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In most animals, mitochondrial DNA is strictly maternally inherited and non-recombining. One exception to these assumptions is called doubly uniparental inheritance (DUI): a phenomenon involving the independent transmission of female and male mitochondrial genomes. DUI is known only from the molluscan class Bivalvia. The phylogenetic distribution of male mitochondrial DNA in bivalves is consistent with several evolutionary scenarios, including multiple independent gains, losses, and varying degrees of recombination with female mitochondrial DNA. In this study, we use phylogenetic methods to test male mitochondrial DNA origination hypotheses and infer the prevalence of mitochondrial recombination in bivalves with DUI. Phylogenetic modeling using site concordance factors supported a single origin of male mitochondrial DNA in bivalves coupled with recombination acting over long evolutionary timescales. Ongoing mitochondrial recombination is present in Mytilida and Venerida, which results in a pattern of concerted evolution of female and male mitochondrial DNA. Mitochondrial recombination could be favored to offset the deleterious effects of asexual inheritance and maintain mitonuclear compatibility across tissues. Cardiida and Unionida have gone without recent recombination, possibly due to an extension of theCOX2gene in male mitochondrial DNA. The loss of recombination may be neutral but could be connected to the role of M mtDNA in sex determination or sexual development. Our results support recombination events in DUI species may occur throughout their genomes. Future investigations may reveal more complex patterns of inheritance of recombinants, which could explain the retention of signal for a single origination of male mitochondrial DNA in protein coding genes.

BACKGROUND: Adjuvant chemotherapy, particularly taxane-based chemotherapies, which are used to treat high-risk breast cancers, has been shown to be efficacious in prolonging overall survival. However, the impact of such therapies on risk of breast cancer-related lymphedema (BCRL) is yet to be fully understood. Available studies have contradictory findings as to whether or not taxanes increase BCRL risk. Unfortunately, methodological flaws, such as not incorporating a preoperative baseline arm volume measurement or utilizing flawed measurement techniques and diagnostic criteria, result in misdiagnosis of the primary outcome of BCRL and it is therefore difficult to draw conclusions from these studies. As such, a more comprehensive understanding of the potential risks associated with these treatment modalities can improve quality of care as patients are better prepared to face a potentially devastating sequela of breast cancer treatment. PURPOSE: The purpose of this study is to determine if chemotherapy administered in the adjuvant setting is an independent risk factor of BCRL, as well as to assess any specific risks of taxane-based chemotherapy on BCRL. METHODS: From 2005 to 2021, 2049 patients treated for breast cancer were enrolled in a prospective BCRL screening trial and screened from preoperative baseline through last follow-up. Screening included objective arm volume measurements via perometry. Chemotherapy data and clinicopathological and demographic characteristics were collected directly from the electronic medical record. Patients who had not received neoadjuvant chemotherapy were eligible for the current study; they were classified based on whether they had received taxane-based chemotherapy, non-taxane chemotherapy only, or no chemotherapy. Relative volume change (RVC) increase ≥10% from preoperative baseline >3 months postoperatively was used to define BCRL. Patients were censored at cancer recurrence or most recent clinic visit. We fit a Cox regression model to estimate adjusted hazard ratios (aHR) for BCRL. The model was adjusted for baseline BMI, axillary lymph node dissection (ALND), regional lymph node radiation (RLNR), age at diagnosis, and smoking history. RESULTS: The eligible cohort included 1759 patients, including 564 (32%) who received taxane-based chemotherapy and 104 (6%) who received non-taxane chemotherapy only. The median follow-up time for the entire cohort was 58 months. 141/1759 (8%) of patients developed BCRL. The median time to develop BCRL was 21 months post-operatively. Compared to no chemotherapy, the aHR associated with taxane-based chemotherapy was 1.04 (95% CI 0.37, 1.8; p = 0.62). Compared to no chemotherapy, the aHR for non-taxane chemotherapy was 0.82 (95% CI 0.67, 1.6; p = 0.86). There was no significant difference between taxane and non-taxane therapies in terms of BCRL risk (p = 0.55). ALND, RLNR, and high BMI remained independent risk factors for BCRL, consistent with the published literature. CONCLUSION: The receipt of adjuvant chemotherapy and specifically adjuvant taxane-based chemotherapy were not associated with increased risk of BCRL in this cohort of 1759 patients at risk of and prospectively screened for BCRL. Citation Format: Amanda W. Jung, Brooke Juhel, Louisa H. Smith, Cheryl L. Brunelle, Elizabeth K. Hausman, Loryn K. Bucci, George E. Naoum, Alphonse G. Taghian. The Impact of Adjuvant Chemotherapy, Including Taxanes, on Breast Cancer-Related Lymphedema Risk [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-12-05.

