Preventive Therapy Research Articles

Autism Among Adults with Down Syndrome: Prevalence, Medicaid Usage, and Co-Occurring Conditions.

Our objective was to examine occurrence of both conditions in Medicaid; and compare Medicaid service use and cost, and chronic conditions among adults with Down syndrome and autism to those with Down syndrome alone and those with autism alone. We used ICD9 and ICD10 codes in Medicaid claims and encounters from 2011 to 2019 to identify autism and Down syndrome in adults > 18 years. We then calculated costs, claims, hospitalizations, long term care days, and chronic conditions, and compared by group- autism alone, Down syndrome alone, Down syndrome + autism. Between 2011 and 2019, there were 519,450 adult Medicaid enrollees who met our criteria for autism (N = 396,426), Down syndrome (N = 116,422), or both Down syndrome and autism (N = 6,602). In 2011, 4.1% of enrollees with Down syndrome had co-occurring autism; by 2011 it was 6.6%. The autism group had the fewest claims and inpatient hospitalizations, followed by the Down syndrome group, then the Down syndrome + autism group. After age adjustment, those with Down syndrome alone and Down syndrome + autism had elevated prevalence of atrial fibrillation, dementia, heart failure, kidney disease, and obesity compared to the autism alone group. Both groups also had decreased occurrence of depression and hypertension compared to the autism alone group. Prevalence of autism is higher among people with Down syndrome than in peers. The increased costs and service use for those with both conditions highlight the extent to which this population need health care and signal the need for more effective preventative care and therapies.

Emerging therapeutic strategies targeting bone signaling pathways in periodontitis.

Periodontitis is a multifactorial immune-mediated disease exacerbated by dysregulated alveolar bone homeostasis. Timely intervention is crucial for disease management to prevent tooth loss. To successfully manage periodontitis, it is imperative to understand the cellular and molecular mechanisms involved in its pathogenesis to develop novel treatment modalities. Non-surgical periodontal therapy (NSPT) such as subgingival instrumentation/debridement has been the underlying treatment strategy over the past decades. However, new NSPT approaches that target key signaling pathways regulating alveolar bone homeostasis have shown positive clinical outcomes. This narrative review aims to discuss endogenous bone homeostasis mechanisms impaired in periodontitis and highlight the clinical outcomes of preventive periodontal therapy to avoid invasive periodontal therapies. Although the anti-resorptive therapeutic adjuncts have demonstrated beneficial outcomes, adverse events have been reported. Diverse immunomodulatory therapies targeting the osteoblast/osteoclast (OB/OC) axis have shown promising outcomes invivo. Future controlled randomized clinical trials (RCT) would help clinicians and patients in the selection of novel preventing therapies targeting key molecules to effectively treat or prevent periodontitis.

Malnutrition is a risk factor for tuberculosis disease among household contacts: a case-control study in Uganda

Household contacts (HHCs) of persons with tuberculosis including rifampicin-resistant or multi-drug-resistant tuberculosis (RR/MDR-TB) are at risk for TB infection. We investigated whether index patient-level clinical and socio-demographic factors of persons with MDR-TB are associated with TB disease among their HHCs in Uganda. We designed an unmatched case-control study. Cases were HHCs of persons with MDR-TB that had TB disease while controls were a random sample of HHCs of persons with MDR-TB that had no TB disease. The case-to-control ratio was 1:3. We identified the factors that significantly differed between the cases and controls in a multivariable binary logistic regression analysis and reported the odds ratio and 95% confidence interval (CI). We found similar demographic and clinical characteristics among the 11 cases and 33 controls. In a multivariable analysis, malnutrition was significantly associated with being a case than a control (adjusted OR 5.01; 95% CI 1.18-24.83). Therefore, TB Control Programs should focus on identifying malnutrition among persons with MDR-TB and providing nutritional counseling and support to improve recovery, and potentially reduce household TB transmission and optimize treatment success. Additionally, rapid screening for TB and preventive therapy should be prioritized to reduce transmission.

Comparison of QuantiFERON Gold In-Tube Versus Tuberculin Skin Tests on the Initiation of Tuberculosis Preventive Therapy Among Patients Newly Diagnosed With Human Immunodeficiency Virus in the North West Province of South Africa (the Teko Study): A Cluster Randomized Trial.

