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Plastics have become ubiquitous in our lives. Due to the ever-increasing population, rapid urbanization, and industrial advancement, the use of plastics has increased manifold. These plastic materials often disintegrate into microplastics (MPs) which are less than 5mm in size. MPs mostly enter aquatic habitats through improper waste management, illegal dumping, and unavoidable and unintentional discharges that take place during construction, manufacturing, farming, domestic consumption, and recreational activities. This review centers on exploring the origin, occurrence, and possible adverse effects of MPs on human well-being. Of the 485 literature reviewed for the study between 2014- 2023, 105 were found to be related to the MPs which were spread over 10 themes. The maximum number of papers were on sources of MPs, followed by MPs in freshwater ecosystems and waste management. The least number of literature was from the themes, transport of MPs and MPs in the soil environment. The literature was published mostly in China, India, Europe, and the Americas. Other countries like Australia, Latin America, Africa, and the Middle East contribute very little. The literature scan reveals that only 9% of all the generated plastic waste material is recycled, 12% is burned, and 79% of plastic litter is dumped in landfills and oceans. The dumped plastic settles and pollutes a variety of environmental matrices. MPs are intentionally manufactured to be added to personal care products that are washed down the drains through sewage or industrial wastewater. These MPs vary in density and colour, subject to the polymer type, and are present in varying sizes and concentrations in aquatic environments. The characterization of MPs originating from different types of polymer materials, in the reviewed literature, was performed based on the data obtained from Scanning Electron Microscopy Energy Dispersive Spectroscopy (SEM-EDS), Attenuated Total Reflection Fourier Transform Infra-Red spectroscopy (ATR-FTIR), Raman spectroscopy, and Atomic Force Microscopy (AFM). MPs have the potential to absorb harmful hydrophobic pollutants from the surroundings resulting in an indirect transfer of contaminants into the food web. Such MPs enter and affect humans, causing problems with the reproductive system, body weight, sex ratio, and live births. MPs pose a serious threat to organisms when ingested since they can obstruct the digestive tract, leading to oxidative and pathological stress, slowing down growth, and interfering with reproduction. Apart from the above, a comprehensive analysis of MP pollution, as well as its effect on human beings and the environment, has been discussed in terms of source identification and abundance. Also, has been discussed is a detailed review of the existing waste material recycled into new materials or reused without alteration or degradation to produce new energy sources. In the end, integrated strategies have been proposed to prevent the input of plastic waste material into the environment, by source control, improved plastic waste management, and techniques for degradation and conversion of MPs.

Abstract Background Colombia, which hosts over 3 million of the Venezuelan diaspora, is lauded for its progressive approach to social integration, including providing migrants access to its universal health coverage system. However, barriers to healthcare persist for both migrant and host populations, with poorly understood disparities in healthcare-seeking behaviors and associated costs. This is the first study to link healthcare-seeking behaviors with costs for Venezuelan migrants in Colombia, encompassing costs of missing work or usual activities due to healthcare events. Methods We use self-reported survey data from Venezuelan migrants and Colombians living in Colombia (September-November 2020) to compare healthcare-seeking behaviors and cost variables by nationality using two-sampled t-tests or Chi-square tests (X 2 ). The International Classification of Diseases was used to compare reported household illnesses for both populations. Average health service direct costs were estimated using the Colombian Government’s Suficiencia database and self-reported out-of-pocket (OOP) payments for laboratory and pharmacy services. Indirect costs were calculated by multiplying self-reported days of missed work or usual activities with estimated income levels, derived by matching characteristics using the Gran Enquesta Integrada de Hogares database. We calculate economic burdens for both populations, combining self-reported healthcare-seeking behaviors and estimated healthcare service unit costs across six healthcare-seeking behavior categories. Results Despite similar disease profiles, Venezuelan migrants are 21.3% more likely to forego formal care than Colombians, with 746.3% more Venezuelans reporting lack of health insurance as their primary reason. Venezuelan women and uninsured report the greatest difficulties in accessing health services, with accessing medications becoming more difficult for Venezuelan women during the COVID-19 pandemic. Colombians cost the health system more per treated illness event (US$40) than Venezuelans (US$26) in our sample, over a thirty-day period. Venezuelans incur higher costs for emergency department visits (123.5% more) and laboratory/ pharmacy OOP payments (24.7% more). Conclusions While Colombians and Venezuelans share similar disease burdens, significant differences exist in access, cost, and health-seeking behaviors. Increasing Venezuelan health insurance enrollment and tackling accessibility barriers are crucial for ensuring healthcare equity and effectively integrating the migrant population. Findings suggest that improving migrant access to primary healthcare would produce savings in Colombian healthcare expenditures.

