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Linear elastic fracture mechanics (LEFM) is used together with shape optimal design methodology in studying the connection between structural geometry and the number of life cycles to failure. LEFM results are used in the fatigue model to predict the life of the structure before failure has occurred. The shape optimal design method is used in changing the shape of the structure. Results show that the life of structural components subjected to fatigue can be improved by appropriate shape changes.

As a result of the low incidence of progression from low grade epithelial abnormalities to cervical intraepithelial neoplasia (CIN) 3 or cervical cancer, a conservative approach to management is supported, especially in young women. Loss to follow-up is a recognised problem with a conservative approach however, with women defaulting known to experience higher rates of cancer.To determine if any routinely collected demographic variables could predict which Australian women would subsequently default from care having initially elected to have conservative management of CIN 1 lesions.Prospectively collected data was audited on 279 women with a colposcopically directed biopsy diagnosis of CIN 1, confirmed on external review, who were enroled by their own choice into a conservative management program and monitored until a definitive lesion outcome was determined. Women who defaulted from follow-up and were lost to care providers despite follow-up appointments and reminder letters were compared to women who completed follow-up with either lesion resolution or progression requiring treatment, to establish if there were any demographic variables to predict default from care.Fifty-two (18.5%) women subsequently defaulted from follow-up. There were no significant differences in age, parity, proportion of women who were pregnant at diagnosis, smoking status, immunosuppressed or had a‘human papillomavirus (HPV) effect’ reported on Pap-smear or colposcopic examination.We cannot easily identify a subgroup of women who are more likely to default from follow-up of CIN 1 using routinely collected demographic data. Default from follow-up is a major risk with conservative approaches and further research to reduce default rates are required. [ABSTRACT FROM AUTHOR]

Abstract Introduction The diagnostic efficacy of biochemical and imaging modalities for investigating the causes of Cushing's syndrome are limited. We report a case demonstrating the limitations of these modalities, especially the inability of functional imaging to help localize the site of ectopic adrenocorticotropic hormone secretion. Case presentation A 37-year-old Arabian woman presented with 12 months of progressive Cushing's syndrome-like symptoms. Biochemical evaluation confirmed adrenocorticotropic hormone -dependent Cushing's syndrome. However, the anatomical site of her excess adrenocorticotropic hormone secretion was not clearly delineated by further investigations. Magnetic resonance imaging of our patient's pituitary gland failed to demonstrate the presence of an adenoma. Spiral computed tomography of her chest only revealed the presence of a non-specific 7 mm lesion in her left inferobasal lung segment. Functional imaging, including a positron emission tomography scan using 18-fluorodeoxyglucose and gallium-68-DOTA-D-Phe1-Tyr3-octreotide, also failed to show increased metabolic activity in the lung lesion or in her pituitary gland. Our patient was commenced on medical treatment with ketoconazole and metyrapone to control the clinical features associated with her excess cortisol secretion. Despite initial normalization of her urinary free cortisol excretion rate, levels began to rise eight months after commencement of medical treatment. Repeated imaging of her pituitary gland, chest and pelvis again failed to clearly localize a source of her excess adrenocorticotropic hormone secretion. The bronchial nodule was stable in size on serial imaging and repeatedly reported as having a nonspecific appearance of a small granuloma or lymph node. We re-explored the treatment options and endorsed our patient's favored choice of resection of the bronchial nodule, especially given that her symptoms of cortisol excess were difficult to control and refractory. Subsequently, our patient had the bronchial nodule resected. The histological appearance of the lesion was consistent with that of a carcinoid tumor and immunohistochemical analysis revealed that the tumor stained strongly positive for adrenocorticotropic hormone. Furthermore, removal of the lung lesion resulted in a normalization of our patient's 24-hour urinary free cortisol excretion rate and resolution of her symptoms and signs of hypercortisolemia. Conclusion This case report demonstrates the complexities and challenges in diagnosing the causes of adrenocorticotropic hormone -dependent Cushing's syndrome. Functional imaging may not always localize the site of ectopic adrenocorticotropic hormone secretion.