Tuberculosis (TB) preventive therapy (TPT) reduces the risk of TB disease in people with human immunodeficiency virus (HIV), yet uptake has been suboptimal in many countries. We assessed whether QuantiFERON Gold In-Tube (QGIT) during routine HIV care increased TB infection (TBI) testing and TPT prescriptions. This parallel-arm, 1:1 cluster-randomized controlled trial compared the standard-of-care tuberculin skin test to QGIT in South Africa. We enrolled consenting, TPT-eligible adults diagnosed with HIV ≤30 days prior and used intention-to-treat analyses for the outcomes: proportion of patients with documented TBI results, proportion with documented TPT, and time from enrollment to outcomes. We enrolled 2232 patients across 14 clinics from November 2014 to May 2017 (58% in intervention clinics). At 24 months of follow-up, more participants in intervention clinics had TBI results (69% vs 2%, P < .001) and TPT prescriptions (45% vs 30%, P = .13) than control clinics. Controlling for baseline covariates, intervention clinics had 60% (95% confidence interval, 51-68; P < .001) more participants with TBI results and 12% (95% confidence interval, -6 to 31; P = .18) more with TPT prescriptions. Among participants with results, those in intervention clinics received results and TPT faster (intervention: median of 6 and 29 days after enrollment vs control: 21 and 54 days, respectively). In this setting, QGIT in routine HIV care resulted in more patients with TBI results. Clinicians also initiated more people with HIV on TPT in QGIT intervention clinics, and did so more quickly, than the control arm. NCT02119130.

Endoscopic vacuum therapy (eVAC) combined with continuous perianastomotic irrigation for prevention of anastomotic leak after surgical ampullectomy

PurposeTransduodenal surgical ampullectomy (tAMP) with papillary reimplantation is a valid alternative to pancreaticoduodenectomy for lesions of the periampullary region not amenable to endoscopic resection. As tAMP is burdened by high rates of biliopancreatic-enteric anastomotic leak, we tested preventive endoluminal vacuum therapy (eVAC) combined with post-operative continuous perianastomotic irrigation (CPI) to reduce such anastomotic leak.MethodsBetween 10/2013 and 09/2023, 37 patients undergoing laparotomic tAMP (with or without jejunal transposition) and papillary reimplantation at Hirslanden Klinik Zurich were retrospectively analysed; of these, 16 received prophylactic eVAC combined with CPI, while the remaining represented the historical cohort.ResultsThe eVAC-CPI-group and the historical-cohort were homogeneous in demographic characteristics. Surgery in the prophylactic eVAC-CPI-group lasted about 30 min longer due to eVAC application (p = 0.008). The biliopancreatico-enteric anastomotic leak rates were 6.2% in the eVAC-CIP-group vs. 19.0% in the historical-cohort (p = 0.266). Along, a strong trend of less severe post-operative complications in general (p = 0.073), and borderline-significantly less cases of acute pancreatitis (p = 0.057) and tAMP-related re-operations or re-interventions (p = 0.057) in particular, were observed in the eVAC-CPI-group. The only anastomotic leak in the eVAC-CPI-group was successfully managed through repeated cycles of eVAC. The device was well tolerated by all patients; no vacuum/irrigation-related complications or malfunctioning occurred.ConclusionOur study is the first to provide some technical insights demonstrating the safety and feasibility of a prophylactic approach with eVAC and perianastomotic irrigation to reduce anastomotic leak after tAMP. Increasing the number of subjects will confirm the benefit of our promising results.

Evaluating the integration of CTCA as part of an accelerated diagnostic pathway for patients presenting to the Emergency Department with acute chest pain: a two-year review