Getting around in modern cities has become a daily puzzle for both residents and travelers. As cities increasingly evolve into complex hubs of innovation and development, the demand for efficient transportation solutions has never been higher. In the multifaceted field of urban transportation, cost-effective and efficient mobility remains a high priority. This paper looks at how cities are planning better ways for people to travel and move within the growing scope of multimodal transportation, a paradigm shift beyond traditional single-mode transit systems. Our approach to improving urban transport revolves around a few key principles: integration, innovation, and collaboration. Integration means bringing together different modes of transportation – like buses, trains, bikes, and even new technologies like ride-sharing services to make it easier for people to switch between them. This transformative approach not only aims to reduce congestion and reduce environmental footprints but also prioritizes user experience while ensuring a harmonious blend of convenience, sustainability, and accessibility. We use new technology and ideas to ensure that travel is easy, quick, and good for the environment. Looking at new trends and examples from around the world, this overview shows how cities are shaping a better future for everyone's daily commute. In this paper, we use Lingo software to solve a numerical example related to multi-modal transportation, demonstrating practical solutions for real-world implementation. Through innovation, we can find creative solutions to urban transportation challenges. Additionally, public transportation enhancements, such as the introduction of synchronized bus routes and electric vehicle charging stations, underline the commitment to sustainability and inclusivity. In the dynamic urban transportation landscape, cities will revolutionize our approach to providing cost-effective and efficient mobility solutions.

Abstract Polatuzumab vedotin is a CD79b‐directed antibody–drug conjugate that targets B cells and delivers the cytotoxic payload monomethyl auristatin E (MMAE). The phase III POLARIX study (NCT03274492) evaluated polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R‐CHP) as first‐line treatment of diffuse large B‐cell lymphoma (DLBCL). To examine dosing decisions for this regimen, population pharmacokinetic (popPK) analysis, using a previously developed popPK model, and exposure–response (ER) analysis, were performed. The popPK analysis showed no clinically meaningful relationship between cycle 6 (C6) antibody‐conjugated (acMMAE)/unconjugated MMAE area under the concentration–time curve (AUC) or maximum concentration, and weight, sex, ethnicity, region, mild or moderate renal impairment, mild hepatic impairment, or other patient and disease characteristics. In the ER analysis, C6 acMMAE AUC was significantly associated with longer progression‐free and event‐free survival (both p = 0.01). An increase of

Abstract Pemphigus represents a spectrum of autoimmune‐mediated blistering diseases associated with high morbidity, mortality and reduced quality of life (QoL). Despite an increase in pemphigus clinical trials, the varied instrument measurements of disease severity and QoL outcomes make comparisons between studies challenging. This study aimed to evaluate trends in the use of disease severity and QoL outcome measurements in pemphigus clinical trials. A review of pemphigus clinical trials was conducted using the PubMed, Embase, Cochrane Reviews and ClinicalTrials.gov databases up until September 2023. Only pemphigus randomized clinical trials that assessed at least one disease severity and/or QoL outcome were included. Overall, 53 clinical trials were eligible for this review. All clinical trials evaluated a disease severity outcome, with the Pemphigus Disease Area Index being the most used validated questionnaire (28.3% of trials) and more popular after 2015 (47.8% of trials since). The autoimmune bullous skin disorder intensity score (7.6%) and visual analogue measurements (7.6%) have fallen out of favour. Most studies now include lab parameters (56.5% of trials after 2015), with anti‐desmoglein 1 and 3 antibody levels (30.2%), immunoglobulins (IgG and/or IgM and IgA) (11.3%), and anti‐drug antibody levels (7.6%) being frequently evaluated. A small portion of trials evaluated QoL (26.5% of studies), with the autoimmune bullous quality of life being the most common (15.1%), however QoL utilization as an outcome measure has been increasing since 2015 (61.1% of trials since). Standardising the use of validated outcome measurements allows for better data interpretation, comparability and clinical application of results.

