Epidemiological trends, antifungal drug susceptibility and SQLE point mutations in etiologic species of human dermatophytosis in Al-Diwaneyah, Iraq.

Dermatophytes show a wide geographic distribution and are the main causative agents of skin fungal infections in many regions of the world. Recently, their resistance to antifungal drugs has led to an obstacle to effective treatment. To address the lack of dermatophytosis data in Iraq, this study was designed to investigate the distribution and prevalence of dermatophytes in the human population and single point mutations in squalene epoxidase gene (SQLE) of terbinafine resistant isolates. The identification of 102 dermatophytes isolated from clinical human dermatophytosis was performed through morphological and microscopic characteristics followed by molecular analysis based on ITS and TEF-1α sequencing. Phylogeny was achieved through RAxML analysis. CLSI M38-A2 protocol was used to assess antifungal susceptibility of the isolates to four major antifungal drugs. Additionally, the presence of point mutations in SQLE gene, which are responsible for terbinafine resistance was investigated. Tinea corporis was the most prevalent clinical manifestation accounting for 37.24% of examined cases of dermatophytosis. Based on ITS, T. indotineae (50.98%), T. mentagrophytes (19.61%), and M. canis (29.41%) was identified as an etiologic species. T. indotineae and T. mentagrophytes strains were identified as T. interdigitale based on TEF-1α. Terbinafine showed the highest efficacy among the tested antifungal drugs. T. indotineae and T. mentagrophytes showed the highest resistance to antifungal drugs with MICs of 2-4 and 4 µg/mL, while M. canis was the most susceptible species. Three of T. indotineae isolates showed mutations in SQLE gene Phe397Leu substitution. A non-previously described point mutation, Phe311Leu was identified in T. indotineae and mutations Lys276Asn, Phe397Leu and Leu419Phe were diagnosed in T. mentagrophytes XVII. The results of mutation analysis showed that Phe397Leu was a destabilizing mutation; protein stability has decreased with variations in pH, and point mutations affected the interatomic interaction, resulting in bond disruption. These results could help to control the progression of disease effectively and make decisions regarding the selection of appropriate drugs for dermatophyte infections.

Effects of an Intervention to Improve Evidence-Based Care for People With Diabetes and Cardiovascular Disease Across Sex, Race, and Ethnicity Subgroups: Insights From the COORDINATE-Diabetes Trial.

BACKGROUND: Results from the COORDINATE-Diabetes trial (Coordinating Cardiology Clinics Randomized Trial of Interventions to Improve Outcomes - Diabetes) demonstrated that a multifaceted, clinic-based intervention increased prescription of evidence-based medical therapies to participants with type 2 diabetes and atherosclerotic cardiovascular disease. This secondary analysis assessed whether intervention success was consistent across sex, race, and ethnicity. METHODS: COORDINATE-Diabetes, a cluster randomized trial, recruited participants from 43 US cardiology clinics (20 randomized to intervention and 23 randomized to usual care). The primary outcome was the proportion of participants prescribed all 3 groups of evidence-based therapy (high-intensity statin, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and sodium-glucose cotransporter-2 inhibitor or glucagon-like peptide 1 receptor agonist) at last trial assessment (6 to 12 months). In this prespecified analysis, mixed-effects logistic regression models were used to assess the outcome by self-reported sex, race, and ethnicity in the intervention and usual care groups, with adjustment for baseline characteristics, medications, comorbidities, and site location. RESULTS: Among 1045 participants with type 2 diabetes and atherosclerotic cardiovascular disease, the median age was 70 years, 32% were female, 16% were Black, and 9% were Hispanic. At the last trial assessment, there was an absolute increase in the proportion of participants prescribed all 3 groups of evidence-based therapy in women (36% versus 15%), Black participants (41% versus 18%), and Hispanic participants (46% versus 18%) with the intervention compared with usual care, with consistent benefit across sex (male versus female; Pinteraction=0.44), race (Black versus White; Pinteraction=0.59), and ethnicity (Hispanic versus Non-Hispanic; Pinteraction= 0.78). CONCLUSIONS: The COORDINATE-Diabetes intervention successfully improved delivery of evidence-based care, regardless of sex, race, or ethnicity. Widespread dissemination of this intervention could improve equitable health care quality, particularly among women and minority communities who are frequently underrepresented in clinical trials. REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03936660.

