Relapse after cessation of weekly tocilizumab for giant cell arteritis: a multicentre service evaluation in England.

OBJECTIVES: The National Health Service in England funds 12 months of weekly subcutaneous tocilizumab (qwTCZ) for patients with relapsing or refractory giant cell arteritis (GCA). During the COVID-19 pandemic, some patients were allowed longer treatment. We sought to describe what happened to patients after cessation of qwTCZ. METHODS: Multicentre service evaluation of relapse after stopping qwTCZ for GCA. The log-rank test was used to identify significant differences in time to relapse. RESULTS: 336 GCA patients were analysed from 40 centres, treated with qwTCZ for a median (interquartile range, IQR) of 12 (12-17) months. At time of stopping qwTCZ, median (IQR) prednisolone dose was 2 (0-5) mg/day. By 6, 12 and 24 months after stopping qwTCZ, 21.4%, 35.4% and 48.6% respectively had relapsed, requiring an increase in prednisolone dose to a median (IQR) of 20 (10-40) mg/day. 33.6% of relapsers had a major relapse as defined by EULAR. Time to relapse was shorter in those that had previously also relapsed during qwTCZ treatment (P = 0.0017); in those not in remission at qwTCZ cessation (P = 0.0036); and in those with large vessel involvement on imaging (P = 0.0296). Age ≥65, gender, GCA-related sight loss, qwTCZ treatment duration, TCZ taper, prednisolone dosing, and conventional synthetic DMARD use were not associated with time to relapse. CONCLUSION: Up to half our patients with GCA relapsed after stopping qwTCZ, often requiring a substantial increase in prednisolone dose. One third of relapsers had a major relapse. Extended use of TCZ or repeat treatment for relapse should be considered for these patients.

Duodenal ulcer perforation and its consequences.

Duodenal ulcer perforation, a frequent surgical emergency, needs simple closure with indirect Graham's Omentopexy which is effective with excellent results in majority of cases despite patients' late presentation. The objective of the study was to determine the frequency of postoperative complications of perforated duodenal ulcer, conducted in the Surgery Department, Jinnah Postgraduate Medical Centre, Karachi, from March 20, 2018 to September 20, 2018. The study was a descriptive case series of 108 patients of both genders with perforated duodenal ulcer > 1 week old with ASA score I & II. Patients with trauma and comorbidities were excluded. The patients underwent laparotomy and peritoneal toilet, and after noting the site of perforation indirect Graham's Omentopexy was performed. Complications like duodenal fistula, peritonitis, and paralytic ileus, and patient's death within 10 days of surgery were noted. Age ranged from 18 to 50 years with mean age of 35.027±5.13 years, mean weight 71.120±12.77 kg, mean height 1.541 ±0.09 metres, mean BMI 29.975±4.99 kg/m2, and the mean duration of complaint was 4.194±1.30 weeks. Male predominance in 75 (69.4%) patients. Duodenal fistula was seen in 10 (9.3%) patients, peritonitis 12 (11.1%), paralytic ileus 14 (13%) and mortality was in 11 (10.2%) patients.

Approaches towards improving the quality of maternal and newborn health services in South Asia: challenges and opportunities for healthcare systems.

BACKGROUND: South Asia is experiencing a dismal state of maternal and newborn health (MNH) as the region has been falling behind in reducing the levels of maternal and neonatal mortality. Most of the efforts are focused on enhancing coverage of MNH services; however, quality remains a serious concern if the region is to achieve expected outcomes in terms of standardised MNH services within healthcare delivery systems. This research consists of a review of South Asian quality improvement (QI) approaches/interventions, specifically implemented for MNH improvement. METHODS: A literature review of QI approaches/interventions was conducted using the PRISMA guidelines. Online databases, including PubMed, the Cochrane Library and Google Scholar, were searched. Primary studies published between 1998 and 2013 were considered. Studies were initially screened and selected based upon the selection criteria for data extraction. A thematic synthesis/analysis was performed to organise, group and interpret the key findings according to prominent themes. RESULTS: Thirty studies from six South Asian countries were included in the review. Findings from these selected studies were grouped under eight broad, cross-cutting themes, which emerged from a deductive approach, representing the most commonly employed QI approaches for improving MNH services within different geographical settings. These consist of capacity building of healthcare providers on clinical quality, clinical audits and feedback, financial incentives to beneficiaries, pay-for-performance, supportive supervision, community engagement, collaborative efforts and multidimensional interventions. CONCLUSIONS: Employing and documenting QI approaches is essential in order to measure the potential of an intervention, considering its cost-effectiveness, feasibility and acceptability to communities. This research concluded that QI approaches are very diverse and cross-cutting, because they are subject to the varied requirements of regional health systems. This high level of variability leads to implementation and knowledge-management challenges for MNH programme planners and managers in the countries of the South Asia region.