Background Recent trials have confirmed the effectiveness of promising dengue control technologies – two vaccines and Wolbachia. These would generally be applied at the municipal level. To help local officials decide which, if any, control strategy to implement, they need affordable, timely, and accurate data on dengue burden. Building on our previous work in Mexico, Indonesia, and Thailand, we developed a streamlined prospective method to estimate dengue burden at the municipal level quickly, accurately, and efficiently. Methods The method entails enrolling and repeatedly interviewing 100 patients with laboratory-confirmed dengue. They will be selected after screening and testing about 1,000 patients with clinical dengue. The method will capture both acute and chronic effects relating to disease, economic burden, and psychological impacts (presenteeism). The total time requirements are 1.5 years, comprised of 0.25 years for planning and approvals, 1 year for data collection (a full dengue cycle), and 0 .25 years for data cleaning and analysis. A collaboration with municipal and academic colleagues in the city of Semarang, Central Java, Indonesia shows how the method could be readily applied in Indonesia’s eighth largest city (population 1.8 million). Conclusions Many surveillance studies gather only information on numbers of cases. This proposed method will provide a comprehensive picture of the dengue burden to the health system, payers, and households at the local level.

The presence of small-sized (

Abstract A study to determine the impact of cyclosporine (Neoral), an inhibitor of P‐gp, on the pharmacokinetics of pralsetinib (trade name GAVRETO®) was conducted in 15 healthy adult volunteers. A single 200 mg dose of pralsetinib was administered orally alone and in combination with cyclosporine with a 9‐day washout between treatments. Co‐administration with cyclosporine resulted in a clinically relevant increase in pralsetinib maximum plasma concentration (Cmax) and area under the plasma concentration–time curve extrapolated to infinity (AUC0–∞) with associated geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of 148% (109, 201) and 181% (136, 241), respectively. These findings provide insight into concomitant dosing of pralsetinib with inhibitors of P‐gp given the increases in pralsetinib exposure observed when administered with cyclosporine. Based on these results, co‐administration of pralsetinib with P‐gp inhibitors is not recommended. In the event that co‐administration cannot be avoided, it is recommended that the dose of pralsetinib be reduced.

Abstract This ethnic sensitivity analysis used data from the phase III POLARIX study (NCT03274492) to assess polatuzumab vedotin pharmacokinetics (PKs) in Asian versus non‐Asian patients with previously untreated diffuse large B‐cell lymphoma and examined the appropriateness of extrapolating global study findings to Asian patients. PK and population PK (PopPK) analyses assessed polatuzumab vedotin analyte exposures by ethnicity (Asian [n = 84] vs. non‐Asian [n = 345] patients) and region (patients enrolled from Asia [n = 80] vs. outside Asia [n = 349]). In patients from Asia versus outside Asia, observed mean antibody‐conjugated monomethyl auristatin E (acMMAE) concentrations were comparable (1.2% lower at cycle [C]1 postdose, 4.4% higher at C4 predose; and 6.8% lower at C4 postdose in patients from Asia). Observed mean unconjugated MMAE was lower in patients from Asia by 6.5% (C1 postdose), 20.0% (C4 predose), and 15.3% (C4 postdose). In the PopPK analysis, C6 area under the curve and peak plasma concentrations were also comparable for acMMAE (6.3% and 3.0% lower in Asian vs. non‐Asian patients, respectively) and lower for unconjugated MMAE by 19.1% and 16.7%, respectively. By region, C6 mean acMMAE concentrations were similar, and C6 mean unconjugated MMAE concentrations were lower, in patients enrolled from Asia versus outside Asia, by 3.9%–7.0% and 17.3%–19.7%, respectively. In conclusion, polatuzumab vedotin PKs were similar between Asian and non‐Asian patients by ethnicity and region, suggesting PKs are not sensitive to Asian ethnicity and dose adjustments are not required in Asian patients to maintain efficacy and safety.

Abstract Alectinib, approved as 150 mg capsules for the treatment of adults with advanced ALK‐positive non‐small cell lung cancer, is being assessed in children with ALK‐positive solid and central nervous system tumors. An ad hoc pediatric‐friendly suspension of alectinib, prepared from capsule contents, is under investigation as an alternative formulation for children who cannot swallow capsules. This randomized, crossover, relative bioavailability, and food effect study evaluated alectinib administered as an oral suspension versus capsule formulation following conventional venipuncture and capillary microsampling. A total of 28 healthy adult subjects received a 600 mg single dose of alectinib in two groups: fasted (n = 14) and mixed fed (n = 14; seven receiving high‐fat meal and seven receiving low‐fat meal). Combined alectinib + M4 (active metabolite) exposure was higher for suspension versus capsule, with geometric mean ratio (GMR) of 2.6 for area under the concentration–time curve extrapolated to infinity (AUC0‐∞) and 3.0 for maximum observed concentration (Cmax) under fasted conditions, and 1.7 for both parameters for mixed fed. The suspension showed increased alectinib + M4 AUC0‐∞ following a high‐fat meal versus fasted conditions (GMR 1.7 [90% confidence interval 1.4–2.2]). Alectinib AUC0‐∞ and Cmax measured in venous and capillary samples were generally similar for the suspension and capsule. Single oral doses of 600 mg alectinib suspension and capsule were well tolerated, with no safety concerns. Based on these findings, the oral suspension of alectinib appears suitable for use in pediatric studies after appropriate dose adjustment relative to the capsule.