Using structured problem solving to promote fluid consumption in the prevention of urinary stones with hydration (PUSH) trial.

BACKGROUND: Structured Problem Solving (SPS) is a patient-centered approach to promoting behavior change that relies on productive collaboration between coaches and participants and reinforces participant autonomy. We aimed to describe the design, implementation, and assessment of SPS in the multicenter Prevention of Urinary Stones with Hydration (PUSH) randomized trial. METHODS: In the PUSH trial, individuals with a history of urinary stone disease and low urine output were randomized to control versus a multicomponent intervention including SPS that was designed to promote fluid consumption and thereby prevent recurrent stones. We provide details specifically about training and fidelity assessment of the SPS coaches. We report on implementation experiences related to SPS during the initial conduct of the trial. RESULTS: With training and fidelity assessment, coaches in the PUSH trial applied SPS to help participants overcome barriers to fluid consumption. In some cases, coaches faced implementation barriers such as variable participant engagement that required tailoring their work with specific participants. The coaches also faced challenges including balancing rapport with problem solving, and role clarity for the coaches. CONCLUSIONS: We adapted SPS to the setting of kidney stone prevention and overcame challenges in implementation, such as variable patient engagement. Tools from the PUSH trial may be useful to apply to other health behavior change settings in nephrology and other areas of clinical care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03244189.

Prognostic Impact of Sinus Rhythm in Atrial Fibrillation Patients: Separating Rhythm Outcomes From Randomized Strategy Findings From the CABANA Trial.

BACKGROUND: Clinically detected atrial fibrillation (AF) is associated with a significant increase in mortality and other adverse cardiovascular events. Since the advent of effective methods for AF rhythm control, investigators have attempted to determine how much these adverse prognostic AF effects could be mitigated by the restoration of sinus rhythm (SR) and whether the method used mattered. METHODS: The CABANA trial (Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation) randomized 2204 AF patients to ablation versus drug therapy, of which 1240 patients were monitored in follow-up using the CABANA ECG rhythm monitoring system. To assess the prognostic benefits of SR, we performed a prespecified analysis using Cox survival modeling with heart rhythm as a time-dependent variable and randomized treatment group as a stratification factor. RESULTS: In the 1240 patient study cohort, 883 (71.2%) had documented AF at some point during their postblanking follow-up. Among the 883 patients, 671 (76.0%) experienced AF within the first year of postblanking follow-up, and 212 (24.0%) experienced their first AF after ≥1 year of postblanking follow-up. The primary CABANA end point (death, disabling stroke, serious bleeding, or cardiac arrest) occurred in 95 (10.8%) of the 883 patients with documented AF and in 29 (8.1%) of the 357 patients with no AF recorded during follow-up. In multivariable time-dependent analysis, the presence of SR (compared with non-SR) was associated with a significantly reduced risk of the primary end point (adjusted hazard ratio, 0.57 [95% CI, 0.38-0.85]; P=0.006; independent of treatment strategy [ablation versus drugs]). Corresponding results for all-cause mortality were adjusted hazard ratio of 0.59 [95% CI, 0.35-1.01]; P=0.053). CONCLUSIONS: In patients in the CABANA trial with detailed long-term rhythm follow-up, increased time in SR was associated with a clinically consequential decrease in mortality and other adverse prognostic events. The predictive value of SR was independent of the therapeutic approach responsible for reducing the burden of detectable AF. REGISTRATION: URL: https://clinicaltrials.gov; Unique Identifier: NCT00911508.

Remote Follow-up in a Heart Failure Pragmatic Trial: Insights From the CONNECT-HF.