Small ubiquitin-like modifier (SUMO)-mediated repression of the Xenopus Oocyte 5 S rRNA genes.

The 5 S rRNA gene-specific transcription factor IIIA (TFIIIA) interacts with the small ubiquitin-like modifier (SUMO) E3 ligase PIAS2b and with one of its targets, the transcriptional corepressor, XCtBP. PIAS2b is restricted to the cytoplasm of Xenopus oocytes but relocates to the nucleus immediately after fertilization. Following the midblastula transition, PIAS2b and XCtBP are present on oocyte-type, but not somatic-type, 5 S rRNA genes up through the neurula stage, as is a limiting amount of TFIIIA. Histone H3 methylation, coincident with the binding of XCtBP, also occurs exclusively on the oocyte-type genes. Immunohistochemical staining of embryos confirms the occupancy of a subset of the oocyte-type genes by TFIIIA that become positioned at the nuclear periphery shortly after the midblastula transition. Inhibition of SUMOylation activity relieves repression of oocyte-type 5 S rRNA genes and is correlated with a decrease in methylation of H3K9 and H3K27 and disruption of subnuclear localization. These results reveal a novel function for TFIIIA as a negative regulator that recruits histone modification activity through the CtBP repressor complex exclusively to the oocyte-type 5 S rRNA genes, leading to their terminal repression.

Inducible NOS-induced chloride intracellular channel 4 (CLIC4) nuclear translocation regulates macrophage deactivation.

Nuclear translocation of cytosolic CLIC4 is an essential feature of its proapoptotic and prodifferentiation functions. Here we demonstrate that CLIC4 is induced concurrently with inducible nitric oxide synthase (iNOS) and S-nitrosylated in proinflammatory peritoneal macrophages. Chemical inhibition or genetic ablation of iNOS inhibits S-nitrosylation and nuclear translocation of CLIC4. In macrophages, iNOS-induced nuclear CLIC4 coincides with the pro- to anti-inflammatory transition of the cells because IL-1ß and CXCL1 mRNA remain elevated in CLIC4 and iNOS knockout macrophages at late time points, whereas TNFα mRNA is elevated only in the iNOS knockout macrophages. Active IL-1ß remains elevated in CLIC4 knockout macrophages and in macrophages in which CLIC4 nuclear translocation is prevented by the NOS inhibitor l-NAME. Moreover, overexpression of nuclear-targeted CLIC4 down-regulates IL-1ß in stimulated macrophages. In mice, genetically null for CLIC4, the number of phagocytosing macrophages stimulated by LPS is reduced. Thus, iNOS-induced nuclear CLIC4 is an essential part of the macrophage deactivation program.

Determining the potential scalability of transport interventions for improving maternal, child, and newborn health in Pakistan.

BACKGROUND: Pakistan is far behind in achieving the Millennium Development Goals regarding the reduction of child and maternal mortality. Amongst other factors, transport barriers make the requisite obstetric care inaccessible for women during pregnancy and at birth, when complications may become life threatening for mother and child. The significance of efficient transport in maternal and neonatal health calls for identifying which currently implemented transport interventions have potential for scalability. METHODS: A qualitative appraisal of data and information about selected transport interventions generated primarily by beneficiaries, coordinators, and heads of organizations working with maternal, child, and newborn health programs was conducted against the CORRECT criteria of Credibility, Observability, Relevance, Relative Advantage, Easy-Transferability, Compatibility and Testability. Qualitative comparative analysis (QCA) techniques were used to analyse seven interventions against operational indicators. Logical inference was drawn to assess the implications of each intervention. QCA was used to determine simplifying and complicating factors to measure potential for scaling up of the selected transport intervention. RESULTS: Despite challenges like deficient in-journey care and need for greater community involvement, community-based ambulance services were managed with the support of the community and had a relatively simple model, and therefore had high scalability potential. Other interventions, including facility-based services, public-sector emergency services, and transport voucher schemes, had limitations of governance, long-term sustainability, large capital expenditures, and need for management agencies that adversely affected their scalability potential. CONCLUSION: To reduce maternal and child morbidity and mortality and increase accessibility of health facilities, it is important to build effective referral linkages through efficient transport systems. Effective linkages between community-based models, facility-based models, and public sector emergency services should be established to provide comprehensive coverage. Voucher scheme integrated with community-based services may bring improvements in service utilization.

