Cervical cancer screening using DNA methylation triage in a real-world population.

Cervical cancer (CC) screening in women comprises human papillomavirus (HPV) testing followed by cytology triage of positive cases. Drawbacks, including cytology's low reproducibility and requirement for short screening intervals, raise the need for alternative triage methods. Here we used an innovative triage technique, the WID-qCIN test, to assess the DNA methylation of human genes DPP6, RALYL and GSX1 in a real-life cohort of 28,017 women aged ≥30 years who attended CC screening in Stockholm between January and March 2017. In the analysis of all 2,377 HPV-positive samples, a combination of WID-qCIN (with a predefined threshold) and HPV16 and/or HPV18 (HPV16/18) detected 93.4% of cervical intraepithelial neoplasia grade 3 and 100% of invasive CCs. The WID-qCIN/HPV16/18 combination predicted 69.4% of incident cervical intraepithelial neoplasia grade 2 or worse compared with 18.2% predicted by cytology. Cytology or WID-qCIN/HPV16/18 triage would require 4.1 and 2.4 colposcopy referrals to detect one cervical intraepithelial neoplasia grade 2 or worse, respectively, during the 6 year period. These findings support the use of WID-qCIN/HPV16/18 as an improved triage strategy for HPV-positive women.

Predicting Rubisco-Linker Condensation from Titration in the Dilute Phase.

The condensation of Rubisco holoenzymes and linker proteins into "pyrenoids," a crucial supercharger of photosynthesis in algae, is qualitatively understood in terms of "sticker-and-spacer" theory. We derive semianalytical partition sums for small Rubisco-linker aggregates, which enable the calculation of both dilute-phase titration curves and dimerization diagrams. By fitting the titration curves to surface plasmon resonance and single-molecule fluorescence microscopy data, we extract the molecular properties needed to predict dimerization diagrams. We use these to estimate typical concentrations for condensation, and successfully compare these to microscopy observations.

A historical perspective and recent advances on the evolution of the relationship between acute and chronic pain and cardiovascular disease.

The relationship between acute pain and the cardiovascular system was recognized approximately 50 years ago following the initial observation, along with several subsequent experimental studies, that hypertension can result in decreases in the perception of pain. These studies provided a strong impetus to study potential mechanisms to clarify commonalities between the regulatory pathways associated with pain and the cardiovascular system. Attention subsequently shifted to an emphasis on the impact of chronic pain on cardiovascular diseases and mortality with several large meta-analyses of longitudinal studies providing clear evidence that chronic widespread pain increases the risk for developing cardiovascular disease and is associated with excess morbidity and mortality. Cardiovascular associated mortality from myocardial infarction and stroke appears to be directly related to the duration and severity of chronic pain, a result often characterized as a 'dose-response' relationship. The availability and reproducibility of extensive large-scale observational and retrospective studies have emphasized the critical need for more research, including prospective studies, along with the need for the development of preclinical animal models, to better understand the relationship(s) and underlying mechanisms between chronic pain, associated comorbidities, and cardiovascular disease. Elucidation and a deeper understanding of these relationships, including a focus on the link between chronic pain, cardiovascular disease, and depression, could provide valuable information to guide the development of potential treatment interventions to aid in attenuating pain while preventing pain-associated cardiovascular disease, comorbidities, and mortality.

Share of Adult Suicides After Recent Jail Release.

