Tumor growth and overall survival modeling to support decision making in phase Ib/II trials: A comparison of the joint and two-stage approaches.

Model-based tumor growth inhibition (TGI) metrics are increasingly used to predict overall survival (OS) data in Phase III immunotherapy clinical trials. However, there is still a lack of understanding regarding the differences between two-stage or joint modeling methods to leverage Phase I/II trial data and help early decision-making. A recent study showed that TGI metrics such as the tumor growth rate constant KG may have good operating characteristics as early endpoints. This previous study used a two-stage approach that is easy to implement and intuitive but prone to bias as it does not account for the relationship between the longitudinal and time-to-event processes. A relevant alternative is to use a joint modeling approach. In the present article, we evaluated the operating characteristics of TGI metrics using joint modeling, assuming an OS model previously developed using historical data. To that end, we used TGI and OS data from IMpower150-a study investigating atezolizumab in over 750 patients suffering from non-small cell lung cancer-to mimic randomized Phase Ib/II trials varying in terms of number of patients included (40 to 15 patients per arm) and follow-up duration (24 to 6 weeks after the last patient included). In this context, joint modeling did not outperform the two-stage approach and provided similar operating characteristics in all the investigated scenarios. Our results suggest that KG geometric mean ratio could be used to support early decision-making provided that 30 or more patients per arm are included and followed for at least 12 weeks.

SQSTM1 Pro392Leu presenting as a corticobasal syndrome with progressive nonfluent aphasia.

Corticobasal syndrome is generally considered to be a sporadic condition. There are familial and isolated genetic cases, associated with GRN, MAPT, c9orf72 or PNRP variants. Some reports implicate other genes: LRRK2, CHMP2B, GBA, CYP27A1, PSEN1, APP, TARDBP and TBK1. Here, we report a case of a patient carrying a SQSTM1 Pro392Leu variant. We report a 57-year-old right-handed-woman with a history of progressive speech impairment, marked right side rigidity and bradykinesia, with rest tremor and stimulus sensitive myoclonus. She had predominantly right-sided apraxia. She had right side agraphestesia and astereognosis. MRI showed asymmetrical left frontotemporoparietal atrophy. DaTSCAN showed predominantly left involvement, PiB-PET was negative. CSF NfL was of 9356.5pg/mL. She carried a heterozygous variant P392L in SQSTM1. This case report expands the spectrum of phenotypes associated with SQSTM1 pathogenic variants. It also expands the list of genes associated with corticobasal syndrome, supporting the involvement of the ubiquitin-proteasome system in this condition.

Transoral endoscopic vestibular approach Sistrunk procedure (TEVAS)-case report and scoping review.

Background: Thyroglossal duct cyst (TGDC) is the most common congenital neck mass among the pediatric population. Less than 10% of the cases occur in adults. The standard of care for TGDC is surgical treatment with the Sistrunk procedure via a traditional transverse cervicotomy. This technique involves the resection of the cyst with its tract and the central portion of the hyoid bone body to avoid recurrence. The transoral vestibular approach has gained popularity as an alternative approach to open neck surgery in order to eliminate the transcervical scar associated with these procedures. Methods: We describe a case of an endoscopic Sistrunk procedure performed by the transoral vestibular approach. A scoping review of the transoral endoscopic vestibular approach Sistrunk procedure (TEVAS) was performed. The PubMed, Medline, Cochrane, Lilacs, Scielo, Mary Ann Libert and Scopus databases were systematically searched by using a Medical Subject Heading (MeSH)-optimized search strategy. The selection of papers followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines after setting inclusion and exclusion criteria. Results: The case was successful and without complications. Five studies were included in the final analysis for this review. Conclusions: This novel approach to the Sistrunk procedure is an effective alternative way to treat TGDC in selected patients who are motivated to avoid a visible neck scar.

Engineering protein nanoparticles for drug delivery.