Lost Connection: A Case Report of Interrupted Pituitary Stalk Syndrome.

Pituitary stalk interruption syndrome is a triad of thin (<1 mm) or complete absence of the pituitary stalk with either an aplastic or ectopic posterior lobe of the pituitary gland and a hypoplastic or absent anterior lobe of the pituitary. Patients present with growth retardation, short height, seizures, intellectual disability, and absence of sexual maturation at the expected time. Here, we presented a case of a 12-year-old male with stunted growth. Upon examination, there was reduced height, more than 3 standard deviations below the average for his chronological age. Laboratory results showed reduced levels of growth hormone and thyrotropin. Dual-energy X-ray absorptiometry revealed osteoporosis, while an X-ray of the wrist for bone age corresponded to seven years. MRI imaging confirmed the classical triad of findings for pituitary stalk interruption syndrome. Consequently, the patient was referred back to the endocrinology clinic for further management.

Age-specific mortality trends in heart failure over 25 years: a retrospective Danish nationwide cohort study.

BACKGROUND: Despite advances in heart failure care reducing mortality in clinical trials, it remains unclear whether real-life cohorts have had similar improvements in life expectancy across the age spectrum. We aimed to investigate how mortality trends changed in patients with heart failure over the past 25 years, stratified by age groups. METHODS: Using Danish nationwide registries, we identified patients with new-onset heart failure aged 18-95 years. The 5-year all-cause mortality risk and the absolute risk difference of mortality between patients with heart failure and age-matched and sex-matched heart failure-free controls were assessed using Kaplan-Meier estimates and multivariable Cox regression models. Mortality trends were analysed across five calendar periods (1996-2000, 2001-05, 2006-10, 2011-15, and 2016-20) and three age groups (<65 years, 65-79 years, and ≥80 years). FINDINGS: 194 997 patients with heart failure were included. Mortality significantly decreased from 1996-2000 (66% [95% CI 65·5-66·4]) to 2016-20 (43% [42·1-43·4]), with similar results shown in all age groups (<65 years: 35% [33·9-36·1] to 15% [14·6-16·3]; 65-79 years: 64% [63·1-64·5] to 39% [37·6-39·6]; and ≥80 years: 84% [83·1-84·3] to 73% [71·7-73·9]). Adjusted mortality rates supported these associations. The absolute risk difference declined notably in younger age groups (<65 years: 29·9% [28·8-31·0] to 12·7% [12·0-13·4] and 65-79 years: 41·1% [40·3-41·9] to 25·1% [24·4-25·8]), remaining relatively stable in those aged 80 years or older (30·6% [29·9-31·3] to 28% [27·2-28·8]). INTERPRETATION: Over 25 years, there has been a consistent decrease in mortality among patients with heart failure across age groups, albeit less prominently in patients aged 80 years or older. Further insight is needed to identify effective strategies for improving disease burden in older patients with heart failure. FUNDING: None. TRANSLATION: For the Danish translation of the abstract see Supplementary Materials section.

Temporal Trends in the Initiation of Dialysis Among Patients With Heart Failure With or Without Diabetes: A Nationwide Study From 2002 to 2016.