Background: The introduction of the novel COVID-19 vaccination raised concerns regarding side effects from patients who had undergone breast cancer treatment. Lymph node swelling after the mRNA vaccines (Moderna, Pfizer) is a distressing side effect for women treated for breast cancer as it may indicate cancer progression or recurrence. Patients at risk of breast cancer-related lymphedema (BCRL) are fearful that lymph node swelling from the vaccine could incite or worsen BCRL. Data investigating associated side effects in this population is essential for patient education and future self-advocacy. Purpose: The purpose of this study was to elicit side effects associated with the COVID vaccine in women treated for breast cancer. Methods: 4,945 surveys were sent to women over the age of 18 who had received breast cancer treatment and had been prospectively screened for BCRL with perometry. 621 participants who received an mRNA vaccine and responded to the survey were included in analysis, 469 of whom completed booster dose surveys. Participants were asked about type and duration of side effects after each vaccine dose. Solicited side effects included injection site soreness, swelling, or redness; swelling, numbness, or heaviness of the arm; generalized muscle soreness (GMS); fatigue; headache; joint pain; chills; nausea; vomiting; fever; Bell’s palsy; axillary or supraclavicular lymph node swelling; other; or none of the above. We computed frequencies and the median duration of side effects for each dose. To investigate predictors of side effects, we fit multivariable logistic regression models separately for each side effect, with random effects for participants to account for clustered responses. We considered significant predictors those with p < 0.05. Results: Of the 621 participants, the median follow-up time between breast surgery and date of first vaccine dose was 69 months. The distribution of the top 5 side effects is presented in Table 1. Of note, the majority of participants who reported lymph node swelling (9.8% dose 1, 12.9% dose 2, 11.3% dose 3) reported it in the axilla ipsilateral to the vaccine (54.1% D1, 61.3% D2, 71.7% D3). Lymph node swelling was also reported in the axilla contralateral to the vaccine (45.9% D1, 45% D2, 24.5% D3), supraclavicular region ipsilateral (29.5% D1, 26.3% D2, 32.1% D3) and contralateral (18% D1, 18.8% D2, 9.4% D3) to the vaccine. Older patients reported each side effect significantly less frequently. Those who had received neoadjuvant chemotherapy reported significantly more GMS and headache than those who did not. Those who had received regional lymph node radiation were less likely to report GMS, as were patients who had sentinel lymph node biopsies (vs. no lymph node surgery). The median duration of side effects for all three doses was 48 hours or less, with the plurality (41.0% D1, 38.7% D2, 44.1% D3) of participants reporting side effects lasting 24 hours or less. While all side effects apart from injection site soreness were significantly more common in the second than the first doses, the duration of side effects only increased for 28.1% of participants. Conclusion: Over 86% of women treated for breast cancer may experience at least one side effect after any dose of the COVID-19 vaccine. This data, collected specifically for patients with breast cancer, will help enhance guidelines for structured and universal education regarding additional doses of the vaccine in the future. This will allow patients to better understand COVID vaccine side effect profiles after breast cancer treatment and self-advocate prior to future doses. Table 1. Top 5 Side Effects Reported Citation Format: Brooke Juhel, Cheryl L. Brunelle, Madison C. Bernstein, Louisa H. Smith, Amanda W. Jung, Elizabeth K. Hausman, Loryn K. Bucci, George E. Naoum, Alphonse G. Taghian. Side Effects of the mRNA COVID-19 Vaccines in Women Treated for Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-12-04.

