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Proteins have evolved to function in an aqueous environment. Collagen, which provides the bodily scaffold for animals, has a special need to retain its integrity. This need was addressed early on, as intact collagen has been detected in dinosaur fossils, even though peptide bonds have a half-life of only ∼500 years in a neutral aqueous solution. We sought to discover the physicochemical basis for this remarkable resistance to hydrolysis. Using experimental and computational methods, we found that a main-chain acyl group can be protected from hydrolysis by an O···C=O n→π* interaction with a neighboring acyl group. These interactions engage virtually every peptide bond in a collagen triple helix. This protection, which arises from the Pauli exclusion principle, could underlie the preservation of ancient collagen., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: The global population is ageing rapidly, with low- and middle-income countries (LMICs) undergoing a fast demographic transition. As the number of older adults in LMICs increases, services able to effectively address their physical and mental health needs will be increasingly important., Objective: We review the health and socioeconomic resources currently available for older people in South Asian countries, Bangladesh, India, Nepal, Pakistan and Sri Lanka, to identify gaps in available resources and assess areas for improvement., Methods: We conducted a search of grey and published literature via Google Search, Compendex, EBSCO, JSTOR, Medline, Ovid, ProQuest databases, Scopus and Web of Science. Data on population demographics, human resources, health funding and social protection for older people were extracted. Local informants were consulted to supplement and verify the data., Results: In the study countries, the number of health professionals with expertise in elderly care was largely unknown, with minimal postgraduate training programmes available in elderly medicine or psychiatry. Older adults are therefore cared for by general physicians, nurses and community health workers, all of whom are present in insufficient numbers per capita. Total average healthcare expenditure was 2.5-5.5% of GDP, with 48.1-72.0% of healthcare costs covered by out-of-pocket payments. Pakistan did not have a social pension; only India and Nepal offered financial assistance to people with dementia; and all countries had disproportionately low numbers of care elderly homes., Conclusions: Inadequate healthcare funding, a shortage of healthcare professionals and insufficient government pension and social security schemes are significant barriers to achieving universal health coverage in LMICs. Governing bodies must expand training programmes for healthcare providers for older adults, alongside increasing social protection to improve access to those in need and to prevent catastrophic health expenditure.

We assessed the impact of the updated guidelines on tuberculin skin test interpretation in the North East of England. Data on 241 children screened for latent tuberculosis infection (LTBI) between January 2011 and July 2018 were analyzed; 12.4% of children screened under the previous guidelines were treated for LTBI, compared to 33.3% under the new ones ( P < 0.001)., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The 60 individual halopyridine isomers that contain one bromine, chlorine, fluorine, iodine, and H are valuable potential building blocks in medicinal chemistry research, but surprisingly, there has been only one report on the synthesis of just two of them. Herein, we describe simple syntheses of the unique 5-bromo-2-chloro-4-fluoro-3-iodopyridine ( 10 ) and 3-bromo-6-chloro-4-fluoro-2-iodopyridine ( 32 ) using halogen dance reactions. C6 magnesiation of 10 and its 3-phenyl analogue 22 followed by trapping with electrophiles generated a variety of pentasubstituted pyridines with desired functionalities for further chemical manipulations.

Purpose: Randomised controlled trials (RCTs) are considered the gold standard for evaluating the efficacy of an intervention. However, previous research has shown that RCTs in several surgical specialities are poorly reported, making it difficult to ascertain if various biases have been appropriately minimised. This systematic review assesses the reporting quality of surgical head and neck cancer RCTs., Methods: A literature search of PubMed and Embase was performed. Papers were included if they reported RCTs which assessed a surgical technique used to treat or diagnose head and neck cancer published during or after 2011. The CONSORT 2010 checklist was used to evaluate the reporting quality of these trials., Results: 41 papers were included. The mean CONSORT score was 16.5/25 (66% adherence) and the scores ranged from 7.5 (30%) to 25. The most common omissions were full trial protocol (found in 14.6%), participant recruitment method (22%) and effect size with a precision estimate for all outcome measures (29.3%). The full design and implementation of the randomisation methods were reported in 6 (14.6%). Papers published in journals which endorsed CONSORT had significantly higher scores (p = 0.02) and the journal impact factor was significantly correlated with CONSORT score (p = 0.01)., Conclusion: We have identified several pieces of information that are underreported in surgical head and neck cancer RCTs. These omissions make understanding and comparing the methodologies and conclusions of RCTs more difficult. The endorsement of CONSORT by journals improved adherence, suggesting that wider adoption of the checklist may improve reporting., (© 2021. The Author(s).)