Importance: Although people released from jail have an elevated suicide risk, the potentially large proportion of this population in all adult suicides is unknown. Objective: To estimate what percentage of adults who died by suicide within 1 year or 2 years after jail release could be reached if the jail release triggered community suicide risk screening and prevention efforts. Design, Setting, and Participants: This cohort modeling study used estimates from meta-analyses and jail census counts instead of unit record data. The cohort included all adults who were released from US jails in 2019. Data analysis and calculations were performed between June 2021 and February 2024. Main Outcomes and Measures: The outcomes were percentage of total adult suicides within years 1 and 2 after jail release and associated crude mortality rates (CMRs), standardized mortality ratios (SMRs), and relative risks (RRs) of suicide in incarcerated vs not recently incarcerated adults. Taylor expansion formulas were used to calculate the variances of CMRs, SMRs, and other ratios. Random-effects restricted maximum likelihood meta-analyses were used to estimate suicide SMRs in postrelease years 1 and 2 from 10 jurisdictions. Alternate estimate was computed using the ratio of suicides after release to suicides while incarcerated. Results: Included in the analysis were 2019 estimates for 7 091 897 adults (2.8% of US adult population; 76.7% males and 23.3% females) who were released from incarceration at least once, typically after brief pretrial stays. The RR of suicide was 8.95 (95% CI, 7.21-10.69) within 1 year after jail release and 6.98 (95% CI, 4.21-9.76) across 2 years after release. A total of 27.2% (95% CI, 18.0%-41.7%) of all adult suicide deaths occurred in formerly incarcerated individuals within 2 years of jail release, and 19.9% (95% CI, 16.2%-24.1%) of all adult suicides occurred within 1 year of release (males: 23.3% [95% CI, 20.8%-25.6%]; females: 24.0% [95% CI, 19.7%-36.8%]). The alternate method yielded slightly larger estimates. Another 0.8% of adult suicide deaths occurred during jail stays. Conclusions and Relevance: This cohort modeling study found that adults who were released from incarceration at least once make up a large, concentrated population at greatly elevated risk for death by suicide; therefore, suicide prevention efforts focused on return to the community after jail release could reach many adults within 1 to 2 years of jail release, when suicide is likely to occur. Health systems could develop infrastructure to identify these high-risk adults and provide community-based suicide screening and prevention.

High performance of the DNA methylation-based WID-qEC test for detecting uterine cancers independent of sampling modalities.

Endometrial cancer (EC) is the most prevalent gynaecological cancer in high-income countries and its incidence is continuing to rise sharply. Simple and objective tools to reliably detect women with EC are urgently needed. We recently developed and validated the DNA methylation (DNAme)-based women's cancer risk identification-quantitative polymerase chain reaction test for endometrial cancer (WID-qEC) test that could address this need. Here, we demonstrate that the stability of the WID-qEC test remains consistent regardless of: (i) the cervicovaginal collection device and sample media used (Cervex brush and PreservCyt or FLOQSwab and eNAT), (ii) the collector of the specimen (gynaecologist- or patient-based), and (iii) the precise sampling site (cervical, cervicovaginal and vaginal). Furthermore, we demonstrate sample stability in eNAT medium for 7 days at room temperature, greatly facilitating the implementation of the test into diagnostic laboratory workflows. When applying FLOQSwabs (Copan) in combination with the eNAT (Copan) sample collection media, the sensitivity and specificity of the WID-qEC test to detect uterine (i.e., endometrial and cervical) cancers in gynaecologist-taken samples was 92.9% (95% confidence interval [CI] = 75.0%-98.8%) and 98.6% (95% CI = 91.7%-99.9%), respectively, whilst the sensitivity and specificity in patient collected self-samples was 75.0% (95% CI = 47.4%-91.7%) and 100.0% (95% CI = 93.9%-100.0%), respectively. Taken together these data confirm the robustness and clinical potential of the WID-qEC test.

Interaction of high-fat diet and brain trauma alters adipose tissue macrophages and brain microglia associated with exacerbated cognitive dysfunction.