Abstract Introduction Chest pain accounts for 8.8% of all presentations to an Hospital Emergency Department. In line with ESC guidelines (2019), an adapted HEART pathway, utilising CT Coronary Angiogram (CTCA) is delivered by our Emergency Cardiology Advanced Nurse Practitioners (ANP) and Clinical Nurse Specialists (CNS) as part of an ambulatory chest pain pathway. It is our first line diagnostic test for patients with a non-ischaemic 12-lead ECG and normal cardiac biomarkers, with a low-to-intermediate HEART score. Responsibility for the referral of patients onto the pathway is shared with the Cardiology Registrars. This is a collaborative interdisciplinary pathway between Emergency Medicine, Cardiology, and Radiology. Purpose To evaluate the effectiveness and safety of CTCA as part of an Accelerated Diagnostic Pathway (ADP), for evaluation of chest pain of possible cardiac origin in low-to-intermediate risk chest pain patients. Methods We examined the CTCA and safety outcomes of patients presenting between Jan 1st 2022 – Dec 31st 2023 who were risk stratified as low-to-intermediate risk for coronary artery disease, based on Heart score, 12-lead ECG and biomarker testing, using the electronic patient records. Institutional ethics was in place. Results Between January 1st and December 31st 2022, 290 patients were referred for CTCA, with a total of 268 CTCAs completed. The number of patients referred on the ADP increased by 53.4% in 2023 with 445 being referred for CTCA, 416 of which have been completed, with 12 pending completion. 38% of patients were found to have evidence of coronary artery disease (CAD). Coronary artery disease causing at least 50% stenosis was identified in 11% of patients. 4.5% of these patients required revascularisation, 17 of whom underwent Percutaneous Coronary Intervention (PCI) with a further 13 being referred for Coronary Artery Bypass Grafting. A positive family history was the most dominant risk factor associated with significant CAD. An equivalent number of males to females were referred for CTCA, however, men were more than 7 times more likely to have severe disease. (12% vs 88%). All patients referred for CTCA via the chest pain pathway were followed up by the Emergency Cardiology ANP/CNS in a virtual clinic, delivering risk factor modification advice and preventative therapies, when indicated. There was no evidence of any major adverse cardiovascular events within a 30-day period for this patient cohort. Conclusion The integration of CTCA into an adapted HEART pathway has resulted a safe and timely discharge for patients presenting to ED with acute chest pain, of possible cardiac origin. CTCA offers excellent early detection of coronary artery disease in this patient cohort with normal ECGs and cardiac biomarkers, but with a history of chest pain suggestive of CAD.

High disease burden and healthcare resource usage in patients with acute porphyria-A population-based analysis.

Acute porphyria is a chronic recurrent disease with late diagnosis, heterogeneous clinical presentations and potentially devastating complications. The study aimed at providing real-world evidence on the natural course of acute porphyria, patient characteristics, disease burden, and healthcare utilization before diagnosis. This observational study used anonymized claims data covering 8 365 867 persons from German statutory health insurance, spanning 6 years (2015-2020). Patients with at least one diagnosis of acute porphyria during the index period (2019-2020) were classified into three groups by attack frequency. These findings were compared with two age- and sex-adjusted reference groups: the general population and fibromyalgia patients. Prevalence over the index period was calculated for all porphyria patients and those with active acute porphyria. We revealed a prevalence of 79.8 per 1 000 000 for acute porphyria, with 12.9 per 1 000 000 being active cases. Acute porphyria patients, particularly with frequent attacks, demonstrated a higher comorbidity burden compared to the general population. Within the year before the recorded diagnosis, patients with acute porphyria required a median of 23.0 physician visits, significantly higher than the general population's 16.0. Additionally, 33.8% were hospitalized at least once during this period, a notably higher proportion than the general population (19.3%). This study's findings, collected before the introduction of givosiran, as the first approved preventive therapy for acute porphyria in Europe, highlight the need for healthcare strategies and policies tailored to the complex needs of acute porphyria patients. The significant healthcare demands, heightened comorbidity burden, and increased healthcare system utilization emphasize the urgency of developing a comprehensive support infrastructure for these patients. Also, these acute porphyria real-world findings provide additional insights on disease characteristics in Germany.

Risk score prediction for bacteriologically confirmed tuberculosis among adults with HIV on antiretroviral therapy in northwest Ethiopia: prognostic model development.

This study was aimed at developing a risk score prediction model for bacteriologically confirmed tuberculosis (TB) among adults with HIV receiving antiretroviral therapy in Ethiopia. An institutional-based retrospective follow-up study was conducted among 569 adults with HIV on ART. We used demographic and clinical prognostic factors to develop a risk prediction model. Model performance was evaluated by discrimination and calibration using the area under the receiver operating characteristic (AUROC) curve and calibration plot. Bootstrapping was used for internal validation. A decision curve analysis was used to evaluate the clinical utility. Opportunistic infection, functional status, anemia, isoniazid preventive therapy, and WHO clinical stages were used to develop risk prediction. The AUROC curve of the original model was 87.53% [95% confidence interval (CI): 83.88-91.25] and the calibration plot ( P -value = 0.51). After internal validation, the AUROC curve of 86.61% (95% CI: 82.92-90.29%) was comparable with the original model, with an optimism coefficient of 0.0096 and good calibration ( P -value = 0.10). Our model revealed excellent sensitivity (92.65%) and negative predictive value (NPV) (98.60%) with very good specificity (70.06%) and accuracy (72.76%). After validation, accuracy (74.85%) and specificity (76.27%) were improved, but sensitivity (86.76%) and NPV (97.66%) were relatively reduced. The risk prediction model had a net benefit up to 7.5 threshold probabilities. This prognostic model had very good performance. Moreover, it had very good sensitivity and excellent NPV. The model could help clinicians use risk estimation and stratification for early diagnosis and treatment to improve patient outcomes and quality of life.