BACKGROUND: Randomized controlled trials typically require study-specific visits, which can burden participants and sites. Remote follow-up, such as centralized call centers for participant-reported or site-reported, holds promise for reducing costs and enhancing the pragmatism of trials. In this secondary analysis of the CONNECT-HF (Care Optimization Through Patient and Hospital Engagement For HF) trial, we aimed to evaluate the completeness and validity of the remote follow-up process. METHODS AND RESULTS: The CONNECT-HF trial evaluated the effect of a post-discharge quality-improvement intervention for heart failure compared to usual care for up to 1 year. Suspected events were reported either by participants or by health care proxies through a centralized call center or by sites through medical-record queries. When potential hospitalization events were suspected, additional medical records were collected and adjudicated. Among 5942 potential hospitalizations, 18% were only participant-reported, 28% were reported by both participants and sites, and 50% were only site-reported. Concordance rates between the participant/site reports and adjudication for hospitalization were high: 87% participant-reported, 86% both, and 86% site-reported. Rates of adjudicated heart failure hospitalization events among adjudicated all-cause hospitalization were lower but also consistent: 45% participant-reported, 50% both, and 50% site-reported. CONCLUSIONS: Participant-only and site-only reports missed a substantial number of hospitalization events. We observed similar concordance between participant/site reports and adjudication for hospitalizations. Combining participant-reported and site-reported outcomes data is important to capture and validate hospitalizations effectively in pragmatic heart failure trials.

Effects of pharmacogenetics on pharmacokinetics and toxicity of doxorubicin in Egyptian breast cancer patients.

This study investigates the impact of single nucleotide polymorphisms in genes (SLC22A16 and CBR1) involved in the pharmacokinetics and toxicity of doxorubicin (DOX) in Egyptian female patients with breast cancer.Patients administered DOX (60 mg/m2) for 4 cycles every 3 weeks. The peak DOX plasma concentration was measured using a validated chromatographic method. The genotyping for the selected SNPs, SLC22A16 T > C (rs714368), and CBR1 C > T (rs20572), was performed by RT-PCR. Patients were monitored for hematological and cardiac toxicities.The variant carriers of CBR1 C > T (rs20572) exhibited significantly higher DOX concentration, but no significant association to DOX-induced hematological toxicity. On the other hand, SLC22A16 T > C (rs714368) had no significant influence on DOX plasma concentration, but was significantly correlated with lower risk of neutropenia (OR 0.31, 95% CI 0.12-0.75, p = 0.01) and leukopoenia (OR 0.18, 95% CI 0.07-0.5, p = 0.001). DOX-related cardiotoxicity was correlated with the cumulative dose of DOX (R = 0.238, p = 0.017), but not with any of the two examined SNPs.Genetic polymorphisms in SLC22A16 and CBR1 may explain the inter-individual variations in DOX pharmacokinetics and toxicity. Using pharmacogenetic testing is important to customise drug therapy for cancer patients treated with anthracyclines.

Synthesis and characterization of Cu-Doped ZnO nanostructures for UV sensing application.

In this work, Fabrication, and characterization of Cu-doped ZnO thin films deposited on porous silicon (PSi) substrates have been reported using electrochemical deposition (ECD) technique. The influence of Cu-doping concentrations on morphology, structure, and electrical characteristics of zinc oxide (ZnO) thin films were presented. X-ray diffraction analysis (XRD) has been used to characterize the lattice constants, average size, in-plane (along a-axis) and out of plane (along c-axis) strains for the Cu-ZnO crystals. The effects of Cu-doping concentration on crystal parameters were also investigated from the XRD analysis. The samples were used for UV-sensing applications. In addition, Cu-doped ZnO and pure ZnO metal-semiconductor-metal photodetector, with Cu as electrode contacts were successfully produced for ultraviolet (UV) detection. The I-V (current-voltage) characteristics were used to study the sensing enhancement. Finally, the UV photodetector based on Cu-doped ZnO films was successfully fabricated and shows a five times enhancement in the sensitivity to UV light compared to that of pure ZnO photodetector.

Cost-effectiveness analysis of Manuka honey-Omega-3 combination treatments in treating oxidative stress of pediatric ß-thalassemia major.

