Sputum culture reversion in longer treatments with bedaquiline, delamanid, and repurposed drugs for drug-resistant tuberculosis.

Sputum culture reversion after conversion is an indicator of tuberculosis (TB) treatment failure. We analyze data from the endTB multi-country prospective observational cohort (NCT03259269) to estimate the frequency (primary endpoint) among individuals receiving a longer (18-to-20 month) regimen for multidrug- or rifampicin-resistant (MDR/RR) TB who experienced culture conversion. We also conduct Cox proportional hazard regression analyses to identify factors associated with reversion, including comorbidities, previous treatment, cavitary disease at conversion, low body mass index (BMI) at conversion, time to conversion, and number of likely-effective drugs. Of 1,286 patients, 54 (4.2%) experienced reversion, a median of 173 days (97-306) after conversion. Cavitary disease, BMI < 18.5, hepatitis C, prior treatment with second-line drugs, and longer time to initial culture conversion were positively associated with reversion. Reversion was uncommon. Those with cavitary disease, low BMI, hepatitis C, prior treatment with second-line drugs, and in whom culture conversion is delayed may benefit from close monitoring following conversion.

Effectiveness of a bedaquiline, linezolid, clofazimine "core" for multidrug-resistant tuberculosis.

Rationale: Treatment outcomes may be compromised among patients with multidrug- or rifampicin-resistant tuberculosis with additional fluoroquinolone resistance. Evidence is needed to inform optimal treatment for these patients. Objectives: We compared the effectiveness of longer individualized regimens comprised of bedaquiline for 5 to 8 months, linezolid, and clofazimine to those reinforced with at least 1 third-tier drug and/or longer duration of bedaquiline. Methods: We emulated a target trial to compare the effectiveness of initiating and remaining on the core regimen to one of five regimens reinforced with (1) bedaquiline for ≥9 months, (2) bedaquiline for ≥9 months and delamanid, (3) imipenem, (4) a second-line injectable, or (5) delamanid and imipenem. We included patients in whom a fluoroquinolone was unlikely to be effective based on drug susceptibility testing and/or prior exposure. Our analysis consisted of cloning, censoring, and inverse-probability weighting to estimate the probability of successful treatment. Measurements and Main Results: Adjusted probabilities of successful treatment were high across regimens, ranging from 0.75 (95%CI:0.61, 0.89) to 0.84 (95%CI:0.76, 0.91). We found no substantial evidence that any of the reinforced regimens improved effectiveness of the core regimen, with ratios of treatment success ranging from 1.01 for regimens reinforced with bedaquiline ≥9 months (95%CI:0.79, 1.28) and bedaquiline ≥9 months plus delamanid (95%CI:0.81, 1.31) to 1.11 for regimens reinforced by a second-line injectable (95%CI:0.92, 1.39) and delamanid and imipenem (95%CI:0.90, 1.41). Conclusions: High treatment success underscores the effectiveness of regimens comprised of bedaquiline, linezolid, and clofazimine, highlighting the need for expanded access to these drugs.

Prevalence of chronic conditions and multimorbidity among healthcare workers in Zimbabwe: Results from a screening intervention.

