Vaccine Rate Coverage Forecast in Brazil: Is It Possible to Keep Polio Eradicated?

Objectives: Brazil's annual vaccination coverage rate (AVCR) for Polio has risen to alarming levels in recent years. Given the imminent possibility of the return of the disease eradicated 32 years ago in Brazil, the objective was to assess the historical data of AVCR and foresee the Brazilian performance in the next five years. Method(s): We apply a classic linear forecasting model Holt Winter (HW), composed of a forecasting equation and three corresponding smoothing equations alpha, beta, and gamma. The Polio AVCR between 1994 and 2022 was collected from the National Immunization Program and was evaluated in two stages using the R software involving (i) analysis of data, (ii) application of the HW using least squares adjustment. Result(s): The AVCR showed a growing trend between 1994 (38%) and 1999 (86%). From 2000 to 2015, the average AVCR was 78.72%, with the best coverage in 2015 (95.07%). Between 2016 and 2022, the AVCR was 66.75%, with a tendency to reduce over time. Between 2020 and 2022, AVCR had its lower result (64.44%), which can be explained by the postponement of Polio vaccination due to the COVID-19 pandemic. The best adjustment of smoothing alpha, beta and gamma was achieved (0.67, 0, 0) by HW. The forecast showed positive results in the average AVCR, with a growth of 16.71% in the next five years and with an AVCR projection of just 75.89%, in the case of no public health action is endowed by the country. To reach the best AVCR achieved in 2015, it is necessary to expand it by 48.5%. Conclusion(s): Forecasts using HW are recommended for public health monitoring, helping managers make decisions with limited resources. The results indicate that it is necessary to develop a strategic plan to expand AVCR to keep Polio eradicated from Brazil, mainly due to both disease gravity and treatment unavailability.Copyright © 2023

Comparing effects of invasive versus non-invasive ventilation on P/F ratio, CRP and respiratory rate of COVID patients, a retrospective observational study

Introduction: Some of the COVID pneumonitis patients are happily hypoxic and not showing signs of severe respiratory distress despite being significantly hypoxic,1 leading to a delay to start a timely treatment and may worsen the prognosis.2 Studies have shown that non-invasive ventilation could be used in severe COVID pneumonitis and could avoid intubation in some of those patients.3 Effects of different modalities of ventilation on the oxygenation of COVID-19 patients and on the inflammatory process accompanying COVID-19 pneumonitis need thorough investigation in a trial to reach to an understanding of the pathophysiological process and may be a guide to formulate the optimum protocol to ventilate COVID-19 patients. Objective(s): Comparing the effects of invasive versus non-invasive ventilation on P/F ratio, CRP and respiratory rate of COVID-19 patients. Method(s): In this retrospective observational study, we compared the effect of NIV on the P/F ratio, CRP trends and Respiratory rates of COVID patients during their ITU admission in comparison with intubated ventilated patients. The study was carried out in a single center in England before introduction of the Tocilizumab in the guidelines of COVID treatment and included 74 COVID patients divided in to two groups, group A which included 15 patients who were non-invasively ventilated and avoided intubation during their ITU admission while group B included 59 patients who were intubated at certain point of their course of admission. Patients Respiratory rate, modality of ventilation, time of intubation (if any), modes of ventilation, FIO2, P/F ratio and CRP trends were followed during their admission. The collected data of 3 variable (CRP, RR and P/F ratio) has been blotted and a summative means were calculated. The least square means of the linear models of the ventilated and non-ventilated patients were used to compare both groups. Result(s): 36.4 % of intubations was done before or during the first 20 hours of the ITU admissions and 50% during the first 40 hours. The study also has shown the probabilities in the difference between slopes as following. Firstly, regarding P/F ratio the probability was 0.058 in favor of non-invasive ventilation. Secondly, RR probability was <0.0001 significantly in favor of non-invasive ventilation. Lastly, CRP probability was 0.024 significantly in favor of non-invasively ventilated patients. Conclusion(s): CRP and respiratory rate were significantly less in non-invasively ventilated COVID pneumonitis patients in comparison with ventilated patients while there was no significant difference in P/F ratio trends between both groups.

Covid19 Impact OnTwelve Sectors Of The Indian Economy

This study aims to investigate the reaction of COVID-19 cases (confirmed, deaths, recovered, & active) on twelve sectors of Indian economy by using sectoral indices of national stock exchange. Daily frequency of COVID-19 case categories was obtained from Worldometer from January 30, 2020 to June 30, 2020 and dataset of daily closing prices of twelve sectoral indices (auto, banks, financial services, fast moving consumer goods, information technology, media, metal, oil & gas, pharmaceutical, public sector banks, private banks, realty sector) was obtained from national stock exchange web portal for the same period as of COVID-19. In this study, the ordinary least square regression was used to study the significance of COVID-19 cases (confirmed, deaths, recovered, & active) on twelve sectoral indices. Empirical evidence suggested no significant impact of COVID-19 cases on daily returns of twelve major sectors represented by sectoral indices except in the case of pharmaceutical sector, where daily growth in number of deaths is impacting daily returns on pharmaceutical sectoral index in a positive way. The twelve sectoral indices went into a downward spiral at the beginning of COVID-19 pandemic, but as government and central bank introduced various policy measures, the impact of COVID-19 pandemic on sectoral indices faded away.Copyright © 2020 Ubiquity Press. All rights reserved.