OBJECTIVE: Oxidative stress represents a ruthless complication of ß-thalassemia that worsens the severity of that medical condition. There is no conclusive evidence on the best antioxidant used for that issue. Our earlier clinical study concluded that omega-3 and Manuka honey add-on to the conventional therapy had a potential therapeutic impact on reducing oxidative stress. However, there is no research evaluating their cost-effectiveness. This paper compares the cost-effectiveness of Omega-3 and Manuka honey supplementation to conventional therapy in treating oxidative stress among children with ß-thalassemia major. SUBJECTS AND METHODS: Cost-effectiveness evaluation of daily supplementation of Omega-3-Manuka honey and Manuka honey alone to the conventional therapy was performed. The economic evaluation was performed on data from a prospective 10-month randomized clinical trial. Fifty patients were recruited into the Omega-3-Manuka honey plus conventional therapy group, 50 patients were included in the Manuka honey alone plus conventional therapy group, and 50 patients receiving the conventional therapy alone served as a control group. Effectiveness measures from the randomized clinical trial were used to determine incremental effectiveness. Cost estimates were calculated from the healthcare payer's perspective. The analysis considered the improvement in oxidative stress biomarkers presented here as a percent change from baseline to determine the incremental effectiveness and cost for the treatment by both interventions. RESULTS: Adding Omega-3 or Manuka honey to conventional therapy was a more cost-effective add-on than conventional treatment alone. Omega-3-Manuka honey was more cost-effective than Manuka honey alone in treating oxidative stress in that condition. Oxidative stress biomarkers were significantly reduced with both experimental medications compared to the conventional therapy alone. CONCLUSIONS: The present study showed that using Manuka honey and Omega-3 as add-on treatments for oxidative stress in pediatric ß-thalassemia disease could have significant cost-saving and clinical improvement.

Regional differences in outcomes with ablation versus drug therapy for atrial fibrillation: Results from the CABANA trial.

BACKGROUND: The finding of unexpected variations in treatment benefits by geographic region in international clinical trials raises complex questions about the interpretation and generalizability of trial findings. We observed such geographical variations in outcome and in the effectiveness of atrial fibrillation (AF) ablation versus drug therapy in the Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial. This paper describes these differences and investigates potential causes. METHODS: The examination of treatment effects by geographic region was a prespecified analysis. CABANA enrolled patients from 10 countries, with 1,285 patients at 85 North American (NA) sites and 919 at 41 non-NA sites. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Death and first atrial fibrillation recurrence were secondary endpoints. RESULTS: At least 1 primary endpoint event occurred in 157 patients (12.2%) from NA and 33 (3.6%) from non-NA sites over a median 54.9 and 40.5 months of follow-up, respectively (NA/non-NA adjusted hazard ratio (HR) 2.18, 95% confidence interval (CI) 1.48-3.21, P < .001). In NA patients, 78 events occurred in the ablation and 79 in the drug arm, (HR 0.91, 95% CI 0.66, 1.24) while 11 and 22 events occurred in non-NA patients (HR 0.51, 95% CI 0.25,1.05, interaction P = .154). Death occurred in 53 ablation and 51 drug therapy patients in the NA group (HR 0.96, 95% CI 0.65,1.42) and in 5 ablation and 16 drug therapy patients in the non-NA group (HR 0.32, 95% CI 0.12,0.86, interaction P = .044). Adjusting for baseline regional differences or prognostic risk variables did not account for the regional differences in treatment effects. Atrial fibrillation recurrence was reduced by ablation in both regions (NA: HR 0.54, 95% CI 0.46, 0.63; non-NA: HR 0.44, 95% CI 0.30, 0.64, interaction P = .322). CONCLUSIONS: In CABANA, primary outcome events occurred significantly more often in the NA group but assignment to ablation significantly reduced all-cause mortality in the non-NA group only. These differences were not explained by regional variations in procedure effectiveness, safety, or patient characteristics. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0091150; https://clinicaltrials.gov/study/NCT00911508.

Depression following small vessel stroke is common and more prevalent in women.

OBJECTIVES: We sought to examine the frequency of depression after small vessel-type stroke (SVS) and associated risk factors. MATERIALS AND METHODS: We conducted a retrospective analysis of a prospective cohort of patients enrolled in the American Stroke Association-Bugher SVS Study, which included 200 participants within 2-years of SVS and 79 controls without a history of stroke from 2007 to 2012 at four sites. The primary outcome was PHQ-8, with scores ≥10 consistent with post-stroke depression (PSD). A logistic regression adjusted for age, race, sex, history of diabetes and Short-Form Montreal Cognitive Assessment score (SF-MoCA) was used to compare the risk of having depression after SVS compared to controls. Another logistic regression, adjusted for age, sex, race, level of education, SF-MoCA, white matter disease (WMD) burden, stroke severity (NIHSS), time between stroke and depression screen, history of diabetes, and history of hypertension was used to identify factors independently associated with depression in participants with SVS. RESULTS: The cohort included 161 participants with SVS (39 excluded due to missing data) and 79 controls. The mean interval between stroke and depression screening was 74 days. Among participants with SVS, 31.7% (n = 51) had PSD compared to 6.3% (n = 5) of controls (RR = 5.44, 95% CI = 2.21-13.38, p = 0.0002). The only two variables independently associated with PSD in participants with SVS were female sex (RR = 1.84, 95% CI = 1.09-3.09, p = 0.020) and diabetes (RR 1.69, 95% CI 1.03-2.79). CONCLUSIONS: After adjusting for several demographic and clinical variables, having a SVS was associated with an approximate 5-fold increased risk of depression and was more frequent in women and in those with diabetes. The extent of WMD was not independently associated with PSD, suggesting that small vessel disease in the setting of an overt SVS may not account for the increased prevalence of depression.