Obesity increases the morbidity and mortality of traumatic brain injury (TBI). Detailed analyses of transcriptomic changes in the brain and adipose tissue were performed to elucidate the interactive effects between high-fat diet-induced obesity (DIO) and TBI. Adult male mice were fed a high-fat diet (HFD) for 12 weeks prior to experimental TBI and continuing after injury. High-throughput transcriptomic analysis using Nanostring panels of the total visceral adipose tissue (VAT) and cellular components in the brain, followed by unsupervised clustering, principal component analysis, and IPA pathway analysis were used to determine shifts in gene expression patterns and molecular pathway activity. Cellular populations in the cortex and hippocampus, as well as in VAT, during the chronic phase after combined TBI-HFD showed amplification of central and peripheral microglia/macrophage responses, including superadditive changes in selected gene expression signatures and pathways. Furthermore, combined TBI and HFD caused additive dysfunction in Y-Maze, Novel Object Recognition (NOR), and Morris water maze (MWM) cognitive function tests. These novel data suggest that HFD-induced obesity and TBI can independently prime and support the development of altered states in brain microglia and VAT, including the disease-associated microglia/macrophage (DAM) phenotype observed in neurodegenerative disorders. The interaction between HFD and TBI promotes a shift toward chronic reactive microglia/macrophage transcriptomic signatures and associated pro-inflammatory disease-altered states that may, in part, underlie the exacerbation of cognitive deficits. Thus, targeting of HFD-induced reactive cellular phenotypes, including in peripheral adipose tissue immune cell populations, may serve to reduce microglial maladaptive states after TBI, attenuating post-traumatic neurodegeneration and neurological dysfunction.

Archaeological evidence of resource utilisation of the great whales over the past two millennia: A systematic review protocol.

Archaeological faunal remains provide key insights into human societies in the past, alongside information on previous resource utilisation and exploitation of wildlife populations. The great whales (Mysticete and sperm whales) were hunted unsustainably throughout the 16th - 20th centuries (herein defined as the modern period) leading to large population declines and variable recovery patterns among species. Humans have utilised whales as a resource through carcass scavenging for millennia; however, increasing local and regional ethnographic and archaeological evidence suggests that, prior to the modern period, hunting of the great whales was more common than previously thought; impacts of earlier hunting pressures on the population ecology of many whale species remains relatively unknown. Hunting guided by traditional ecological knowledge may have been sustainable and likely originated in societies that also incorporated opportunistic use of stranded individuals. The collation of georeferenced zooarchaeological data of the great whales between the 1st - 20th centuries CE worldwide will provide insight into the timescale and distribution of resource utilisation of the great whales and how this varied within and between societies, and may have changed over time. By comparing regions of known resource utilisation and breeding and feeding grounds of current-day whale populations, this information will subsequently be used to infer regions where whale populations were possibly lost or extirpated prior to detailed historical records. This systematic review protocol also provides a template for archaeologists, ecologists, and historians interested in using faunal remains to infer historical ecology and resource use of wild animal populations. The transparency of our data collection approach provides opportunities for reproducibility and comparability with future datasets.

The impact of Longitudinal Integrated Foundation Training: preliminary experiences in the United Kingdom.

BACKGROUND: The United Kingdom health system is challenged with retaining doctors entering specialty training directly after their second foundation year. Improving doctors' training experience during the foundation programme may aid such retention. The Longitudinal Integrated Foundation Training (LIFT) pilot scheme aimed to provide a programme that improves the quality of their foundation training experience, advance patient-centred care and provide doctors with more experience in the primary care settings. METHODS: During this pilot study, three methods were employed to evaluate and compare doctors' experiences across their 2-year foundation training programme: Horus ePortfolio assessment of six domains for good medical practice analysed using a T-test, online survey assessments analysed using a 2-tailed chi-square test, and focus group feedback sessions with thematic analysis. RESULTS: Doctors completing LIFT (n = 47) scored a higher but non-significant mean score on all six domains for good medical practice versus doctors completing traditional foundation training (n = 94). By the end of foundation training, 100% of LIFT doctors rated their understanding of how primary and secondary care work together as high versus 78.7% of traditional doctors (p < 0.05). Improvements in wellbeing were observed among LIFT doctors, along with a reduction in the proportion of doctors considering leaving medical training. A significantly greater number of LIFT doctors versus traditional doctors rated their compassion for patients as high (100% versus 86.8%; p < 0.05), intended to become general practitioners (23.1% versus 13.5%; p < 0.05) and rated the extent to which they felt well informed and able to consider a general practice career rather than a hospital career as high (91.7% versus 72.3%, respectively; p < 0.05). Some LIFT doctors felt they had reduced exposure to secondary care, received less on-call experience and considered working a half-day to be problematic; challenges ameliorated by the end of the 2-year foundation programme. CONCLUSION: The LIFT programme enhanced the quality of foundation training and improved doctors' experiences and competencies, generating valuable insights for the future of education and healthcare delivery. Applying the principles of LIFT to foundation training helps doctors to be more compassionate and patient-centred, leading to enhanced individualised patient care.

