Identification and characterisation of G-quadruplex DNA-forming sequences in the Pseudomonas aeruginosa genome

A number of Gram-negative bacteria such as Pseudomonas aeruginosa are becoming resistant to front-line antibiotics. Consequently, there is a pressing need to find alternative bio-molecular targets for the development of new drugs. Since non-canonical DNA structures such as guanine-quadruplexes (G4s) have been implicated in regulating transcription, we were interested in determining whether there are putative quadruplex-forming sequences (PQS) in the genome of Pseudomonas aeruginosa. Using bioinformatic tools, we screened 36 genes potentially relevant to drug resistance for the presence of PQS and 10 of these were selected for biophysical characterisation (i.e. circular dichroism and thermal difference UV/Vis spectroscopy). These studies showed that three of these G-rich sequences (linked to murE, ftsB and mexC genes) form stable guanine-quadruplexes which were studied by NMR spectroscopy; detailed analysis of one of the sequences (mexC) confirmed that it adopts a two-quartet antiparallel quadruplex structure in the presence of K+ ions. We also show by FRET melting assays that small molecules can stabilise these three new G4 DNA structures under physiological conditions. These initial results could be of future interest in the development of new antibiotics with alternative bio-molecular targets which in turn would help tackle antimicrobial resistance

Costos de la licencia de maternidad para apoyar la lactancia materna en Brasil, Ghana y México

Objective To develop a method to assess the cost of extending the duration of maternity leave for formally-employed women at the national level and apply it in Brazil, Ghana and Mexico. Methods We adapted a World Bank costing method into a five-step method to estimate the costs of extending the length of maternity leave mandates. Our method used the unit cost of maternity leave based on working women’s weekly wages; the number of additional weeks of maternity leave to be analysed for a given year; and the weighted population of women of reproductive and legal working age in a given country in that year. We weighted the population by the probability of having a baby that year among women in formal employment, according to individual characteristics. We applied nationally representative cross-sectional data from fertility, employment and population surveys to estimate the costs of maternity leave for mothers employed in the formal sector in Brazil, Ghana and Mexico for periods from 12 weeks up to 26 weeks, the WHO target for exclusive breastfeeding. Findings We estimated that 640 742 women in Brazil, 33 869 in Ghana and 288 655 in Mexico would require formal maternity leave annually. The median weekly cost of extending maternity leave for formally working women was purchasing power parity international dollars (PPP$) 195.07 per woman in Brazil, PPP$ 109.68 in Ghana and PPP$ 168.83 in Mexico. Conclusion Our costing method could facilitate evidence-based policy decisions across countries to improve maternity protection benefits and support breastfeeding

The yearly financing need of providing paid maternity leave in the informal sector in Indonesia

Background: The economic cost of not breastfeeding in Indonesia is estimated at US$1.5–9.4 billion annually, the highest in South East Asia. Half of the 33.6 million working women of reproductive age (WRA) in Indonesia (15–49 years) are informal employees, meaning they are working as casual workers or they are self-employed (small scale business) and assisted by unpaid/family worker(s). No specific maternity protection entitlements are currently available for WRA working informally in Indonesia. This study aims to estimate the financing need of providing maternity leave cash transfer (MCT) for WRA working in the informal sector in Indonesia. Method: The costing methodology used is the adapted version of the World Bank methodology by Vilar-Compte et al, following pre-set steps to estimate costs using national secondary data. We used the 2018 Indonesian National Socio-Economic Survey to estimate the number of women working informally who gave birth within the last year. The population covered, potential cash transfer’s unitary cost, the incremental coverage of the policy in terms of time and coverage, and the administrative costs were used to estimate the cost of MCT for the informal sector. Result: At 100$175million (US$152/woman) to US$669million (US$583/woman). The share of the yearly financing need did not exceed 0.5% of Indonesian Gross Domestic Product (GDP). Conclusions: The yearly financing need of providing MCT for eligible WRA working in the informal sector is economically attractive as it amounts to less than 0.5% of GDP nominal of Indonesia. While such a program would be perceived as a marked increase from current public health spending at the onset, such an investment could substantially contribute to the success of breastfeeding and substantial corresponding public health savings given that more than half of working Indonesian WRA are employed in the informal sector. Such policies should be further explored while taking into consideration realistic budget constraints and implementation capacity