Protein nanoparticles offer a highly tunable platform for engineering multifunctional drug delivery vehicles that can improve drug efficacy and reduce off-target effects. While many protein nanoparticles have demonstrated the ability to tolerate genetic and posttranslational modifications for drug delivery applications, this review will focus on three protein nanoparticles of increasing size. Each protein nanoparticle possesses distinct properties such as highly tunable stability, capacity for splitting or fusing subunits for modular surface decoration, and well-characterized conformational changes with impressive capacity for large protein cargos. While many of the genetic and posttranslational modifications leverage these protein nanoparticle's properties, the shared techniques highlight engineering approaches that have been generalized across many protein nanoparticle platforms.

Comparison of two-stage and joint TGI-OS modeling using data from six atezolizumab clinical studies in patients with metastatic non-small cell lung cancer.

Two-stage and joint modeling approaches are the two main approaches to investigate the link between longitudinal tumor size data and overall survival (OS) and anticipate clinical trial outcome. We here used a large database composed of one phase II and five phase III clinical trials evaluating atezolizumab (an immunotherapy) in monotherapy or in combination with chemotherapies in 3699 patients with non-small cell lung cancer to evaluate the differences between both approaches in terms of parameter estimates, magnitude of covariate effects, and ability to predict OS. Although the two-stage approach may underestimate the magnitude of the impact of tumor growth rate (KG ) on OS compared to joint modeling approach (hazard ratios [HRs] of 0.42-2.52 vs. 0.25-2.85, respectively, for individual KG varying from the 5th and 95th percentiles), this difference did not lead into poorer performance of the two-stage approach to describe the OS distribution in the six clinical studies. Overall, two-stage and joint modeling approaches accurately predicted OS HR with a median (range) difference with the observed OS HR of 0.02 (0.01-0.18) and 0.03 (0.00-0.19), in all cases considered, respectively (e.g., for IMpower150: 0.80 [0.66-0.95] vs. 0.82 [0.70-0.95], respectively, whereas the observed OS HR was 0.80). In our setting, the two-stage approach accurately predicted the benefit of atezolizumab on OS. Further work is needed to verify if similar results are achieved using phase Ib or phase II clinical trials where the number of patients and measurements is limited as well as in other cancer indications.

Population Pharmacokinetics and Exposure-Response Analysis for the CTLA-4 Inhibitor Tremelimumab in Metastatic NSCLC Patients in the Phase III POSEIDON Study.

Blockade of CTLA-4 by tremelimumab combined with anti-PD-L1 durvalumab and chemotherapy provided increased antitumor activity and long-term survival benefits in first-line metastatic non-small cell lung cancer (mNSCLC) in the phase III POSEIDON study. We performed population pharmacokinetic modeling for tremelimumab using data from 1,605 patients across 6 studies (including POSEIDON) in multiple tumors (lung cancer, bladder cancer, malignant mesothelioma, and other solid tumors), and identified a 2-compartment model with linear and time-varying clearance for tremelimumab. Cox proportional hazard regression models were applied to 326 patients with mNSCLC from POSEIDON to evaluate the association between exposure metrics and efficacy end points, adjusting for baseline prognostic covariates. Improved progression-free survival (PFS) and overall survival (OS) in the tremelimumab arm (in combination with durvalumab and chemotherapy) was associated with higher tremelimumab exposure (e.g., minimum concentration at 5th dose (Cmin,dose5 ) and area under the curve at 5th dose (AUCdose5 )). However, further case-matching analyses yielded hazard ratios for the comparison of tremelimumab-treated patients in the Cmin,dose5 quartile 1 (Q1) subgroup with matched chemotherapy-treated patients of 1.04 (95% confidence interval (CI): 0.76-1.44) for OS and 0.99 (95% CI: 0.72-1.36) for PFS, suggesting that the observed apparent exposure-response relationship might be confounded. No relationship between tremelimumab exposure and safety (grade ≥3 treatment-emergent adverse events [AEs], AEs of special interest, or discontinuation due to AEs) was identified. These results support the consistent benefit observed with tremelimumab 75 mg every 3 weeks for up to 5 doses in combination with durvalumab and chemotherapy in POSEIDON as first-line therapy for mNSCLC.