The role of BST4 in the pyrenoid of Chlamydomonas reinhardtii.

In many eukaryotic algae, CO2 fixation by Rubisco is enhanced by a CO2-concentrating mechanism, which utilizes a Rubisco-rich organelle called the pyrenoid. The pyrenoid is traversed by a network of thylakoid-membranes called pyrenoid tubules, proposed to deliver CO2. In the model alga Chlamydomonas reinhardtii (Chlamydomonas), the pyrenoid tubules have been proposed to be tethered to the Rubisco matrix by a bestrophin-like transmembrane protein, BST4. Here, we show that BST4 forms a complex that localizes to the pyrenoid tubules. A Chlamydomonas mutant impaired in the accumulation of BST4 (bst4) formed normal pyrenoid tubules and heterologous expression of BST4 in Arabidopsis thaliana did not lead to the incorporation of thylakoids into a reconstituted Rubisco condensate. Chlamydomonas bst4 mutant did not show impaired growth at air level CO2. By quantifying the non-photochemical quenching (NPQ) of chlorophyll fluorescence, we show that bst4 displays a transiently lower thylakoid lumenal pH during dark to light transition compared to control strains. When acclimated to high light, bst4 had sustained higher NPQ and elevated levels of light-induced H2O2 production. We conclude that BST4 is not a tethering protein, but rather is an ion channel involved in lumenal pH regulation possibly by mediating bicarbonate transport across the pyrenoid tubules.

Young persons and healthcare professionals experience of virtual gastroenterology consultations: a multicentre survey conducted during the COVID-19 pandemic.

Objective: To explore Young Persons (YP) and healthcare professionals (HCP) experiences of virtual consultations (VC) and establish whether developmentally appropriate healthcare can be delivered virtually. Method: YP and HCP questionnaire surveys were designed and piloted. Electronic questionnaire links were sent by post, email or text message January-April 2021 to YP aged 13-25 years old, with predefined chronic gastrointestinal conditions, attending a gastroenterology/hepatology VC. HCP undertaking VC were invited to complete staff questionnaire. Results were anonymous and collated using Excel version 2302. Results: Five UK hospital trusts participated, with 35 HCP responses. Of the 100 YP completing the survey 66% were female and 34% male aged between 13 years and 25 years (median: 18 years). 13% were new appointments and 87% follow ups, 29% were by video, 69% by phone and 2% gave no response. 80% of HCP spoke to YP directly but not privately (69%). 87% of YP and 88% HCP found VC useful. 83% of YP want VC again, although 20% preferred face to face. 43% of HCP required improved phone/internet connection. 77% of YP required hospital appointments for tests following VC. Conclusions: Overall respondents were satisfied with VC, finding them useful, convenient and time saving. Successful VC rely on appropriate patient selection and availability of reliable technology. Patient preference is key which may alter with time.

The prelude to industrial whaling: identifying the targets of ancient European whaling using zooarchaeology and collagen mass-peptide fingerprinting.