Neutralizing Antibodies Targeting BK Polyomavirus

Abstract The majority of the world’s adult population is latently infected by the BK polyomavirus. It causes asymptomatic infection in healthy individuals but emerged as a threat to kidney transplant recipients because of virus associated nephropathy caused by immunosuppressive therapy. In these conditions, when a functional cellular response is impaired by immunosuppression, neutralizing antibodies may play a major role, since they can directly prevent infection of target cells, independently of cell mediated immunity, by binding to the viral particles. Studying the contribution of anti-BK virus neutralizing antibodies in viral control has long been hampered by the lack of convenient in vitro models but major progress has been made in the last decade. The four BK virus genotypes have been demonstrated to behave as distinct serotypes. A low recipient neutralizing antibody titer against the donor’s serotype before kidney transplant has been significantly associated with BK virus replication after transplant. Different mechanisms exploited by the BK virus to evade neutralizing antibodies have been described. Recent studies also support the potential benefit of administering intravenous immunoglobulins or monoclonal neutralizing antibodies as a therapeutic strategy and, more interestingly, this could also be used as preventive or pre-emptive therapy, before advanced kidney damage has occurred. Besides, neutralizing antibodies could be induced by vaccination. In this review, we summarize accumulated knowledge on anti-BK virus neutralizing antibodies as well as their clinical importance and therapeutic potential for kidney transplant recipients.

Glycoprotein Nonmetastatic Melanoma Protein B: A Potential Therapeutic Target in Chronic Intestinal Fibrosis Induced by Dextran Sulfate Sodium

Abstract Background: Intestinal fibrosis is a complication of inflammatory bowel disease (IBD). Currently, there are no effective preventive measures or medical therapies for intestinal fibrosis. Surgery remains the only available strategy in the management of fibro stenotic enteropathies. However, more than 50% of patients undergoing surgery experience recurrence of stenosis. We assessed effects of glycoprotein nonmetastatic melanoma protein B (Gpnmb) on chronic colonic fibrosis induced by dextran sulfate sodium (DSS) in mice. Materials and Methods: GSE42768 mRNA microarray dataset was selected to carry out GEO2R bioinformatics analysis to predict differentially expressed genes. Chronic colonic inflammation-associated fibrosis was induced by DSS in mice. Twenty-four healthy male BALB/c were assigned to four groups: Control, model, T1: Intragastric administration of Thalidomide (Thal) 100 mg/kg.day beginning at day 18, T2: Intragastric administration of Thal (100 mg/kg.day) beginning at day 0 (n = 6 in each group). The colon was removed after modeling and assessed by pathological staining, Western blot, and reverse-transcription polymerase chain reaction. Col1α2, Gpnmb, Wnt1, and β-catenin antibodies were used. Results: The degree of chronic colitis and fibrosis was highest in the model group, and lowest in the control group. Thal treatment significantly alleviated DSS-induced chronic colitis and intestinal fibrosis, decreasing Gpnmb at both mRNA and Western blot levels. Expressions of Col1α2, Wnt1, and β-catenin got the same results. Conclusions: From bioinformatic analysis and fundamental experiment, we have illustrated that Gpnmb may stimulate the occurrence of intestinal fibrosis via Wnt1/β-catenin pathway. It may be a new therapeutic target for IBD-related intestinal fibrosis.