Background: Antibiotic resistance is a major problem in every region of the globe and Sub-Saharan Africa (SSA) is no exception. Several systematic reviews have addressed the prevalence of resistant organisms but few have examined the underlying causes in this region. This systematic review of qualitative literature aims to highlight barriers and facilitators to antimicrobial stewardship in SSA., Methods: A literature search of Embase and MEDLINE(R) was carried out. Studies were included if they were in English, conducted in SSA, and reported qualitative data on the barriers and facilitators of antimicrobial stewardship or on attitudes towards resistance promoting behaviours. Studies were screened with a simple critical appraisal tool. Secondary constructs were extracted and coded into concepts, which were then reviewed and grouped into themes in light of the complete dataset., Results: The literature search yielded 169 results, of which 14 studies from 11 countries were included in the final analysis. No studies were excluded as a result of the critical appraisal. Eight concepts emerged from initial coding, which were consolidated into five major themes: ineffective regulation, health system factors, clinical governance, patient factors and lack of resources. The ineffective regulation theme highlighted the balance between tightening drugstore regulation, reducing over-the-counter sale of antibiotics, and maintaining access to medicines for rural communities. Meanwhile, health system factors explored the tension between antimicrobial stewardship and the need of pharmacy workers to maintain profitable businesses. Additionally, a lack of resources, actions by patients and the day-to-day challenges of providing healthcare were shown to directly impede antimicrobial stewardship and exacerbate other factors which promote resistance., Conclusion: Antibiotic resistance in SSA is a multi-faceted issue and while limited resources contribute to the problem they should be viewed in the context of other factors. We identify several contextual factors that affect resistance and stewardship that should be considered by policy makers when planning interventions. This literature base is also incomplete, with only 11 nations accounted for and many studies being confined to regions within countries, so more research is needed. Specifically, further studies on implementing stewardship interventions, successful or not, would be beneficial to inform future efforts., (© 2021. The Author(s).)

Intramolecular alkoxylation of C-H bonds can rapidly introduce structural and functional group complexities into seemingly simple or inert precursors. The transformation is particularly important due to the ubiquitous presence of tetrahydrofuran (THF) motifs as fundamental building blocks in a wide range of pharmaceuticals, agrochemicals, and natural products. Despite the various synthetic methodologies known for generating functionalized THFs, most show limited functional group tolerance and lack demonstration for the preparation of spiro or fused bi- and tricyclic ether units prevalent in molecules for pharmacological purposes. Herein we report an intramolecular C-H alkoxylation to furnish oxacycles from easily prepared α-diazo-β-ketoesters using commercially available iron acetylacetonate (Fe(acac) 2 ) as a catalyst. The reaction is proposed to proceed through the formation of a vinylic carboradical arising from N 2 extrusion, which mediates a proximal H-atom abstraction followed by a rapid C-O bond forming radical recombination step. The radical mechanism is probed using an isotopic labeling study (vinyl C-D incorporation), ring opening of a radical clock substrate, and Hammett analysis and is further corroborated by density functional theory (DFT) calculations. Heightened reactivity is observed for electron-rich C-H bonds (tertiary, ethereal), while greater catalyst loadings or elevated reaction temperatures are required to fully convert substrates with benzylic, secondary, and primary C-H bonds. The transformation is highly functional group tolerant and operates under mild reaction conditions to provide rapid access to complex structures such as spiro and fused bi-/tricyclic O-heterocycles from readily available precursors.