BACKGROUND: The incidence and distribution of acute and chronic dialysis among patients with heart failure (HF), stratified by diabetes, remain uncertain. We hypothesized that with improved survival and rising comorbidities, the demand for dialysis would increase over time. METHODS AND RESULTS: Patients with incident HF, aged 18 to 100 years, between 2002 and 2016, were identified using Danish nationwide registers. Primary outcomes included acute and chronic dialysis initiation, HF-related hospitalization, and all-cause mortality. These outcomes were assessed in 2002 to 2006, 2007 to 2011, and 2012 to 2016, stratified by diabetes. We calculated incidence rates (IRs) per 1000 person-years and hazard ratios (HR) using multivariable Cox regression. Of 115 533 patients with HF, 2734 patients received acute dialysis and 1193 patients received chronic dialysis. The IR was 8.0 per 1000 and 3.5 per 1000 person-years for acute and chronic dialysis, respectively. Acute dialysis rates increased significantly among patients with diabetes over time, while no significant changes occurred in those without diabetes, chronic dialysis, HF-related hospitalization, or overall mortality. Diabetes was associated with significantly higher HRs of acute and chronic dialysis, respectively, compared with patients without diabetes (HR, 2.07 [95% CI, 1.80-2.39] and 2.93 [95% CI, 2.40-3.58] in 2002 to 2006; HR, 2.45 [95% CI, 2.14-2.80] and 2.86 [95% CI, 2.32-3.52] in 2007 to 2011; and 2.69 [95% CI, 2.33-3.10] and 3.30 [95% CI, 2.69-4.06] in 2012 to 2016). CONCLUSIONS: The IR of acute and chronic dialysis remained low compared with HF-related hospitalizations and mortality. Acute dialysis rates increased significantly over time, contrasting no significant trends in other outcomes. Diabetes exhibited over 2-fold increased rates of the outcomes. These findings emphasize the importance of continued monitoring and renal care in patients with HF, especially with diabetes, to optimize outcomes and prevent adverse events.

Beliefs and attitudes about breast cancer and screening practices among Arab women living in Qatar: a cross-sectional study.

BACKGROUND: Despite rising breast cancer incidence and mortality rates, breast cancer screening (BCS) rates among women in Qatar remain low. Previous studies indicate the need to better understand the many complex beliefs, values, and attitudes that influence Arab women's health seeking behavior for the development of culturally appropriate and effective intervention strategies to address breast cancer in the Middle East. This study investigates beliefs, attitudes, and BCS practices of Arabic-speaking women in Qatar. METHODS: A multicenter, cross-sectional quantitative survey of 1,063 (87.5% response rate) Arabic-speaking female Qatari citizens and non-Qatari residents, 35 years of age or older, was conducted in Qatar from March 2011 to July 2011. Associations between beliefs and BCS practice were estimated using chi-square tests and multivariate logistic regression analyses. Participants who adhered to BCS guidelines (BCS practice = Yes) were compared to those who did not (BCS practice = No). RESULTS: In addition to low levels of awareness and low participation rates in BCS, one quarter of the participants stated their doctors talked to them about breast cancer, and less than half of the women interviewed believed breast cancer can be prevented. Women who engaged in BCS practice were more likely to have a doctor who talked to them about breast cancer, to believe they were in good-excellent health, that cancer can be prevented, or that cancer might be hereditary. The majority wanted to know if they had cancer and felt their health care needs were being met. The main reasons given for not planning BCS were lack of a doctor's recommendation, fear, and embarrassment. CONCLUSIONS: These findings indicate that a variety of channels (health care providers, media, breast cancer survivors, community leaders) should be utilized to create culturally appropriate breast cancer intervention programs and increased awareness of breast cancer, BCS, and the benefits of early detection of breast cancer. Employment of these measures will reduce breast cancer mortality rates among Arabic-speaking women living in the State of Qatar.

Ferrous Illusion: A Unique Case of Welding Fume Particles Appearing as Metallic Artifacts in MRI.

A rare cause of metallic artifacts over the scalp on magnetic resonance imaging (MRI) is welding fume particles that contain paramagnetic iron oxide particles. These introduce distortion of the magnetic field homogeneity and result in susceptibility artifacts. They may erroneously be reported as a pathology such as calcified lesions; therefore, awareness among radiologists is required. We report a case of a 52-year-old male, an industrial inspector by profession, who presented to the neurology clinic with headaches for which an MRI of the brain without contrast was advised. There was no brain parenchymal signal abnormality; however, numerous small rounded altered signal foci were identified along the scalp, especially in the vertex region, which returned central hypointense and marginal hyperintense signal on all sequences. The imaging signals were suspicious for calcified scalp lesions, and the patient was recalled for clinical examination, which was unremarkable for cutaneous or subcutaneous abnormality on the scalp or elsewhere over the body. A detailed history was taken retrospectively, revealing that the patient had walked through a room where welding was being done before presenting for an MRI exam, without taking a shower. The various altered signal foci over the scalp on MRI based on their shape were hence identified as welding fume particles. These were fine enough not to be visible by the naked eye but determined by the MRI machine because of their magnetic susceptibility artifact. We aim to increase radiologists' awareness of such artifacts that may be seen in patients with occupational exposure to these particles to avoid misdiagnosis of other pathologies.