Taxonomic identification of whale bones found during archaeological excavations is problematic due to their typically fragmented state. This difficulty limits understanding of both the past spatio-temporal distributions of whale populations and of possible early whaling activities. To overcome this challenge, we performed zooarchaeology by mass spectrometry on an unprecedented 719 archaeological and palaeontological specimens of probable whale bone from Atlantic European contexts, predominantly dating from ca 3500 BCE to the eighteenth century CE. The results show high numbers of Balaenidae (many probably North Atlantic right whale (Eubalaena glacialis)) and grey whale (Eschrichtius robustus) specimens, two taxa no longer present in the eastern North Atlantic. This discovery matches expectations regarding the past utilization of North Atlantic right whales, but was unanticipated for grey whales, which have hitherto rarely been identified in the European zooarchaeological record. Many of these specimens derive from contexts associated with mediaeval cultures frequently linked to whaling: the Basques, northern Spaniards, Normans, Flemish, Frisians, Anglo-Saxons and Scandinavians. This association raises the likelihood that early whaling impacted these taxa, contributing to their extirpation and extinction. Much lower numbers of other large cetacean taxa were identified, suggesting that what are now the most depleted whales were once those most frequently used.

The impact of immunocompromise on outcomes of COVID-19 in children and young people-a systematic review and meta-analysis.

Background: Despite children and young people (CYP) having a low risk for severe coronavirus disease 2019 (COVID-19) outcomes, there is still a degree of uncertainty related to their risk in the context of immunodeficiency or immunosuppression, primarily due to significant reporting bias in most studies, as CYP characteristically experience milder or asymptomatic COVID-19 infection and the severe outcomes tend to be overestimated. Methods: A comprehensive systematic review to identify globally relevant studies in immunosuppressed CYP and CYP in general population (defined as younger than 25 years of age) up to 31 October 2021 (to exclude vaccinated populations) was performed. Studies were included if they reported the two primary outcomes of our study, admission to intensive therapy unit (ITU) and mortality, while data on other outcomes, such as hospitalization and need for mechanical ventilation were also collected. A meta-analysis estimated the pooled proportion for each severe COVID-19 outcome, using the inverse variance method. Random effects models were used to account for interstudy heterogeneity. Findings: The systematic review identified 30 eligible studies for each of the two populations investigated: immunosuppressed CYP (n = 793) and CYP in general population (n = 102,022). Our meta-analysis found higher estimated prevalence for hospitalization (46% vs. 16%), ITU admission (12% vs. 2%), mechanical ventilation (8% vs. 1%), and increased mortality due to severe COVID-19 infection (6.5% vs. 0.2%) in immunocompromised CYP compared with CYP in general population. This shows an overall trend for more severe outcomes of COVID-19 infection in immunocompromised CYP, similar to adult studies. Interpretation: This is the only up-to-date meta-analysis in immunocompromised CYP with high global relevance, which excluded reports from hospitalized cohorts alone and included 35% studies from low- and middle-income countries. Future research is required to characterize individual subgroups of immunocompromised patients, as well as impact of vaccination on severe COVID-19 outcomes. Systematic Review Registration: PROSPERO identifier, CRD42021278598.

Holocene deglaciation drove rapid genetic diversification of Atlantic walrus.

Rapid global warming is severely impacting Arctic ecosystems and is predicted to transform the abundance, distribution and genetic diversity of Arctic species, though these linkages are poorly understood. We address this gap in knowledge using palaeogenomics to examine how earlier periods of global warming influenced the genetic diversity of Atlantic walrus (Odobenus rosmarus rosmarus), a species closely associated with sea ice and shallow-water habitats. We analysed 82 ancient and historical Atlantic walrus mitochondrial genomes (mitogenomes), including now-extinct populations in Iceland and the Canadian Maritimes, to reconstruct the Atlantic walrus' response to Arctic deglaciation. Our results demonstrate that the phylogeography and genetic diversity of Atlantic walrus populations was initially shaped by the last glacial maximum (LGM), surviving in distinct glacial refugia, and subsequently expanding rapidly in multiple migration waves during the late Pleistocene and early Holocene. The timing of diversification and establishment of distinct populations corresponds closely with the chronology of the glacial retreat, pointing to a strong link between walrus phylogeography and sea ice. Our results indicate that accelerated ice loss in the modern Arctic may trigger further dispersal events, likely increasing the connectivity of northern stocks while isolating more southerly stocks putatively caught in small pockets of suitable habitat.