Cardiopulmonary Exercise Testing in Patients with Heart Failure: Impact of Gender in Predictive Value for Heart Transplantation Listing.

BACKGROUND: Exercise testing is key in the risk stratification of patients with heart failure (HF). There are scarce data on its prognostic power in women. Our aim was to assess the predictive value of the heart transplantation (HTx) thresholds in HF in women and in men. METHODS: Prospective evaluation of HF patients who underwent cardiopulmonary exercise testing (CPET) from 2009 to 2018 for the composite endpoint of cardiovascular mortality and urgent HTx. RESULTS: A total of 458 patients underwent CPET, with a composite endpoint frequency of 10.5% in females vs. 16.0% in males in 36-month follow-up. Peak VO2 (pVO2), VE/VCO2 slope and percent of predicted pVO2 were independent discriminators of the composite endpoint, particularly in women. The International Society for Heart Lung Transplantation recommended values of pVO2 ≤ 12 mL/kg/min or ≤14 if the patient is intolerant to ß-blockers, VE/VCO2 slope > 35, and percent of predicted pVO2 ≤ 50% showed a higher diagnostic effectiveness in women. Specific pVO2, VE/VCO2 slope and percent of predicted pVO2 cut-offs in each sex group presented a higher prognostic power than the recommended thresholds. CONCLUSION: Individualized sex-specific thresholds may improve patient selection for HTx. More evidence is needed to address sex differences in HF risk stratification.

Age Differences in Cardiopulmonary Exercise Testing Parameters in Heart Failure with Reduced Ejection Fraction.

Background and Objectives: Cardiopulmonary exercise testing (CPET) is a cornerstone of risk stratification in heart failure with reduced ejection fraction (HFrEF). However, there is a paucity of evidence on its predictive power in older patients. The aim of this study was to evaluate the prognostic power of current heart transplantation (HTx) listing criteria in HFrEF stratified according to age groups. Materials and Methods: Consecutive patients with HFrEF undergoing CPET between 2009 and 2018 were followed-up for cardiac death and urgent HTx. Results: CPET was performed in 458 patients with HFrEF. The composite endpoint occurred in 16.8% of patients ≤50 years vs. 14.1% of patients ≥50 years in a 36-month follow-up. Peak VO2 (pVO2), VE/VCO2 slope and percentage of predicted pVO2 were strong independent predictors of outcomes. The International Society for Heart and Lung Transplantation thresholds of pVO2 ≤ 12 mL/kg/min (≤14 if intolerant to ß-blockers), VE/VCO2 slope > 35 and percentage of predicted pVO2 ≤ 50% presented a higher overall diagnostic effectiveness in younger patients (≤50 years). Specific thresholds for each age subgroup outperformed the traditional cut-offs. Conclusions: Personalized age-specific thresholds may contribute to an accurate risk stratification in HFrEF. Further studies are needed to address the gap in evidence between younger and older patients.

Cardiopulmonary Exercise Testing in the Age of New Heart Failure Therapies: Still a Powerful Tool?

BACKGROUND: New therapies with prognostic benefits have been recently introduced in heart failure with reduced ejection fraction (HFrEF) management. The aim of this study was to evaluate the prognostic power of current listing criteria for heart transplantation (HT) in an HFrEF cohort submitted to cardiopulmonary exercise testing (CPET) between 2009 and 2014 (group A) and between 2015 and 2018 (group B). METHODS: Consecutive patients with HFrEF who underwent CPET were followed-up for cardiac death and urgent HT. RESULTS: CPET was performed in 487 patients. The composite endpoint occurred in 19.4% of group A vs. 7.4% of group B in a 36-month follow-up. Peak VO2 (pVO2) and VE/VCO2 slope were the strongest independent predictors of mortality. International Society for Heart and Lung Transplantation (ISHLT) thresholds of pVO2 ≤ 12 mL/kg/min (≤14 if intolerant to ß-blockers) and VE/VCO2 slope > 35 presented a similar and lower Youden index, respectively, in group B compared to group A, and a lower positive predictive value. pVO2 ≤ 10 mL/kg/min and VE/VCO2 slope > 40 outperformed the traditional cut-offs. An ischemic etiology subanalysis showed similar results. CONCLUSION: ISHLT thresholds showed a lower overall prognostic effectiveness in a contemporary HFrEF population. Novel parameters may be needed to improve risk stratification.