The Impact of Work Stress on Doctor's Performance through Employee Engagement and Moderation of the COVID-19 Pandemic (Study on Primary Health Care)

BACKGROUND: Doctors at primary health care are prone to have work stress and it can affect their performance. Employee engagement may have close relationship with the doctor's performance during the COVID-19 pandemic. AIM: This study aims to determine the relationship between work stress and the doctor's performance at primary health care using employee engagement mediation and COVID-19 pandemic moderation. METHOD(S): This research is a descriptive study using a quantitative approach which was conducted on 354 doctors at Malang primary health care. The questionnaire was analyzed using partial least square. RESULT(S): The work stress had a significant positive effect on the doctor's performances (beta = 0.257, t-stat = 3.324). Work stress has a significant positive effect on employee engagement (beta = 0.726, t-stat = 22,967). Employee engagement does not significantly affect the doctor's performance (beta = 0.044, t-stat 0.105). Employee engagement does not mediate the work stress effect on doctor's performance (beta = 0.032, t-stat = 0.105). The COVID-19 pandemic did not moderate the work stress effect on doctors' performance (beta = -0.222, t-stat = 0.981). CONCLUSION(S): Primary health care leaders still need to pay attention to factors that can reduce the doctor's performance and employee engagement, include factors that can increase the work stress during the COVID-19 Pandemic.Copyright © 2023 Fida Rahmayanti, Noermijati Noermijati, Armanu Armanu, Fatchur Rohman.

The COVID-19 Pandemic Influence on Doctor's Service Performance Using Workload as a Mediation Variable

BACKGROUND: The COVID-19 pandemic greatly affected doctors' increasing workload, especially in Primary Health Care Facilities. If this is not addressed immediately, it will affect the performance or quality of a doctor's service. AIM: This research objective is to identify the role of Primary Healthcare Facility doctors' workload in moderating the impact of the COVID-19 Pandemic on their performance. METHOD(S): The explanatory-descriptive research was conducted using a quantitative approach. The research respondents were 103 general practitioners who worked at a Primary Healthcare Facility in Malang City (35.0% male and 65.0% female, the most extensive age range was 26-35 years (74.8%), with a working period of 1-5 years. 57 (55.3%) The research instrument was a questionnaire declared valid and reliable, distributed online, and analyzed using Partial Least Square. RESULT(S): The findings demonstrated that the COVID-19 pandemic significantly positively affected the performance of Primary Healthcare Facility doctors (beta = 0.455, t stat = 11.390). The pandemic also significantly impacted workload (beta = 0.283, t stat = 4.347). Workload impacted performance significantly and positively (beta = 0.224, t stat 4.157). Workload mediates the COVID-19 Pandemic influence on doctors' performance (beta = 0.063, t stat = 3.005). CONCLUSION(S): Doctors at Primary Health Care have not all experienced a decline in performance despite the increased workload due to the COVID-19 Pandemic. It forces doctors to juggle between completing their tasks, fighting against disease, and improving their performance.Copyright © 2023.

Computed Tomography Simulator (Ctlab)

University of Oulu and Oulu University of Applied Sciences have established a unique medical imaging teaching and testing laboratory in collaboration with Oulu University Hospital in a European Regional Development Fund -project. Virtually implemented medical imaging devices (CT, MRI, radiography) are unique features of the lab. Many of the virtual tools have been developed by the universities themselves. One of the virtual tools implemented during the project is the CTlab simulator, which can be widely used in computed tomography training for all professionals who use radiation in their work. The CTlab provides fast, comprehensive, and efficient solutions for numerical CT simulations with low hardware requirements. The simulator has been developed to introduce the basic operations and workflow behind the CT imaging modality and to illustrate how the polychromatic x-ray spectrum, various imaging parameters, scan geometry and CT reconstruction algorithm affect the quality of the detected images. Key user groups for the simulator include medical physics, engineering, and radiographer students. CTlab has been created with MATLAB's app designer feature. It offers its user the opportunity to select the virtual imaging target, to adjust CT imaging parameters (image volume, scan angles, detector element size and detector width, noise, algorithm/geometry specific parameters), to select specific scan geometry, to observe projection data from selected imaging target with polychromatic x-ray spectrum, and to select the specific algorithm for image reconstruction (FBP, least squares, Tikhonov regularization). The CTlab has so far been used at a postgraduate course on computed tomography technology with encouraging feedback from the students. At the course, teaching of CT modality were performed by using the simulator, giving students unlimited opportunity to practice the use of virtual imaging device and participate demonstrations remotely during the Covid-19 pandemic. Using CTlab in teaching enhances and deepens the learning experience in the physics behind computed tomography. CTlab can be used remotely (https://www.oulu.fi/fi/projektit/laaketieteellisen-kuvantamisen-opetus-ja-testilaboratorio-0), which makes teaching and training of CT scanner usage successful regardless of time and place. The simulator enables more illustrative and in-depth teaching and offers cost-effectiveness, versatility, and flexibility in education. CTlab can also be used to support teaching in special situations, such as during the Covid-19 pandemic when simulator is utilized remotely to perform teaching-related demonstrations flexibly and safely.Copyright © 2023 Southern Society for Clinical Investigation.