The trityl-substituted bisoxazoline ( TrH BOX) was prepared as a chiral analogue to a previously reported nickel dipyrrin system capable of ring-closing amination catalysis. Ligand metalation with divalent NiI 2 (py) 4 followed by potassium graphite reduction afforded the monovalent ( TrH BOX)Ni(py) ( 4 ). Slow addition of 1.4 equiv of a benzene solution of 1-adamantylazide to 4 generated the tetrazido ( TrH BOX)Ni(κ 2 -N 4 Ad 2 ) ( 5 ) and terminal iminyl adduct ( TrH BOX)Ni(NAd) ( 6 ). Investigation of 6 via single-crystal X-ray crystallography, NMR and EPR spectroscopies, and computations revealed a Ni(II)-iminyl radical formulation, similar to its dipyrrinato congener. Complex 4 exhibits enantioselective intramolecular C-H bond amination to afford N -heterocyclic products from 4-aryl-2-methyl-2-azidopentanes. Catalytic C-H amination occurs under mild conditions (5 mol % catalyst, 60 °C) and provides pyrrolidine products in decent yield (29%-87%) with moderate ee (up to 73%). Substrates with a 3,5-dialkyl substitution on the 4-aryl position maximized the observed enantioselectivity. Kinetic studies to probe the reaction mechanism were conducted using 1 H and 19 F NMR spectroscopies. A small, intermolecular kinetic isotope effect (1.35 ± 0.03) suggests an H-atom abstraction step with an asymmetric transition state while the reaction rate is measured to be first order in catalyst and zeroth order in substrate concentrations. Enantiospecific deuterium labeling studies show that the enantioselectivity is dictated by both the H-atom abstraction and radical recombination steps due to the comparable rate between radical rotation and C-N bond formation. Furthermore, the competing elements of the two-step reaction where H-removal from the pro -R configuration is preferred while the preferential radical capture occurs with the Si face of the carboradical likely lead to the diminished ee observed, as corroborated by theoretical calculations. Based on these enantio-determining steps, catalytic enantioselective synthesis of 2,5-bis-tertiary pyrrolidines is demonstrated with good yield (50-78%) and moderate ee (up to 79%).

A dipyrrin-supported nickel catalyst ( AdF L)Ni(py) ( AdF L: 1,9-di(1-adamantyl)-5-perfluorophenyldipyrrin; py: pyridine) displays productive intramolecular C-H bond amination to afford N-heterocyclic products using aliphatic azide substrates. The catalytic amination conditions are mild, requiring 0.1-2 mol% catalyst loading and operational at room temperature. The scope of C-H bond substrates was explored and benzylic, tertiary, secondary, and primary C-H bonds are successfully aminated. The amination chemoselectivity was examined using substrates featuring multiple activatable C-H bonds. Uniformly, the catalyst showcases high chemoselectivity favoring C-H bonds with lower bond dissociation energy as well as a wide range of functional group tolerance (e.g., ethers, halides, thioetheres, esters, etc.). Sequential cyclization of substrates with ester groups could be achieved, providing facile preparation of an indolizidine framework commonly found in a variety of alkaloids. The amination cyclization reaction mechanism was examined employing nuclear magnetic resonance (NMR) spectroscopy to determine the reaction kinetic profile. A large, primary intermolecular kinetic isotope effect (KIE = 31.9 ± 1.0) suggests H-atom abstraction (HAA) is the rate-determining step, indicative of H-atom tunneling being operative. The reaction rate has first order dependence in the catalyst and zeroth order in substrate, consistent with the resting state of the catalyst as the corresponding nickel iminyl radical. The presence of the nickel iminyl was determined by multinuclear NMR spectroscopy observed during catalysis. The activation parameters (Δ H‡ = 13.4 ± 0.5 kcal/mol; Δ S‡ = -24.3 ± 1.7 cal/mol·K) were measured using Eyring analysis, implying a highly ordered transition state during the HAA step. The proposed mechanism of rapid iminyl formation, rate-determining HAA, and subsequent radical recombination was corroborated by intramolecular isotope labeling experiments and theoretical calculations.