The burden of non-communicable diseases (NCDs) in southern Africa is expanding and is superimposed on high HIV prevalence. Healthcare workers are a scarce resource; yet are vital to health systems. There are very limited studies on the burden of chronic conditions among healthcare workers in Africa, and none exploring multimorbidity (≥2 chronic conditions). We describe the epidemiology of infectious (HIV) and non-communicable chronic conditions, and multimorbidity, among Zimbabwean healthcare workers. Healthcare workers (≥18 years) in eight Zimbabwean provinces were invited to a voluntary, cross-sectional health-check, including HIV, diabetes, hypertension and mental health screening. Statistical analyses described the prevalence and risk factors for multimorbidity (two or more of HIV, diabetes, hypertension or common mental disorder) and each condition. Missing data were handled using multiple imputation. Among 6598 healthcare workers (July 2020-July 2022) participating in the health-check, median age was 37 years (interquartile range 29-44), 79% were women and 10% knew they were living with HIV. Half had at least one chronic condition: 11% were living with HIV, 36% had elevated blood pressure, 12% had elevated HbA1c and 11% had symptoms of common mental disorder. The overall prevalence of multimorbidity was 15% (95% CI: 13-17%); 39% (95% CI: 36-43%) among people aged 50 and older. Whilst most HIV was diagnosed and treated, other chronic conditions were usually undiagnosed or uncontrolled. Limiting our definition of multimorbidity to two or more screened conditions sought to reduce bias due to access to diagnosis, however, may have led to a lower reported prevalence than that found using a wider definition. Half of healthcare workers screened were living with a chronic condition; one in seven had multimorbidity. Other than HIV, most conditions were undiagnosed or untreated. Multisectoral action to implement contextually relevant, chronic disease services in Africa is urgently needed. Specific attention on health workers is required to protect and retain this critical workforce.

Estimating Post-treatment Recurrence After Multidrug-Resistant Tuberculosis Treatment Among Patients With and Without Human Immunodeficiency Virus: The Impact of Assumptions About Death and Missing Follow-up.

BACKGROUND: Quantification of recurrence risk following successful treatment is crucial to evaluating regimens for multidrug- or rifampicin-resistant (MDR/RR) tuberculosis (TB). However, such analyses are complicated when some patients die or become lost during post-treatment follow-up. METHODS: We analyzed data on 1991 patients who successfully completed a longer MDR/RR-TB regimen containing bedaquiline and/or delamanid between 2015 and 2018 in 16 countries. Using 5 approaches for handling post-treatment deaths, we estimated 6-month post-treatment TB recurrence risk overall and by HIV status. We used inverse-probability weighting to account for patients with missing follow-up and investigated the impact of potential bias from excluding these patients without applying inverse-probability weights. RESULTS: The estimated TB recurrence risk was 7.4/1000 (95% credible interval: 3.3-12.8) when deaths were handled as non-recurrences and 7.6/1000 (3.3-13.0) when deaths were censored and inverse-probability weights were applied to account for the excluded deaths. The estimated risks of composite recurrence outcomes were 25.5 (15.3-38.1), 11.7 (6.4-18.2), and 8.6 (4.1-14.4) per 1000 for recurrence or (1) any death, (2) death with unknown or TB-related cause, or (3) TB-related death, respectively. Corresponding relative risks for HIV status varied in direction and magnitude. Exclusion of patients with missing follow-up without inverse-probability weighting had a small impact on estimates. CONCLUSIONS: The estimated 6-month TB recurrence risk was low, and the association with HIV status was inconclusive due to few recurrence events. Estimation of post-treatment recurrence will be enhanced by explicit assumptions about deaths and appropriate adjustment for missing follow-up data.

Pregnancy and Birth Outcomes in Patients With Multidrug-Resistant Tuberculosis Treated With Regimens That Include New and Repurposed Drugs.

Among 43 pregnant women receiving multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment with bedaquiline and/or delamanid, 98% had favorable treatment outcomes. Of 31 continued pregnancies, 81% had live births with no reported malformations, and 68% of neonates had normal birth weights. Effective MDR/RR-TB treatment during pregnancy can improve maternal outcomes without harming neonates.

Essential Oil from Tagetes minuta Has Antiquorum Sensing and Antibiofilm Potential against Pseudomonas aeruginosa Strain PAO1.