After 15 months of preparation by task force chairs and teams, ISCD's 9th Position Development Conference (PDC) convened in Northbrook, IL, USA on March 28th and 29th, 2023 to approve new ISCD Official Positions in the topic areas of DXA Reporting, Follow-up BMD Testing and TBS Application and Reporting. Three teams of participants work to bring the PDC to fruition: the Steering Committee, Task Forces and Chairs, and the Expert Panel. To reach agreement on draft Official Positions, the PDC follows a scripted process with the UCLA/RAND Appropriateness Method (UCLA/RAM) as its foundation. Multiple rounds of data review, public debate and voting resulted in 32 new or modified Official Positions. Six companion position papers are also published along with this Executive Summary, serving as the detailed substantiation for the Official Positions. This Executive Summary reviews the personnel groups, activities and products of the 2023 PDC, with the entirety of the updated 2023 Official Positions presented in Appendix A. New Official Positions are highlighted in bold., (Copyright © 2023 The International Society for Clinical Densitometry. All rights reserved.)

Introduction: Long-term proton pump inhibitor (PPI) use has been associated with hypomagnesemia. It is unknown how frequently PPI use is implicated in patients with severe hypomagnesemia, and its clinical course or risk factors. Methods: All patients with severe hypomagnesemia from 2013 to 2016 in a tertiary center were assessed for likelihood of PPI-related hypomagnesemia using Naranjo algorithm, and we described the clinical course. The clinical characteristics of each case of PPI-related severe hypomagnesemia was compared with three controls on long-term PPI without hypomagnesemia, to assess for risk factors of developing severe hypomagnesemia. Results: Amongst 53,149 patients with serum magnesium measurements, 360 patients had severe hypomagnesemia (<0.4 mmol/L). 189 of 360 (52.5%) patients had at least possible PPI-related hypomagnesemia (128 possible, 59 probable, two definite). 49 of 189 (24.7%) patients had no other etiology for hypomagnesemia. PPI was stopped in 43 (22.8%) patients. Seventy (37.0%) patients had no indication for long-term PPI use. Hypomagnesemia resolved in most patients after supplementation, but recurrence was higher in patients who continued PPI, 69.7% versus 35.7%, p = 0.009. On multivariate analysis, risk factors for hypomagnesemia were female gender (OR 1.73; 95% CI: 1.17-2.57), diabetes mellitus (OR, 4.62; 95% CI: 3.05-7.00), low BMI (OR, 0.90; 95% CI: 0.86-0.94), high-dose PPI (OR, 1.96; 95% CI: 1.29-2.98), renal impairment (OR, 3.85; 95% CI: 2.58-5.75), and diuretic use (OR, 1.68; 95% CI: 1.09-2.61). Conclusion: In patients with severe hypomagnesemia, clinicians should consider the possibility of PPI-related hypomagnesemia and re-examine the indication for continued PPI use, or consider a lower dose., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Seah, Tan, Teh, Loh, Tan, Goh, Malakar, Aw, Lau, Dhalliwal, Kui, Kam, Khoo, Tay, Tan, Au, Soh, Zhang, King, Gani and Puar.)