Using Telehealth through the Mobile Channel to Reduce Health Inequality and Disparity: A Real-World Study Examining Patients with Type 2 Diabetes Mellitus

Background and Aims: COVID-19 led to digital acceleration, raising alarms that minorities (Black/Hispanic) would be left further behind. Did patients with type 2 diabetes (PwT2D) who rely on routine care change their use of health IT resources? Methods: Using longitudinal patient portal usage data of 55,548 PwT2Dfroman urban hospital in the U.S.,we examinedmobile-vsdesktop internet access before-and-after COVID-19. We constructed threemodels using the panel dataset: pooled Ordinary Least Squares (OLS), random effect (RE), and fixed effect (FE). Result(s): The interaction of COVID-PeriodxMinority across the three models (OLS/RE/FE) was significant and showed racial disparity is increasing for desktop use (beta= -0.052/-0.053/-0.054) and decreasing for mobile use (beta = 0.026/0.025/0.025). COVID- 19 has reduced the gap by 34% (0.025/0.073) according to the RE model. Table 1 shows that racial disparity shrinkage is largely driven by the use of mobile communication. Conclusion(s): COVID-19 is a natural experiment providing the opportunity to investigate whether accelerated digitization impacted health inequality and disparity among PwT2D. The effect is mostly driven by mobile device access and cannot be explained by pre-COVID-19 trends. First, COVID-19 has been cited as a ''great magnifier'' of pre-existing racial inequality in health;however, telehealth can become a ''great equalizer'' for reducing inequity. Second, in the U.S., much effort in combating the digital divide has focused on the broadband connectivity gap;the transformative potential of mobile health is overlooked. Third, the lack of access to patient portals has disadvantaged PwT2D minorities;so long as they have access, they can ''catch up.'' NIH Award 5UL1TR001425-03.

Proteomic profiling of severe lung diffusion impairment in the recovery stage of COVID-19-induced ARDS

Background: Around 80% of patients who developed COVID-19-driven ARDS present lung ailment. There is a lack of knowledge of the mechanisms that mediate the pulmonary outcomes. Aim(s): To characterize the factors linked to diffusion impairment in survivors of severe COVID-19. Method(s): Prospective cohort study including 87 COVID-19-induced ARDS survivors. A complete pulmonary evaluation was performed 3 months after hospital discharge. 364 proteins were quantified using the proximity extension assay (PEA). Partial least square-discriminant analysis (PLS-DA) and random forest (RF) were used for multivariable analyses. Result(s): Moderate to severe diffusion impairment (DLCO<60% predicted) was observed in the 30% of the cohort. 15 proteins were differentially detected [false discovery rate (FDR)<0.05] in the univariate analysis. Pleiotrophin showed the highest differences (fold change=2.22 and FDR=0.001). In continuous analysis, proteins were inversely and independently associated with DLCO, and in some cases showed a robust dose-response relationship. PLS-DA and RF identified proteomic profiles related to the severity of diffusion capacity. Clusters identified were enriched in mediators of cell proliferation and differentiation, tissue remodeling, angiogenesis, coagulation, inflammation, immune response and fibrosis. Proteins are expressed in immune and non-immune lung cells. Conclusion(s): In survivors of COVID-19-driven ARDS, lung dysfunction is linked to plasma factors involved in injury and repair mechanisms. The host proteomic profile provides a novel understanding of post-acute sequelae and may be source of therapeutic strategies and biomarkers.

Empirical Modeling for Reported Cases and Deaths of Covid-19 in Egypt during the Accelerated Spread and Prediction of the Delayed Phase

This is a newly developed conceivable mathematical model for analyzing the spreading behavior of COVID-19 during the first wave of the pandemic in Egypt. We emphasized the impact of detection and control measures in flattening the spread of disease. This knowledge of the early spread dynamics of infection and assessing the efficiency of control measures is critical for reviewing and evaluating the potential for sustained transmission to occur during the coming waves. This proposed empirical model for the accelerated spread phase is based on non-linear regression technique, interpolations, tangents, least-square, and optimization methods to delimit different phases of the pandemic and predict the delayed phase. We prove that our model is mathematically consistent and present various simulation results using the best-estimated parameter value. The model can be easily updated when restrictions and other issues become changed. These simulation results may guide the local authorities to make timely right decisions. Copyright © 2022 Assiut University. All rights reserved.

Impact of the SARS-CoV-2-Neutralizing Antibody Combination AZD7442 (Tixagevimab/Cilgavimab) on the Severity and Progression of COVID-19 Symptoms in the Phase 3 TACKLE Trial