Interaction of high-fat diet and brain trauma alters adipose tissue macrophages and brain microglia associated with exacerbated cognitive dysfunction.

Obesity increases the morbidity and mortality of traumatic brain injury (TBI). We performed a detailed analysis of transcriptomic changes in the brain and adipose tissue to examine the interactive effects between high-fat diet-induced obesity (DIO) and TBI in relation to central and peripheral inflammatory pathways, as well as neurological function. Adult male mice were fed a high-fat diet (HFD) for 12 weeks prior to experimental TBI and continuing after injury. Combined TBI and HFD resulted in additive dysfunction in the Y-Maze, novel object recognition (NOR), and Morris water maze (MWM) cognitive function tests. We also performed high-throughput transcriptomic analysis using Nanostring panels of cellular compartments in the brain and total visceral adipose tissue (VAT), followed by unsupervised clustering, principal component analysis, and IPA pathway analysis to determine shifts in gene expression programs and molecular pathway activity. Analysis of cellular populations in the cortex and hippocampus as well as in visceral adipose tissue during the chronic phase after combined TBI-HFD showed amplification of central and peripheral microglia/macrophage responses, including superadditive changes in select gene expression signatures and pathways. These data suggest that HFD-induced obesity and TBI can independently prime and support the development of altered states in brain microglia and visceral adipose tissue macrophages, including the disease-associated microglia/macrophage (DAM) phenotype observed in neurodegenerative disorders. The interaction between HFD and TBI promotes a shift toward chronic reactive microglia/macrophage transcriptomic signatures and associated pro-inflammatory disease-altered states that may, in part, underlie the exacerbation of cognitive deficits. Targeting of HFD-induced reactive cellular phenotypes, including in peripheral adipose tissue macrophages, may serve to reduce microglial maladaptive states after TBI, attenuating post-traumatic neurodegeneration and neurological dysfunction.

Changes in medication safety indicators in England throughout the covid-19 pandemic using OpenSAFELY: population based, retrospective cohort study of 57 million patients using federated analytics.

Objective: To implement complex, PINCER (pharmacist led information technology intervention) prescribing indicators, on a national scale with general practice data to describe the impact of the covid-19 pandemic on safe prescribing. Design: Population based, retrospective cohort study using federated analytics. Setting: Electronic general practice health record data from 56.8 million NHS patients by use of the OpenSAFELY platform, with the approval of the National Health Service (NHS) England. Participants: NHS patients (aged 18-120 years) who were alive and registered at a general practice that used TPP or EMIS computer systems and were recorded as at risk of at least one potentially hazardous PINCER indicator. Main outcome measure: Between 1 September 2019 and 1 September 2021, monthly trends and between practice variation for compliance with 13 PINCER indicators, as calculated on the first of every month, were reported. Prescriptions that do not adhere to these indicators are potentially hazardous and can cause gastrointestinal bleeds; are cautioned against in specific conditions (specifically heart failure, asthma, and chronic renal failure); or require blood test monitoring. The percentage for each indicator is formed of a numerator of patients deemed to be at risk of a potentially hazardous prescribing event and the denominator is of patients for which assessment of the indicator is clinically meaningful. Higher indicator percentages represent potentially poorer performance on medication safety. Results: The PINCER indicators were successfully implemented across general practice data for 56.8 million patient records from 6367 practices in OpenSAFELY. Hazardous prescribing remained largely unchanged during the covid-19 pandemic, with no evidence of increases in indicators of harm as captured by the PINCER indicators. The percentage of patients at risk of potentially hazardous prescribing, as defined by each PINCER indicator, at mean quarter 1 (Q1) 2020 (representing before the pandemic) ranged from 1.11% (age ≥65 years and non-steroidal anti-inflammatory drugs) to 36.20% (amiodarone and no thyroid function test), while Q1 2021 (representing after the pandemic) percentages ranged from 0.75% (age ≥65 years and non-steroidal anti-inflammatory drugs) to 39.23% (amiodarone and no thyroid function test). Transient delays occurred in blood test monitoring for some medications, particularly angiotensin-converting enzyme inhibitors (where blood monitoring worsened from a mean of 5.16% in Q1 2020 to 12.14% in Q1 2021, and began to recover in June 2021). All indicators substantially recovered by September 2021. We identified 1 813 058 patients (3.1%) at risk of at least one potentially hazardous prescribing event. Conclusion: NHS data from general practices can be analysed at national scale to generate insights into service delivery. Potentially hazardous prescribing was largely unaffected by the covid-19 pandemic in primary care health records in England.

Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments.

Oxycodone, a semisynthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for more than 100 years. Although thebaine cannot be used therapeutically due to the occurrence of convulsions at higher doses, it has been converted to a number of other widely used compounds that include naloxone, naltrexone, buprenorphine, and oxycodone. Despite the early identification of oxycodone, it was not until the 1990s that clinical studies began to explore its analgesic efficacy. These studies were followed by the pursuit of several preclinical studies to examine the analgesic effects and abuse liability of oxycodone in laboratory animals and the subjective effects in human volunteers. For a number of years oxycodone was at the forefront of the opioid crisis, playing a significant role in contributing to opioid misuse and abuse, with suggestions that it led to transitioning to other opioids. Several concerns were expressed as early as the 1940s that oxycodone had significant abuse potential similar to heroin and morphine. Both animal and human abuse liability studies have confirmed, and in some cases amplified, these early warnings. Despite sharing a similar structure with morphine and pharmacological actions also mediated by the µ-opioid receptor, there are several differences in the pharmacology and neurobiology of oxycodone. The data that have emerged from the many efforts to analyze the pharmacological and molecular mechanism of oxycodone have generated considerable insight into its many actions, reviewed here, which, in turn, have provided new information on opioid receptor pharmacology. SIGNIFICANCE STATEMENT: Oxycodone, a µ-opioid receptor agonist, was synthesized in 1916 and introduced into clinical use in Germany in 1917. It has been studied extensively as a therapeutic analgesic for acute and chronic neuropathic pain as an alternative to morphine. Oxycodone emerged as a drug with widespread abuse. This article brings together an integrated, detailed review of the pharmacology of oxycodone, preclinical and clinical studies of pain and abuse, and recent advances to identify potential opioid analgesics without abuse liability.

HPV-induced host epigenetic reprogramming is lost upon progression to high-grade cervical intraepithelial neoplasia.

The impact of a pathogen on host disease can only be studied in samples covering the entire spectrum of pathogenesis. Persistent oncogenic human papilloma virus (HPV) infection is the most common cause for cervical cancer. Here, we investigate HPV-induced host epigenome-wide changes prior to development of cytological abnormalities. Using cervical sample methylation array data from disease-free women with or without an oncogenic HPV infection, we develop the WID (Women's cancer risk identification)-HPV, a signature reflective of changes in the healthy host epigenome related to high-risk HPV strains (AUC = 0.78, 95% CI: 0.72-0.85, in nondiseased women). Looking at HPV-associated changes across disease development, HPV-infected women with minor cytological alterations (cervical intraepithelial neoplasia grade 1/2, CIN1/2), but surprisingly not those with precancerous changes or invasive cervical cancer (CIN3+), show an increased WID-HPV index, indicating the WID-HPV may reflect a successful viral clearance response absent in progression to cancer. Further investigation revealed the WID-HPV is positively associated with apoptosis (ρ = 0.48; P < .001) and negatively associated with epigenetic replicative age (ρ = -0.43; P < .001). Taken together, our data suggest the WID-HPV captures a clearance response associated with apoptosis of HPV-infected cells. This response may be dampened or lost with increased underlying replicative age of infected cells, resulting in progression to cancer.