Biofilms are complex communities of microorganisms that are enclosed in a matrix that shows increased resistance to antimicrobial and immunological encounters. Mostly, the traditional methods to control biofilm are exhausted; therefore, the aim is to evaluate the potential of essential oil (EO) from Tagetes minuta to encounter biofilm and other related virulence factors. The EO of T. minuta was extracted through steam-distillation, analyzed on gas chromatography-mass spectrometry, and the biofilm inhibition assays were performed with various concentrations of EO. Mainly the EO from T. minuta contains cis-ß-ocimene (29.1%), trans-tagetenone (23.1%), and cis-tagetenone (17.7%). The virulence factors were monitored while applying different concentrations of EO and it was recorded that the EO from T. minuta significantly inhibited the virulence factors linked with quorum sensing (QS), such as pyocyanin production, protease production, and swarming motility. Biofilm formation is one of the most important virulence factors associated with the QS pathway and was inhibited up to 79% in the presence of EO. Antibacterial activity against the PAO1 of EO was not so promising particularly and it has high MIC (325 µg/mL) and MBC (5000 µg/mL). EO is quite efficient to inhibit biofilm in a very small concentration of 20 µg/mL, which confirms that the biofilm inhibition by EO is not by killing bacterial cells but by inhibiting the QS pathway. The study on PAO1 constructs carrying various QS reported genes confirmed that the EO interferes with the QS pathway that ultimately controls various virulence factors caused by PAO1.

Estimating post-treatment recurrence after multidrug-resistant tuberculosis treatment among patients with and without HIV: the impact of assumptions about death and missing follow-up.

Background: Quantification of recurrence risk following successful treatment is crucial to evaluating regimens for multidrug- or rifampicin-resistant (MDR/RR) tuberculosis (TB). However, such analyses are complicated when some patients die or become lost during post-treatment-follow-up. Methods: We analyzed data on 1,991 patients who successfully completed a longer MDR/RR-TB regimen containing bedaquiline and/or delamanid between 2015 and 2018 in 16 countries. Using five approaches for handling post-treatment deaths, we estimated the six-month post-treatment TB recurrence risk overall, and by HIV status. We used inverse-probability-weighting to account for patients with missing follow-up and investigated the impact of potential bias from excluding these patients without applying inverse-probability weights. Results: The estimated TB recurrence risk was 6.6 per 1000 (95% confidence interval (CI):3.2,11.2) when deaths were handled as non-recurrences, and 6.7 per 1000 (95% CI:2.8,12.2) when deaths were censored and inverse-probability weights were applied to account for the excluded deaths. The estimated risk of composite recurrence outcomes were 24.2 (95% CI:14.1,37.0), 10.5 (95% CI:5.6,16.6), and 7.8 (95% CI:3.9,13.2) per 1000 for recurrence or 1) any death, 2) death with unknown or TB-related cause, 3) TB-related death, respectively. Corresponding relative risks for HIV status varied in direction and magnitude. Exclusion of patients with missing follow-up without inverse-probability-weighting had a small but apparent impact on estimates. Conclusion: The estimated six-month TB recurrence risk was low, and the association with HIV status was inconclusive due to few recurrence events. Estimation of post-treatment recurrence will be enhanced by explicit assumptions about deaths and appropriate adjustment for missing follow-up data.

The effect of internal displacement due to armed conflict on tuberculosis treatment outcomes in northwest Syria, 2019-2020.

Background: Northwest Syria accounts for over 4 million people of whom more than half are internally displaced persons (IDPs). More than 1 million IDPs reside in camps and many more live in settings which are overcrowded and poorly ventilated. Suboptimal social living conditions leave these populations susceptible to tuberculosis (TB) morbidity and mortality. This study aimed to assess the effect of internal displacement due to armed conflict on the risk of unsuccessful treatment outcomes among TB patients in northwest Syria. Methods: All patients registered to start TB treatment at three centres in northwest Syria between the 1st June 2019 to the 31st December 2020 were included. Unsuccessful TB treatment outcome was defined as a composite outcome combining the WHO TB treatment outcomes of treatment failure, loss to follow-up, and death. We assessed the association between internal displacement and unsuccessful TB treatment outcomes using multivariable logistic regression. We also explored the risk of an unsuccessful treatment outcome by internal displacement setting (camp, village or city). Results: Of the total 737 registered patients included in the analysis, 400 (54%) were documented as internally displaced. The median age of IDPs was 30 (IQR: 21.5-48) and the median age of residents was 34 (IQR:22-50). A significantly higher percentage of those who were IDPs had an unsuccessful treatment outcome compared to residents (40% vs 18%, p<0.001). After adjustment for confounders, the relative risk of having unsuccessful TB treatment was two-fold higher in internally displaced TB patients compared to residents (95% CI: 1.5-2.6). IDPs living in villages had a 30% lower risk of an unsuccessful treatment outcome compared to IDPs living in camps (RR 95% CI: 0.50-0.91), and IDPs living in cities had a 13% lower risk of an unsuccessful treatment outcome (RR 95% CI: 0.57-1.18). Conclusion: This is one of few studies which aims to quantify the effect of internal displacement on TB treatment outcomes during times of conflict. Our findings starkly highlight how social determinants contribute to poor TB outcomes and act as a starting point for much needed research on how best to manage TB in humanitarian crisis settings.