Background. Outpatient treatment with SARS-CoV-2-neutralizing antibody combination AZD7442 (tixagevimab/cilgavimab) in adults with mild to moderate COVID-19 significantly reduced progression to severe disease or death through Day 29 and was well-tolerated in the Phase 3 TACKLE study (NCT04723394). We report a post hoc analysis of the impact of AZD7442 in reducing self-reported COVID-19 symptom severity and time to symptom resolution through Day 29 in TACKLE. Methods. In TACKLE, non-hospitalized adults with mild to moderate COVID-19 were randomized 1:1 and dosed <=7 days from symptom onset with a single 600mg AZD7442 dose (2 consecutive intramuscular (IM) injections, 300 mg of each antibody;n=452) or placebo (n=451). Symptom occurrence and severity were self reported daily by participants through study Day 29. Participants rated each symptom as not experienced, mild, moderate, severe, or emergency room (ER) or hospital visit. Symptom progression was compared between AZD7442 and placebo using a stratified Cochran-Mantel-Haenszel test. Change from baseline in symptom severity was compared using a mixed model for repeated measures. Time to symptom resolution was compared using Kaplan-Meier and Cox proportional hazards methods. Missing symptom data for those who were hospitalized or died were imputed as either failures or as severity scores of ER or hospital visit. Results. Progression of >=1 symptoms to a worse severity score occurred in 170 (55.7%) AZD7442- versus 204 (63.4%) placebo-treated participants, translating to a nominally significant relative risk reduction of 12.5% (95% confidence interval 0.5- 23.0;P=0.041). Over 29 days, the overall mean improvement from baseline in severity of body aches, chills, cough, diarrhea, fatigue, headache, muscle aches, nausea, and runny nose was significantly greater with AZD7442 versus placebo (Figure). The greatest improvements were observed with cough, fatigue, and muscle aches. Significant differences were observed for most symptoms within 1 and 2 weeks post AZD7442 dosing. Figure. Forest plot for LS difference in severity of COVID-19 symptoms between AZD7442 and placebo through Day 29 CI, confidence interval;LS, least squares. The overall P value is calculated using a mixed model for repeated measures, including terms for symptom severity baseline value, time from symptom onset (<=5 vs >5 days), risk of progression to severe COVID-19 (high vs low), treatment, visit, and treatment by visit interaction. Conclusion. For the treatmentofmildtomoderateCOVID-19,a single IM600-mg AZD7442 dose was associated with reductions in progression of COVID-19 symptom severity and may hasten symptom improvement through Day 29.

Possible Impact of functional active GPCRautoantibodies on retinal microcirculation in Long-COVID

Purpose : Long-COVID is assumed to have an autoimmune component. As a seropositivity of functional active autoantibodies against G-protein coupled receptors (GPCR-AAb) and an impaired retinal microcirculation, measured by OCT-angiography (OCT-A), was observed after COVID-19 infection, it was the aim of the present study to investigate the impact of GPCR-AAbs on retinal microcirculation in patients with LongCOVID. Methods : Seventy-six patients with Long-COVID (COVID-19 infection was confirmed by real time rt-PCR) were recruited. A seropositivity for GPCR-AAbs (Nociceptin-AAb, ß2-AAb, AT1-AAb, α1-AAb, MAS-AAb, M2-AAb, ETA-AAb) was analyzed by a specific rat cardiomyocyte bioassay in vitro. Macular (superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP)) and peripapillary vessel density (VD) were measured by OCT-A (Spectralis II, Heidelberg, Germany). VD analysis was done by the Erlangen-Angio tool, including an APSifyed and Bruch's membrane opening (BMO) based analysis. Data were analyzed by mixed model (SAS version 9.4). Gender and age were set as covariates. The study was approved by the local ethics committee and was done in accordance with the tenets of the Declaration of Helsinki. Informed consent was achieved. Results : All patients with Long-COVID showed a seropositivity for GPCR-AAbs (100%). Female patients with Long-COVID showed lower macular and peripapillary VD compared to men. A significant effect of a seropositivity of AT1-AAb on age-corrected least squares means (LS-means) overall VD of DCP ([CI: 0,25;6.07], p=0.03). A seropositivity of α1-AAb showed a significant effect on age-corrected LS-mean overall VD of SVP ([CI: 0.07;2.69], p=0.04), of DCP ([CI: 0.36;3.25], p=0.01), and of PH ([CI: 1.17;5.59], p=0.01), respectively. A seropositivity of MAS-AAb yielded a significant effect on age-corrected LS-mean overall VD of DH (CI: 1.48;6.07, p=0.001). A seropositivity of ß2-AAb has a significant effect on agecorrected LS-mean overall VD of MH (CI: 0,02;1,94, p=0.04). For those effects, the covariate age was significant in the type III tests (p<0.05), thus analysis was done considering this age-effect. Conclusions : As autoimmune mechanisms were reported to be involved in the pathogenesis of Long-COVID, we postulate that functional active GPCR-AAb may have an impact on retinal microcirculation, being a propable correlate to systemic disease.

E-books Purchase Intention During the Covid-19 Pandemic in Southern Region of Malaysia

This study aims to explore the effects of price, accessibility, and brand image on e-books purchase intention in Southern Region of Malaysia. A total of 237 questionnaires were collected online from e-book users.Partial least square structure equation modeling was employed to evaluate the research model and hypotheses.The results showed that only price had a positive effect on e-books purchase intention, but accessibility and brand image do not have significant effect on e-books purchase intention.This research givesremarkable theoretical contributionsby exploringthese elements amidst the COVID-19 situation as components of theory of reasoned action,and their effects on e-books purchase intention. This study likewise gives imperative insights to business organizations especially book publisher to consider better price as the business initiative to gain a competitive advantage in the market.