Medically Smart, Fiscally Illiterate: Lack of Financial Education Leads to Poor Retirement Savings Strategies in Surgical Trainees.

INTRODUCTION: Resident physicians are uniquely at high financial risk given their long training programs, lack of financial education, and documented poor financial literacy. Budgeting for retirement savings is an important metric for financial literacy. METHODS: Semi-structured interviews were conducted with residents from two distinct surgery programs to assess their current financial status and their knowledge of and attitudes toward retirement savings strategies. Qualitative analysis was performed and the themes identified were examined in the context of previously reported quantitative survey data. RESULTS: As previously reported, 105 residents at Site 1 completed a comprehensive financial survey 56% of respondents reported having no retirement savings. On additional analysis, only 26% residents surveyed reported optimal savings habits defined as contributing $5000/year to a retirement account starting their first year of training. 23 residents from both sites and representing all post-graduate-year (PGY) levels then participated in the focused, semi-structured interviews. Site 2 residents were less likely to be female (P = .02) and carried a significantly larger debt burden (p < .01) but were otherwise comparable to residents from Site 1. On qualitative analysis three consistent themes emerged: (1) Resident understanding of strategies for retirement savings is poor; (2) Lack of knowledge is the primary barrier; (3) Surgical residents desire financial education. CONCLUSIONS: Surgery residents have a large debt burden, minimal retirement savings and an overall lack of understanding of savings strategies. Well-designed, early, and accessible educational interventions may improve the "financial vital signs" of surgical trainees and establish habits for long-term financial success.

Urological and Gynaecological Considerations for the Use of Gonadotropin-releasing Hormone Analogues in Transgender and Nonbinary Adolescents: A Narrative Review.

CONTEXT: Gonadotropin-releasing hormone analogues (GnRHAs) delay the progression of puberty in transgender and nonbinary (TGNB) adolescents and reduce the impact of dysphoria due to ongoing physical development. The intervention remains contentious despite growing evidence to support this practice. OBJECTIVE: To stimulate discussion on this topical issue in the urological and gynaecological community given potential ramifications for future fertility, physical development, and options for gender affirmation surgery (GAS). EVIDENCE ACQUISITION: We conducted searches of the MEDLINE (from 1946) and Embase (from 1974) databases for the benefits and potential challenges of hormone blockade in TGNB adolescents on February 1, 2022. Evidence with a primary focus on clinical issues of interest to urologists and gynaecologists was objectively synthesised and reported. EVIDENCE SYNTHESIS: The onset of puberty represents a period of distress for TGNB adolescents as secondary sexual characteristics develop. GnRHAs are prescribed to inhibit sex hormone production, but the decision to treat should be balanced against the known (and unknown) adverse effects. Fertility preservation is more likely to be successful if GnRHA treatment is delayed for as long as possible. Some adolescents may decide to stop GnRHA use to harvest spermatozoa or oocytes before starting gender-affirming hormone treatment. Transfeminine individuals should consider that options for genital GAS may become more limited, as vaginoplasty with penile skin inversion requires an adequate stretched penile length. Transmasculine individuals may no longer require chest reconstruction for breast development. CONCLUSIONS: Offers of GnRHA treatment to TGNB adolescents should be balanced by careful preparation and counselling. Urologists and gynaecologists can complement the expertise of specialist psychosocial and adolescent endocrinology teams, and should be involved early in and throughout the treatment pathway to maximise future functional and surgical outcomes. PATIENT SUMMARY: Puberty blockers for transgender and nonbinary adolescents have benefits, but timing is important to preserve fertility and surgical options.