Clinical and Pathophysiologic Insights of Free triiodothyronine/Free thyroxine Ratio in Patients with Heart Failure with Preserved Ejection Fraction: Data from the NETDiamond Cohort.

BACKGROUND: Thyroid dysfunction is common in patients with heart failure (HF). Impaired conversion of free T4 (FT4) into free T3 (FT3) is thought to occur in these patients, decreasing the availability of FT3 and contributing to HF progression. In HF with preserved ejection fraction (HFpEF), it is not known whether changes in conversion of thyroid hormones (THs) are associated with clinical status and outcomes. OBJECTIVES: The objective of this study was to evaluate the association of FT3/FT4 ratio and TH with clinical, analytical, and echocardiographic parameters, as well as their prognostic impact in individuals with stable HFpEF. METHODS: We evaluated 74 HFpEF participants of the NETDiamond cohort without known thyroid disease. We performed regression modeling to study the associations of TH and FT3/FT4 ratio with clinical, anthropometric, analytical, and echocardiographic parameters, and survival analysis to evaluate associations with the composite of diuretic intensification, urgent HF visit, HF hospitalization, or cardiovascular death over a median follow-up of 2.8 years. RESULTS: The mean age was 73.7 years and 62% were men. The mean FT3/FT4 ratio was 2.63 (standard deviation: 0.43). Subjects with lower FT3/FT4 ratio were more likely to be obese and have atrial fibrillation. Lower FT3/FT4 ratio was associated with higher body fat (ß = -5.60 kg per FT3/FT4 unit, p = 0.034), higher pulmonary arterial systolic pressure (PASP) (ß = -10.26 mm Hg per FT3/FT4 unit, p = 0.002), and lower left ventricular ejection fraction (LVEF) (ß = 3.60% per FT3/FT4 unit, p = 0.008). Lower FT3/FT4 ratio was associated with higher risk for the composite HF outcome (HR = 2.50, 95% CI: 1.04-5.88, per 1-unit decrease in FT3/FT4, p = 0.041). CONCLUSIONS: In patients with HFpEF, lower FT3/FT4 ratio was associated with higher body fat, higher PASP, and lower LVEF. Lower FT3/FT4 predicted a higher risk of diuretic intensification, urgent HF visits, HF hospitalization, or cardiovascular death. These findings suggest that decreased FT4 to FT3 conversion might be a mechanism associated with HFpEF progression.

Early Decision Making in a Randomized Phase II Trial of Atezolizumab in Biliary Tract Cancer Using a Tumor Growth Inhibition-Survival Modeling Framework.

