{A new class of diphenylurea was identified as a novel antibacterial scaffold with an antibacterial spectrum that includes highly resistant staphylococcal isolates, namely methicillin-and vancomycin-resistant Staphylococcus aureus (MRSA & VRSA). Starting with a lead compound 3 that carries an aminoguanidine functionality from one side and a n-butyl moiety on the other ring, several analogues were prepared. Considering the pharmacokinetic parameters as a key factor in structural optimization, the structureactivity-relationships (SARs) at the lipophilic side chain were rigorously examined leading to the discovery of the cycloheptyloxyl analogue 21n as a potential drug-candidate. This compound has several notable advantages over vancomycin and linezolid including rapid killing kinetics against MRSA and the ability to target and reduce the burden of MRSA harboring inside immune cells (macrophages). Furthermore, the potent anti-MRSA activity of 21n was confirmed in vivo using a Caenorhabditis elegans animal model. The present study provides a foundation for further development of diphenylurea compounds as potential therapeutic agents to address the burgeoning challenge of bacterial resistance to antibiotics. (C) 2017 Elsevier Masson SAS. All rights reserved.}

Gastroesophageal reflux disease (GERD) is a common condition in children. Complete fundoplication provides better reflux control but it results in more dysphagia and gas-bloat symptoms. Antireflux surgery without wrap has fewer adverse effects but a higher failure rate in controlling reflux. Until now, there is little evidence as to whether complete or partial fundoplication is the optimal procedure in this age group.

Background: Maintaining good oral hygiene is key to preventing dental caries and periodontal disease. Children and adolescents with good oral hygiene behaviours are likely to grow into adults with the same behaviours. This study assessed the frequency of using various oral hygiene methods among children and adolescents from different countries and individual, familial and country-level factors associated with the use of these methods. Methods: A multi-country online survey collected data from caregivers of children in 2020–21 about children’s use of oral hygiene methods including toothbrush, fluoridated toothpaste, mouthwash, dental floss and miswak using self-administered, close-ended questions. Adjusted multilevel logistic regression models were used to assess the relationship between each of the five oral hygiene methods (dependent variables) and the independent factors: sex, age, and history of dental visits (individual factors), mother's education and area of residence (familial factors) as well as country income and region (country-level factors). Results: A total of 4766 parents/caregivers were included from 20 countries (77.4% Eastern Mediterranean-region and 41.6% lower middle income countries). The most frequent oral hygiene methods were using toothbrush and toothpaste (90% and 60.3%). The use of oral hygiene methods differed by age, sex and history of dental visits as well as mother’s education and area of residence (P < 0.05). In addition, children from low income countries had significantly lower odds of using mouthwashes and dental floss than those from high income countries (AOR = 0.55, 95% CI 0.31, 0.98 and AOR = 0.34, 95% CI 0.12, 0.97) whereas children from the European region had higher odds of using mouthwash (AOR = 2.82, 95% CI 1.27, 6.26) and those from the region of the Americas had higher odds of using dental floss (AOR = 3.84, 95% CI 1.28, 11.52) than those from the Eastern Mediterranean region. Conclusions: The use of various oral hygiene methods is associated with individual, familial and country-level factors. Oral health promotion programs should be developed taking into account these influences.

The Bakun-Murum (BM) catchment region of the Rajang River Basin (RRB), Sarawak, Malaysia, has been under severe threat for the last few years due to urbanization, global warming, and climate change. The present study aimed to evaluate the time series analysis and impact assessment of the temperature changes on the vegetation/agricultural lands and the water availability within the BM region. For this purpose, the Landsat data for the past thirty years (1990–2020) were used. Remote sensing techniques for estimating the surface temperatures and variation within the vegetation and water bodies were utilized, and validation was done using on-ground weather stations. Google Earth Engine (GEE) and other RS & GIS tools were used for analyzing the time series trends of land surface temperature (LST), normalized difference vegetation index (NDVI), and normalized difference water index (NDWI). The results exposed an overall rise of 1.06 °C in the annual mean temperatures over the last thirty years. A maximum annual mean NDVI of 0.48 was recorded for 2018 and 2019. The lowest annual mean NDVI (0.27) was observed in 2005. The annual mean NDWI increased to 0.48 in 2018 and 2019, respectively. The statistical correlation results revealed the coefficient of determination (R2) of 0.09 and 0.13 for the annual mean LST and annual mean NDVI and the annual mean LST and annual mean NDWI, respectively. Moreover, the Mann-Kendall trend test for the annual mean temperature series indicates a slightly increasing trend with Sen's slope of 0.03 °C/year. It is found that there is a positive trend in the annual mean rainfall patterns, as Sen's slope indicates a yearly increase of 50.58 mm/year. This study found significant changes in the LST, NDVI, and NDWI of the BM catchment region during the last thirty years, demanding the concerned authorities' instant attention to alleviate the adverse effects of such changes to protect the ecosystem.