Emerging Anti-Diabetic Drugs for Beta-Cell Protection in Type 1 Diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disorder that damages beta cells in the pancreatic islets of Langerhans and results in hyperglycemia due to the loss of insulin. Exogenous insulin therapy can save lives but does not halt disease progression. Thus, an effective therapy may require beta-cell restoration and suppression of the autoimmune response. However, currently, there are no treatment options available that can halt T1D. Within the National Clinical Trial (NCT) database, a vast majority of over 3000 trials to treat T1D are devoted to insulin therapy. This review focuses on non-insulin pharmacological therapies. Many investigational new drugs fall under the category of immunomodulators, such as the recently FDA-approved CD-3 monoclonal antibody teplizumab. Four intriguing candidate drugs fall outside the category of immunomodulators, which are the focus of this review. Specifically, we discuss several non-immunomodulators that may have more direct action on beta cells, such as verapamil (a voltage-dependent calcium channel blocker), gamma aminobutyric acid (GABA, a major neurotransmitter with effects on beta cells), tauroursodeoxycholic acid (TUDCA, an endoplasmic reticulum chaperone), and volagidemab (a glucagon receptor antagonist). These emerging anti-diabetic drugs are expected to provide promising results in both beta-cell restoration and in suppressing cytokine-derived inflammation.

High-Contrast PET Imaging with [18F]NT160, a Class-IIa Histone Deacetylase Probe for In Vivo Imaging of Epigenetic Machinery in the Central Nervous System.

We utilized positron emission tomography (PET) imaging in vivo to map the spatiotemporal biodistribution/expression of class-IIa histone deacetylases (class-IIa HDACs) in the central nervous system (CNS). Herein we report an improved radiosynthesis of [18F]NT160 using 4-hydroxy-TEMPO which led to a significant improvement in radiochemical yield and molar activity. PET imaging with [18F]NT160, a highly potent class-IIa HDAC inhibitor, led to high-quality and high-contrast images of the brain. [18F]NT160 displayed excellent pharmacokinetic and imaging characteristics: brain uptake is high in gray matter regions, tissue kinetics are appropriate for a 18F-tracer, and specific binding for class-IIa HDACs is demonstrated by self-blockade. Higher uptake with [18F]NT160 was observed in the hippocampus, thalamus, and cortex while the uptake in the cerebellum was relatively low. Overall, our current studies with [18F]NT160 will likely facilitate the development and clinical translation of PET tracers for imaging of class-IIa HDACs biodistribution/expression in cancer and the CNS.

Comparative effectiveness of adding delamanid to a multidrug-resistant tuberculosis regimen comprised of three drugs likely to be effective.