We assess the longitudinal tumor growth inhibition (TGI) metrics and overall survival (OS) predictions applied to patients with advanced biliary tract cancer (BTC) enrolled in IMbrave151 a multicenter randomized phase II, double-blind, placebo-controlled trial evaluating the efficacy and safety of atezolizumab with or without bevacizumab in combination with cisplatin plus gemcitabine. Tumor growth rate (KG) was estimated for patients in IMbrave151. A pre-existing TGI-OS model for patients with hepatocellular carcinoma in IMbrave150 was modified to include available IMbrave151 study covariates and KG estimates and used to simulate IMbrave151 study outcomes. At the interim progression-free survival (PFS) analysis (98 patients, 27 weeks follow-up), clear separation in tumor dynamic profiles with a faster shrinkage rate and slower KG (0.0103 vs. 0.0117 week-1 ; tumor doubling time 67 vs. 59 weeks; KG geometric mean ratio of 0.84) favoring the bevacizumab containing arm was observed. At the first interim analysis for PFS, the simulated OS hazard ratio (HR) 95% prediction interval (PI) of 0.74 (95% PI: 0.58-0.94) offered an early prediction of treatment benefit later confirmed at the final analysis, observed HR of 0.76 based on 159 treated patients and 34 weeks of follow-up. This is the first prospective application of a TGI-OS modeling framework supporting gating of a phase III trial. The findings demonstrate the utility for longitudinal TGI and KG geometric mean ratio as relevant end points in oncology studies to support go/no-go decision making and facilitate interpretation of the IMbrave151 results to support future development efforts for novel therapeutics for patients with advanced BTC.

Transoral thyroid and parathyroid surgery in Brazil: where are we?

INTRODUCTION: thyroid surgery through the transoral vestibular approach is a reality in many countries. While several competing remote access techniques have been developed in the last 20 years, many were not reproducible. Transoral Endoscopic Neck Surgery (TNS) has been shown to be reproducible in different centers around the world, and approximately five years after its description it has been adopted relatively quickly for various reasons. To date, there are at least 7 Brazilian studies published, including a series of more than 400 cases. The aim of this work is to study the progression of Transoral Neck Surgery in Brazil and describe the profile of surgeons involved in this new approach. METHODS: this is a retrospective study with descriptive statistics. A REDCap based survey about transoral endoscopic thyroidectomy and parathyroidectomy vestibular approach (TOETVA/TOEPVA) was done with 66 Brazilian surgeons regarding surgeon profile, numbers of cases performed by geographic region, what kind of training was necessary prior to the first case and behavior of the surgeon proposing these new approaches. RESULTS: response rate of this survey was 53%. To date, 1275 TOETVA/TOEPVA cases had been performed in Brazil, 1229 thyroidectomies (96.4%), 42 parathyroidectomies (3.3%) and 4 combined procedures (0.3%). Most of the cases were done in the southeast region (821, 64.4%), 538 (42.2%) cases in the State of São Paulo and 283 (22.2%) cases in the State of Rio de Janeiro. CONCLUSIONS: TOETVA is becoming popular in Brazil. Younger surgeons, especially those between 30 and 50 years old were more likely to adopt this approach.

Changes in health-related quality of life and treatment effects in chronic heart failure: a meta-analysis.

BACKGROUND: Heart failure (HF) is associated with poor health status, and high morbi-mortality. However, it is not well established how health status changes correlate with treatment effects on clinical outcomes. Our aim was to study the association between treatment-induced changes in health-status, assessed by Kansas City Cardiomyopathy Questionnaire 23 (KCCQ-23), and clinical outcomes in chronic HF. METHODS: Systematic search of phase III-IV pharmacological RCTs in chronic HF that assessed KCCQ-23 changes and clinical outcomes throughout follow-up. We studied the association between treatment induced changes in KCCQ-23 and treatment effects on clinical outcomes (HF hospitalization or cardiovascular death, HF hospitalization, cardiovascular death, and all-cause death) using weighted random-effects meta-regression. RESULTS: Sixteen trials were included, enrolling a total of 65,608 participants. Treatment induced KCCQ-23 changes were moderately correlated with treatment effects on the combined outcome of HF hospitalization or cardiovascular mortality (regression coefficient (RC) = -0.047, 95%CI: -0.085 to -0.009; R2 = 49%), a correlation that was mainly driven by HF hospitalization (RC = -0.076, 95%CI: -0.124 to -0.029; R2 = 56%). Correlations of treatment induced KCCQ-23 changes with cardiovascular death (RC = -0.029, 95%CI: -0.073 to 0.015; R2 = 10%) and all-cause death (RC = -0.019, 95%CI: -0.057 to 0.019; R2 = 0%) were weak and non-significant. CONCLUSIONS: Treatment-induced changes in KCCQ-23 were moderately correlated with treatment-effects on HF hospitalizations but were not correlated with the effects on cardiovascular and all-cause mortality. Treatment-induced changes in patient-centered outcomes (i.e., KCCQ-23) may reflect non-fatal symptomatic changes in the clinical course of HF leading to hospitalization.