Introduction: Studies have found that not all atypical femoral fractures (AFF) are associated with bisphosphonate (BP) use. There are limited data on AFF in non-BP patients. In this study, we characterise factors associated with BP and non-BP related AFF and its mortality in a single centre in Singapore., Methods: We conducted a cohort study of subjects above 50 years old admitted to Changi General Hospital (CGH), Singapore with fragility subtrochanteric and femoral fractures from 2009 to 2015. Using the ASBMR 2014 criteria fractures are classified into atypical and typical femoral fractures. CGH uses a nationalised electronic health record that allows review of information on patient's demographics, clinical history and previous investigations. Mortality was assessed as of 31st December 2019., Results: Between 2009 and 2015, there were 3097 hip fractures, of which 393 were subtrochanteric and femoral fractures and 69 were classified as AFF by ASBMR 2014 criteria. 35 of AFF occurred in BP exposed and 34 occurred in non-BP exposed patients. There were no significant demographic differences in patients with BP and non-BP related AFF. There were also similar incidences of type 2 diabetes, rheumatoid arthritis and glucocorticoid use. Notably, there were a higher percentage of previous fragility fractures (35.3 % vs 9.4 %) in BP related AFF. Time to healing of fracture was slightly longer in BP related AFF at median (3 months vs 2 month, p = 0.02), however there were no differences in incidence of delayed healing. Mortality between BP and non-BP related AFF were similar., Conclusion: In a South East Asian population in Singapore, 47.8 % of AFF were found to be non-BP related. We found no major demographic and clinical differences between BP and non-BP related AFF. Mortality between BP and non-BP related AFF was similar. Further studies are needed to better understand the optimal treatment of osteoporosis in AFF prone patients in the Asian population., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: Primary aldosteronism (PA) is associated with increased risk of cardiovascular events. However, treatment of PA has not been shown to improve left ventricular (LV) systolic function using the conventional assessment with LV ejection fraction (LVEF). We aim to use speckle-tracking echocardiography to assess for improvement in subclinical systolic function after treatment of PA., Methods: We prospectively recruited 57 patients with PA, who underwent 24-h ambulatory blood pressure (BP) measurements and echocardiography, including global longitudinal strain (GLS) assessment of left ventricle, at baseline and 12 months post-treatment., Results: At baseline, GLS was low in 14 of 50 (28.0%) patients. On multivariable analysis, GLS was associated with diastolic BP ( P = 0.038) and glomerular filtration rate ( P = 0.026). GLS improved post-surgery by -2.3, 95% CI: -3.9 to -0.6, P = 0.010, and post-medications by -1.3, 95% CI: -2.6 to 0.03, P = 0.089, whereas there were no changes in LVEF in either group. Improvement in GLS was independently correlated with baseline GLS ( P < 0.001) and increase in plasma renin activity ( P = 0.007). Patients with post-treatment plasma renin activity ≥1 ng/ml/h had improvements in GLS ( P = 0.0019), whereas patients with persistently suppressed renin had no improvement. Post-adrenalectomy, there were also improvements in LV mass index ( P = 0.012), left atrial volume index ( P = 0.002), and mitral E/e' ( P = 0.006), whereas it was not statistically significant in patients treated with medications., Conclusion: Treatment of hyperaldosteronism is effective in improving subclinical LV systolic dysfunction. Elevation of renin levels after treatment, which reflects adequate reversal of sodium overload state, is associated with better systolic function after treatment., Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03174847., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Puar, Cheong, Foo, Saffari, Tu, Chee, Zhang, Ng, Wong, Wong, Ng, Aw, Khoo, Gani, King, Loh, Soh, Au, Tay, Tan, Mae, Yew, Tan, Tong, Lee and Chai.)

Background: In addition to increased cardiovascular risk, patients with primary aldosteronism (PA) also suffer from impaired health-related quality of life (HRQoL) and psychological symptoms. We assessed for changes in HRQoL and depressive symptoms in a cohort of Asian patients with PA, after surgical and medical therapy., Methods: Thirty-four patients with PA were prospectively recruited and completed questionnaires from 2017 to 2020. HRQoL was assessed using RAND-36 and EQ-5D-3L, and depressive symptoms were assessed using Beck Depression Inventory (BDI-II) at baseline, 6 months, and 1 year post-treatment., Results: At 1 year post-treatment, significant improvement was observed in both physical and mental summative scores of RAND-36, +3.65, P = 0.023, and +3.41, P = 0.033, respectively, as well as four subscale domains (physical functioning, bodily pain, role emotional, and mental health). Significant improvement was also seen in EQ-5D dimension of anxiety/depression at 1 year post-treatment. Patients treated with surgery (n = 21) had significant improvement in EQ-5D index score post-treatment and better EQ-5D outcomes compared to the medical group (n = 13) at 1 year post-treatment. 37.9, 41.6 and 58.6% of patients had symptoms in the cognitive, affective and somatic domains of BDI-II, respectively. There was a significant improvement in the affective domain of BDI-II at 1 year post-treatment., Conclusion: Both surgical and medical therapy improve HRQoL and psychological symptoms in patients with PA, with surgery providing better outcomes. This highlights the importance of early diagnosis, accurate subtyping and appropriate treatment of PA.

