Point of care ultrasound findings in critically ill SARS-COV2 patients in an HIV endemic, resourced constrained setting.

Objectives: To describe the incidence of venous thromboembolism (VTE) in mechanically ventilated COVID-19 patients in an HIV endemic, resourced constrained setting. To describe the incidence of VTE in relation to HIV status and anticoagulant therapy, and to evaluate VTE-associated cardio-respiratory changes. To establish the contribution of HIV, anticoagulation therapy and other risk factors to mortality. Design: Prospective descriptive study. Setting: Single-center tertiary teaching hospital. Participants: One hundred and one consecutively admitted critically ill adult patients with COVID-19 acute respiratory distress syndrome. Interventions: Point of care ultrasound (POCUS) assessment of the lower limbs and the cardio-respiratory system was performed on intensive care unit (ICU) admission and repeated if clinically indicated. Measurements and main results: DVT was diagnosed by POCUS, whilst pulmonary embolism was diagnosed using a combination of clinical criteria and POCUS (echocardiography and chest wall ultrasound). VTE was diagnosed in 16/101 (16%) patients, despite 14/16 (88%) receiving prior therapeutic dosage of low molecular weight heparin. Clinically significant PE was diagnosed in 5/16 (31%) with 11/16 (69%) having DVT only. The majority of VTE patients, 12/16 (75%), demised 16/101 (16%) patients had HIV co-infection, and 4/16 (25%) with HIV had VTE. Valvular abnormalities were the most common cardiac abnormality with marked tricuspid regurgitation detected in 51/101 (51%). The absence of right atrial enlargement had a 93% negative predictive value for the absence of VTE. Univariate analysis did not demonstrate statistically significant individual risk factors for mortality. Conclusions: Mechanically ventilated COVID- 19 patients at ICU admission had a low incidence of VTE (16%). Therapeutic dose anticoagulation did not reduce mortality compared to prophylactic dosage. In contrast to findings from other studies, no individual risk factor contributed significantly to mortality, likely due to small sample size. POCUS is an ideal screening tool to aid in the assessment of critically ill patients.

Vascular thrombosis after single dose Ad26.COV2.S vaccine in healthcare workers in South Africa: open label, single arm, phase 3B study (Sisonke study).

Objective: To assess the rates of vascular thrombotic adverse events in the first 35 days after one dose of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in healthcare workers in South Africa and to compare these rates with those observed in the general population. Design: Open label, single arm, phase 3B study. Setting: Sisonke study, South Africa, 17 February to 15 June 2021. Participants: The Sisonke cohort of 477 234 healthcare workers, aged ≥18 years, who received one dose of the Ad26.COV2.S vaccine. Main outcome measures: Observed rates of venous arterial thromboembolism and vaccine induced immune thrombocytopenia and thrombosis in individuals who were vaccinated, compared with expected rates, based on age and sex specific background rates from the Clinical Practice Research Datalink GOLD database (database of longitudinal routinely collected electronic health records from UK primary care practices using Vision general practice patient management software). Results: Most of the study participants were women (74.9%) and median age was 42 years (interquartile range 33-51). Twenty nine (30.6 per 100 000 person years, 95% confidence interval 20.5 to 44.0) vascular thrombotic events occurred at a median of 14 days (7-29) after vaccination. Of these 29 participants, 93.1% were women, median age 46 (37-55) years, and 51.7% had comorbidities. The observed to expected ratios for cerebral venous sinus thrombosis with thrombocytopenia and pulmonary embolism with thrombocytopenia were 10.6 (95% confidence interval 0.3 to 58.8) and 1.2 (0.1 to 6.5), respectively. Because of the small number of adverse events and wide confidence intervals, no conclusions were drawn between these estimates and the expected incidence rates in the population. Conclusions: Vaccine induced immune thrombocytopenia and thrombosis after one dose of the Ad26.COV2.S vaccine was found in only a few patients in this South African population of healthcare workers. These findings are reassuring if considered in terms of the beneficial effects of vaccination against covid-19 disease. These data support the continued use of this vaccine, but surveillance is recommended to identify other incidences of venous and arterial thromboembolism and to improve confidence in the data estimates. Trial registration: ClinicalTrials.gov NCT04838795.

My Early Relational Trust-Informed Learning (MERTIL) for Parents: A study protocol for a brief, universal, online, preventative parenting program to enhance relational health.

BACKGROUND: Early relational health is a key determinant of childhood development, while relational trauma in the parent-infant dyad can instigate a cascading pattern of infant risk. Fortunately, early relational trauma is detectable and modifiable. In 2018, Australian Maternal and Child Health (MCH) nurses participated in MERTIL (My Early Relational Trauma-Informed Learning), a program to identify and prevent relational trauma. Program evaluations revealed nurses felt competent and confident to identify and respond to relational trauma; however, response capacity was inhibited by inadequate parent referral options. In response, MERTIL for Parents (My Early Relational Trust-Informed Learning) was developed, which is an online, evidence-based, self-paced parenting program that focuses on enhancing parental knowledge of relational trust and its significance for infant development. This low-cost, accessible prevention resource targets emerging relational concerns to reduce later service system engagement. The potential for universal preventative online programs that target parental and relational wellbeing remains under-explored. This paper reports on a protocol for implementing a MERTIL for Parents pilot study describing practitioners' and parents' perspectives on program feasibility and efficacy. METHODS: This study is a mixed methods, parallel armed, uncontrolled, repeated measures design. We aim to recruit 48 Australian MCH practitioners from the states of Victoria and New South Wales. These professionals will in turn recruit 480 parents with a child aged 0-5 years. All parents will receive MERTIL for Parents, which entails a 40-minute video, tipsheets, posters, and support resources. Parent data will be obtained at three periods: pre-program, program exit, and program follow-up. Practitioner data will be collected at two periods: pre-parent recruitment and program follow-up. Data collection will occur through surveys and focus groups. Primary parent outcomes will be socioemotional assessments of program efficacy. Practitioners and parents will each report on program feasibility. DISCUSSION: This protocol describes the feasibility and efficacy of a new online parenting program, MERTIL for Parents, with pilot field studies commencing in March 2023. We anticipate that this resource will be a valuable addition to various child and family services, for use in individual support and group work.