A line-field confocal optical coherence tomography (LC-OCT) combines confocal microscopy and optical coherence tomography into a single, rapid, easy-to-use device. This meta-analysis was performed to determine the reliability of LC-OCT for diagnosing malignant skin tumors. PubMed, EMBASE, Web of Science databases, and the Cochrane Library were searched for research studies in the English language from inception till December 2023. To assess quality and the risk of bias, the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was used. The sensitivity and specificity of each study were calculated. The bivariate summary sensitivity and specificity were calculated using the linear mixed model. Five studies with 904 reported per lesion analyses in our study; the specificity and sensitivity ranged from 67% to 97% and 72% to 92%, respectively. The pooled specificity and sensitivity were 91% (95% CI: 76–97%) and 86.9% (95% CI: 81.8–90.8%), respectively. The summary sensitivity and specificity from the bivariate approach are 86.9% (95% CI: 81.8–90.8%) and 91.1% (95% CI: 76.7–97.0%), respectively. The area under the curve is 0.914. LC-OCT shows great sensitivity and specificity in diagnosing malignant skin tumors. However, due to the limited number of studies included in our meta-analysis, it is premature to elucidate the true potential of LC-OCT.

Holliday Junction (HJ) is an important intermediate in homologous recombination and is involved in DNA break repair. It is a highly dynamic structure and transitions between two stacked isomers through an intermediate open conformer. However, the insight into the effect of environmental confinement on HJ conformation population is incomplete. The understanding would be an important bridge between studies generally carried out in aqueous buffers and confined environments, as found in vivo. By employing fluorescence-based techniques we investigated the effect of confinement on HJ conformation using reverse micelle encapsulation as a model for confined space. We observed that inside the confinement of reverse micelle, HJ prefers to adopt stacked conformation. Most strikingly, even at lower divalent cation concentrations, the preference for stacked conformation is prevalent over an open conformation. The conformational heterogeneity also reduces with increasing degree of confinement. Our finding suggests that such confinement-induced changes in the conformer population might influence the interaction and activity of the HJ-recognizing proteins in the cellular environment.

Abstract Background and Aims Dengue is endemic in Thailand and imposes a high burden on the health system and society. We conducted a prospective cohort study in Umphang District, Tak Province, Thailand, to investigate the share of dengue cases with long symptoms and their duration. Here we present the results of the enrollment process during the COVID‐19 pandemic with implications and challenges for research and policy. Methods In a prospective cohort study conducted in Umphang District, Thailand, we examined the prevalence of persistent symptoms in dengue cases. Clinically diagnosed cases were offered free laboratory testing, We enrolled ambulatory dengue patients regardless of age who were confirmed through a highly sensitive laboratory strategy (positive NS1 and/or IgM), agreed to follow‐up visits, and gave informed consent. We used multivariate logistic regressions to assess the probability of clinical dengue being laboratory confirmed. To determine the factors associated with study enrollment, we analyzed the relationship of patient characteristics and month of screening to the likelihood of participation. To identify underrepresented groups, we compared the enrolled cohort to external data sources. Results The 150 clinical cases ranged from 1 to 85 years old. Most clinical cases (78%) were confirmed by a positive laboratory test, but only 19% of those confirmed enrolled in the cohort study. Women, who were half as likely to enroll as men, were underrepresented in the cohort. Conclusions The Thai physicians' clinical diagnoses at this rural district hospital had good agreement with laboratory diagnoses. By identifying underrepresented groups and disparities, future studies can ensure the creation of statistically representative cohorts to maximize their scientific value. This involves recruiting and retaining underrepresented groups in health research, such as women in this study. Promising strategies for meaningful inclusion include multi‐site enrollment, offering in‐home or virtual services, and providing in‐kind benefits like childcare for underrepresented groups.