Study design Systematic review. Background Although degenerative cervical myelopathy (DCM) is the most prevalent spinal cord condition worldwide, the pathophysiology remains poorly understood. Our objective was to evaluate existing histological findings of DCM on cadaveric human spinal cord tissue and explore their consistency with animal models. Methods MEDLINE and Embase were systematically searched (CRD42021281462) for primary research reporting on histological findings of DCM in human cadaveric spinal cord tissue. Data was extracted using a piloted proforma. Risk of bias was assessed using Joanna Briggs Institute critical appraisal tools. Findings were compared to a systematic review of animal models (Ahkter et al. 2020 Front Neurosci 14). Results The search yielded 4127 unique records. After abstract and full-text screening, 19 were included in the final analysis, reporting on 150 autopsies (71% male) with an average age at death of 67.3 years. All findings were based on haematoxylin and eosin (H&E) staining. The most commonly reported grey matter findings included neuronal loss and cavity formation. The most commonly reported white matter finding was demyelination. Axon loss, gliosis, necrosis and Schwann cell proliferation were also reported. Findings were consistent amongst cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament. Cavitation was notably more prevalent in human autopsies compared to animal models. Conclusion Few human spinal cord tissue studies have been performed. Neuronal loss, demyelination and cavitation were common findings. Investigating the biological basis of DCM is a critical research priority. Human spinal cord specimen may be an underutilised but complimentary approach.

Background: Older adults occasionally receive seizure prophylaxis in an acute ischemic stroke (AIS) setting, despite safety concerns. There are no trial data available about the net impact of early seizure prophylaxis on post-AIS survival. Methods: Using a stroke registry (American Heart Association’s Get With The Guidelines) individually linked to electronic health records, we examined the effect of initiating seizure prophylaxis (ie, epilepsy-specific antiseizure drugs) within 7 days of an AIS admission versus not initiating in patients ≥65 years admitted for a new, nonsevere AIS (National Institutes of Health Stroke Severity score ≤20) between 2014 and 2021 with no recorded use of epilepsy-specific antiseizure drugs in the previous 3 months. We addressed confounding by using inverse-probability weights. We performed standardization accounting for pertinent clinical and health care factors (eg, National Institutes of Health Stroke Severity scale, prescription counts, seizure-like events). Results: The study sample included 151 patients who received antiseizure drugs and 3020 who did not. The crude 30-day mortality risks were 219 deaths per 1000 patients among epilepsy-specific antiseizure drugs initiators and 120 deaths per 1000 among noninitiators. After standardization, the estimated mortality was 251 (95% CI, 190–307) deaths per 1000 among initiators and 120 (95% CI, 86–144) deaths per 1000 among noninitiators, corresponding to a risk difference of 131 (95% CI, 65–200) excess deaths per 1000 patients. In the prespecified subgroup analyses, the risk difference was 52 (95% CI, 11–72) among patients with minor AIS and 138 (95% CI, 52–222) among moderate-to-severe AIS patients. Similarly, the risk differences were 86 (95% CI, 18–118) and 157 (95% CI, 57–219) among patients aged 65 to 74 years and ≥75 years, respectively. Conclusions: There was a higher risk of 30-day mortality associated with initiating versus not initiating seizure prophylaxis within 7 days post-AIS. This study does not support the role of seizure prophylaxis in reducing 30-day poststroke mortality.

Three North Carolina Medicaid surveys conducted from 2000 to 2012 reported increasing numbers of Hispanic children enrolled in Medicaid and much lower trust in providers expressed by their adult caregiver respondents compared with responses for non-Hispanic Black and White children. To verify and explain this apparent trust chasm, we used bivariate and regression analyses. The variables employed included trust (dependent variable); child’s race/ethnicity, age, and sex; satisfaction and health status scales; two utilization measures; respondent’s age, sex, and education; geographical region; and population density of county of residence. Race/ethnicity was strongly associated with trust (p < .001), controlling for other independent variables. Access, satisfaction, and respondent’s age and education were also significant. Our results fit the Behavioral Model for Vulnerable Populations, which maps the role of significant variables in health-seeking behavior. After analyzing the concept of trust, we argue that lower acculturation explains lower Hispanic trust compared with non-Hispanic Blacks. We suggest policies to improve acculturation.