A RANDOMISED PHASE i PHARMACOKINETIC STUDY COMPARING HIGH-CONCENTRATION, LOW-VOLUME, and CITRATE-FREE SB5 (40 MG/0.4 ML) with PRIOR SB5 FORMULATION, and ADALIMUMAB BIOSIMILAR, in HEALTHY MALE SUBJECTS

Background: SB5, an adalimumab (ADL) biosimilar, was developed in a low-concentration (40 mg/0.8 mL, SB5-LC) aligned with the reference ADL product. Pharmacokinetics (PK) equivalence of SB5 and reference ADL was demonstrated in a Phase I study conducted in healthy subjects1. Equivalent efficacy and comparable safety between 40 mg/0.8 mL SB5 and 40 mg/0.8 mL reference ADL were demonstrated in a Phase III study conducted in patients with rheumatoid arthritis2. High-concentration, low-volume, citrate-free SB5 (40 mg/0.4 mL, SB5-HC) has been developed as a part of life cycle management in line with the reference ADL formulation. Objectives: To compare the PK, safety, and tolerability of the newly developed SB5-HC (40 mg/0.4 mL) to prior SB5-LC (40 mg/0.8 mL) in healthy male subjects. Methods: This study was a randomised, single-blind, two-arm, parallel group, single-dose study in healthy male subjects. Subjects were randomised in a ratio of 1:1 to receive a single dose of either SB5-HC or SB5-LC by subcutaneous injection on Day 1 and then observed for 57 days during which the PK, safety, and immunogenicity were evaluated. The serum concentration of ADL was measured using an enzyme-linked immunosorbent assay. The primary PK parameters were area under the concentration-time curve from time zero to infnity (AUCinf) and maximum serum concentration (Cmax). Equivalence for the primary PK parameters was to be concluded if the 90% confdence intervals (CIs) for the ratio of geometric least squares means (LSMeans) of the treatment groups compared were completely contained within the pre-defned equivalence margin of 0.80 to 1.25 using an analysis of variance. Results: Of 188 randomised subjects, 187 subjects were analysed as PK Analysis Set (PKS) (n=93 in SB5-HC and n=94 in SB5-LC). One subject was excluded from the PKS in SB5-HC group (major protocol deviation for not being withdrawn in the event of confrmed COVID-19). The geometric LSMeans ratios for the comparison of SB5-HC and SB5-LC for AUCinf and Cmax were 0.920 and 0.984, respectively, and the corresponding 90% CIs were within the pre-defned equivalence margin of 0.80 to 1.25 (Table 1), indicating the two treatment groups are bioequivalent. There were no deaths, serious adverse events or discontinuation of the study due to treatment-emergent adverse events (TEAEs) during the study. The proportions of subjects who experienced TEAEs were comparable between the two treatment groups (44.7% in SB5-HC vs 51.1% in SB5-LC). The most frequent TEAEs were headache (10.6% in SB5-HC vs 12.8% in SB5-LC). Conclusion: This study demonstrated PK equivalence between SB5-HC and SB5-LC in healthy subjects. Both SB5-HC and SB5-LC were generally well tolerated with similar safety profiles.

Temporal analysis of meningitis and its sociodemographic risk factors in Brazil over the last decade

Background and aims: This paper aims to evaluate the risk factors for hospitalizations for meningitis in Brazil and whether COVID-19 has an influence on this process. Methods: The patients' data is from the Notifiable Diseases Information System of Brazil's Ministry of Health. The lethality and odds ratio analyses were performed in the OpenEpi software using the Taylor Series with an IC95%. The temporal analysis is from January 2010 to November 2021, collected from the Hospitals' Information System of the Unified Health System. The statistical modelling used Gretl software and the US Census Bureau's X-13-ARIMASEATS tool (1.1). The adjustment statistics were calculated using MS Excel. We also checked the influence of COVID- 19 on the subject. Results: Aetiology, age, ethnicity, region and municipal income were considered statistically significant risk factors for unfavourable outcomes in meningitis. The sex category did not show a significant difference in meningitis lethality (Table 1). Regarding the temporal analysis, the best ARIMA models were (0,1,1,) x (0,0,0) for the North region and (0,1,1) x (0,1,1) for the others regions. All models proved to be more efficient than the naive prediction (MASE <1;Theil's U<1) and obtained R2 above 85% (Table 2). The trend of hospitalizations has been negative since 2020. Least squares regression showed that the COVID-19 was statistically significant in reducing hospitalization values in all Brazilian regions. Conclusion: It is possible that the measures against Sars- CoV-2 have contributed to reducing the hospitalizations by meningitis. (Figure Presented).

JAPAN PROSPECTIVE MULTICENTER STUDY FOR OPTIMIZATION OF COVID-19 VACCINATIONS BASED ON THE IMMUNE RESPONSE AND SAFETY PROFILE IN INFLAMMATORY BOWEL DISEASE PATIENTS: INTERIM ANALYSES