Introduction: Most women who have screening mammography and undergo subsequent open biopsy following an indeterminate core biopsy result are eventually found to have benign disease. However, a significant number have malignant disease and the rate of malignancy in such cases may be influenced by various factors. This study examined the effect of the type of screening round (prevalent or incident) on the likelihood of breast cancer being present., Methods: A total of 199 women who had NHS breast screening mammograms and subsequent indeterminate (B3) core biopsy results followed by excision biopsy over an 11-year period in a single breast screening unit were reviewed., Results: The rate of malignancy following excision of a lesion graded as B3 on core biopsy was 21% for women in the prevalent screening round compared to 33% in subsequent rounds (Fisher's exact test, p=0.038)., Conclusions: The incidence of malignancy associated with a B3 core biopsy result appears to be related to the screening round in which the lesion is detected, being approximately 50% higher in the subsequent incident rounds compared to the initial prevalent round. This finding may be useful in formulating management plans for women who have an indeterminate biopsy result.

The management of a core biopsy diagnosis of lobular neoplasia is controversial. Detailed radiological-pathological review of 47 patients with cores showing classical lobular neoplasia was performed (patients with pleomorphic lobular carcinoma in situ (LCIS) or associated risk lesions were considered separately). Immediate surgical excision in 25 patients showed invasive carcinoma in 7, ductal carcinoma in situ (DCIS) in 1 and pleomorphic LCIS in 1; radiological-pathological review showed that the core biopsy missed a mass in 5, missed calcification in 2 and that calcification appeared adequately sampled in 2. Nineteen patients had follow-up of at least 2 years. Four patients developed malignancy at the site of the core biopsy (invasive carcinoma in three, DCIS in one); one carcinoma was mammographically occult, one patient had dense original mammograms and two had calcifications apparently adequately sampled by the core. In conclusion, most carcinomas identified at the site of core biopsy showing lobular neoplasia were the result of the core missing the radiological lesion, emphasising the importance of multidisciplinary review and investigation of any discordance. Some carcinomas were found after apparently adequate core biopsy, raising the question of whether excision biopsy should be considered after all core biopsy diagnoses of lobular neoplasia.

Aim: To assess whether there are differences in the pathological features or survival between the new National Health Service Breast Screening Programme (NHSBSP) interval cancer classification system category of type 1 interval cancers, and the previously used, separate categories of occult, unclassified, and true interval cancers., Materials and Methods: The prognostic pathological features (grade, lymph node stage, size, vascular invasion, oestrogen receptor status, and histological type) and survival of 428 type 1 interval invasive breast cancers were analysed by subgroup (occult, unclassified and true interval)., Results: Occult cancers compared with other type 1 interval cancers were of significantly lower grade [38 of 52 (73%) versus 151 of 340 (44%) grade 1 or 2, p=0.0005], more likely to be smaller size [37 of 51 (73%) versus 158 of 341 (46%) <20mm, p=0.0003] and more frequently of lobular type at histology [14 of 42 (32%) versus 50 of 286 (17%), p=0.03]. There was no significant difference in pathological features of unclassified tumours compared with other type 1 tumours. There was no significant survival difference between different type 1 subgroups (p=0.12)., Conclusion: The NHSBSP type 1 interval cancers are a heterogeneous grouping with markedly differing pathological features. However, no significant survival difference is seen between the different type 1 subgroups.