Feeding difficulties are widely acknowledged following oesophageal atresia/tracheo-oesophageal fistula repair. However, little is understood about the nature and severity of these difficulties. This study explored feeding in children with oesophageal atresia/tracheo-oesophageal fistula from the parent perspective.In collaboration with a patient support group, data were collected using a research-specific online discussion forum. Thematic analysis was used to code the data and identify themes.One hundred and twenty-seven parents registered for the online forum, of whom 83 (65%) provided demographic data. Seventy-four (89%) of responders were mothers, 75 (90%) were of white ethnicity, 65 (78%) were from the UK. Six key themes were identified: feeding is a traumatic experience, feeding my child is scary, feeding is isolating and filled with uncertainty, feeding outside of the home is difficult, feeding associated emotions, developing coping strategies. Parents described features of medical, nutritional, feeding skill and psychosocial dysfunction across all stages of eating/drinking development. They described how their child's feeding difficulties had an impacted their own well-being. An interactional model of feeding difficulties in OA/TOF is proposed.Exploring parent experiences provides rich data from which to expand understanding of the complex nature of feeding difficulties in OA/TOF. Feeding should be viewed as a dyadic process, occurring within a family system. Intervention for feeding difficulties should be family-centred, addressing parental anxiety, trauma and uncertainty, as well as the child's underlying medical/surgical needs to optimise outcome. Further study of clinical correlates with parental experience is required.IV (non-experimental, qualitative).

Stress responses are believed to involve corticotropin releasing factor (CRF), its two cognate receptors (CRFWe miniaturized a cell-based assay, where CRFBP(10kD) is fused as a chimera with CRFWe found that CRFBP(10kD) potentiates CRF-intracellular CaThese results provide the first evidence of specific roles for CRF

The aim of this study is to assess effect of hospital walking programs on outcomes for older inpatients and to characterize hospital walking dose reported across studies.A systematic review and meta-analysis examining impact of hospital walking and/or reported walking dose among medical-surgical inpatients. For inclusion, studies were observational or experimental, published in English, enrolled inpatients aged ≥ 65 yrs hospitalized for medical or surgical reasons.Searches of PubMed, CINAHL, Embase, Scopus, NICHSR, OneSearch, ClinicalTrials.gov, and PsycINFO were completed in December 2020. Two reviewers screened sources, extracted data, and performed quality bias appraisal.Hospital walking dose was reported in 6 studies and commonly as steps/24 hr. Length of stay (LOS) was a common outcome reported. Difference in combined mean LOS between walking and control groups was -5.89 days. Heterogeneity across studies was considerable (I

The number of women using long-acting reversible contraception (LARC)-intrauterine devices (IUDs) and implants-is increasing and 14% of contraceptive users in the United States adopt LARC. We examined correlates of LARC never-use in a population-based survey of reproductive-aged women in Ohio.We analyzed data from the 2018-19 Ohio Survey of Women. We examined the prevalence of LARC never-use and reasons for never-use among ever users of contraception (N = 2388). Using Poisson regression to generate prevalence ratios (PRs), we examined associations between selected correlates (demographic factors, healthcare access/quality measures, and religious/political views) and LARC never-use.Most Ohio women (74%) had never used LARC. Commonly reported reasons for not using an IUD or an implant were preferring a different method (46% and 45%, respectively), not wanting an object inside their body (45% and 43%), side effect concerns (39% and 33%), insertion/removal concerns (31% and 25%), and unfamiliarity (13% and 20%). Conservative political views (PR: 1.12, 95% confidence interval [CI]: 1.04-1.22), pro-life affiliation (PR: 1.11, 95% CI: 1.02-1.20), placing high importance on religion in daily life (PR: 1.15, 95% CI: 1.06-1.26), and being non-Hispanic white as compared to non-Hispanic Black (PR: 1.20, 95% CI: 1.02-1.41) were significantly associated with LARC never-use. Findings were generally similar for models analyzing IUD and implant never-use separately.Among ever-users of contraception, LARC never-use was associated with having conservative political views, being religious, and having a pro-life affiliation. Except for race/ethnicity, demographic and healthcare measures were not associated with LARC never-use among women in Ohio.