Background: Immune responses to the SARS-CoV-2 vaccination may be influenced by immunomodulatory drugs (IMDs). We investigated the immune responses and safety in fully vaccinated Japanese patients with IBD. Subjects and Methods: IBD patients and control subjects at 39 institutes were invited to participate in the study from March to October 2021. Blood sample collections to measure anti-SARS-CoV-2 spike IgG antibody titers were planned pre-1st vaccination, pre-2nd vaccination, and at 4 weeks, 3 months and 6 months post-2nd vaccination. Immune responses were compared between groups, considering baseline characteristics and IMD treatments. (UMIN000043545) The interim analyses presented here include mainly data from the 4-weeks post-2nd vaccination time-point. Results: In total, 679 IBD patients and 203 controls were enrolled (Table 1). The IBD group received the BNT162b2 vaccine (86.2%) and the mRNA-1273 vaccine (12.5%), and the control group received the BNT162b2 vaccine (86.9%) and the mRNA-1273 vaccine (12.1%). Only 4 cases (0.7%) in the IBD group and 2 (1.0%) in the control group were infected with COVID-19. Adverse events of 2nd vaccination occurred in 48.4% of the IBD group and 35.1% of the control group. Comparison between administrated and non-administrated IBD patients for each IMD revealed an attenuated genomic mean titer (GMT [U/mL]) in those taking systemic steroids (18.85 vs 31.24), anti-TNF monotherapy (28.31 vs 42.99), anti- TNF therapy+ immunomodulator (IM) (12.86 vs 35.26), vedolizumab+IM (19.49 vs 30.39), ustekinumab+IM (20.44 vs 30.79), and tofacitinib (9.54 vs 32.08), but not in those taking oral 5-ASA (29.50 vs 32.40), or vedolizumab (41.85 vs 40.20) and ustekinumab (55.56 vs 39.26) monotherapies. Estimated least square means of the GMT by a multiple linear regression model are shown in Table 2. GMTs were significantly influenced by increasing age and allergy (51.2, 95%CI 42.1-62.3;p=0.0293), and tended to be influenced by COVID- 19 infection (139.1, 41.0-472.2;p=0.0572). Sex, smoking, drinking, IBD, and adverse events of 2nd vaccination did not affect the GMT. The GMT was significantly higher for mRNA- 1273 (90.3 [60.8-134.1]) than for BNT162b2 (39.6 [35.2-44.6], p= 0.0001). Systemic steroids (22.9 [13.9-37.7], p=0.0119), IM (24.2 [18.7-31.4], p<0.0001), anti-TNF agents (20.8 [15.3-28.3], p<0.0001), vedolizumab (25.2 [15.0-42.2], p=0.0409), ustekinumab (28.9 [18.5-45.0], p=0.0754), and tofacitinib (5.5 [2.8-10.9], p<0.0001), but not oral 5- ASA (39.1 [31.9-47.9], p=0.3225), attenuated GMTs at 4 weeks post-2nd vaccination (Table 2). Conclusion: Aging and most IMD options attenuated immunogenicity in fully vaccinated IBD patients. Prioritization of a booster vaccination should be considered for IBD patients treated with IMDs. (Table Presented) (Table Presented)

Respiratory Safety of Lemborexant in Adult and Elderly Subjects with Moderate to Severe Obstructive Sleep Apnea: A Randomized, Double-blind, Placebo-controlled, Crossover study

Introduction: A safety risk of some commonly prescribed sleep-promoting drugs, including benzodiazepines and nonbenzodiazepine receptor agonists, is central respiratory depression. Subjects with coexisting respiratory disease such as obstructive sleep apnea (OSA), and/or the elderly, are particularly at risk. Lemborexant (LEM) is a dual orexin receptor antagonist (DORA) approved in multiple countries for the treatment of adults with insomnia. In study 102 (E2006-A001-102;NCT03471871), no differences between LEM 10 mg (LEM10) and placebo (PBO) were found on peripheral oxygen saturation (SpO2) and the apnea-hypopnea index (AHI) in adult and elderly subjects with mild OSA following a single dose and multiple doses. Study 113 (E2006-A001-113;NCT04647383) is the first to investigate the effect of LEM on respiratory safety in adults and elderly subjects with moderate to severe OSA. Materials and Methods: This was a multicenter, multiple-dose, randomized, double-blind, PBO-controlled, 2-period crossover study in adult (age ≥45 to <65y) and elderly (age ≥65 to ≤90y) subjects with moderate (15≤AHI<30) to severe (AHI≥30) OSA. Subjects were randomized to two 8-night treatment periods (separated by a washout ≥14d) with either LEM10 or PBO. In-lab polysomnography and transmissive pulse oximetry were performed at screening, on Day 1 (after a single dose) and Day 8 of study drug during both treatment periods. Treatment-emergent adverse events (TEAEs) were recorded throughout the study. Results: Forty-eight subjects were screened;33 (68.8%) were randomized;of these n=13 had moderate OSA and n=20 had severe OSA. Mean age was 60.6y;22/33 subjects (66.7%) were age ≥45 to <65y and 11/33 (33.3%) were ≥65 to ≤90y. During total sleep time, mean baseline SpO2 was 93.5% and mean AHI for moderate OSA and severe OSA groups together (n=33) was 44.2. No significant difference was found in AHI (least squares mean [LSM]) after a single dose or multiple doses of LEM10 versus PBO in subjects with moderate (single: LEM10, 31.49;PBO, 32.41, P=0.818;multiple: LEM10, 34.66;PBO, 37.16, P=0.442) or severe (single: LEM10, 48.22;PBO, 52.69, P=0.172;multiple: LEM10, 51.48;PBO, 51.15, P=0.902) OSA. LEM10 versus PBO was also not significantly different for SpO2 (LSM with moderate [single: LEM10, 93.68;PBO, 93.86, P=0.696;multiple: LEM10, 93.74;PBO, 93.86%, P=0.784] or severe [single: LEM10, 92.57;PBO, 92.65, P=0.841;multiple: LEM10, 92.63;PBO, 93.02, P=0.283] OSA). Furthermore, no significant difference was found in percentage of total sleep time during which SpO2 was below the thresholds of <90%, <85%, <80% for LEM10 vs PBO following a single dose (P=0.694, P=0.134, P=0.195, respectively) or multiple doses (P=0.481, P=0.711, P=0.699, respectively) in subjects with moderate or severe OSA. TEAEs were higher with LEM10 (18.2%) versus PBO (9.1%). One subject did not complete treatment due to an adverse event unrelated to LEM10 (COVID-19). Overall, LEM was well tolerated, and most TEAEs were mild. Conclusion: As objectively measured by AHI and SpO2 during TST, LEM, a DORA, demonstrated respiratory safety with single and multiple dosing in subjects with moderate and severe OSA, and was well tolerated. Acknowledgements: Supported by Eisai, Inc.

