanding of bacterial virulence and host response pathways for the development of novel therapeutics. Dual RNA sequencing (dual RNA-Seq) has recently been developed to simultaneously capture host and bacterial transcriptomes from an infected cell. Leveraging the sensitivity and resolution allowed by RNA-seq, dual RNA-Seq can be applied to any bacteria-eukaryotic host interaction. We pioneered dual RNA-Seq to simultaneously capture Chlamydia and host expression profiles during an in vitro infection as proof of principle. Here we provide a detailed laboratory protocol and bioinformatics analysis guidelines for dual RNA-seq experiments focusing on Chlamydia as the organism of interest.