Background: Addressing nursing students' lack of interest in providing care for the aged population is a global challenge for nursing educators. Despite global interest in student nurses' readiness for older people care, almost all the literature has been identified from single countries, predominantly with high income per capita. At present, no study has been conducted to provide evidence-based data related to this topic from a multi-country perspective.Objective: The study's purpose was to examine the willingness to work with older persons and associated factors among student nurses from nine countries (or regions).
Design: This study utilized correlational and cross-sectional designs.
Settings: This was a multi-country survey study conducted in China, Chile, Egypt, Hong Kong, India, Greece, the State of Palestine (henceforth Palestine), the Philippines, and Saudi Arabia.
Participants: 2250 baccalaureate nursing students were recruited from nine universities in this study.
Methods: The survey that was used to collect data comprised four parts: socio-demographic data, attitude toward aging, older persons care perception, and willingness to work with such group.
Results: Respondents in five regions (including Mainland China, Greece, Hong Kong, Palestine, and Saudi Arabia) stated that older persons were the least favored group for future career choices. In comparison with mainland China, respondents in Chile, India, and the Philippines were significantly more likely to be willing to care for older patients, but those in Egypt and Greece indicated a lower tendency to choose this option. Favorable attitudes toward aging and older person care perception were significantly associated with having the willingness to provide care to gerontologic patients in the future.
Conclusions: Although attitudes toward aging and older person care perceptions have long been confirmed as important factors that are linked with willingness in caring for older people, this study adds that location is a more influential factor. Additional research in other countries is needed to advance the knowledge in this important area.

SummaryBackground
The 2015 Lancet Commission on global surgery identified surgery and anaesthesia as indispensable parts of holistic health-care systems. However, COVID-19 exposed the fragility of planned surgical services around the world, which have also been neglected in pandemic recovery planning. This study aimed to develop and validate a novel index to support local elective surgical system strengthening and address growing backlogs.
Methods
First, we performed an international consultation through a four-stage consensus process to develop a multidomain index for hospital-level assessment (surgical preparedness index; SPI). Second, we measured surgical preparedness across a global network of hospitals in high-income countries (HICs), middle-income countries (MICs), and low-income countries (LICs) to explore the distribution of the SPI at national, subnational, and hospital levels. Finally, using COVID-19 as an example of an external system shock, we compared hospitals' SPI to their planned surgical volume ratio (SVR; ie, operations for which the decision for surgery was made before hospital admission), calculated as the ratio of the observed surgical volume over a 1-month assessment period between June 6 and Aug 5, 2021, against the expected surgical volume based on hospital administrative data from the same period in 2019 (ie, a pre-pandemic baseline). A linear mixed-effects regression model was used to determine the effect of increasing SPI score.
Findings
In the first phase, from a longlist of 103 candidate indicators, 23 were prioritised as core indicators of elective surgical system preparedness by 69 clinicians (23 [33%] women; 46 [67%] men; 41 from HICs, 22 from MICs, and six from LICs) from 32 countries. The multidomain SPI included 11 indicators on facilities and consumables, two on staffing, two on prioritisation, and eight on systems. Hospitals were scored from 23 (least prepared) to 115 points (most prepared). In the second phase, surgical preparedness was measured in 1632 hospitals by 4714 clinicians from 119 countries. 745 (45·6%) of 1632 hospitals were in MICs or LICs. The mean SPI score was 84·5 (95% CI 84·1–84·9), which varied between HIC (88·5 [89·0–88·0]), MIC (81·8 [82·5–81·1]), and LIC (66·8 [64·9–68·7]) settings. In the third phase, 1217 (74·6%) hospitals did not maintain their expected SVR during the COVID-19 pandemic, of which 625 (51·4%) were from HIC, 538 (44·2%) from MIC, and 54 (4·4%) from LIC settings. In the mixed-effects model, a 10-point increase in SPI corresponded to a 3·6% (95% CI 3·0–4·1; p<0·0001) increase in SVR. This was consistent in HIC (4·8% [4·1–5·5]; p<0·0001), MIC (2·8 [2·0–3·7]; p<0·0001), and LIC (3·8 [1·3–6·7%]; p<0·0001) settings.
Interpretation
The SPI contains 23 indicators that are globally applicable, relevant across different system stressors, vary at a subnational level, and are collectable by front-line teams. In the case study of COVID-19, a higher SPI was associated with an increased planned surgical volume ratio independent of country income status, COVID-19 burden, and hospital type. Hospitals should perform annual self-assessment of their surgical preparedness to identify areas that can be improved, create resilience in local surgical systems, and upscale capacity to address elective surgery backlogs.
Funding
National Institute for Health Research (NIHR) Global Health Research Unit on Global Surgery, NIHR Academy, Association of Coloproctology of Great Britain and Ireland, Bowel Research UK, British Association of Surgical Oncology, British Gynaecological Cancer Society, and Medtronic.