Millennial’s Decision to Pay ZISWAF During the Covid-19 Pandemic in Indonesia

The purpose of this study aims to analyze the effect of the level of altruism, trust and income on the millennial decision to pay ZISWAF during the Covid-19 pandemic and analyze the effect of the level of religiosity moderating the influence of altruism, trust and income on the millennial decision to pay ZISWAF during the Covid-19 pandemic. This research uses a quantitative with data analysis Partial Least Square-Structural Equation Modeling (PLS-SEM). The result of this study shows the level of altruism and income has a positive and significant impact on millennials' decisions to pay ZISWAF during the Covid-19 pandemic. However, trust in institutions has no significant effect on millennials' decisions to pay ZISWAF during the Covid-19 pandemic. Meanwhile, the moderating effect of the level of religiosity on altruism and trust was not able to strengthen the millennial decision to pay ZISWAF during the Covid-19 pandemic, while the moderating effect of religiosity on income was able to strengthen the millennial decision to pay ZISWAF during the Covid-19 pandemic. Based on research, factors of altruism, trust and income will affect it. Therefore, it is hoped that the role of the government or relevant stakeholders is to optimize the potential and opportunities that exist.

VOCLOSPORIN FOR LUPUS NEPHRITIS: RESULTS OF THE TWO-YEAR AURORA 2 CONTINUATION STUDY

BACKGROUND AND AIMS: Voclosporin, a novel calcineurin inhibitor, was approved in the USA in January 2021 for the treatment of adult patients with active lupus nephritis in combination with background immunosuppressive therapy. Voclosporin has a favorable metabolic profile and a consistent dose-concentration relationship, eliminating the need for therapeutic drug monitoring. Previously reported results from the Phase 2 AURA-LV and Phase 3 AURORA 1 studies showed that the addition of voclosporin to mycophenolate mofetil (MMF) and low-dose steroids in patients with lupus nephritis significantly increased rates of complete renal response at 48 weeks (AURA-LV) and 52 weeks (AURORA 1). Here we report the results of the completed continuation study, AURORA 2, which assessed the long-term safety and tolerability of voclosporin compared with placebo in patients with lupus nephritis receiving treatment for an additional 24 months following completion of the AURORA 1 study. METHOD: Key inclusion criteria for the parent AURORA 1 study included a diagnosis of biopsy-proven active lupus nephritis (Class III, IV, or V ± III/IV), proteinuria ≥ 1.5 mg/mg (≥2 mg/mg for Class V) and estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2. Patients who completed AURORA 1 were eligible to enroll in AURORA 2 and continued with the same blinded treatment of voclosporin (23.7 mg BID) or placebo in combination with MMF (target dose 2 g/day) and lowdose oral steroids. Safety and tolerability were evaluated by monitoring adverse events and laboratory assessments including eGFR;changes in urine protein creatinine ratio (UPCR) were also assessed. RESULTS: In total, 116 patients in the voclosporin arm and 100 patients in the control arm enrolled in AURORA 2, with 92 (79.3%) and 73 (73.0%) patients in each respective arm completing treatment to the end of AURORA 2. There were no new or unexpected safety signals detected in patients who continued on treatment with voclosporin compared to control-treated patients. Rates of serious adverse events in the voclosporin (19.0%) and control arms (24.0%) were similar, with eight serious adverse events of infection in each arm. Estimated glomerular filtration rate remained stable through the end of AURORA 2 (Figure 1). The slopes of the least-squares (LS) mean change in corrected eGFR from AURORA 2 baseline to end of study were -0.2 [95% confidence interval (CI) -3.0 to 2.7' in the voclosporin arm and -5.4 (95% CI -8.4 to -2.3) in the control arm. There were no deaths in the voclosporin arm during AURORA 2;four deaths were reported in the control arm due to pulmonary embolism (n = 1) and coronavirus infection (n = 3). The LS mean reductions in UPCR observed in AURORA 1 were maintained in AURORA 2 with no increase in UPCR noted at the follow-up visit 4 weeks after study drug discontinuation (Figure 2). CONCLUSION: Voclosporin was well-tolerated over three years of treatment with a similar safety profile to control and no unexpected safety signals detected. Further, the significant and meaningful reductions in proteinuria initially achieved in AURORA 1 were maintained throughout AURORA 2. These data provide evidence of a long-term treatment benefit of voclosporin in patients with lupus nephritis. (Figure Presented).