Background: Diabetes mellitus is associated with inadequate delivery of oxygen to tissues. Cellular hypoxia is associated with mitochondrial dysfunction which increases oxidative stress and hyperglycaemia. Hyperbaric oxygenation therapy, which was shown to improve insulin sensitivity, is impractical for regular use. We evaluated the effects of water which is stably-enriched with oxygen (ELO water) to increase arterial blood oxygen levels, on mitochondrial function in the presence of normal- or high-glucose environments, and as glucose-lowering therapy in humans., Methods: We compared arterial blood oxygen levels in Sprague-Dawley rats after 7 days of ad libitum ELO or tap water consumption. Mitochondrial stress testing, and flow cytometry analysis of mitochondrial mass and membrane potential, were performed on human HepG2 cells cultured in four Dulbecco's Modified Eagle Medium media, made with ELO water or regular (control) water, at normal (5.5 mM) or high (25 mM) glucose concentrations. We also randomized 150 adults with type 2 diabetes (mean age 53 years, glycated haemoglobin HbA1c 8.9% [74 mmol/mol], average duration of diabetes 12 years) to drink 1.5 litres daily of bottled ELO water or drinking water., Results: ELO water raised arterial oxygen tension pO2 significantly (335 ± 26 vs. 188 ± 18 mmHg, p = 0.006) compared with tap water. In cells cultured in control water, mitochondrial mass and membrane potential were both significantly lower at 25 mM glucose compared with 5.5 mM glucose; in contrast, mitochondrial mass and membrane potential did not differ significantly at normal or high glucose concentrations in cells cultured in ELO water. The high-glucose environment induced a greater mitochondrial proton leak in cells cultured in ELO water compared to cells cultured in control medium at similar glucose concentration. In type 2 diabetic adults, HbA1c decreased significantly (p = 0.002) by 0.3 ± 0.7% (4 ± 8 mmol/mol), with ELO water after 12 weeks of treatment but was unchanged with placebo., Conclusions: ELO water raises arterial blood oxygen levels, appears to have a protective effect on hyperglycaemia-induced reduction in mitochondrial mass and mitochondrial dysfunction, and may be effective adjuvant therapy for type 2 diabetes., Competing Interests: Sponsorship of this study by Elomart Pte Ltd does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Bisphosphonates (BP) are the most commonly prescribed effective form of osteoporosis treatment with adverse effects associated with prolonged use such as atypical femoral fractures (AFF). Asians have an elevated risk of AFF at 5 to 6 times those of whites and Hispanics. In this study, we characterize factors associated with AFF and its mortality in a single center in Singapore. We conducted a cohort study of subjects older than 50 years admitted to Changi General Hospital (CGH), Singapore, with fragility subtrochanteric femoral fractures from 2009 to 2015. Using the ASBMR 2014 criteria, fractures are classified into atypical and typical subtrochanteric femoral fractures. CGH uses a nationalized electronic health record that allows review of information on patients' demographics, clinical history and previous investigations. Mortality was assessed as of December 31, 2019. Between 2009 and 2015, there were 3097 hip fractures, of which 393 were subtrochanteric femoral fractures and 69 were classified as AFF by ASBMR 2014 criteria. A total of 52.2% of AFF occurred with BP exposure of median duration 56.5 (28 to 66) months. Multivariate regression showed that BP exposure was associated with the highest risk of AFF (odds ratio [OR] = 6.65 [2.35-18.9]). AFF patients had higher 5-year survival (0.85 versus 0.62, p  = 0.001) compared with typical subtrochanteric fracture patients. However, after adjusting for variables, the type of subtrochanteric femoral fractures were no longer significantly associated with progression to death, whereas older age, higher mean Charlson comorbidity score, and Malay ethnicity were the strongest predictors of death. AFF constitutes a small proportion of hip and femoral fractures with prolonged BP use being the highest risk factor for its development. There is no evidence of increased mortality or morbidity in patients with AFF compared with the typical subtrochanteric fracture. The fear of AFF should not impede treatment of typical osteoporotic fractures in this population. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Context: Studies find surgery superior to medications in the treatment of primary aldosteronism (PA). It would be ideal to compare surgical and medical therapy in patients with unilateral PA only, who have the option between these treatment modalities. However, this is challenging as most patients with unilateral PA on adrenal vein sampling (AVS) undergo surgery., Objective: To compare outcomes of surgery and medications in patients with confirmed or likely unilateral PA., Design: Retrospective cohort study of 274 patients with PA managed at two referral centres from 2000 to 2019., Patients: 154 patients identified with unilateral PA using AVS and a validated clinical prediction model were treated with surgical (n = 86) or medical (n = 68) therapy., Measurements: Primary outcome was a composite incident cardiovascular event comprising acute myocardial infarction, coronary revascularization, stroke, atrial fibrillation or congestive cardiac failure. Secondary outcomes were clinical and biochemical control., Results: Cardiovascular outcomes were comparable, with the surgery group having an adjusted hazard ratio of 0.93 (95% CI: 0.32-2.67), p = .89. Both treatments improved clinical and biochemical control, but surgery resulted in better systolic blood pressure, 133.0 ± 11.7 mmHg versus 137.9 ± 14.6 mmHg, p = .02, and lower defined daily dosages of antihypertensive medications, 1.0 (IQR 0.0-2.0) versus 2.6 (IQR 0.8-4.3), p < .001. In addition, 12 of 86 patients in the surgery group failed medical therapy before opting for surgery., Conclusion: In patients with unilateral PA who can tolerate medications, medical therapy improves clinical and biochemical control, and may offer similar cardiovascular protection. However, surgery reduces pill burden, may cure hypertension and is recommended for unilateral PA., (© 2020 John Wiley & Sons Ltd.)