Abstract Modification at the 5??-position of 4,5-disubstituted aminoglycoside antibiotics (AGAs) to circumvent inactivation by aminoglycoside modifying enzymes (AMEs) is well known. Such modifications, however, unpredictably impact activity and affect target selectivity thereby hindering drug development. A survey of 5??-modifications of the 4,5-AGAs and the related 5-O-furanosyl apramycin derivatives is presented. In the neomycin and the apralog series, all modifications were well-tolerated, but other 4,5-AGAs require a hydrogen bonding group at the 5??-position for maintenance of antibacterial activity. The 5??-amino modification resulted in parent-like activity, but reduced selectivity against the human cytosolic decoding A site rendering this modification unfavorable in paromomycin, propylamycin, and ribostamycin. Installation of a 5??-formamido group and, to a lesser degree, a 5??-ureido group resulted in parent-like activity without loss of selectivity. These lessons will aid the design of next-generation AGAs capable of circumventing AME action while maintaining high antibacterial activity and target selectivity.

OBJECTIVE: To characterize 414 patients with primary SS who developed hematological malignancies and to analyze how the main SS- and lymphoma-related features can modify the presentation patterns and outcomes.

METHODS: By January 2021, the Big Data Sjögren Project Consortium database included 11 966 patients fulfilling the 2002/2016 classification criteria. Hematological malignancies diagnosed according to the World Health Organization (WHO) classification were retrospectively identified.

RESULTS: There were 414 patients (355 women, mean age 57 years) with hematological malignancies (in 43, malignancy preceded at least one year the SS diagnosis). 376 (91%) patients had mature B cell malignancy, nearly half MALT lymphoma (n = 197), followed by DLBCL (n = 67), nodal MZL lymphoma (n = 29), CLL/SLL (n = 19) and follicular lymphoma (n = 17). Rates of complete response, relapses and death were 80%, 34% and 13%, respectively, with a 5-year survival rate of 86.5% after a mean follow-up of 8 years. There were significant differences in age at diagnosis (younger in MALT, older in CLL/SLL), predominant clinical presentation (glandular enlargement in MALT lymphoma, peripheral lymphadenopathy in nodal MZL and FL, constitutional symptoms in DLBCL, incidental diagnosis in CLL/SLL), therapeutic response (higher in MALT lymphoma, lower in DLBCL) and survival (better in MALT, nodal MZL and FL, worse in DLBCL).

CONCLUSION: In the largest reported study of hematological malignancies complicating primary SS, we confirm the overwhelming predominance of B cell lymphomas, especially MALT, with the salivary glands being the primary site of involvement. This highly-specific histopathological scenario is linked with the overall good prognosis with a 5-year survival rate of nearly 90%.

Currently, cancer ranks as the second leading cause of death worldwide, and at the same time, the burden of cancer continues to increase. The underlying molecular pathways involved in the initiation and development of cancer are the subject of considerable research worldwide. Further understanding of these pathways may lead to new cancer treatments. Growing data suggest that Tribble's homolog 3 (TRIB3) is essential in oncogenesis in many types of cancer. The mammalian tribbles family's proteins regulate various cellular and physiological functions, such as the cell cycle, stress response, signal transduction, propagation, development, differentiation, immunity, inflammatory processes, and metabolism. To exert their activities, Tribbles proteins must alter key signaling pathways, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K)/AKT pathways. Recent evidence supports that TRIB3 dysregulation has been linked to various diseases, including tumor development and chemoresistance. It has been speculated that TRIB3 may either promote or inhibit the onset and development of cancer. However, it is still unclear how TRIB3 performs this dual function in cancer. In this review, we present and discuss the most recent data on the role of TRIB3 in cancer pathophysiology and chemoresistance. Furthermore, we describe in detail the molecular mechanism TRIB3 regulates in cancer.