Glycoprotein Nonmetastatic Melanoma Protein B: A Potential Therapeutic Target in Chronic Intestinal Fibrosis Induced by Dextran Sulfate Sodium

Abstract Background: Intestinal fibrosis is a complication of inflammatory bowel disease (IBD). Currently, there are no effective preventive measures or medical therapies for intestinal fibrosis. Surgery remains the only available strategy in the management of fibro stenotic enteropathies. However, more than 50% of patients undergoing surgery experience recurrence of stenosis. We assessed effects of glycoprotein nonmetastatic melanoma protein B (Gpnmb) on chronic colonic fibrosis induced by dextran sulfate sodium (DSS) in mice. Materials and Methods: GSE42768 mRNA microarray dataset was selected to carry out GEO2R bioinformatics analysis to predict differentially expressed genes. Chronic colonic inflammation-associated fibrosis was induced by DSS in mice. Twenty-four healthy male BALB/c were assigned to four groups: Control, model, T1: Intragastric administration of Thalidomide (Thal) 100 mg/kg.day beginning at day 18, T2: Intragastric administration of Thal (100 mg/kg.day) beginning at day 0 (n = 6 in each group). The colon was removed after modeling and assessed by pathological staining, Western blot, and reverse-transcription polymerase chain reaction. Col1α2, Gpnmb, Wnt1, and β-catenin antibodies were used. Results: The degree of chronic colitis and fibrosis was highest in the model group, and lowest in the control group. Thal treatment significantly alleviated DSS-induced chronic colitis and intestinal fibrosis, decreasing Gpnmb at both mRNA and Western blot levels. Expressions of Col1α2, Wnt1, and β-catenin got the same results. Conclusions: From bioinformatic analysis and fundamental experiment, we have illustrated that Gpnmb may stimulate the occurrence of intestinal fibrosis via Wnt1/β-catenin pathway. It may be a new therapeutic target for IBD-related intestinal fibrosis.

Pharmacokinetics of piperaquine and its association with intermittent malaria preventive therapy outcomes during pregnancy

BackgroundDihydroartemisinin-piperaquine (DHP) recently showed superior effectiveness over sulfadoxine-pyrimethamine for malaria intermittent preventive treatment in pregnancy (IPTp). We investigated day 7 piperaquine pharmacokinetics and its therapeutic efficacy in preventing malaria during pregnancy.MethodsMalaria-free (mRDT) pregnant women (n = 400) who received monthly IPTp-DHP were enrolled and followed till delivery. Day 7 Plasma piperaquine concentrations were determined after each IPTp dose using UPLC/MS/MS. IPTp outcomes (symptomatic malaria and parasitemia during pregnancy, placental malaria, and maternal malaria at delivery) were monitored. Linear mixed model and Cox regression were used to assess predictors of day 7 piperaquine concentration and treatment outcome, respectively.ResultsThe incidences of symptomatic malaria and parasitemia during pregnancy per 100 person-year at risk were 2 and 33, respectively. The prevalence of histopathologically confirmed placental malaria and maternal malaria at delivery were 3% and 9.8%, respectively. Repeated monthly IPTp-DHP resulted in significantly increased day 7 plasma piperaquine concentration (p < 0.001). Following the 1st, 2nd, and 3rd monthly IPTp-DHP doses, the proportions of women with day 7 piperaquine concentration below the therapeutic threshold (< 30 ng/mL) were 6.1%, 4.1% and 3.6%, respectively. Factors such as maternal age, body weight and trimester were not significant predictors of day 7 piperaquine concentration. However, having a low day 7 piperaquine plasma concentration (< 30 ng/mL) was significantly associated with a higher risk of parasitemia during pregnancy (p = 0.004).ConclusionLower day 7 piperaquine plasma concentration is a risk factor for parasitemia during pregnancy. Single plasma sampling at day 7 can be used to monitor piperaquine effectiveness during IPTp-DHP.Trial registrationRegistered 09/12/2016, PACTR201612001901313.

Comparison of thrombodynamic methods and routine hemostasis tests in the evaluation of hypercoagulable syndrome in chronic glomerulonephritis