Best Practices in Nuclear Imaging for the Diagnosis of Transthyretin Amyloid Cardiomyopathy (ATTR-CM) in KSA: The Eagle Eyes of Local Experts.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a complex and serious form of heart failure caused by the accumulation of transthyretin amyloid protein in the heart muscle. Variable symptoms of ATTR-CM can lead to a delayed diagnosis. Recognizing the diagnostic indicators is crucial to promptly detect this condition. A targeted literature review was conducted to examine the latest international consensus recommendations on a comprehensive diagnosis of ATTR-CM. Additionally, a panel consisting of nuclear medicine expert consultants (n = 10) and nuclear imaging technicians (n = 2) convened virtually from the Kingdom of Saudi Arabia (KSA) to formulate best practices for ATTR-CM diagnosis. The panel reached a consensus on a standard diagnostic pathway for ATTR-CM, which commences by evaluating the presence of clinical red flags and initiating a cardiac workup to assess the patient's echocardiogram. Cardiac magnetic resonance imaging may be needed, in uncertain cases. When there is a high suspicion of ATTR-CM, patients undergo nuclear scintigraphy and hematologic tests to rule out primary or light-chain amyloidosis. The expert panel emphasized that implementing best practices will support healthcare professionals in KSA to improve their ability to detect and diagnose ATTR-CM more accurately and promptly. Diagnosing ATTR-CM accurately and early can reduce morbidity and mortality rates through appropriate treatment.

Contribution of Hypersensitivity to Postureteroscopy Ureteral Stent Pain: Findings From Study to Enhance Understanding of Stent-associated Symptoms.

OBJECTIVE: To examine the relationships between preoperative hypersensitivity to pain and central sensitization, and postoperative ureteral stent pain after ureteroscopy (URS) for urinary stones. METHODS: Adults enrolled in the STudy to Enhance uNderstanding of sTent-associated Symptoms (STENTS) underwent quantitative sensory testing (QST) prior to URS and stent placement. Hypersensitivity to mechanical pain was assessed using a pressure algometer. Participants rated their pain intensity to pressure applied to the ipsilateral flank area and lower abdominal quadrant on the side of planned stent placement, and the contralateral forearm (control). Pressure pain thresholds were also assessed. Central sensitization was assessed by applying a pointed stimulator (pinprick) and calculating the temporal summation. Postoperative stent pain intensity and interference were assessed using PROMIS questionnaires. Data were analyzed using repeated-measures mixed-effects linear models. RESULTS: Among the 412 participants, the median age was 54.0years, and 46% were female. Higher preoperative pain ratings to 2 kg and 4 kg mechanical pressure to the ipsilateral flank and abdominal areas were associated with higher postoperative stent pain intensity with the stent in situ. Greater degree of central sensitization preoperatively, manifesting as higher temporal summation, was associated with higher postoperative pain intensity. Factors associated with preoperative hypersensitivity on QST included female sex, presence of chronic pain conditions, widespread pain, and depression. CONCLUSION: Hypersensitivity to pain and central sensitization preoperatively was associated with postoperative ureteral stent pain, suggesting a physiologic basis for stent symptom variation. QST may identify patients more likely to develop stent pain after URS and could inform selection for preventive and interventional strategies.

Validity and reliability of Squegg device in measuring isometric handgrip strength.