Introduction: A border zone infarct (BI) is defined as an infarction that is localized to watersheds or border zones in the brain. BI is further classified into cortical border zone infarct (CBZ) and internal border zone infarct (IBZ). This study was conducted to explore the clinical and radiological characteristics of BI. Materials and Method: The study was conducted on eligible 400 acute ischemic stroke patients out of which 52 BI patients (diagnosed by the radiologist on DWI MRI images), patients >18 yrs of age were selected and divided into two groups of IBZ and CBZ infarct patients. The degree of intracranial and extracranial stenosis and characteristics on clinical presentation were assessed. The data were collected and analyzed using SPSS version 20.0 software at significance level p-value 0.05). Conclusion: Association of BI with events causing hypotension or hypovolemia is well-established in our study, association of BI with large vessel atherosclerosis is common, and its contribution to CBZ and IBZ seems to be equal.

Abstract Ipatasertib, an AKT inhibitor, in combination with prednisone and abiraterone, is under evaluation for the treatment of metastatic castration‐resistant prostate cancer (mCRPC). Hyperglycemia is an on‐target effect of ipatasertib. An open‐label, single‐arm, single‐sequence, signal‐seeking study (n = 25 mCRPC patients) was conducted to evaluate the glucose changes across four different treatment periods: ipatasertib alone, ipatasertib‐prednisone combination, ipatasertib‐prednisone‐abiraterone combination (morning dose), and ipatasertib‐prednisone‐abiraterone combination (evening dose). Continuous glucose monitoring (CGM) was used in this study to compare the dynamic glucose changes across the different treatment periods. Four key parameters: average glucose, peak glucose and % time in range (70–180 and >180 mg/dl) were evaluated for this comparison. Ipatasertib‐prednisone‐abiraterone combination when administered in the morning after an overnight fast significantly increased average glucose, peak glucose and % time in range >180 mg/dl compared to ipatasertib monotherapy. Ipatasertib, when co‐administered with abiraterone, increased ipatasertib and M1 (G‐037720) metabolite exposures by approximately 1.5‐ and 2.2‐fold, respectively. Exposure–response analysis results show that increased exposures of ipatasertib in combination with abiraterone are associated with increased glucose levels. When ipatasertib‐prednisone‐abiraterone combination was administered as an evening dose compared to a morning dose, lowered peak glucose and improved % time in range was observed. The results from this study suggest that dosing ipatasertib after an evening meal followed by overnight fasting can be an effective strategy for managing increased glucose levels.

Pralsetinib is a kinase inhibitor indicated for the treatment of metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer. Pralsetinib is primarily eliminated by the liver and hence hepatic impairment (HI) is likely alter its pharmacokinetics (PK). Mild HI has been shown to have minimal impact on the PK of pralsetinib. This hepatic impairment study aimed to determine the pralsetinib PK, safety and tolerability in subjects with moderate and severe HI, as defined by the Child–Pugh and National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification systems, in comparison to subjects with normal hepatic function. Based on the Child–Pugh classification, subjects with moderate and severe HI had similar systemic exposure (area under the plasma concentration time curve from time 0 to infinity [AUC0–∞]) to pralsetinib, with AUC0–∞ geometric mean ratios (GMR) of 1.12 and 0.858, respectively, compared to subjects with normal hepatic function. Results based on the NCI-ODWG classification criteria were comparable; the AUC0–∞ GMR were 1.22 and 0.858, respectively, for subjects with moderate and severe HI per NCI-ODWG versus those with normal hepatic function. These results suggested that moderate and severe hepatic impairment did not have a meaningful impact on the exposure to pralsetinib, thus not warranting a dose adjustment in this population.

Mostly produced as a by-product of zinc (Zn) mining, cadmium (Cd) is used in solar photovoltaic cells, battery storage, alloys, pigments, plating, and in nuclear reactors. However, it is also a regulated toxic substance with a long history of environmental and health impacts. As the mining of both Zn and Cd will need to increase to support the global energy transition, the status of Cd as either a resource or a pollutant has major implications for global supply chains and environmental management. Here, we present a new global, site-specific database and analysis of Cd resources in Zn-bearing mineral deposits and mines. Our database, which exceeds past Cd studies in scope, transparency and replicability is made available in full to support future assessments of Cd and Zn resources, mine production and associated risks. It includes 927 sites subject to detailed geological data compilation and analysis. Collectively, these sites suggest a new global resource estimate of 3.3 Mt Cd (95% confidence interval: 2.7–6.1 Mt). A preliminary geospatial analysis of sites in our database and mine toxicity indicators was also conducted. It shows that: As ∼27% of Cd resources are in countries that do not refine it, our study highlights the need for further research exploring global Cd trade flows and associated emissions. Heavy metal pollution in mining and metal production regions is an ongoing challenge, and our global dataset refines our understanding of its magnitude and distribution.