Background. Nephrotic syndrome (NS) is associated with a high risk of thrombotic complications. In this group of patients, routine local tests for assessing hemostasis do not accurately reflect hypercoagulable state. Global functional tests for assessing hemostasis, including thrombodynamics (TD), are considered promising for assessing disorders in the blood coagulation system of these patients. Aim. To compare the rate of hypercoagulability according to routine hemostatic tests and TD and to evaluate the factors associated with increased risk of thrombotic complications in patients with chronic glomerulonephritis (CGN). Materials and methods. The study included 94 patients with active CGN who were not receiving anticoagulant therapy; 63 (80.3%) patients had NS, and 31 (19.7%) had active CGN without NS. Hemostasis parameters were assessed using local coagulation tests and TD test. Using logistic regression analysis, factors associated with the risk of thrombosis were assessed. Results. Of the 94 patients with active CGN in 63 without preventive anticoagulant therapy, hypercoagulability according to routine tests was detected in 6 (9.5%) patients with NS and in 3 (9.7%) patients without NS (p0.05). Hypercoagulability according to the TD test was detected in 24 (53.9%) patients with NS and in 5 (32.2%) without NS (p0.05). The formation of spontaneous clots was observed in 29 (30.9%) of patients with CGN, most of them 24 (83%) with NS. 10.6% of patients in our cohort experienced thromboembolic events. The risk of thromboembolic events according to the univariate regression analysis was associated with older age, higher lipid levels, use of glucocorticosteroids and detection of spontaneous clots by the TD test. No association of thromboembolic events with abnormalities in routine hemostasis tests was obtained. Conclusion. In patients with CGN with nephrotic syndrome, hypercoagulability is detected in 9.5% of cases with routine coagulation tests and in 53.9% of cases with TD test. Detection of spontaneous clots by TD test is associated with a risk of thromboembolic events.

Advances in nucleic acid-targeted therapies for cardiovascular disease prevention.

Nucleic acid-based therapies are being rapidly developed for prevention and management of cardiovascular diseases (CVD). Remarkable advancements have been achieved in the delivery, safety, and effectiveness of these therapeutics in the past decade. These therapies can also modulate therapeutic targets that cannot be sufficiently addressed using traditional drugs or antibodies. Among the nucleic acid-targeted therapeutics under development for CVD prevention are RNA-targeted approaches, including antisense oligonucleotides (ASO), small interfering RNAs (siRNA), and novel genome editing techniques. Genetic studies have identified potential therapeutic targets that are suggested to play a causative role in development and progression of CVD. RNA- and DNA-targeted therapeutics can be particularly well delivered to the liver, where atherogenic lipoproteins and angiotensinogen are produced. Lipoproteins currently targeted include proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein A (Apo(a)), apolipoprotein C3 (APOC3), angiopoietin-like 3 (ANGPTL3). Several large-scale clinical development programs for nucleic acid-targeted therapies in cardiovascular prevention are under way, which may also be attractive from a therapy adherence point of view, given the long action of these therapeutics. In addition to genome editing, the concept of gene transfer is presently under assessment in preclinical and clinical investigations as a potential approach for addressing LDL-R deficiency. Furthermore, ongoing research is exploring the use of RNA-targeted therapies to treat arterial hypertension by reducing hepatic angiotensinogen (AGT) production. This review summarizes the rapid translation of siRNA and ASO therapeutics as well as gene editing into clinical studies to treat dyslipidemia and arterial hypertension for CVD prevention. It also outlines potential innovative therapeutic options that are likely relevant to the future of cardiovascular medicine.

Modeling mechanisms of chemotherapy-induced peripheral neuropathy and chemotherapy transport using induced pluripotent stem cell-derived sensory neurons

Backgroundand Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) constitutes a significant health problem due to the increasing prevalence and lack of therapies for treatment and prevention. While pivotal for routine cancer treatment, paclitaxel and vincristine frequently cause CIPN and impact the quality of life among cancer patients and survivors. Here, we investigate molecular mechanisms and drug transport in CIPN. Experimental approachHuman sensory neurons were derived from induced pluripotent stem cells (iPSC-SNs), which were characterized using flow cytometry and immunolabeling. These iPSC-SNs were exposed to different concentrations of the two microtubule-targeting agents, paclitaxel and vincristine, with and without pre-exposure to inhibitors and inducers of efflux transporters. Neuronal networks were quantified via fluorescent staining against sensory neuron markers. Transcriptional effects of the chemotherapeutics were examined using quantitative polymerase chain reactions (qPCR). Key resultsPaclitaxel exposure resulted in axonal retraction and thickening, while vincristine caused fragmentation and abolishment of axons. Both agents increased the mRNA expression of the pain receptor, transient receptor potential vanilloid (TRPV1), and highly induced neuronal damage, as measured by activating transcription factor 3 (ATF3) mRNA. iPSC-SNs express the efflux transporters, P-glycoprotein (P-gp, encoded by ABCB1) and multidrug resistance-associated protein 1 (MPR1, encoded by ABCC1). Modulation of efflux transporters indicate that P-gp and MRP1 play a role in modulating neuronal accumulation and neurotoxicity in preliminary experiments. Conclusionand Implications: iPSC-SNs are a valuable and robust model to study the role of efflux transporters and other mechanistic targets in CIPN. Efflux transporters may play a role in CIPN pathogenesis as they regulate the disposition of chemotherapy to the peripheral nervous system, and they may present potential therapeutic targets for CIPN.