Purpose of Review SARS-CoV-2 has had a devastating global effect, with vaccinations being paramount in the public health strategy against COVID-19. Vaccinations have uncoupled infection from adverse COVID-19 outcomes worldwide. While immune-modifying therapies are effective for the management of skin diseases such as psoriasis and atopic dermatitis, these medications also impair protective immune responses. There has been longstanding uncertainty and concern over the impact of immune-modifying therapies on the effectiveness of vaccines; for example, it is well recognised that methotrexate impairs humoral responses to both influenza and pneumococcal vaccines. This narrative review aims to discuss the evidence to date on the impact of immune-modifying therapies on the immune response to COVID-19 vaccines, with a focus on the first two vaccine doses. Recent Findings Individuals receiving immune-modifying therapy are more likely to have attenuated humoral responses to a single dose of COVID-19 vaccine compared to healthy controls; however, this may be improved by a complete course of vaccination. B cell targeted biologics such as rituximab markedly impair the humoral response to both the first and second COVID-19 vaccination. There remains a paucity of data on cellular immune responses, with the few available studies indicating lower responses to two vaccine doses in individuals receiving immune-modifying therapies compared to healthy controls, which may impact the durability of immune responses. Summary Inadequate humoral immune responses to a single dose of vaccine in the context of immune-modifying therapy are improved by a complete course of vaccination. Individuals receiving immune-modifying treatments should be encouraged to take up a complete vaccine course to mitigate their risk against COVID-19. Research in large patient populations on the longevity/kinetics of the complex humoral and cellular response to subsequent vaccine doses, including against newer variants of concern, is warranted, in addition to data on immune correlates of vaccine clinical effectiveness.

BACKGROUND: Amniotic membrane tissue has been thought to potentiate healing in many soft tissue conditions. Specifically, recent studies have shown its therapeutic potential for treatment in the setting of spinal pathologies. The purpose of this study is to thoroughly review the existing scientific literature and evidence concerning the clinical use of amniotic membrane–derived biologic agents on postoperative outcomes following spinal surgery. METHODS: A systematic review was conducted following preferred reporting items for systematic reviews and meta-analyses guidelines using PubMed, Embase, and Cochrane databases up to December 2020 to identify animal and clinical studies examining the therapeutic potential for amniotic membrane tissue in the setting of spinal pathologies (including disc herniation, prevention of epidural fibrosis, and spinal fusion). Studies were broken down into 2 categories: experimental model type and the type of amnion product being analyzed. RESULTS: A total of 12 studies (4 clinical studies and 8 studies utilizing animal models) met inclusion criteria. Additionally, the major types of amnion product were divided into cryopreserved/freeze-dried amniotic membrane, human amniotic fluid, human amniotic membrane, cross-linked amniotic membrane, and amnion-derived epithelial cells. While heterogeneity of study design precludes definitive specific results reporting, most studies showed positive benefits on healing/outcomes with amniotic augmentation. Specifically, amnion products have shown promising effects in reducing epidural adhesions and scar tissue after spine surgery, improving spinal fusion rate and postoperative pain scores, and promoting better functional outcomes after spine surgery. CONCLUSIONS: A review of the limited number of reported studies revealed a wide variety of amniotic membrane preparations, treatment regimens, and indications, which limit definitive conclusions. To date, while there is no definitive clinical proof that amniotic tissues enhance tissue repair or regeneration, the aggregate results demonstrate promising basic science and outcomes potential in spinal surgery. Further study is warranted to determine whether this application is appropriate in the clinical setting. CLINICAL RELEVANCE: This systematic review provides a summary of the existing literature regarding the use of amniotic membrane preparations, treatment regimens, and indications within spinal surgery. With the growing popularity and utilization of biologic agents such as amniotic membrane-derived products in orthopedic and neurologic surgery, this systematic review gives physicians a concise summary on the outcomes and indications associated with amniotic membrane products. LEVEL OF EVIDENCE: 4.

