Hypoxia is known to act as a general stimulator of cells derived from marrow precursors. We investigated the effect of oxygen tension on the formation and function of osteoclasts, the cells responsible for bore resorption, which are of promonocytic origin. Using 7-and 13-day cultures of mouse marrow cells on ivory discs, we found that reducing oxygen tension from the ambient atmospheric level of 20% by increasing the proportion of nitrogen caused progressive increases in the formation of multinucleated osteoclasts and resorption pits. Peak effects occurred in 2% oxygen, where stimulations of resorption up to 21-fold were measured. Significant stimulations of osteoclast formation and resorption were observed even in severely hypoxic cultures gassed with 0.2% oxygen. Short-term cultures of cells disaggregated from rat bones indicated that hypoxia did not alter the resorptive activity of mature osteoclasts, but reduced their survival or adherence. In 3-day organ cultures of mouse calvarial bones, exposure to 2% oxygen resulted in maximal, fivefold stimulation of osteoclast-mediated calcium release, an effect equivalent to that of prostaglandin E 2 (PGE 2 ), a reference osteolytic agent. Hypoxia also caused a moderate acidosis in calvarial cultures, presumably as a result of increased anaerobic metabolism; this observation is significant because osteoclast activation is dependent on extracellular acidification. Our experiments reveal a previously-overlooked mechanism of considerable potential importance for the regulation of bone destruction. These findings may help explain the bone loss associated with a wide range of pathological states involving local or systemic hypoxia, and emphasize the importance of the vasculature in bone.

Background

There is consistency amongst polyposis registries in documenting the incidence and risk factors for DT development. Having a positive family history for DT is of greater significance than a 3' mutation, suggesting the existence of modifier genes, independent of the APC genotype-phenotype correlation. Few of these risk factors are modifiable. Delaying prophylactic surgery could be appropriate in female patients with a 3' APC mutation and attenuated polyposis.

A service evaluation of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) testing and result notification in patients attending a rapid testing service (Dean Street Express [DSE]) compared with those attending an existing ‘standard’ sexual health clinic (56 Dean Street [56DS]), and modelling the impact of the new service from 1 June 2014 to 31 May 2015. Primary outcome: time from patients’ sample collection to notification of test results at DSE compared with 56DS. Secondary outcomes estimated using a model: number of transmissions prevented and the number of new partner visits avoided and associated cost savings achieved due to rapid testing at DSE. In 2014/15, there were a total of 81,352 visits for CT/NG testing across 56DS (21,086) and DSE (60,266). Rapid testing resulted in a reduced mean time to notification of 8.68 days: 8.95 days for 56DS (95% CI 8.91–8.99) compared to 0.27 days for DSE (95% CI 0.26–0.28). Our model estimates that rapid testing at DSE would lead to 196 CT and/or NG transmissions prevented (2.5–97.5% centile range = 6–956) and lead to annual savings attributable to reduced numbers of partner attendances of £124,283 (2.5–97.5% centile range = £4260–590,331). DSE, a rapid testing service for asymptomatic infections, delivers faster time to result notification for CT and/or NG which enables faster treatment, reduces infectious periods and leads to fewer transmissions, partner attendances and clinic costs.

Introduction: There is limited real-world evidence surrounding the effectiveness of early, mild-to-moderate COVID-19 treatments following the emergence and dominance of Omicron SARS-CoV-2 subvariants. Here, characteristics and acute clinical outcomes are described for patients with COVID-19 treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or patients at highest risk per NHS criteria but who were untreated. Methods: Retrospective cohort study of non-hospitalised patients who received early treatment for, or were diagnosed with, COVID-19 between 1 December 2021 and 31 May 2022, using data from the Discover dataset in north-west London. Patients were included if aged ≥12 years and treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or were untreated but expected to be eligible for early treatment per NHS highest-risk criteria at time of diagnosis. Outcomes were reported for 28 days from COVID-19 diagnosis (index). Subgroup analyses were conducted in patients with advanced renal disease, those aged 18-64 and ≥65 years and by period of Omicron BA.1, BA.2 and BA.5 (post-hoc exploratory analysis) predominance. Results: A total of 696 patients prescribed sotrovimab, 337 prescribed nirmatrelvir/ritonavir, 470 prescribed molnupiravir and 4,044 eligible high-risk untreated patients were included. A high proportion of patients on sotrovimab had advanced renal disease (29.3%), ≥3 high-risk comorbidities (47.6%) and were aged ≥65 years (36.9%). In total, 5/696 (0.7%) patients on sotrovimab, <5/337 (0.3-1.2%) patients on nirmatrelvir/ritonavir, 10/470 (2.1%) patients on molnupiravir and 114/4,044 (2.8%) untreated patients were hospitalised with COVID-19 as the primary diagnosis. Similar results were observed across all subgroups and during Omicron subvariant periods. Conclusion: Patients who received sotrovimab appeared to show evidence of multiple comorbidities that may increase risk of severe COVID-19. Low hospitalisation rates were observed for all treated cohorts across subgroups and periods of predominant variants of concern. These descriptive results require confirmation with comparative effectiveness analyses adjusting for differences in underlying patient characteristics.