Aims/introduction: Biosimilar insulin can reduce treatment costs, although the extent of its use is largely unknown. We examined biosimilar insulin use and its associations with the quality of glycemic control using the Joint Asia Diabetes Evaluation register., Materials and Methods: We carried out a cross-sectional analysis in 81,531 patients with type 1 and type 2 diabetes enrolled into the Joint Asia Diabetes Evaluation Program from 2007 to 2014. All insulin related terms are extracted from the Joint Asia Diabetes Evaluation portal, and compared clinical profiles between biosimilar and originator insulin users. Multivariate analysis was performed to assess the association of biosimilar insulin compared with originator insulin with dosage, glycated hemoglobin and hypoglycemia events., Results: Amongst 81,531 patients, 20.5% (n = 16,738) were insulin-treated. In four countries with high use of biosimilar insulin, 4.7% (n = 719) of insulin users (n = 10,197) were treated with biosimilar insulin (India n = 507, 70.3%; the Philippines n = 90, 12.5%; China n = 62, 8.6%; Vietnam n = 60, 8.3%). Biosimilar insulin users were younger and had higher body mass index, glycated hemoglobin, insulin dosage and more frequent hypoglycemia than originator insulin users. These associations were non-significant after adjustment for confounders. Only age, college education, diabetes education, lipid control, physical activity and history of cardiovascular complications were independently associated with these quality measures., Conclusions: Biosimilar insulin use is not uncommon in Asia. Data exclusion due to incomplete capturing of brand names suggests possibly higher use. The multiple determinants of the quality of glycemic control call for establishment of prospective cohorts and diabetes registers to monitor the safety and efficacy of different brands of biosimilar insulin and their impacts on clinical outcomes., (© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