Introduction In April 2021, the U.S. Food and Drug Administration announced its intention to issue a product standard banning menthol as a characterizing flavor in cigarettes. Given the potential relevance of national estimates of menthol use to pending legislation, this study estimated the prevalence of menthol use among U.S. adults who smoke cigarettes in 2020 and investigated changes in menthol use from 2008 to 2019 by sociodemographics, mental health, and substance use. Aims and Methods Nationally representative annual, cross-sectional data from the National Survey on Drug Use and Health, which included participants ages 18 years and older residing in the United States from 2008 to 2019 and the 2020. Data were analyzed using logistic and linear regression models to estimate trends in menthol use among adults who smoke cigarettes by sociodemographic, mental health and substance use variables (total analytic sample 2008–2019 n = 128 327). Results In 2020, 43.4% of adults who smoked cigarettes in the past month used menthol. Menthol use was most common among black adults (80%) and over 50% of those Hispanic, female, young (ages 18–34 years), lesbian/gay, with serious psychological distress, and with cigar use used menthol. Menthol use increased among adults who used cigarettes from 2008 to 2019, overall, and grew more rapidly among adults ages 26–34 years, Hispanic, light cigarette use (1–5 per day), and those who smoked cigars. Conclusions Menthol use has increased among U.S. adults who smoke cigarettes over the past decade. Enacting menthol bans could have a widespread public health impact, especially among younger and minoritized groups. Implications Menthol cigarette use increased among individuals who smoke cigarettes from 2008 to 2019 in the United States. In 2020, over 40% of smokers used menthol, and menthol use was considerably higher among adult smokers from racial/ethnic minoritized groups, who were younger and who reported mental health problems. The U.S. Food and Drug Administration seeks to ban menthol as a characterizing flavor in cigarettes; our results suggest that such a ban is likely to have a wide-ranging impact on public health.

Complement 3 glomerulopathy (C3G) is a rare kidney disease characterized by dysregulation of the alternative pathway (AP) of the complement system. About 50% of patients with C3G progress to kidney failure within 10 years of diagnosis. Currently, there are no approved therapeutic agents for C3G. Iptacopan is an oral, first-in-class, potent, and selective inhibitor of factor B, a key component of the AP. In a Phase II study, treatment with iptacopan was associated with a reduction in proteinuria and C3 deposit scores in C3G patients with native and transplanted kidneys, respectively.APPEAR-C3G (NCT04817618) is a randomized, double-blind, and placebo-controlled Phase III study to evaluate the efficacy and safety of iptacopan in C3G patients, enrolling 68 adults with biopsy-confirmed C3G, reduced C3 (77 mg/dl), proteinuria ≥1.0 g/g, and estimated glomerular filtration rate (eGFR) ≥30 ml/min per 1.73 mThis study aims to demonstrate the clinical benefits of AP inhibition with iptacopan in C3G.

Cardiac arrest in the peri-operative period is rare but associated with significant morbidity and mortality. Current reporting systems do not capture many such events, so there is an incomplete understanding of incidence and outcomes. As peri-operative cardiac arrest is rare, many hospitals may only see a small number of cases over long periods, and anaesthetists may not be involved in such cases for years. Therefore, a large-scale prospective cohort is needed to gain a deep understanding of events leading up to cardiac arrest, management of the arrest itself and patient outcomes. Consequently, the Royal College of Anaesthetists chose peri-operative cardiac arrest as the 7th National Audit Project topic. The study was open to all UK hospitals offering anaesthetic services and had a three-part design. First, baseline surveys of all anaesthetic departments and anaesthetists in the UK, examining respondents' prior peri-operative cardiac arrest experience, resuscitation training and local departmental preparedness. Second, an activity survey to record anonymised details of all anaesthetic activity in each site over 4 days, enabling national estimates of annual anaesthetic activity, complexity and complication rates. Third, a case registry of all instances of peri-operative cardiac arrest in the UK, reported confidentially and anonymously, over 1 year starting 16 June 2021, followed by expert review using a structured process to minimise bias. The definition of peri-operative cardiac arrest was the delivery of five or more chest compressions and/or defibrillation in a patient having a procedure under the care of an anaesthetist. The peri-operative period began with the World Health Organization 'sign-in' checklist or first hands-on contact with the patient and ended either 24 h after the patient handover (e.g. to the recovery room or intensive care unit) or at discharge if this occured earlier than 24 h. These components described the epidemiology of peri-operative cardiac arrest in the UK and provide a basis for developing guidelines and interventional studies.