Abstract Baseline patient characteristics and prognostic factors are important considerations in oncology when evaluating the impact of immunogenicity on pharmacokinetics (PK) and efficacy. Here, we assessed the impact of anti‐drug antibodies (ADA) on the PK of the immune checkpoint inhibitor atezolizumab (an anti–PD‐L1 monoclonal antibody). We evaluated data from ≈ 4500 patients from 12 clinical trials across different tumor types, treatment settings, and dosing regimens. In our dataset, ~ 30% of patients (range, 13–54%) developed treatment‐emergent ADA, and in vitro neutralizing antibodies (NAb) were seen in ~ 50% of ADA‐positive (+) patients. Pooled time course data showed a trend toward lower atezolizumab exposure in ADA+ patients, which was more pronounced in ADA+/NAb+ patients. However, the atezolizumab concentration distributions overlapped, and drug concentrations exceeded 6 µg/ml, the target concentration required for receptor saturation, in greater than 95% of patients. Patients had sufficient exposure regardless of ADA status. The dose selected to allow for dosing over effects from ADA resulted in a flat exposure‐response relationship. Analysis of study results by ADA titer showed that exposure and overall survival were not affected in a clinically meaningful way. High tumor burden, low albumin, and high CRP at baseline showed the greatest association with ADA development but not with subsequent NAb development. These imbalanced factors at baseline can confound analysis of ADA impact. ADA increases atezolizumab clearance minimally (9%), and its impact on exposure based on the totality of the clinical pharmacology assessment does not appear to be clinically meaningful.

Smoking is still a major public health issue that causes morbidity and mortality all over the world. The percentage of deaths caused by tobacco smoking has escalated from 1.4% in 1990 to 13.3% by 2020. There are numerous evidence-based tobacco control strategies available, and newer ones are always being developed. However, on ceasing the habit, cigarettes users go through a period of withdrawal with an increased percentage of relapse before entering to a more stable condition of sobriety in the long run. In this review, Endnote software was used as resource material to collect literature, which was then carefully arranged in a synchronised way. The Markov model captures the dynamic character of the quitting/relapse process, allowing for more accurate figures of abstinence rate, treatment outcomes and evaluating the performance of newer cessation initiatives during tobacco cessation counselling, as well as suggesting pathways for survivability.

ObjectiveColombia hosts 1.8 million displaced Venezuelans, the second highest number of displaced persons globally. Colombia's constitution entitles all residents, including migrants, to life-saving health care, but actual performance data are rare. This study assessed Colombia's COVID-era achievements.MethodsWe compared utilization of comprehensive (primarily consultations) and safety-net (primarily hospitalization) services, COVID-19 case rates, and mortality between Colombian citizens and Venezuelans in Colombia across 60 municipalities (local governments). We employed ratios, log transformations, correlations, and regressions using national databases for population, health services, disease surveillance, and deaths. We analyzed March through November 2020 (during COVID-19) and the corresponding months in 2019 (pre-COVID-19).ResultsCompared to Venezuelans, Colombians used vastly more comprehensive services than Venezuelans (608% more consultations), in part due to their 25-fold higher enrollment rates in contributory insurance. For safety-net services, however, the gap in utilization was smaller and narrowed. From 2019 to 2020, Colombians' hospitalization rate per person declined by 37% compared to Venezuelans' 24%. In 2020, Colombians had only moderately (55%) more hospitalizations per person than Venezuelans. In 2020, rates by municipality between Colombians and Venezuelans were positively correlated for consultations (r = 0.28, p = 0.04) but uncorrelated for hospitalizations (r = 0.10, p = 0.46). From 2019 to 2020, Colombians' age-adjusted mortality rate rose by 26% while Venezuelans' rate fell by 11%, strengthening Venezuelans' mortality advantage to 14.5-fold.ConclusionsThe contrasting patterns between comprehensive and safety net services suggest that the complementary systems behaved independently. Venezuelans' lower 2019 mortality rate likely reflects the healthy migrant effect (selective migration) and Colombia's safety net healthcare system providing Venezuelans with reasonable access to life-saving treatment. However, in 2020, Venezuelans still faced large gaps in utilization of comprehensive services. Colombia's 2021 authorization of 10-year residence to most Venezuelans is encouraging, but additional policy changes are recommended to further integrate Venezuelans into the Colombian health care system.