Objectives Paediatric cancer is a leading cause of death for children. Children in low-income and middle-income countries (LMICs) were four times more likely to die than children in high-income countries (HICs). This study aimed to test the hypothesis that the COVID-19 pandemic had affected the delivery of healthcare services worldwide, and exacerbated the disparity in paediatric cancer outcomes between LMICs and HICs.Design A multicentre, international, collaborative cohort study.Setting 91 hospitals and cancer centres in 39 countries providing cancer treatment to paediatric patients between March and December 2020.Participants Patients were included if they were under the age of 18 years, and newly diagnosed with or undergoing active cancer treatment for Acute lymphoblastic leukaemia, non-Hodgkin’s lymphoma, Hodgkin lymphoma, Wilms’ tumour, sarcoma, retinoblastoma, gliomas, medulloblastomas or neuroblastomas, in keeping with the WHO Global Initiative for Childhood Cancer.Main outcome measure All-cause mortality at 30 days and 90 days.Results 1660 patients were recruited. 219 children had changes to their treatment due to the pandemic. Patients in LMICs were primarily affected (n=182/219, 83.1%). Relative to patients with paediatric cancer in HICs, patients with paediatric cancer in LMICs had 12.1 (95% CI 2.93 to 50.3) and 7.9 (95% CI 3.2 to 19.7) times the odds of death at 30 days and 90 days, respectively, after presentation during the COVID-19 pandemic (p<0.001). After adjusting for confounders, patients with paediatric cancer in LMICs had 15.6 (95% CI 3.7 to 65.8) times the odds of death at 30 days (p<0.001).Conclusions The COVID-19 pandemic has affected paediatric oncology service provision. It has disproportionately affected patients in LMICs, highlighting and compounding existing disparities in healthcare systems globally that need addressing urgently. However, many patients with paediatric cancer continued to receive their normal standard of care. This speaks to the adaptability and resilience of healthcare systems and healthcare workers globally.Data are available on reasonable request. Deidentified date will be shared on request.

Objectives Paediatric cancer is a leading cause of death for children. Children in low-income and middle-income countries (LMICs) were four times more likely to die than children in high-income countries (HICs). This study aimed to test the hypothesis that the COVID-19 pandemic had affected the delivery of healthcare services worldwide, and exacerbated the disparity in paediatric cancer outcomes between LMICs and HICs.Design A multicentre, international, collaborative cohort study.Setting 91 hospitals and cancer centres in 39 countries providing cancer treatment to paediatric patients between March and December 2020.Participants Patients were included if they were under the age of 18 years, and newly diagnosed with or undergoing active cancer treatment for Acute lymphoblastic leukaemia, non-Hodgkin’s lymphoma, Hodgkin lymphoma, Wilms’ tumour, sarcoma, retinoblastoma, gliomas, medulloblastomas or neuroblastomas, in keeping with the WHO Global Initiative for Childhood Cancer.Main outcome measure All-cause mortality at 30 days and 90 days.Results 1660 patients were recruited. 219 children had changes to their treatment due to the pandemic. Patients in LMICs were primarily affected (n=182/219, 83.1%). Relative to patients with paediatric cancer in HICs, patients with paediatric cancer in LMICs had 12.1 (95% CI 2.93 to 50.3) and 7.9 (95% CI 3.2 to 19.7) times the odds of death at 30 days and 90 days, respectively, after presentation during the COVID-19 pandemic (p<0.001). After adjusting for confounders, patients with paediatric cancer in LMICs had 15.6 (95% CI 3.7 to 65.8) times the odds of death at 30 days (p<0.001).Conclusions The COVID-19 pandemic has affected paediatric oncology service provision. It has disproportionately affected patients in LMICs, highlighting and compounding existing disparities in healthcare systems globally that need addressing urgently. However, many patients with paediatric cancer continued to receive their normal standard of care. This speaks to the adaptability and resilience of healthcare systems and healthcare workers globally.Data are available on reasonable request. Deidentified date will be shared on request.