Microvascular Dysfunction Is Associated With Impaired Myocardial Work in Obstructive and Nonobstructive Hypertrophic Cardiomyopathy: A Multimodality Study.

Background Two-dimensional speckle tracking echocardiography has been shown to correlate with microvascular dysfunction, a hallmark of hypertrophic cardiomyopathy (HCM). We hypothesized that there is an association between myocardial work and left ventricular ischemia, with incremental value to global longitudinal strain, in patients with HCM. Methods and Results We performed a prospective assessment of patients with HCM, undergoing 2-dimensional speckle tracking echocardiography and stress perfusion cardiac magnetic resonance. Results were stratified according to obstructive or nonobstructive HCM and the presence of significant replacement fibrosis (late gadolinium enhancement ≥15% of left ventricular mass). Seventy-five patients with HCM (63% men, age 55±15 years) were evaluated, 28% with obstructive HCM (mean gradient 89±60 mm Hg). Perfusion defects were found in 90.7%, involving 22.5±16.9% of left ventricular mass, and 38.7% had late gadolinium enhancement ≥15%. In a multivariable analysis, a lower global work index (r=-0.519, ß-estimate -10.822; P=0.001), lower global work efficiency (r=-0.379, ß-estimate -0.123; P=0.041), and impaired global constructive work (r=-0.532, ß-estimate -13.788; P<0.001) significantly correlated with ischemia. A segmental analysis supported these findings, albeit with lower correlation coefficients. A global work index cutoff ≤1755 mm Hg% was associated with hypoperfusion with a sensitivity of 88% and a specificity of 71%, while the best cutoff for global longitudinal strain (>-15.5%) had a sensitivity of 64% and a specificity of 57%. The association between myocardial work and perfusion defects was significant independently of late gadolinium enhancement ≥15% and obstructive HCM. Conclusions Impaired myocardial work was significantly correlated with the extent of ischemia in cardiac magnetic resonance, independently of the degree of left ventricular hypertrophy or fibrosis, with a higher predictive power than global longitudinal strain.

Sacubitril/Valsartan Improves Left Atrial and Ventricular Strain and Strain Rate in Patients with Heart Failure with Reduced Ejection Fraction.

BACKGROUND: Data on the impact of sacubitril/valsartan (SV) therapy on phasic left atrial (LA) and left ventricular (LV) strain in heart failure with reduced ejection fraction (HFrEF) are limited. The aim of this study was to evaluate changes in two-dimensional speckle tracking (2D-STE) parameters with SV therapy in HFrEF patients. METHODS: Prospective evaluation of HFrEF patients receiving optimized medical therapy. Two-dimensional speckle tracking (2D-STE) parameters were assessed at baseline and after 6 months of SV therapy. LA strain and strain rate (SR) in reservoir, conduit, and contraction phases were compared with LV longitudinal, radial, and circumferential strain and SR and stratified according to heart rhythm and HFrEF etiology. RESULTS: A total of 35 patients completed the 6-month follow-up, with a mean age of 59 ± 11 years, 40% in atrial fibrillation, 43% with ischemic etiology, and LVEF of 29 ± 6%. There were significant improvements in LA reservoir, conduit, and contractile strain and SR following SV therapy, particularly among patients in sinus rhythm. There were significant improvements in longitudinal, radial, and circumferential LV function indices. CONCLUSION: SV therapy in HFrEF was associated with improved longitudinal, radial, and circumferential function, particularly among patients in sinus rhythm. These findings can provide insights into the mechanisms underlying the improvement of cardiac function and help assess subclinical responses to the treatment.