When The Silence Prevails, Images Talk: The Characteristic Ct Features Of Vocal Cord Paralysis, Causes Of Missed Palsy By Radiologists And Mimics Of Vocal Cord Palsy Unveiled.

BACKGROUND: Causes of vocal cord palsy (VCP) can be identified even before its clinical presentation if a radiologist has knowledge about signs of vocal cord palsy, its various mimics and the anatomy of recurrent laryngeal nerve. Objectives are to know the signs and underlying causes leading to VCP and various mimics which may lead to the false positive diagnosis of VCP. METHODS: A retrospective cross-sectional pilot study comprising 54 patients with vocal cord palsy proven by IDL was conducted. 3 groups were identified. The first group comprised missed VCP on cross-sectional imaging. The second group was, of missed cause of VCP in patients with clinical diagnoses. The third group was patients with mimics of the palsy. RESULTS: Thirteen (76.5%) patients had missed diagnosis due to lack of knowledge of signs and 23.5% due to lack of time, overwork and tiredness. A vigilant search for the cause was not done in 31.6% of patients and in 68.4% of patients, the cause was identified but not correlated. A total of 8 patients had false positive diagnoses due to failure to differentiate from mimics. CONCLUSIONS: There is an increasing trend of missed diagnosis of vocal cord palsy on cross-sectional imaging in patients with established clinical diagnosis due to a lack of knowledge of VCP signs and missed causes along the course of recurrent laryngeal nerve.

Dual biologic therapy for the treatment of rheumatic diseases and asthma: a case series.

Objective: Combination biological therapies are being considered increasingly for patients with multiple co-morbidities requiring biologics. There are limited data available on this approach, and concerns remain about the possible risk of adverse events, particularly infection. Methods: We present three patients on dual biologics for rheumatic disease and asthma. The biologic combinations used were etanercept and mepolizumab, infliximab and omalizumab, and etanercept and omalizumab. The time on combination biologic therapies ranged from 24 to 36 months. Patients were monitored for any serious adverse events. Results: All three patients were able to tolerate combined biologic therapies, with no serious adverse events. All three patients gained improvement in their rheumatic and asthma disease control, with reduction in disease activity scores and reduction in steroid usage. Conclusion: The decision to start dual biologic therapy should be considered carefully, on a case-by-case basis. The number of patients who are on combination biological therapy is small, and data are sparse. Real-world data are needed to examine the long-term benefits and risks of different forms of combination biologic therapies.

Can Artificial Intelligence Beat Humans in Detecting Breast Malignancy on Mammograms?

BACKGROUND: The study was aimed at identifying how useful Computer-Aided Detection (CAD) could be in reducing false-negative reporting in mammography and early detection of breast cancer at an early stage as the best protection is early detection. MATERIALS AND METHODS: This retrospective study was conducted in a tertiary care setup of Atomic Energy Cancer Hospital, Nuclear Medicine, Oncology and Radiotherapy Institute (AECH-NORI), where 33 patients with suspicious findings on mammography and subsequent biopsy-proven malignancy were included. The findings of mammography including the lesion type, breast parenchymal density, and sensitivity of CAD detection, as well as the final biopsy results, were recorded. A second group of 40 normal screening mammograms was also included who had no symptoms, had Breast Imaging-Reporting and Data System category I(BI-RADS I) mammograms, and had no pathology identified on correlative sonomammography as well. RESULTS: A total of 35 masses, 11 pleomorphic clusters of microcalcification, five clustered foci of macrocalcification, and nine lesions with pleomorphic clusters of microcalcification and two with pleomorphic clusters of microcalcification only were included. The CAD system was able to identify 26 masses (74%), eight lesions with pleomorphic clusters of microcalcification (72%), five foci of macrocalcification (100%), six lesions with pleomorphic clusters of microcalcification (66%), and two pleomorphic clusters of microcalcification without formed mass (100%). The overall sensitivity of the CAD system was 75.8%. CAD was able to identify 13 out of 16 masses with invasive ductal carcinoma (81.3%), eight out of nine lesions proven as invasive ductal carcinoma with ductal carcinoma in situ (DCIS) (88.9%), two out of five masses with invasive lobular carcinoma (40%), four out of four masses with invasive mammary carcinoma (100%), and zero out of one lesion identified as medullary carcinoma (0%). There was 100% detection for pleomorphic clusters of microcalcification without formed mass with CAD marking two out of two mammograms. CONCLUSION: CAD performed better with combined lesions, accurately marked pleomorphic clusters of microcalcification, and identified small lesions in predominant fibrofatty parenchymal density but was not reliable in dense breast, areas of asymmetric increased density, summation artifacts, edematous breast parenchyma, and retroareolar lesions. It also performed poorly with ill-defined lesions of invasive lobular carcinoma. Human intelligence hence beats CAD for the diagnosis of breast malignancy in mammograms as per our experience.