OBJECTIVE: The quantitative measurement of handgrip strength is important in assessing and charting the progress of patients with neuromuscular diseases. The aim of this research was to determine the intra-rater and inter-rater reliability and the validity of the Squegg digital dynamometer. SUBJECTS AND METHODS: Twenty-one females and nine male participants with an age range between 18 and 40 years volunteered for the study. Three testers each took three measurements with a Squegg device and a Jamar dynamometer using standardized measurement techniques. Intra- and inter-tester reliability were calculated using the intra-class correlation coefficient (ICC). To investigate the relationship between hand measures and isometric handgrip strength, the Pearson correlation coefficient test was used. To determine the agreement between the two devices, a Bland Altman plot was constructed, and the concurrent validity of Squegg was calculated. RESULTS: The intra-rater reliability coefficients for both Jamar and Squegg were greater than 0.99 for all three testers, indicating excellent intra-rater reliability. The inter-rater reliability of Jamar (ICC=0.93) and Squegg (ICC=0.87) was excellent. With an ICC of 0.844 and an r-value of 0.720, Squegg with Jamar demonstrates good validity and statistical significance (p=0.001). CONCLUSIONS: The isometric handgrip strength and hand measures showed a moderate correlation in the study population. The Squegg isometric handgrip dynamometer has good concurrent validity and great intra- and inter-rater reliability in healthy individuals. The validity of Squegg in patients with neuromuscular diseases that affect hand function has to be investigated further.

Detection of brain lesions after catheter ablation depends on imaging criteria: insights from AXAFA-AFNET 5 trial.

AIMS: Left atrial catheter ablation is well established in patients with symptomatic atrial fibrillation (AF) but associated with risk of embolism to the brain. The present analysis aims to assess the impact of diffusion-weighted imaging (DWI) slice thickness on the rate of magnetic resonance imaging (MRI)-detected ischaemic brain lesions after ablation. METHODS AND RESULTS: AXAFA-AFNET 5 trial (NCT02227550) participants underwent MRI using high-resolution (hr) DWI (slice thickness: 2.5-3 mm) and standard DWI (slice thickness: 5-6 mm) within 3-48 h after ablation. In 321 patients with analysable brain MRI (mean age 64 years, 33% female, median CHA2DS2-VASc 2), hrDWI detected at least one acute brain lesion in 84 (26.2%) patients and standard DWI in 60 (18.7%; P < 0.01) patients. High-resolution diffusion-weighted imaging detected more lesions compared to standard DWI (165 vs. 104; P < 0.01). The degree of agreement for lesion confirmation using hrDWI vs. standard DWI was substantial (κ = 0769). Comparing the proportion of DWI-detected lesions, lesion distribution, and total lesion volume per patient, there was no difference in the cohort of participants undergoing MRI at 1.5 T (n = 52) vs. 3 T (n = 269). CONCLUSION: The pre-specified AXAFA-AFNET 5 sub-analysis revealed significantly increased rates of MRI-detected acute brain lesions using hrDWI instead of standard DWI in AF patients undergoing ablation. In comparison to DWI slice thickness, MRI field strength had a no significant impact in the trial. Comparing the varying rates of ablation-related MRI-detected brain lesions across previous studies has to consider these technical parameters. Future studies should use hrDWI, as feasibility was demonstrated in the multicentre AXAFA-AFNET 5 trial.

Vibrational-mechanical properties of the highly-mismatched Cd1-xBexTe semiconductor alloy: experiment and ab initio calculations.

The emerging CdTe-BeTe semiconductor alloy that exhibits a dramatic mismatch in bond covalency and bond stiffness clarifying its vibrational-mechanical properties is used as a benchmark to test the limits of the percolation model (PM) worked out to explain the complex Raman spectra of the related but less contrasted Zn1-xBex-chalcogenides. The test is done by way of experiment ([Formula: see text]), combining Raman scattering with X-ray diffraction at high pressure, and ab initio calculations ([Formula: see text] ~ 0-0.5; [Formula: see text]~1). The (macroscopic) bulk modulus [Formula: see text] drops below the CdTe value on minor Be incorporation, at variance with a linear [Formula: see text] versus [Formula: see text] increase predicted ab initio, thus hinting at large anharmonic effects in the real crystal. Yet, no anomaly occurs at the (microscopic) bond scale as the regular bimodal PM-type Raman signal predicted ab initio for Be-Te in minority ([Formula: see text]~0, 0.5) is barely detected experimentally. At large Be content ([Formula: see text]~1), the same bimodal signal relaxes all the way down to inversion, an unprecedented case. However, specific pressure dependencies of the regular ([Formula: see text]~0, 0.5) and inverted ([Formula: see text]~1) Be-Te Raman doublets are in line with the predictions of the PM. Hence, the PM applies as such to Cd1-xBexTe without further refinement, albeit in a "relaxed" form. This enhances the model's validity as a generic descriptor of phonons in alloys.