Abstract Background There is a need for more observational studies across different clinical settings to better understand the epidemiology of the novel COVID-19 infection. Evidence on clinical characteristics of COVID-19 infection is scarce in secondary care settings in Western populations. Methods We describe the clinical characteristics of all consecutive COVID-19 positive patients (n = 215) admitted to the acute medical unit at Fairfield General Hospital (secondary care setting) between 23 March 2020 and 30 April 2020 based on the outcome at discharge (group 1: alive or group 2: deceased). We investigated the risk factors that were associated with mortality using binary logistic regression analysis. Kaplan-Meir (KM) curves were generated by following the outcome in all patients until 12 May 2020. Results The median age of our cohort was 74 years with a predominance of Caucasians (87.4%) and males (62%). Of the 215 patients, 86 (40%) died. A higher proportion of patients who died were frail (group 2: 63 vs group 1: 37%, p

ABSTRACTColombia provides a unique setting to understand the complicated interaction between health systems, health insurance, migrant populations, and COVID-19 due to its system of Universal Health Coverage and its hosting of the second-largest population of displaced persons globally, including approximately 1.8 million Venezuelan migrants. We surveyed 8,130 Venezuelan migrants and Colombian nationals across 60 municipalities using a telephone survey during the first wave of the pandemic (September through November 2020). Using self-reported enrollment in one of the several Colombian health insurance schemes, we analyzed the access to and disparities in the use of health-care services for both Colombians and Venezuelan migrants by insurance status, including access to formal health services, virtual visits, and COVID-19 testing for both groups. We found that compared with 3.6% of Colombians, 73.6% of Venezuelan telephone survey respondents remain uninsured, despite existing policies that allow legally present migrants to enroll in national health insurance schemes. Enrolling migrants in either the subsidized or contributory regime increases their access to health-care services, and equality between Colombians and Venezuelans within the same insurance schemes can be achieved for some services. Colombia’s experience integrating Venezuelan migrants into their current health system through various insurance schemes during the first wave of their COVID-19 pandemic shows that access and equality can be achieved, although there continue to be challenges.

A two‐analyte integrated population pharmacokinetic (PK) model that simultaneously describes concentrations of antibody‐conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE following repeated administrations of polatuzumab vedotin (pola) was developed based on data from four clinical studies of pola in patients with non‐Hodgkin lymphoma. A two‐compartment model with a nonspecific, time‐dependent linear clearance, a linear time‐dependent exponentially declining clearance, and a Michaelis–Menten clearance provided a good fit of the acMMAE plasma PK profiles. All three acMMAE elimination pathways contributed to the input to the central compartment of unconjugated MMAE, which was also described by a two‐compartment model. Population PK parameters, covariate effects, and interindividual variability of model parameters were estimated. The impact of clinically relevant covariates on PK exposures of each analyte were quantified and reported to support key label claims.

Prediction of human pharmacokinetics (PK) based on preclinical information for antibody–drug conjugates (ADCs) provide important insight into first‐in‐human (FIH) study design. This retrospective analysis was conducted to identify an appropriate scaling method to predict human PK for ADCs from animal PK data in the linear range. Different methods for projecting human clearance (CL) from animal PK data for 11 ADCs exhibiting linear PK over the tested dose ranges were examined: multiple species allometric scaling (CL vs. body weight), allometric scaling with correction factors, allometric scaling based on rule of exponent, and scaling from only cynomolgus monkey PK data. Two analytes of interest for ADCs, namely total antibody and conjugate (measured as conjugated drug or conjugated antibody), were assessed. Percentage prediction errors (PEs) and residual sum of squares (RSS) were compared across methods. Human CL was best estimated using cynomolgus monkey PK data alone and an allometric scaling exponent of 1.0 for CL. This was consistently observed for both conjugate and total antibody analytes. Other scaling methods either underestimated or overestimated human CL, or produced larger average absolute PEs and RSS. Human concentration‐time profiles were also reasonably predicted from the cynomolgus monkey data using species‐invariant time method with a fixed exponent of 1.0 for CL and 1.0 for volume of distribution. In conclusion, results from this retrospective analysis of 11 ADCs indicate that allometric scaling of CL with an exponent of 1.0 using cynomolgus monkey PK data alone can successfully project human PK profiles of an ADC within linear range.