Covid19 Impact OnTwelve Sectors Of The Indian Economy

This study aims to investigate the reaction of COVID-19 cases (confirmed, deaths, recovered, & active) on twelve sectors of Indian economy by using sectoral indices of national stock exchange. Daily frequency of COVID-19 case categories was obtained from Worldometer from January 30, 2020 to June 30, 2020 and dataset of daily closing prices of twelve sectoral indices (auto, banks, financial services, fast moving consumer goods, information technology, media, metal, oil & gas, pharmaceutical, public sector banks, private banks, realty sector) was obtained from national stock exchange web portal for the same period as of COVID-19. In this study, the ordinary least square regression was used to study the significance of COVID-19 cases (confirmed, deaths, recovered, & active) on twelve sectoral indices. Empirical evidence suggested no significant impact of COVID-19 cases on daily returns of twelve major sectors represented by sectoral indices except in the case of pharmaceutical sector, where daily growth in number of deaths is impacting daily returns on pharmaceutical sectoral index in a positive way. The twelve sectoral indices went into a downward spiral at the beginning of COVID-19 pandemic, but as government and central bank introduced various policy measures, the impact of COVID-19 pandemic on sectoral indices faded away.

COMPARISON OF MOVEMENT PATTERN TRAINING AND JOINT MOBILIZATION FOR CHRONIC PREARTHRITIC HIP DISORDERS: A PILOT RANDOMIZED CLINICAL TRIAL

Purpose: A clear need exists to rigorously assess treatment strategies for chronic prearthritic hip disorders (PAHD). We assessed the preliminary effects of two physical therapist-led interventions that target two distinct mechanisms, abnormal movement patterns and sensory disturbances. Abnormal movement patterns, such as excessive hip adduction, may create altered mechanical stresses on hip joint structures, resulting in subsequent injury, pain and activity limitations. Movement pattern training (MoveTrain) may improve movement patterns and patient-reported outcomes, however further investigation is needed to be definitive. Sensory disturbances such as peripheral sensitization and central sensitization (aka nociplastic pain) may also contribute to pain persistence long after an initial injury. Joint mobilization (JtMob) is proposed to impart a neurophysiological response within the peripheral and central nervous system that results in pain reduction and improved mobility, yet the investigation of JtMob for the treatment of PAHD is limited. Methods: Patients, 18-40 years, with chronic PAHD were recruited. Baseline assessment included self-report questionnaire completion, clinical examination and quantitative sensory testing. The primary outcome was the Hip disability and Osteoarthritis Outcome Score (HOOS), a hip-specific, patient-reported outcome measure. Secondary outcomes included movement evoked pain assessed with a repetitive step down task and a repetitive deep squat task, and pain pressure threshold assessed at the anterior groin of the most bothersome hip (local pressure hypersensitivity) and the dominant thenar eminence (generalized pressure hypersensitivity). After baseline assessment, patients were randomized into 1 of 2 treatment groups, MoveTrain or JtMob. Randomization was stratified by sex and HOOS Symptoms quartile, as determined from data collected during previous study. Treatment was provided by 4 experienced physical therapists (2 in each treatment arm) who were trained in standardized procedures. Treatment for both groups included 10 supervised sessions over 12 weeks and incorporated assessment of patient goals, patient education and instruction in a home program. Patient education focused on patient-specific tasks, such as work or fitness activities, identified by each patient to be symptom-producing. The goal of MoveTrain was to reduce stresses on the hip joint by optimizing the biomechanics of daily and patient-specific tasks. The key element of MoveTrain was task-specific instruction to correct abnormal movement patterns demonstrated during daily tasks and patient-specific tasks. For example, hip adduction and femoral internal rotation were minimized during step-down tasks. The home program included repeated practice of the modified tasks. Difficulty of the tasks were progressed based on each patient’s performance. The goal of JtMob was to reduce pain and improve pain-free motion of the hip. The key element of JtMob was manual techniques provided by the physical therapist. Specific criteria were used to determine the joint mobilization techniques and parameters used for each patient. The patient’s symptom report to each technique was monitored and if indicated, the technique modified according to our outlined procedures. The home program included flexibility exercises. Immediately after treatment completion, patients returned for follow up assessment. Data collected at baseline and post-treatment were analyzed with analysis of covariance (ANCOVA) using a generalized linear model where change is the dependent variable and baseline is the covariate. The adjusted immediate treatment effect was calculated by subtracting the least squares mean change between baseline and post for MoveTrain minus JtMob from the ANCOVA, and assesses the between-group difference in change after adjusting for baseline. Results: Thirty-three patients with PAHD were randomized. Demographics are provided in Table 1. Four patients did not complete treatment or post-treatment testing (3 due to COVID pandemic, 1 lost t follow up);7 patients did not complete post-treatment laboratory testing (due to COVID), but did complete post-treatment questionnaires. Both groups demonstrated clinically important within-group improvements in the HOOS subscales and movement evoked pain ratings after treatment (Table 2). No changes were noted in pain pressure threshold for either group. After adjusting for baseline, there were no between-group differences in change in outcomes when comparing MoveTrain and JtMob. Conclusions: Our preliminary findings suggest that 12 weeks of physical therapist-led intervention, including either MoveTrain or JtMob, may result in improvements in patient-reported pain and activities limitations. Further investigation is needed to determine the sustained effects of each treatment and to determine if specific patient factors are associated with treatment prognosis. [Formula presented] [Formula presented]