Comparison of an Initial Risk-Based Testing Strategy vs Usual Testing in Stable Symptomatic Patients With Suspected Coronary Artery Disease: The PRECISE Randomized Clinical Trial.

Importance: Trials showing equivalent or better outcomes with initial evaluation using coronary computed tomography angiography (cCTA) compared with stress testing in patients with stable chest pain have informed guidelines but raise questions about overtesting and excess catheterization. Objective: To test a modified initial cCTA strategy designed to improve clinical efficiency vs usual testing (UT). Design, Setting, and Participants: This was a pragmatic randomized clinical trial enrolling participants from December 3, 2018, to May 18, 2021, with a median of 11.8 months of follow-up. Patients from 65 North American and European sites with stable symptoms of suspected coronary artery disease (CAD) and no prior testing were randomly assigned 1:1 to precision strategy (PS) or UT. Interventions: PS incorporated the Prospective Multicenter Imaging Study for the Evaluation of Chest Pain (PROMISE) minimal risk score to quantitatively select minimal-risk participants for deferred testing, assigning all others to cCTA with selective CT-derived fractional flow reserve (FFR-CT). UT included site-selected stress testing or catheterization. Site clinicians determined subsequent care. Main Outcomes and Measures: Outcomes were clinical efficiency (invasive catheterization without obstructive CAD) and safety (death or nonfatal myocardial infarction [MI]) combined into a composite primary end point. Secondary end points included safety components of the primary outcome and medication use. Results: A total of 2103 participants (mean [SD] age, 58.4 [11.5] years; 1056 male [50.2%]) were included in the study, and 422 [20.1%] were classified as minimal risk. The primary end point occurred in 44 of 1057 participants (4.2%) in the PS group and in 118 of 1046 participants (11.3%) in the UT group (hazard ratio [HR], 0.35; 95% CI, 0.25-0.50). Clinical efficiency was higher with PS, with lower rates of catheterization without obstructive disease (27 [2.6%]) vs UT participants (107 [10.2%]; HR, 0.24; 95% CI, 0.16-0.36). The safety composite of death/MI was similar (HR, 1.52; 95% CI, 0.73-3.15). Death occurred in 5 individuals (0.5%) in the PS group vs 7 (0.7%) in the UT group (HR, 0.71; 95% CI, 0.23-2.23), and nonfatal MI occurred in 13 individuals (1.2%) in the PS group vs 5 (0.5%) in the UT group (HR, 2.65; 95% CI, 0.96-7.36). Use of lipid-lowering (450 of 900 [50.0%] vs 365 of 873 [41.8%]) and antiplatelet (321 of 900 [35.7%] vs 237 of 873 [27.1%]) medications at 1 year was higher in the PS group compared with the UT group (both P < .001). Conclusions and Relevance: An initial diagnostic approach to stable chest pain starting with quantitative risk stratification and deferred testing for minimal-risk patients and cCTA with selective FFR-CT in all others increased clinical efficiency relative to UT at 1 year. Additional randomized clinical trials are needed to verify these findings, including safety. Trial Registration: ClinicalTrials.gov Identifier: NCT03702244.

Deferred Testing in Stable Outpatients With Suspected Coronary Artery Disease: A Prespecified Secondary Analysis of the PRECISE Randomized Clinical Trial.