Introduction: Aloe vera has various pharmacological actions due to which it has been selected as an alternative treatment modality in treating various oral diseases. It has antibacterial, antifungal, antiinflammatory, antioxidant, antitumor, and immune boosting. It has been used for the management of oral lesions such as oral lichen planus, oral submucous fibrosis, radiation-induced mucositis, burning mouth syndrome, xerostomia, recurrent aphthous ulcers. Aim: The aim of this study is to the compare the effects of the topical aloe vera gel and triamcinolone acetonide 0.1% in patients with minor ulcers of aphthous stomatitis. Materials and Methods: Thirty-four patients presenting with clinical signs and symptoms of aphthous stomatitis were included for the randomized single blinded study after informed consent. Group A patients received topical aloe vera gel (Forever Bright Aloe vera Gel), and Group B patients received topical triamcinolone acetonide 0.1% (kenacort oral paste) three times a day for 7 days or till the ulcer heals completely. The parameters such as the size of the ulcer, burning sensation, and pain were recorded at each visit. Results: In this study, kenacort oral paste was found to be effective than aloe vera in wound healing (measured by the diameter of ulcer). In contrast, aloe vera gel had a better response in terms of pain and burning sensation. Conclusion: Aloe vera has a wide spectrum of unique properties and uses. It is a promising agent in treating oral lesion in the field of oral medicine. It can be used as an alternative medicine and in patients who are allergic to steroid medication.

Introduction: A large proportion of the population suffers from disturbed sleep and a majority of these present to clinicians with the complaint of insomnia. Many of these people possibly suffer from other primary sleep disorders such as sleep apnea; however, insomnia disorder also remains an extremely common condition directly impacting the quality of life and work efficiency of affected people. While a number of approaches are used for treatment by many clinicians, a much smaller percentage can seek help from specialty sleep clinics. Since very little data are available regarding the effectiveness of treatment offered, this retrospective study aims at examining the outcome of chronic insomnia patients attending to a quaternary care specialty sleep center. Methods: Consecutive patients with the presenting complaint of and diagnosis of insomnia, during a study period of 2 years between 2013 and 2015, were identified and analyzed. Patients were classified based on the comorbidity and types of treatment received. Life stressors were also identified and analyzed. Outcomes were reviewed for those who had follow-up data available. Results: Based on the defined inclusion criteria, 102 patients could be analyzed. Among these, at least 3-month follow-up was available for 48 patients. It was observed that among patients for whom at least 3-month follow-up was available, 91.4% (43/48) showed a good response to treatment with physician-administered cognitive behavioral therapy for insomnia along with treatment for comorbid conditions. Conclusion: With correct diagnostic classification, as well as appropriate and easily available treatment strategies, excellent treatment outcomes are observed at specialty sleep clinics.

vc-MMAE antibody–drug conjugates (ADCs) consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile valine-citrulline (vc) linker. The objective of this study was to characterize the pharmacokinetics (PK) and explore exposure–response relationships of eight vc-MMAE ADCs, against different targets and for diverse tumor indications, using data from eight first-in-human Phase 1 studies. PK parameters of the three analytes, namely antibody-conjugated MMAE (acMMAE), total antibody, and unconjugated MMAE, were estimated using non-compartmental approaches and compared across the eight vc-MMAE ADCs. Relationships between analytes were assessed by linear regression. Exposure–response relationships were explored with key efficacy (objective response rate) and safety (Grade 2+ peripheral neuropathy) endpoints. PK profiles of acMMAE, total antibody and unconjugated MMAE following the first dose of 2.4 mg/kg were comparable across the eight ADCs; the exposure differences between molecules were small relative to the inter-subject variability. acMMAE exposure was strongly correlated with total antibody exposure for all the eight ADCs, but such correlation was less evident between acMMAE and unconjugated MMAE exposure. For multiple ADCs evaluated, efficacy and safety endpoints appeared to correlate well with acMMAE exposure, but not with unconjugated MMAE over the doses tested. PK of vc-MMAE ADCs was well characterized and demonstrated remarkable similarity at 2.4 mg/kg across the eight ADCs. Results from analyte correlation and exposure–response relationship analyses suggest that measurement of acMMAE analyte alone might be adequate for vc-MMAE ADCs to support the clinical pharmacology strategy used during late-stage clinical development.

Surgery is an established and increasingly utilized treatment option in medically refractory temporal lobe epilepsy. Many psychiatric problems are known to complicate in the postoperative period. Most studies have a follow-up period of less than 24 months. We report the cases of three patients who developed severe psychiatric problems in the late postoperative period after successful temporal lobectomy for refractory epilepsy - Psychosis, major depression with psychosis, and severe anxiety disorder, respectively. None of the patients had past or family history of psychiatric disease. All three patients had undergone anterior temporal lobectomy on the right side for intractable epilepsy. They remained absolutely seizure-free after surgery. We conclude that psychiatric morbidity may arise de novo long after temporal lobectomy. This association between temporal lobectomy for epilepsy and late onset psychiatric morbidity should be carefully studied. Mechanisms underlying this late complication require deeper understanding of the effects of epilepsy surgery.