Clinical cardiovascular phenotypes and the pattern of future events in patients with type 2 diabetes.

IMPORTANCE: Updated guidelines on diabetes recommend targeting sodium-glucose cotransporter-2 inhibitors (SGLT2i) at patients at risk of heart failure (HF) and glucagon-like peptide-1 receptor agonists (GLP1-RA) at those at greater risk of atherothrombotic events. OBJECTIVE: We estimated the risk of different cardiovascular events in patients with type 2 diabetes (T2D) and newly established cardiovascular disease. DESIGN, SETTING AND PARTICIPANTS: Patients with T2D and newly established cardiovascular disease from 1998 to 2016 were identified using Danish healthcare registers and divided into one of four phenotype groups: (1) HF, (2) ischemic heart disease (IHD), (3) transient ischemic stroke (TIA)/ischemic stroke, and (4) peripheral artery disease (PAD). The absolute 5-year risk of the first HF- or atherothrombotic event occurring after inclusion was calculated, along with the risk of death. MAIN OUTCOMES AND MEASURES: The main outcome was the first event of either HF or an atherothrombotic event (IHD, TIA/ischemic stroke or PAD) in patients with T2D and  new-onset cardiovascular disease. RESULTS: Of the 37,850 patients included, 40% were female and the median age was 70 years. Patients with HF were at higher 5-year risk of a subsequent HF event (17.9%; 95% confidence interval (CI) 17.1-18.8%) than an atherothrombotic event (15.8%; 15.0-16.6%). Patients with IHD were at higher risk of a subsequent atherothrombotic event (24.6%; 23.9-25.3%) than developing HF, although the risk of HF was still substantial (10.6%; 10.2-11.1%). Conversely, patients with PAD were at low risk of developing HF (4.4%; 3.8-5.1%) but at high risk of developing an atherothrombotic event (15.9%; 14.9-17.1%). Patients with TIA/ischemic stroke had the lowest risk of HF (3.2%; 2.9-3.6%) and the highest risk of an atherothrombotic event (20.6%; 19.8-21.4). CONCLUSIONS: In T2D, a patient's cardiovascular phenotype can help predict the pattern of future cardiovascular events.

Initiation of Medical Therapy for Heart Failure Patients According to Kidney Function: A Danish Nationwide Study.

Background: Use of medical therapies for heart failure (HF) patients with moderate kidney dysfunction is low. We hypothesized that lack of initiation of HF therapy reflects the clinicians' reluctance in very elderly and frail patients more than kidney dysfunction itself. Methods: HF patients were identified from nationwide registers between 2014 and 2021. Information was obtained on eGFR, frailty status, and prescription of HF therapy. Patients were divided into three groups: normal kidney function (eGFR ≥ 60); moderate kidney dysfunction (GFR between 30 and 59); and severe kidney dysfunction (GFR < 30). Multivariate Cox models were used to study the association of eGFR, age, and frailty with use of HF therapy. Results: Of the 42,320 HF patients included those with lower eGFR were significantly older and frailer (median age 74.3 years and 37.8% frail). The crude initiation rate of all three drug classes decreased with decreasing eGFR in a stepwise fashion. After adjusting for age and frailty status, initiation of MRA decreased with decreasing kidney function (moderate kidney function HR 0.80(95% CI 0.77-0.84) and severe kidney function HR 0.24(0.21-0.27)). After adjusting for age and frailty status, initiation of RAS inhibitor and BB was not significantly lower for moderate kidney dysfunction (HR 0.97(0.93-1.02), and HR 1.06(0.97-1.16, respectively)). Initiation of RAS inhibitor was significantly lower for patients with severe kidney dysfunction, HR 0.45(0.41-0.50), but not for BB initiation HR 1.09(1.05-1.14). Conclusion: In a real-world HF cohort, patients with moderate and severe kidney dysfunction were associated with reduced use of MRA irrespective of age and frailty. Reduced use of RASi was associated with severe kidney dysfunction, whereas for patients with moderate kidney dysfunction, reduced use was mainly driven by aging and frailty. Reduced use of BB seemed to be primarily explained by aging and frailty.