OA06.06 Impact of Systemic Anti-cancer Treatments on Outcomes of COVID-19 in Patients with Thoracic Cancers: CCC19 Registry Analysis

Introduction: Patients with thoracic cancers (TC) have one of the highest rates of mortality among patients with cancer and COVID-19. Data evaluating the impact of recent anti-cancer therapies on COVID-19 outcomes in patients with TC are confined to small heterogenous retrospective studies, with limited follow-up data. We analyzed data from the COVID-19 and Cancer Consortium (CCC19) (NCT04354701) to examine the impact of recent systemic therapies on the clinical outcomes of COVID-19 in patients with TC. Methods: The CCC19 registry was queried for adult patients with TC and lab-confirmed SARS-CoV-2 infection. Only patients with data quality scores of 0-4 were included in the analysis. The primary outcome was 30-day all-cause mortality. Secondary outcomes were need for oxygen supplementation, hospitalization, ICU admission, and mechanical ventilation. The outcomes were further stratified by demographics, smoking history, ECOG PS (0, 1, \u3e2), cancer status (remission, responding/stable, progressing) and type of systemic treatment \u3c3 months prior to COVID-19 (chemotherapy with or without immunotherapy, chemotherapy plus radiation, immunotherapy alone or targeted therapy). Results: From January 2020 to December 2021, 900 patients with thoracic cancer met the inclusion criteria. The median age was 70 years (IQR 62-77), 53% were female, 79% were former or current tobacco users, 56% of patients had ECOG PS of 0 or 1, and 34% of patients had active but stable or responding cancer. Fifty-three percent (N=477) of patients received at least one anti-cancer systemic therapy \u3c3 months prior to COVID-19 diagnosis. Chemotherapy with or without immunotherapy was the most prevalent treatment exposure (51%; N=242). After a median follow-up of 70 days (IQR 28-180), 30-day all-cause mortality was similar in patients who received any systemic cancer treatment versus no cancer treatment (23% and 22% respectively). Patients treated with immunotherapy and targeted therapy had the lowest mortality (15% and 18% respectively), the majority of whom were treated with palliative intent. Similar trends were also noted with secondary outcomes (Table 1). Conclusions: We report one of the largest studies evaluating the clinical outcomes of COVID-19 in the context of recent systemic anti-cancer treatments for TC. While continued caution is required when utilizing systemic treatments, delays in treatment may not be justified. The study provides reassuring data that patients receiving immunotherapy or targeted therapy even in the context of palliative treatment appear to have a lower risk for all-cause COVID-19 mortality. Further analysis exploring the prognostic factors associated with poor outcomes in patients with chemoradiation is planned

Impact of the COVID-19 Pandemic on Loneliness and Social Isolation: A Multi-Country Study

Copyright: © 2021 by the authors. The COVID-19 global pandemic and subsequent public health social measures have challenged our social and economic life, with increasing concerns around potentially rising levels of social isolation and loneliness. This paper is based on cross-sectional online survey data (available in 10 languages, from 2 June to 16 November 2020) with 20,398 respondents from 101 different countries. It aims to help increase our understanding of the global risk factors that are associated with social isolation and loneliness, irrespective of culture or country, to support evidence-based policy, services and public health interventions. We found the prevalence of severe loneliness was 21% during COVID-19 with 6% retrospectively reporting severe loneliness prior to the pandemic. A fifth were defined as isolated based on their usual connections, with 13% reporting a substantial increase in isolation during COVID-19. Personal finances and mental health were overarching and consistently cross-cutting predictors of loneliness and social isolation, both before and during the pandemic. With the likelihood of future waves of COVID-19 and related restrictions, it must be a public health priority to address the root causes of loneliness and social isolation and, in particular, address the needs of specific groups such as carers or those living alone