Clarity about the role of delamanid in longer regimens for multidrug-resistant TB is needed after discordant Phase IIb and Phase III randomized controlled trial results. The Phase IIb trial found that the addition of delamanid to a background regimen hastened culture conversion; the results of the Phase III trial were equivocal. We evaluated the effect of adding delamanid for 24 weeks to three-drug MDR/RR-TB regimens on two- and six-month culture conversion in the endTB observational study. We used pooled logistic regression to estimate the observational analogue of the intention-to-treat effect (aITT) adjusting for baseline confounders and to estimate the observational analogue of the per-protocol effect (aPP) using inverse probability of censoring weighting to control for time-varying confounding. At treatment initiation, 362 patients received three likely effective drugs (delamanid-free) or three likely effective drugs plus delamanid (delamanid-containing). Over 80% of patients received two to three Group A drugs (bedaquiline, linezolid, moxifloxacin/levofloxacin) in their regimen. We found no evidence the addition of delamanid to a three-drug regimen increased two-month (aITT relative risk: 0.90 (95% CI: 0.73-1.11), aPP relative risk: 0.89 (95% CI: 0.66-1.21)) or six-month culture conversion (aITT relative risk: 0.94 (95% CI: 0.84, 1.02), aPP relative risk: 0.93 (95% CI: 0.83, 1.04)). In regimens containing combinations of three likely effective, highly active anti-TB drugs the addition of delamanid had no discernible effect on culture conversion at two or six months. As the standard of care for MDR/RR-TB treatment becomes more potent, it may become increasingly difficult to detect the benefit of adding a single agent to standard of care MDR/RR-TB regimens. Novel approaches like those implemented may help account for background regimens and establish effectiveness of new chemical entities.

Effectiveness of Bedaquiline Use beyond Six Months in Patients with Multidrug-Resistant Tuberculosis.

Rationale: Current recommendations for the treatment of rifampicin- and multidrug-resistant tuberculosis include bedaquiline (BDQ) used for 6 months or longer. Evidence is needed to inform the optimal duration of BDQ. Objectives: We emulated a target trial to estimate the effect of three BDQ duration treatment strategies (6, 7-11, and ⩾12 mo) on the probability of successful treatment among patients receiving a longer individualized regimen for multidrug-resistant tuberculosis. Methods: To estimate the probability of successful treatment, we implemented a three-step approach comprising cloning, censoring, and inverse probability weighting. Measurements and Main Results: The 1,468 eligible individuals received a median of 4 (interquartile range, 4-5) likely effective drugs. In 87.1% and 77.7% of participants, this included linezolid and clofazimine, respectively. The adjusted probability of successful treatment was 0.85 (95% confidence interval [CI], 0.81-0.88) for 6 months of BDQ, 0.77 (95% CI, 0.73-0.81) for 7-11 months, and 0.86 (95% CI, 0.83-0.88) for ⩾12 months. Compared with 6 months of BDQ, the ratio of treatment success was 0.91 (95% CI, 0.85-0.96) for 7-11 months and 1.01 (95% CI, 0.96-1.06) for ⩾12 months. Naive analyses that did not account for bias revealed a higher probability of successful treatment with ⩾12 months (ratio, 1.09 [95% CI, 1.05-1.14]). Conclusions: BDQ use beyond 6 months did not increase the probability of successful treatment among patients receiving longer regimens that commonly included new and repurposed drugs. When not properly accounted for, immortal person-time bias can influence estimates of the effects of treatment duration. Future analyses should explore the effect of treatment duration of BDQ and other drugs in subgroups with advanced disease and/or receiving less potent regimens.

Contribution of remote M.tuberculosis infection to tuberculosis disease: A 30-year population study.