Discontinuation and reinitiation of SGLT-2 inhibitors and GLP-1R agonists in patients with type 2 diabetes: a nationwide study from 2013 to 2021.

Background: Small observational studies have observed poor persistency to sodium-glucose cotransporter-2 inhibitors (SGLT2-i) and glucacon-like-peptide-1-receptor agonists (GLP1-RA), contrary to what has been reported in clinical trials. Therefore, we investigated the risk of discontinuing SGLT2-is and GLP1-RAs in patients with type 2 diabetes (T2D) in a nationwide population. Methods: From Danish nationwide registers, all first-time users of SGLT2-is and GLP1-RAs from 2013 to 2021 were identified. Adherence over the first year of therapy, the five-year risk of discontinuing therapy for the first time and the subsequent one-year probability of reinitiating therapy, was assessed. The Aalen-Johansen estimator was used to account for censoring and competing risks and multivariable Cox regression models were used to identify covariates associated with discontinuation. Findings: A total of 77,745 first-time users of SGLT2-is (64% male, median age 64 [interquartile range 56-72]) and 56,037 first-time users of GLP1-RAs (56% male, median age 61 [53-70]) were included. The absolute five-year risk of discontinuing therapy was 56% (95% CI: 55-57) and 45% (45-46) for SGLT2-i- and GLP1-RA users, respectively, with a significantly decreased risk over the period studied. The subsequent one-year probability of reinitiating therapy was 24% (95% CI: 24-25) for initial SGLT2-i users and 26% (25-27) for GLP1-RA users. Interpretation: Approximately half of the users of SGLT2-is and GLP1-RAs discontinued therapy within five years, respectively. However, a large proportion of these patients reinitiated therapy during the following year. Further insight into the reasons for discontinuation and initiatives to reduce the time to reinitiation in eligible patients are warranted. Funding: The work was funded by an unrestricted research grant from 'Department of Cardiology, Herlev and Gentofte University Hospital'.

Heart Failure Following Anti-Inflammatory Medications in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Fluid retention and endothelial dysfunction have been related to use of nonsteroidal anti-inflammatory drugs (NSAIDs), and type 2 diabetes mellitus (T2DM) has been linked to both a decline in kidney function and subclinical cardiomyopathy. OBJECTIVES: The authors hypothesized that short-term use of NSAIDs could lead to subsequent development of incident heart failure (HF) in patients with T2DM. METHODS: Using nationwide Danish registers, we identified patients diagnosed with T2DM during 1998 to 2021 and included patients without previous HF, rheumatic disease, or use of NSAIDs 120 days before diagnosis. Associations between NSAIDs and first-time HF hospitalization were investigated using a case-crossover design with 28-day exposure windows, and ORs with 95% CIs were reported. RESULTS: Included were 331,189 patients with T2DM: 44.2% female, median age of 62 years (IQR: 52-71 years); 23,308 patients were hospitalized with HF during follow-up, and 16% of patients claimed at least 1 NSAID prescription within 1 year. Short-term use of NSAIDs was associated with increased risk of HF hospitalization (OR: 1.43; 95% CI: 1.27-1.63), most notably in subgroups with age ≥80 years (OR: 1.78; 95% CI: 1.39-2.28), elevated hemoglobin (Hb) A1c levels treated with 0 to 1 antidiabetic drug (OR: 1.68; 95% CI: 1.00-2.88), and without previous use of NSAIDs (OR: 2.71; 95% CI: 1.78-4.23). CONCLUSIONS: NSAIDs were widely used and were associated with an increased risk of first-time HF hospitalization in patients with T2DM. Patients with advanced age, elevated HbA1c levels, and new users of NSAID seemed more susceptible. These findings could guide physicians prescribing NSAIDs.