This study aims at assessing the gap in secondary fracture prevention at a regional general hospital setting in Singapore. Male patients have significantly lower rate of being investigated and treated for osteoporosis than their female counterparts. Vitamin D deficiency is prevalent in our population., Purpose: Secondary fracture prevention services are not routine in Singapore; we seek to assess the treatment gap that exists in the lack of diagnosis and treatment of osteoporosis in fragility fracture patients., Methods: We performed a retrospective analysis of all admissions for fragility fractures between December 2013 and December 2014. Demographic data, rates of BMD performance, serum vitamin D investigation and calcium and vitamin D supplementation as well as antiresorptive initiation 1 year post admission were analysed., Results: There were 125 fragility fractures in patients below 65 and 615 fractures in older patients. There was a slightly higher proportion of males in the younger population, whereas females predominated in the older population. Median vitamin D levels were low in both younger (19.1 μg/L) and older (22.0 μg/L) groups, but supplementation was lower in younger patients (4.8 versus 16.6%, p = 0.003). Rate of BMD performance was lower in younger patients (34.4 versus 64.6%, p < 0.01); there was a significant difference of BMD performance between male and female patients in the younger population (19.1 versus 52.8%, p < 0.01) which was not present in the older age group. Antiresportive initiation was significantly lower in the younger age group versus older (10.4 versus 31.5%, p < 0.01); male patients in the younger and older age groups had significantly lower antiresorptive initiation rate compared to the females., Conclusion: There is a significant treatment gap in diagnosis and treatment of osteoporosis in fragility fracture patients in a regional hospital setting in Singapore. Male osteoporosis remains inadequately investigated and treated in both age groups.

Prostate cancer is a leading cause of cancer death, frequently associated with widespread bone metastases. We report two cases of hypocalcemia following the first dose of denosumab in metastatic hormone refractory prostate cancer, the first case requiring 26 days of intravenous calcium therapy. This is the first report of prolonged hypocalcemia following denosumab in a patient with normal renal function., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the prevalence and prognostic implications of low serum testosterone levels in men with chronic liver disease., Design: We conducted an observational study at a tertiary referral centre., Patients and Measurements: Baseline serum testosterone was measured in 171 men presenting to the Victorian Liver Transplant Unit for liver transplant evaluation. Patients were followed up to liver transplant or death., Results: Sixty-one per cent of men had a low total testosterone level (TT, <10 nm), and 90% of men had a low calculated free testosterone level (cFT, <230 pm). During the available observation time (median 8 months, interquartile range 4-14 months), 56 men (33%) died and 63 (37%) received a liver transplant. Fifty-two (30%) survived without a transplant. Median time to death was 8 months (range 2-13) and to liver transplant was 8 months (4-14). Baseline low TT and cFT levels both (P < 0·0001) predicted mortality. Moreover, in a Cox proportional hazard model, both low total (P = 0·02) and free testosterone (P = 0·007) levels remained predictive of death independently of established prognostic factors, such as the model for end-stage liver disease (MELD) score and serum sodium levels. A decrease in TT by 1 nm and in cFT by 10 pm was associated with an 8% increase in mortality., Conclusions: Low testosterone levels are common in men with severe liver disease and predict mortality independent of MELD, the standard score used to prioritize the allocation of liver transplants., (© 2012 Blackwell Publishing Ltd.)

Prescribing practices of physicians who treat acute childhood diarrhoea in Penjaringan, an urban district of Jakarta, were investigated utilising observations of clinical practice and interviews with physicians. One hundred thirty-four physicians registered in Penjaringan district in their practices; 122 physicians (91%) participated in the survey and 73 (55%) were included in the observational study. Reported and observed practices are compared. Results show that 78% of the physicians reported that they frequently prescribe Oralit, a solution for oral rehydration therapy (ORT). However, observation of clinical cases indicates that Oralit was prescribed less frequently than reported. Although most physicians believed viral infections were a common cause of diarrhoea, antibiotics were prescribed for children in 94 percent of observed cases. Antispasmodic drugs were also commonly prescribed. Factors associated with physicians' prescribing behaviour and practices regarding diarrhoeal diseases include type of practice, concepts about aetiology, perceptions about ORT and parental expectations. The observed discrepancy between knowledge and practice suggests the need for new ways to encourage physicians to prescribe Oralit and to limit use of antibiotics and antidiarrhoeals of doubtful efficacy.