BACKGROUND: The importance of remote infection with M.tuberculosis as a cause of tuberculosis disease (TB) is unclear, with limited evidence of impact on TB rates beyond 10 years. Our objective was to assess rates of tuberculosis over 30 years by M.tuberculosis infection status at baseline in Karonga District, Northern Malawi. MATERIALS AND METHODS: Population-based surveys of tuberculin skin testing (TST) from the 1980s were linked with follow-up and TB surveillance in Karonga district. We compared rates of microbiologically-confirmed TB by baseline TST induration <5mm (no evidence of M.tuberculosis infection) and those with baseline TST >17mm (evidence of M.tuberculosis infection), using hazard ratios by time since baseline and attributable risk percent. The attributable risk percent was calculated to estimate the proportion of TB in those infected that can be attributed to that prior infection. We analysed whole genome sequences of M.tuberculosis strains to identify recent transmission. RESULTS: Over 412,959 person-years, 208 incident TB episodes were recorded. Compared to the small induration group, rates of TB were much higher in the first two years in the large induration group, and remained higher to 20 years: age, sex and area-adjusted hazard ratios (HR) 2-9 years post-TST 4.27 (95%CI 2.56-7.11); 10-19 years after TST 2.15 (1.10-4.21); ≥20 years post-TST 1.88 (0.76-4.65). The attributable risk percent of remote infection was 76.6% (60.9-85.9) 2-9 years post-TST, and 53.5% (9.1-76.2) 10-19 years post-TST. Individuals with large TST indurations had higher rates of unique-strain TB (HR adjusted for age, sex and area = HR 6.56 (95% CI 1.96-22.99)), suggesting disease following remote infection, but not of linked-strain TB (recent transmission). CONCLUSIONS: M.tuberculosis infection can increase the risk of TB far beyond 10 years, accounting for a substantial proportion of TB occurring among those remotely infected.

Cluster Case of Prolidase Deficiency: Varied Clinical Presentations and Management in a Sibling Trio.

Prolidase deficiency (PD) is an exceptionally rare autosomal recessive disorder characterized by impaired collagen degradation, leading to the accumulation of proline-containing dipeptides. We report a cluster case of three siblings aged 17, 19, and 20 years, comprising of two sisters and one brother, who presented with non-healing ulcers on their shins and feet along with facial features of hypertelorism, depressed nasal bridge, reduced intellectual function, and high-arched palate. History and clinical features were consistent with PD. Due to the rarity of the disease and low socioeconomic background of the patients, specialized investigations or treatments were either unavailable or inaccessible. Furthermore, surgical intervention was ill-advised. Despite these challenges, patients were treated using improvised tailored therapy using three different modalities and showed remarkable progress. The evaluation and management took place at the dermatology unit of Hayatabad Medical Complex in Peshawar, Pakistan.

Drug-Resistant Tuberculosis Treatment Outcomes among Children and Adolescents in Karachi, Pakistan.

BACKGROUND: Significant data gaps exist for children and adolescents with drug-resistant (DR) TB, particularly from high TB incidence settings. This report provides a descriptive analysis of programmatic outcomes among children and adolescents treated for DR-TB in Pakistan. METHODS: We extracted programmatic data from January 2014 to December 2019 from a tertiary care hospital with specialised child and adolescent DR-TB services. A physician assessed all children and adolescents (0-19 years) with presumptive DR-TB, including details of exposure to DR-TB, medical history, radiology, and laboratory results. All patients received treatment as per national DR-TB management guidelines based on WHO recommendations. RESULTS: There were 262 treatment episodes for 247 patients enrolled during the study period. The median age of the cohort was 16 years (IQR: 13-18 years) with 16 (6.1%) children being under 5 years; 237 (90.5%) patients had pulmonary TB. The majority of the patients (194 or 74.1%) experienced a favourable treatment outcome and 26 (9.9%) died while on treatment. Female patients (78.5%) were more likely to experience favourable outcomes compared to males (64.7%; chi-sqr p-value = 0.02). CONCLUSIONS: We found high rates of favourable outcomes in children and adolescents treated for DR-TB. However, there were few young children in our cohort and there was a considerable gender gap that enhanced efforts to diagnose DR-TB in young children and to elucidate and mitigate the reasons for poor outcomes amongst males.

Selection bias in multidrug-resistant tuberculosis cohort studies assessing sputum culture conversion.