Large-Scale Colloidal Synthesis of Chalcogenides for Thermoelectric Applications.

A simple and effective preparation of solution-processed chalcogenide thermoelectric materials is described. First, PbTe, PbSe, and SnSe were prepared by gram-scale colloidal synthesis relying on the reaction between metal acetates and diphenyl dichalcogenides in hexadecylamine solvent. The resultant phase-pure chalcogenides consist of highly crystalline and defect-free particles with distinct cubic-, tetrapod-, and rod-like morphologies. The powdered PbTe, PbSe, and SnSe products were subjected to densification by spark plasma sintering (SPS), affording dense pellets of the respective chalcogenides. Scanning electron microscopy shows that the SPS-derived pellets exhibit fine nano-/micro-structures dictated by the original morphology of the key constituting particles, while the powder X-ray diffraction and electron microscopy analyses confirm that the SPS-derived pellets are phase-pure materials, preserving the structure of the colloidal synthesis products. The resultant solution-processed PbTe, PbSe, and SnSe exhibit low thermal conductivity, which might be due to the enhanced phonon scattering developed over fine microstructures. For undoped n-type PbTe and p-type SnSe samples, an expected moderate thermoelectric performance is achieved. In contrast, an outstanding figure-of-merit of 0.73 at 673 K was achieved for undoped n-type PbSe outperforming, the majority of the optimized PbSe-based thermoelectric materials. Overall, our findings facilitate the design of efficient solution-processed chalcogenide thermoelectrics.

Comparative Effectiveness of COVID-19 Vaccines in Preventing Infections and Disease Progression from SARS-CoV-2 Omicron BA.5 and BA.2, Portugal.

We estimated comparative primary and booster vaccine effectiveness (VE) of SARS-CoV-2 Omicron BA.5 and BA.2 lineages against infection and disease progression. During April-June 2022, we implemented a case-case and cohort study and classified lineages using whole-genome sequencing or spike gene target failure. For the case-case study, we estimated the adjusted odds ratios (aORs) of vaccination using a logistic regression. For the cohort study, we estimated VE against disease progression using a penalized logistic regression. We observed no reduced VE for primary (aOR 1.07 [95% CI 0.93-1.23]) or booster (aOR 0.96 [95% CI 0.84-1.09]) vaccination against BA.5 infection. Among BA.5 case-patients, booster VE against progression to hospitalization was lower than that among BA.2 case-patients (VE 77% [95% CI 49%-90%] vs. VE 93% [95% CI 86%-97%]). Although booster vaccination is less effective against BA.5 than against BA.2, it offers substantial protection against progression from BA.5 infection to severe disease.

Thermoelectric Properties of Nickel and Selenium Co-Doped Tetrahedrite.

As the search continues for novel, cheaper, more sustainable, and environmentally friendly thermoelectric materials in order to expand the range of applications of thermoelectric devices, the tetrahedrite mineral (Cu12Sb4S13) stands out as a potential candidate due to its high abundance, low toxicity, and good thermoelectric performance. Unfortunately, as most current thermoelectric materials achieve zTs above 1.0, ternary tetrahedrite is not a suitable alternative. Still, improvement of its thermoelectric performance has been achieved to zTs ≈ 1 via isovalent doping and composition tuning, but most studies were limited to a single doping element. This project explores the effects of simultaneous doping with nickel and selenium in the thermoelectric properties of tetrahedrite. Simulated properties for different stoichiometric contents of these dopants, as well as the measured thermoelectric properties of the correspondent materials, are reported. One of the samples, Cu11.5Ni0.5Sb4S12.5Se0.5, stands out with a high power factor = 1279.99 µW/m·K2 at 300 K. After estimating the thermal conductivity, a zT = 0.325 at 300 K was obtained for this composition, which is the highest for tetrahedrites for this temperature. However, analysis of the weighted mobility shows the presence of detrimental factors, such as grain boundaries, disorder, or ionized impurity scattering, pointing to the possibility of further improvements.