Objective: The aim of our study was to assess the effect of mammographic parenchymal pattern on patient survival, mammographic features, and pathologic features of breast cancer in a screened population., Materials and Methods: We classified the parenchymal pattern (according to BI-RADS) of 759 screened women who presented with a screening-detected (n = 455) or interval (n = 304) invasive breast cancer. Pathologic details (tumor size, histologic grade, lymph node stage, vascular invasion, and histologic type) and mammographic appearances were recorded. Breast cancer-specific survival was ascertained, with a median follow-up of 9.0 years., Results: An excess of interval cancers was seen in women with dense breasts (p < 0.0001). Screening-detected (but not interval) tumors were significantly smaller in fatty breasts (p = 0.014). Tumor grade, lymph node stage, vascular invasion, and histologic type did not vary significantly with mammographic parenchymal pattern in screening-detected or interval cancers. Screening-detected cancers in fatty breasts were more likely to appear as indistinct (p = 0.003) or spiculated (p = 0.002) masses in contrast to cancers in dense breasts, which more commonly appeared as architectural distortions (p < 0.0001). No significant breast cancer-specific survival difference was seen by mammographic parenchymal pattern for screening-detected cancers (p = 0.75), interval cancers (p = 0.82), or both groups combined (p = 0.12)., Conclusion: The prognosis of screened women presenting with breast cancer is unrelated to dense mammographic parenchymal pattern despite an excess of interval cancers and larger screening-detected tumors in this group. These data support the mammographic screening of women with dense parenchymal patterns.

The purpose of this article is to show examples of the radiological (mammography and/or ultrasound) and pathological appearances of unusual benign breast lesions. The conditions covered are granular cell tumours, fibromatosis, nodular fasciitis, myofibroblastomas, haemangiomas, neurofibromas, and leiomyomas. The article includes the first published description of the ultrasound appearance of a myofibroblastoma. Knowledge of these appearances may help confirm or refute radiological-pathological concordance of percutaneous biopsy results during multidisciplinary assessment of these lesions and aid patient management.

Objectives: To investigate the hypothesis that interval cancers arising soon after the previous screen and true interval cancers are biologically aggressive and have a relatively poor prognosis compared with other interval cancers, and to assess which prognostic features are relevant to interval cancers., Methods: Analysis of prognostic pathological features (grade, lymph node stage, size, vascular invasion, oestrogen receptor [ER] status and histological type), radiological features (comedo/non-comedo calcification and spiculation) and survival for 538 invasive interval breast cancer cases by type and time since previous screen., Results: Late interval cancers were less likely to be lymph node positive (13 versus 43%, P = 0.003). Type 1 interval cancers were more likely to be histological grade 3 than type 2 (minimal signs) and type 3 (false-negative) intervals (52 versus 35%, P = 0.05). Type 3 interval cancers were more likely to have lobular features than other intervals (47 versus 20%, P < 0.0001). There was no significant survival difference by interval cancer type (P = 0.64) or interval year (P = 0.83). At univariate analysis of all interval cancers, tumour size, grade, nodal stage, ER status, vascular invasion and comedo calcification were associated with survival. On multivariate analysis of prognostic features significant at univariate analysis, nodal stage (P value = 0.009), tumour size (P = 0.001), ER status (P < 0.0001) and vascular invasion (P < 0.0001) maintained independent significance., Conclusions: Our study shows that true intervals and interval cancers arising quickly after screening do not have a worse prognosis than other interval cancers, and that interval cancers have a unique set of prognostic features.

Aim: To assess if the pattern of metastatic spread of carcinoma of the breast varies according to tumour histological grade., Materials and Methods: The clinical details, histological features of the primary tumour, and imaging findings at presentation of patients with metastatic breast cancer have been recorded prospectively since 1997. The pattern of metastatic spread, age at metastasis, metastasis-free interval (MFI), and length of survival with metastases were analysed by tumour grade., Results: There was a significant association between histological high-grade tumours and high frequency of intra-pulmonary metastases (p=0.013); liver metastases (p=0.039); para-aortic lymphadenopathy (p=0.022) and metastatic presentation under 50 years of age (p=0.003). A significant correlation was also demonstrated between histological low-grade tumours and increased frequency of pleural disease (p=0.020); increased frequency of bone metastases (p=0.004); prolonged MFI (MFI>5 years; p<0.0001); and increased length of survival (p<0.0001)., Conclusion: There is a correlation between patterns of metastatic spread and tumour histological grade. This partly explains the negative prognostic value of high tumour grade, as metastases from grade 3 tumours more commonly occur at sites associated with a worse prognosis. This finding may also prove useful in interpreting imaging in patients who have a history of breast cancer and undergo subsequent imaging because of new symptoms.