Initiation of SGLT2 inhibitors and GLP-1 receptor agonists according to level of frailty in people with type 2 diabetes and cardiovascular disease in Denmark: a cross-sectional, nationwide study.

BACKGROUND: Whether frailty influences the initiation of two cardioprotective diabetes drug therapies (ie, SGLT2 inhibitors and GLP-1 receptor agonists) in people with type 2 diabetes and cardiovascular disease is unknown. We aimed to assess rates of initiation of SGLT2 inhibitors and GLP-1 receptor agonists according to frailty in people with type 2 diabetes and cardiovascular disease. METHODS: For this cross-sectional, nationwide study, all people with type 2 diabetes and cardiovascular disease in Denmark between Jan 1, 2015, and Dec 31, 2021, from six Danish health-data registers were identified. People younger than 40 years, with end-stage renal disease, with registered contraindications to SGLT2 inhibitors or GLP-1 receptor agonists, or with previous use of either drug therapy were excluded. The Hospital Frailty Risk Score was used to categorise people as either non-frail, moderately frail, or severely frail. Cox proportional hazards models were used to analyse the association between frailty and initiation of an SGLT2 inhibitor or a GLP-1 receptor agonist. FINDINGS: Of 119 390 people with type 2 diabetes and cardiovascular disease, 103 790 were included. Median follow-up time was 4·5 years (IQR 2·7-6·1) and median age across the three frailty groups was 71 years (64-79). 65 959 (63·6%) of 103 790 people were male and 37 831 (36·5%) were female. At index date, 66 910 (64·5%) people were non-frail, 29 250 (28·2%) were moderately frail, and 7630 (7·4%) were severely frail. Frailty was associated with a significantly lower probability of initiating therapy with an SGLT2 inhibitor or a GLP-1 receptor agonist than in people who were non-frail (moderately frail hazard ratio 0·91, 95% CI 0·88-0·94, p<0·0001; severely frail 0·75, 0·70-0·80, p<0·0001). This association persisted after adjustment for age, sex, socioeconomic status, year of inclusion, duration of type 2 diabetes, duration of cardiovascular disease, polypharmacy, and comorbidity. INTERPRETATION: In people with type 2 diabetes and cardiovascular disease in Denmark, frailty was associated with a significantly lower probability of SGLT2-inhibitor or GLP-1 receptor-agonist initiation, despite their benefits. Formulating clear and updated guidelines on the use of SGLT2 inhibitors and GLP-1 receptor agonists in people who are frail with type 2 diabetes and cardiovascular disease should be a priority. FUNDING: Department of Cardiology, Herlev and Gentofte University Hospital. TRANSLATION: For the Danish translation of the abstract see Supplementary Materials section.

Biosynthesizing Cassia fistula Extract-Mediated Silver Nanoparticles for MCF-7 Cell Lines Anti-Cancer Assay.

The unique consequence of green synthesis is that the mediator plant is able to release chemicals that are efficacious as reducing as well as stabilizing agents. In this work, the fruit pulp and leaf essences of Cassia fistula have been used to manufacture silver nanoparticles through the green synthesis technique. The sculpturing of nanoparticles was accomplished by utilizing the reduction phenomenon that ensued due to the reaction between plant essences and the precursor solution. These biosynthesized silver nanoparticles were examined, where we used scanning electron microscopy, UV-vis spectroscopy, and X-ray diffraction techniques as means to analyze the structure, optical properties, and crystalline behavior, respectively. The absorption spectra for fruit and leaf extracts obtained from the UV-vis analyses peaked at 401 and 397 nm, and these peaks imply the appearance of optical energy gaps of 2.12 and 2.58 eV, accompanying spherical shapes of particles with diameters in the ranges of 12-20 and 50-80 nm, respectively. These silver nanoparticles together with the adopted green technique have a vast array of applications, specifically in the biomedical realm. In particular, they are being used to treat several diseases and are manifested as strong anti-tumor agents to medicate MCF-7 breast cancer cell lines in order to minimize the cell growth rate depending on their concentrations.