Prolonged and repeated microemboli detection in acute ischemic stroke – The Norwegian Microemboli in Acute Stroke Study (NOR-MASS)

ObjectivesCerebral microemboli can be detected by transcranial Doppler monitoring (TCDM) and may elucidate stroke etiology, the effect of preventive therapy, and the risk of stroke recurrence. Microemboli detection is usually performed for up to 60 minutes, but due to temporal variability, microembolization may be missed if the monitoring time is too short. We aimed to assess the time course of microembolization in acute ischemic stroke and explore the utility of prolonged and repeated microemboli detection. Materials and MethodsPatients with suspected ischemic stroke and symptom onset within 24 hours were examined with bilateral, stationary TCDM for one hour followed by unilateral, ambulatory TCDM for two hours. Unilateral TCDM was repeated for the following two days and after three months. ResultsWe included 47 patients, of which 41 had ischemic stroke, five had transient ischemic attack, and one had amaurosis fugax. Microemboli were detected in 60 % of patients. The occurrence was highest within 24 hours after onset and significantly lower at three months. Prolonged and repeated microemboli detection yielded only one additional microemboli-positive patient. Hence, patients who initially were microemboli negative tended to remain negative. We could not demonstrate an association between microemboli occurrence and clinical outcome or stroke recurrence. ConclusionsMicroembolic signals are frequent within 24 hours after ischemic stroke onset, but prolonged and repeated microemboli detection did not increase the yield of MES positive patients. Clinical Trial Registration-URLhttp://www.clinicaltrials.gov. Unique identifier: NCT03543319.

Role of Dapagliflozin in Prevention of Contrast Induced Nephropathy in Diabetic Patients Undergoing Primary Percutaneous Coronary Intervention

Abstract Background Contrast induced nephropathy (CIN), is a known complication of any coronary intervention regardless the amount of contrast. Studies have shown that patients who develop CIN have a greater risk for death or prolonged hospitalization, as well as for other adverse outcomes, including early or late cardiovascular events especially if after percutaneous coronary intervention (PCI). Research is continuous to find pharmacological interventions to prevent CIN. While many therapies in prevention of CIN have been studied, only good hydration has been proven to be of benefit. This Abstractattempt to provide the role of dapagliflozin in prevention of CIN. Aim and objectives The aim of the study was to study the efficacy of dapagliflozin administration as a preventive tool for Contrast induced nephropathy (CIN), in diabetic patients undergoing primary percutaneous coronary intervention (PCI). Patients and Methods This study included 250 diabetic patients presented to emergency departments of Ain shams university hospitals from July 2021 till June 2022 and diagnosed with STEMI as being defined as Patients with ST elevation myocardial infarction defined as having symptoms of ischemia and ST-segment elevation of at least two contiguous leads with ST-segment elevation ≥ 2.5 mm in men &amp;lt; 40 years, ≥2 mm in men ≥ 40 years, or ≥ 1.5 mm in women in leads V2 – V3 and/or ≥ 1 mm in the other leads 1, that had been revascularized by primary PCI as per the recommendations of The European society of cardiology guidelines for diagnosis and management of ST elevation myocardial infarction published in 2017. CIN was defined by renal function impairment after IV contrast as mirrored by an absolute increase by 0.5mg/dL (or greater) or relative increase by 25% (or greater) of baseline serum creatinine over 48 hours or, better, by a decrease by 25% in the estimated glomerular filtration rate (eGFR(. The patients were randomized using dedicated software programme into two groups. Study group including 125 patients was the dapagliflozin group. Control group including 125 patients was the standard control group. Results Our study had demonstrated that a higher proportion of patients developed CIN in the control group (21 (16.8%)) vs (13 (10.4%)) in the study group (dapagliflozin group) but it didn’t reach a statistically significant difference with P-value =0.139. Conclusion Dapagliflozin failed to prove any statistically significant prevention against CIN.

Initiation of lipid-lowering therapy as primary prevention of cardiovascular disease in the elderly.