BACKGROUND: The Diabetes Prevention Program (DPP) has been translated into digital formats. We report an economic evaluation of a digital DPP implemented in a large, integrated health care system. METHODS: Patients (n = 4148) were invited to participate in digital DPP based on clinical characteristics (HbA1c 5.7%–6.4% and body mass index ≥ 30 kg/m(2)) assessed using electronic medical record data. Using a propensity score we matched (1:1) enrolled and not enrolled patients for a total of 784. We identified high-risk patients (ie, above the 50th percentile of risk; n = 202) by calculating each patient’s 2-year of developing diabetes. We report the cost of the intervention and the costs of medical care over 12- and 24-month follow-up, and the incremental cost-effectiveness ratio as the cost per additional kilogram weight loss at 24 months. RESULTS: At 12 months, enrolled patients had lower total costs ($6,926, 95% CI $5,681–$8,171) than not enrolled patients ($7,538, 95% CI $6,293–$8,783). This pattern attenuated slightly at 24 months (enrolled = $16,255, 95% CI $14,097–$18,412; not enrolled = $16,688, 95% CI $14,531–$18,846). We found an incremental cost-effectiveness ratio of $81.92 per additional kilogram weight loss. For high-risk patients, the digital DPP group had, on average, lower costs and greater weight loss. We found a 55% chance of the digital DPP program being cost-effective at a willingness-to-pay of $150 per additional kilogram of weight loss; at the same willingness-to-pay, there is a 60% chance in the high-risk subgroup. Limitations include the nonrandomized design and potential volunteer bias. CONCLUSION: Digital DPP had a favorable cost-effectiveness profile compared to other lifestyle interventions.

Bacterial DNA gyrase, a type IIA DNA topoisomerase that plays an essential role in bacterial DNA replication and transcription, is a clinically validated target for discovering and developing new antibiotics. In this article, based on a supercoiling-dependent fluorescence quenching (SDFQ) method, we developed a high-throughput screening (HTS) assay to identify inhibitors targeting bacterial DNA gyrase and screened the National Institutes of Health's Molecular Libraries Small Molecule Repository library containing 370,620 compounds in which 2891 potential gyrase inhibitors have been identified. According to these screening results, we acquired 235 compounds to analyze their inhibition activities against bacterial DNA gyrase using gel- and SDFQ-based DNA gyrase inhibition assays and discovered 155 new bacterial DNA gyrase inhibitors with a wide structural diversity. Several of them have potent antibacterial activities. These newly discovered gyrase inhibitors include several DNA gyrase poisons that stabilize the gyrase-DNA cleavage complexes and provide new chemical scaffolds for the design and synthesis of bacterial DNA gyrase inhibitors that may be used to combat multidrug-resistant bacterial pathogens. Additionally, this HTS assay can be applied to screen inhibitors against other DNA topoisomerases.

HPV-associated oral cavity squamous cell carcinoma (SCC) is not well-characterized in the literature, and also has a clinical significance that is poorly understood.We gathered a cohort of oral cavity (OC) SCC with nonkeratinizing morphology, either in the invasive or in situ carcinoma (or both), tested for p16 by immunohistochemistry and high risk HPV E6/E7 mRNA by RTPCR (reference standard for transcriptionally-active high risk HPV) and gathered detailed morphologic and clinicopathologic data.Thirteen patients from two institutions were proven to be HPV-associated by combined p16 and high risk HPV mRNA positivity. All 13 patients (100%) were males, all were heavy smokers (average 57 pack/year), and most were active drinkers (9/11 or 81.8%). All 13 (100%) involved the tongue and/or floor of mouth. All had nonkeratinizing features, but maturing squamous differentiation varied widely (0-90%; mean 37.3%). Nonkeratinizing areas had high N:C ratios and larger nests, frequently with pushing borders, and minimal (or no) stromal desmoplasia. The carcinoma in situ, when present, was Bowenoid/nonkeratinizing with cells with high N:C ratios, full thickness loss of maturation, and abundant apoptosis and mitosis. HPV was type 16 in 11 patients (84.6%) and type 33 in two (15.4%). Nine patients had treatment data available. These underwent primary surgical resection with tumors ranging from 1.6 to 5.2 cm. Most had bone invasion (6/9-66.7% were T4a tumors), and most (6/9-66.7%) had extensive SCC in situ with all 6 of these patients having final margins positive for in situ carcinoma.HPV-associated OCSCC is an uncommon entity that shows certain distinct clinical and pathologic features. Recognition of these features may help pathologic diagnosis and could potentially help guide clinical management.