BackgroundThe annual number of unplanned attendances at accident and emergency (A&E) departments in England increased by 11% (2.2 million attendances) between 2008–2009 and 2012–2013. A national review of urgent and emergency care has emphasised the role of access to primary care services in preventing A&E attendances.AimTo estimate the number of A&E attendances in England in 2012–2013 that were preceded by the attending patient being unable to obtain an appointment or a convenient appointment at their general practice.Design and settingCross-sectional analysis of a national survey of adults registered with a GP in England.MethodThe number of general practice consultations in England in 2012–2013 was estimated by extrapolating the linear trend of published data for 2000–2001 to 2008–2009. This parameter was multiplied by the ratio of attempts to obtain a general practice appointment that resulted in an A&E attendance to attempts that resulted in a general practice consultation estimated using the GP Patient Survey 2012–2013. A sensitivity analysis varied the number of consultations by ±12% and the ratio by ±25%.ResultsAn estimated 5.77 million (99.9% confidence interval = 5.49 to 6.05 million) A&E attendances were preceded by the attending patient being unable to obtain a general practice appointment or a convenient appointment, comprising 26.5% of unplanned A&E attendances in England in 2012–2013. The sensitivity analysis produced values between 17.5% and 37.2% of unplanned A&E attendances.ConclusionA large number of A&E attendances are likely to be preceded by unsuccessful attempts to obtain convenient general practice appointments in England each year.

BackgroundThe minimum age for the legal purchase of tobacco increased from 16 to 18 years in England, Scotland and Wales on 1 October 2007. The authors examined the impact of this legislation on disparities in smoking behaviour and access to cigarettes among youth in England. Methods A multivariate logistic regression analysis was carried out adjusting for secular trends in regular smoking using data from the Smoking, Drinking and Drug Use Survey, a national survey of 11e15 year olds. The primary outcome measure was regular smoking and the predictor variables were the law increasing the minimum age for purchase and eligibility for free school meals (FSM). Results Increasing the minimum age for purchase was associated with a significant reduction in regular smoking among youth (adjusted OR 0.67; 95% CI 0.55 to 0.81, p¼0.0005). This effect was not significantly different in pupils eligible for FSM compared with those that were not (adjusted OR 1.29; 95% CI 0.95 to 1.76, p¼0.10 for interaction term). The percentage of pupils who stated that they found it difficult to buy cigarettes from a shop did not increase in those eligible for FSM (25.2% to 33.3%; p¼0.21) but did increase significantly in others (21.2% to 36.9%; p<0.01) between 2006 and 2008. No differences in ease of purchase were found between pupils eligible for FSM and those not before or after the legislation (2006: p¼0.34, 2008: p¼0.55). Conclusions Increasing the age for the legal purchase of tobacco was associated with reduced regular smoking among youth in England and appeared to have a similar impact in different socio-economic groups.

Introduction Sotrovimab, a recombinant human monoclonal antibody (mAb) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had US Food and Drug Administration Emergency Use Authorization for the treatment of high-risk outpatients with mild-to-moderate coronavirus disease 2019 (COVID-19) from 26 May 2021 to 5 April 2022. Real-world clinical effectiveness of sotrovimab in reducing the risk of 30-day all-cause hospitalization and/or mortality was evaluated for the period when the prevalence of circulating SARS-CoV-2 variants changed between Delta and Omicron in the USA. Methods A retrospective analysis was conducted of de-identified patients diagnosed with COVID-19 between 1 September 2021 to 30 April 2022 in the FAIR Health National Private Insurance Claims database. Patients meeting high-risk criteria were divided into two cohorts: sotrovimab and not treated with a mAb (“no mAb”). All-cause hospitalizations and facility-reported mortality ≤ 30 days of diagnosis (“30-day hospitalization or mortality”) were identified. Multivariable and propensity score-matched Poisson and logistic regressions were conducted to estimate the adjusted relative risk (RR) and odds of 30-day hospitalization or mortality in each cohort. Results Compared with the no mAb cohort ( n = 1,514,868), the sotrovimab cohort ( n = 15,633) was older and had a higher proportion of patients with high-risk conditions. In the no mAb cohort, 84,307 (5.57%) patients were hospitalized and 8167 (0.54%) deaths were identified, while in the sotrovimab cohort, 418 (2.67%) patients were hospitalized and 13 (0.08%) deaths were identified. After adjusting for potential confounders, the sotrovimab cohort had a 55% lower risk of 30-day hospitalization or mortality (RR 0.45, 95% CI 0.41–0.49) and an 85% lower risk of 30-day mortality (RR 0.15, 95% CI 0.08–0.29). Monthly, from September 2021 to April 2022, the RR reduction for 30-day hospitalization or mortality in the sotrovimab cohort was maintained, ranging from 46% to 71% compared with the no mAb cohort; the RR estimate in April 2022 was uncertain, with wide confidence intervals due to the small sample size. Conclusion Sotrovimab was associated with reduced risk of 30-day all-cause hospitalization and mortality versus no mAb treatment. Clinical effectiveness persisted during Delta and early Omicron variant waves and among all high-risk subgroups assessed. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-022-00755-0.