BACKGROUND: Conversion of sputum culture from positive to negative for M. tuberculosis is a key indicator of treatment response. An initial positive culture is a pre-requisite to observe conversion. Consequently, patients with a missing or negative initial culture are excluded from analyses of conversion outcomes. To identify the initial, or "baseline" culture, researchers must define a sample collection interval. An interval extending past treatment initiation can increase sample size but may introduce selection bias because patients without a positive pre-treatment culture must survive and remain in care to have a culture in the post-treatment interval. METHODS: We used simulated data and data from the endTB observational cohort to investigate the potential for bias when extending baseline culture intervals past treatment initiation. We evaluated bias in the proportion with six-month conversion. RESULTS: In simulation studies, the potential for bias depended on the proportion of patients missing a pre-treatment culture, proportion with conversion, proportion culture positive at treatment initiation, and proportion of patients missing a pre-treatment culture who would have been observed to be culture positive, had they had a culture. In observational data, the maximum potential for bias when reporting the proportion with conversion reached five percentage points in some sites. CONCLUSION: Extending the allowable baseline interval past treatment initiation may introduce selection bias. If investigators choose to extend the baseline collection interval past treatment initiation, the proportion missing a pre-treatment culture and the number of deaths and losses to follow up during the post-treatment allowable interval should be clearly enumerated.

Assessment of Brassica oleraceae L. (Brassicaceae) extract loaded ethosomal gel as a versatile vesicular carrier system for dermocosmetic application: A noninvasive split-faced study.

BACKGROUND: Plant extracts with rich ascorbic acid contents have greater antioxidant capability; extensively employed in skin beautifying products and protect skin from detrimental photodamaging environmental effects. Brassica oleraceae is having a substantial prospective toward cosmeceuticals owed by its profound activity against oxidation. AIM: To develop an effective topical ethosomal gel loaded with Brassica oleraceae leaves extract with significant antioxidant activity. METHODOLOGY: Valuation of antioxidant capability of plant leaves extract by 2,2-diphenyl-1-picrylhydrazyl (DPPH), and quantification of ascorbic acid was done through high performance liquid chromatography (HPLC). Ethosomes were prepared by cold method. Optimized suspension containing extract was incorporated in 2% Carbopol gel (test) along with extract solution (control). Noninvasive in vivo studies were performed for final product to assess its effects on skin by measuring melanin and erythema, sebum level, elasticity, moistness level, facial pores count and their area, skin wrinkling, and smoothness. RESULTS: Brassica oleraceae (red cabbage) leaves extract exhibited significant antioxidant potential (85.64 ± 1.28%) with 14.22 µg/g of ascorbic acid; expressed prominent cosmetic effects in terms of skin melanin, erythema, sebum, elasticity, hydration, facial pores, wrinkles, and smoothness when incorporated in ethosomes. ANOVA test also exhibited positive significant (p ≤ 0.05) effects on skin. CONCLUSION: Brassica oleraceae extract is a strong antioxidant with remarkable dermocosmetic benefits for skin.

Causal and Associational Language in Observational Health Research: A Systematic Evaluation.

We estimated the degree to which language used in the high-profile medical/public health/epidemiology literature implied causality using language linking exposures to outcomes and action recommendations; examined disconnects between language and recommendations; identified the most common linking phrases; and estimated how strongly linking phrases imply causality. We searched for and screened 1,170 articles from 18 high-profile journals (65 per journal) published from 2010-2019. Based on written framing and systematic guidance, 3 reviewers rated the degree of causality implied in abstracts and full text for exposure/outcome linking language and action recommendations. Reviewers rated the causal implication of exposure/outcome linking language as none (no causal implication) in 13.8%, weak in 34.2%, moderate in 33.2%, and strong in 18.7% of abstracts. The implied causality of action recommendations was higher than the implied causality of linking sentences for 44.5% or commensurate for 40.3% of articles. The most common linking word in abstracts was "associate" (45.7%). Reviewers' ratings of linking word roots were highly heterogeneous; over half of reviewers rated "association" as having at least some causal implication. This research undercuts the assumption that avoiding "causal" words leads to clarity of interpretation in medical research.