Achieving a Preoperative Target HbA1c of < 69 mmol/mol in Elective Vascular and Orthopedic Surgery: A Retrospective Single Center Observational Study

Introduction Diabetes mellitus (DM) is present in 10–15% of the surgical population. It is a known risk factor for adverse postoperative outcomes. UK perioperative guidance recommends optimizing glycemic control preoperatively, aiming for a target glycated hemoglobin (HbA1c) of < 69 mmol/mol. However, real-world compliance with this guidance remains unknown. The aim of our study was to determine how many patients with DM undergoing elective orthopedic and vascular surgery had a preoperative HbA1c of < 69 mmol/mol. We also reviewed the surgical reasons for non-concordance with the recommended preoperative HbA1c target. Methods This was a retrospective observational study of 1000 consecutive patients who had been referred for elective vascular and orthopedic surgery at a large tertiary center. Data were collected on these patients, both those with and without DM, between January 2016 and February 2017. Electronic databases were used to collect information on the patients’ preoperative HbA1c concentration and to determine whether there was a resulting delay in surgery when the preoperative HbA1c target of < 69 mmol/mol was exceeded. Results Of the 1000 patients referred for surgery (500 orthopedic and 500 vascular patients) included in the study, 201 (20%) had diabetes. Among these 201 people with DM, 155 (77%) had a preoperative HbA1c < 69 mmol/mol. Among the 46 people with DM whose HbA1c exceeded the recommended target, 41 were operated on despite the high HbA1c level, and only five had their surgery deferred or canceled due to suboptimal preoperative glycemic control. Conclusions Our data shows that the majority (77% ) of people undergoing elective vascular and orthopedic surgery were able to achieve a target HbA1c of < 69 mmol/mol. The current preoperative guidance is therefore achievable in a real-life setting. However, as is stated in the national guidance, this target should only be used where it is safe to do so and a degree of clinical discretion is necessary

Body appreciation around the world: Measurement invariance of the Body Appreciation Scale-2 (BAS-2) across 65 nations, 40 languages, gender identities, and age.

The Body Appreciation Scale-2 (BAS-2) is a widely used measure of a core facet of the positive body image construct. However, extant research concerning measurement invariance of the BAS-2 across a large number of nations remains limited. Here, we utilised the Body Image in Nature (BINS) dataset - with data collected between 2020 and 2022 - to assess measurement invariance of the BAS-2 across 65 nations, 40 languages, gender identities, and age groups. Multi-group confirmatory factor analysis indicated that full scalar invariance was upheld across all nations, languages, gender identities, and age groups, suggesting that the unidimensional BAS-2 model has widespread applicability. There were large differences across nations and languages in latent body appreciation, while differences across gender identities and age groups were negligible-to-small. Additionally, greater body appreciation was significantly associated with higher life satisfaction, being single (versus being married or in a committed relationship), and greater rurality (versus urbanicity). Across a subset of nations where nation-level data were available, greater body appreciation was also significantly associated with greater cultural distance from the United States and greater relative income inequality. These findings suggest that the BAS-2 likely captures a near-universal conceptualisation of the body appreciation construct, which should facilitate further cross-cultural research. [Abstract copyright: Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Systemic Anticancer Therapy and Thromboembolic Outcomes in Hospitalized Patients With Cancer and COVID-19

IMPORTANCE: Systematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking. OBJECTIVE: To assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer. DESIGN, SETTING, AND PARTICIPANTS: This registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022. EXPOSURE: Treatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19. MAIN OUTCOMES AND MEASURES: Main outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up. RESULTS: Of 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13). CONCLUSIONS AND RELEVANCE: In this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19-related thromboembolism in patients with cancer