Importance: Guidelines recommend deferral of testing for symptomatic people with suspected coronary artery disease (CAD) and low pretest probability. To our knowledge, no randomized trial has prospectively evaluated such a strategy. Objective: To assess process of care and health outcomes in people identified as minimal risk for CAD when testing is deferred. Design, Setting, and Participants: This randomized, pragmatic effectiveness trial included prespecified subgroup analysis of the PRECISE trial at 65 North American and European sites. Participants identified as minimal risk by the validated PROMISE minimal risk score (PMRS) were included. Intervention: Randomization to a precision strategy using the PMRS to assign those with minimal risk to deferred testing and others to coronary computed tomography angiography with selective computed tomography-derived fractional flow reserve, or to usual testing (stress testing or catheterization with PMRS masked). Randomization was stratified by PMRS risk. Main Outcome: Composite of all-cause death, nonfatal myocardial infarction (MI), or catheterization without obstructive CAD through 12 months. Results: Among 2103 participants, 422 were identified as minimal risk (20%) and randomized to deferred testing (n = 214) or usual testing (n = 208). Mean age (SD) was 46 (8.6) years; 304 were women (72%). During follow-up, 138 of those randomized to deferred testing never had testing (64%), whereas 76 had a downstream test (36%) (at median [IQR] 48 [15-78] days) for worsening (30%), uncontrolled (10%), or new symptoms (6%), or changing clinician preference (19%) or participant preference (10%). Results were normal for 96% of these tests. The primary end point occurred in 2 deferred testing (0.9%) and 13 usual testing participants (6.3%) (hazard ratio, 0.15; 95% CI, 0.03-0.66; P = .01). No death or MI was observed in the deferred testing participants, while 1 noncardiovascular death and 1 MI occurred in the usual testing group. Two participants (0.9%) had catheterizations without obstructive CAD in the deferred testing group and 12 (5.8%) with usual testing (P = .02). At baseline, 70% of participants had frequent angina and there was similar reduction of frequent angina to less than 20% at 12 months in both groups. Conclusion and Relevance: In symptomatic participants with suspected CAD, identification of minimal risk by the PMRS guided a strategy of initially deferred testing. The strategy was safe with no observed adverse outcome events, fewer catheterizations without obstructive CAD, and similar symptom relief compared with usual testing. Trial Registration: ClinicalTrials.gov Identifier: NCT03702244.

Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: Immune dysregulation contributes to poorer outcomes in COVID-19. Objective: To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia. Design, Setting, and Participants: Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021. Interventions: Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day). Main Outcomes and Measures: The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale. Results: Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies. Conclusions and Relevance: Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

Comparative effectiveness of adding omega-3 and Manuka honey combination to conventional therapy in preventing and treating oxidative stress in pediatric ß-thalassemia major - a randomized clinical trial.

OBJECTIVE: ß-thalassemia major is an inherited hematological disorder with significant oxidative stress and iron overload. Oxidative stress results in several pathological complications, including cell death, tissue injury, organ dysfunction, and thyroid dysfunction. The present study examined the effectiveness of omega-3 and Manuka honey combination or Manuka honey alone to the conventional therapy (deferasirox, blood transfusion, and L-carnitine) used for preventing and managing oxidative stress or iron overload-induced oxidative stress conditions in pediatric ß-thalassemic patients (type major). PATIENTS AND METHODS: 165 patients participated in this randomized, double-blind, standard therapy-controlled, parallel-design multisite trial. The patients were randomly allocated into three groups, receiving either 1,000 mg omega-3 fish oil [350 mg eicosapentaenoic acid (EPA) and 250 mg docosahexaenoic acid (DHA)] combined with Manuka honey lozenge (344 mg) daily or Manuka honey alone plus the conventional therapy for ten months. Plasma 8-iso-prostaglandin F2α (8-iso-PGF2α), Lactate dehydrogenase (LDH), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), CRP (C-reactive protein), ferritin level, and serum iron were determined at baseline and month 10. RESULTS: Omega-3 and Manuka honey combination were a significant add-on to conventional therapy of ß-thalassemia in reducing the oxidative stress condition. The combination of Omega-3 and Manuka honey reduced the level of F2-isoprostane(8-iso-PGF2α) significantly compared to the Manuka alone and the control groups. Additionally, they showed an antihemolytic action measured by reduced LDH level. The combination restored the patient's lipid profile (LDL-C and HDL-C) significantly compared to the control group. Manuka honey enhanced the action of omega-3 in reducing oxidative stress by reducing serum iron significantly compared to the control group. CONCLUSIONS: Results showed that omega-3 + Manuka honey was more effective than Manuka alone or the conventional treatment alone in managing oxidative stress of ß-thalassemic patients.