This study aimed to analyse the initiation adherence phase to lipid-lowering therapy for primary prevention of cardiovascular disease in a Spanish population aged 70 years or older. The secondary objective was to identify the determinants of initiation and early discontinuation. This was an observational study conducted in the CArdiovascular Risk factors for HEalth Service research (CARhES) cohort. People aged 70 and older with a first prescription of a lipid-lowering drug and without a previous major adverse cardiovascular event (MACE) were selected (2018-2021). Data on sociodemographics, clinical conditions, drugs and use of health services were collected from clinical and administrative electronic databases. The study population was classified into: non-initiation, early discontinuation (i.e., discontinuation after the first dispensing) and initiation with more than one dispensing. Their characteristics were compared. Determinants of initiation and early discontinuation were explored. Among the 15 019 people studied, 80.2% initiated the medication, 11.2% showed an early discontinuation and 8.6% were non-initiators. An older age or conditions such as dementia, diabetes or depression reduced the likelihood of initiation, while obesity and a high pharmacological burden increased it. People over 90 years of age or those prescribed a statin in combination were more likely to have an early discontinuation. Non-initiation and early discontinuation are common among older people prescribed lipid-lowering drugs as primary prevention of cardiovascular disease for the first time. The presence of chronic pathologies other than cardiovascular ones should be considered when assessing whether or not to prescribe these drugs in the elderly.

Oral anticoagulation with Edoxaban for stroke prevention in patients with atrial fibrillation: Analysis of 1-year follow-up data of routine clinical practice in Germany, Austria and Switzerland (DACH) from the ETNA-AF registry

Non-vitamin-K oral anticoagulants (NOACs) are safe and effective for stroke prevention in patients with atrial fibrillation (AF). Data on the safety and efficacy of Edoxaban in routine care in Germany, Austria and Switzerland (DACH) are limited. We report one-year outcomes in patients with AF treated with Edoxaban in routine care. The ETNA-AF-Europe study (Clinicaltrials.gov:NCT02 944 019) is a multicenter, prospective, observational study that enrolled 13 092 patients with AF treated with Edoxaban from 852 sites across 10 European countries (Austria, Belgium, Germany, Ireland, Italy, the Netherlands, Portugal, Spain, Switzerland, and the United Kingdom). The DACH-cohort consists of 5457 (41,7 %) patients of sites in Germany, Austria and Switzerland. Patients had a mean age of 74 years (2384 [44 %]women) and a mean CHA2DS2-VASc-score of 3.2 ± 1.4. A label-conform dosing of Edoxaban was administered to 4309 patients (78,9 %). At the one-year-follow-up a stroke or systemic embolism occurred in 42 patients (0,8 %/year), and severe bleeding was reported in 36 patients (0,7 %/year). Ten patients (0,2 %/year) suffered intracranial and 13 patients (0,3 %/year)gastrointestinal bleeding. Numbers of death from all causes and cardiovascular death occurred in 179 patients (3,4 %/year) and 85 patients (1,6 %/year), respectively. Age > 75 years, frailty and a CHA2DS2-VASc score ≥ 4 were associated with a higher all-cause mortality - and those patients were more likely to suffer a stroke or a major bleeding event. In Germany, Austria and Switzerland in patients with AF on Edoxaban therapy for stroke prevention the number of stroke and major bleeding events is low. Increasing morbidity is associated with a higher number of important clinical events.

Optimizing the cascade of prevention to protect people from tuberculosis: A potential game changer for reducing global tuberculosis incidence.

The provision of tuberculosis preventive treatment is one of the critical interventions to reduce tuberculosis incidence and ultimately eliminate the disease, yet we still miss appropriate tools for an impactful intervention and treatment coverage remains low. We used recent data, epidemiological estimates, and research findings to analyze the challenges of each step of the cascade of tuberculosis prevention that currently delay the strategy implementation. We addressed research gaps and implementation bottlenecks that withhold key actions in tuberculosis case finding, testing for tuberculosis infection, provision of preventive treatment with safer, shorter regimens and supporting people to complete their treatment. Empowering communities to generate demand for preventive therapy and other prevention services in a holistic manner and providing adequate financial support to sustain implementation are essential requirements. The adoption of an effective, universal monitoring and evaluation system is a prerequisite to provide general and granular insight, and to steer progress of the tuberculosis infection strategy at global and local level.