Safety evaluation of the single-dose Ad26.COV2.S vaccine among healthcare workers in the Sisonke study in South Africa: A phase 3b implementation trial.

BACKGROUND: Real-world evaluation of the safety profile of vaccines after licensure is crucial to accurately characterise safety beyond clinical trials, support continued use, and thereby improve public confidence. The Sisonke study aimed to assess the safety and effectiveness of the Janssen Ad26.COV2.S vaccine among healthcare workers (HCWs) in South Africa. Here, we present the safety data. METHODS AND FINDINGS: In this open-label phase 3b implementation study among all eligible HCWs in South Africa registered in the national Electronic Vaccination Data System (EVDS), we monitored adverse events (AEs) at vaccination sites through self-reporting triggered by text messages after vaccination, healthcare provider reports, and active case finding. The frequency and incidence rate of non-serious and serious AEs were evaluated from the day of first vaccination (17 February 2021) until 28 days after the final vaccination in the study (15 June 2021). COVID-19 breakthrough infections, hospitalisations, and deaths were ascertained via linkage of the electronic vaccination register with existing national databases. Among 477,234 participants, 10,279 AEs were reported, of which 138 (1.3%) were serious AEs (SAEs) or AEs of special interest. Women reported more AEs than men (2.3% versus 1.6%). AE reports decreased with increasing age (3.2% for age 18-30 years, 2.1% for age 31-45 years, 1.8% for age 46-55 years, and 1.5% for age > 55 years). Participants with previous COVID-19 infection reported slightly more AEs (2.6% versus 2.1%). The most common reactogenicity events were headache (n = 4,923) and body aches (n = 4,483), followed by injection site pain (n = 2,767) and fever (n = 2,731), and most occurred within 48 hours of vaccination. Two cases of thrombosis with thrombocytopenia syndrome and 4 cases of Guillain-Barré Syndrome were reported post-vaccination. Most SAEs and AEs of special interest (n = 138) occurred at lower than the expected population rates. Vascular (n = 37; 39.1/100,000 person-years) and nervous system disorders (n = 31; 31.7/100,000 person-years), immune system disorders (n = 24; 24.3/100,000 person-years), and infections and infestations (n = 19; 20.1/100,000 person-years) were the most common reported SAE categories. A limitation of the study was the single-arm design, with limited routinely collected morbidity comparator data in the study setting. CONCLUSIONS: We observed similar patterns of AEs as in phase 3 trials. AEs were mostly expected reactogenicity signs and symptoms. Furthermore, most SAEs occurred below expected rates. The single-dose Ad26.COV2.S vaccine demonstrated an acceptable safety profile, supporting the continued use of this vaccine in this setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT04838795; Pan African Clinical Trials Registry PACTR202102855526180.

Effectiveness of the Ad26.COV2.S vaccine in health-care workers in South Africa (the Sisonke study): results from a single-arm, open-label, phase 3B, implementation study.

BACKGROUND: We aimed to assess the effectiveness of a single dose of the Ad26.COV2.S vaccine (Johnson & Johnson) in health-care workers in South Africa during two waves of the South African COVID-19 epidemic. METHODS: In the single-arm, open-label, phase 3B implementation Sisonke study, health-care workers aged 18 years and older were invited for vaccination at one of 122 vaccination sites nationally. Participants received a single dose of 5 × 1010 viral particles of the Ad26.COV2.S vaccine. Vaccinated participants were linked with their person-level data from one of two national medical insurance schemes (scheme A and scheme B) and matched for COVID-19 risk with an unvaccinated member of the general population. The primary outcome was vaccine effectiveness against severe COVID-19, defined as COVID-19-related admission to hospital, hospitalisation requiring critical or intensive care, or death, in health-care workers compared with the general population, ascertained 28 days or more after vaccination or matching, up to data cutoff. This study is registered with the South African National Clinical Trial Registry, DOH-27-022021-6844, ClinicalTrials.gov, NCT04838795, and the Pan African Clinical Trials Registry, PACTR202102855526180, and is closed to accrual. FINDINGS: Between Feb 17 and May 17, 2021, 477 102 health-care workers were enrolled and vaccinated, of whom 357 401 (74·9%) were female and 119 701 (25·1%) were male, with a median age of 42·0 years (33·0-51·0). 215 813 vaccinated individuals were matched with 215 813 unvaccinated individuals. As of data cutoff (July 17, 2021), vaccine effectiveness derived from the total matched cohort was 83% (95% CI 75-89) to prevent COVID-19-related deaths, 75% (69-82) to prevent COVID-19-related hospital admissions requiring critical or intensive care, and 67% (62-71) to prevent COVID-19-related hospitalisations. The vaccine effectiveness for all three outcomes were consistent across scheme A and scheme B. The vaccine effectiveness was maintained in older health-care workers and those with comorbidities including HIV infection. During the course of the study, the beta (B.1.351) and then the delta (B.1.617.2) SARS-CoV-2 variants of concerns were dominant, and vaccine effectiveness remained consistent (for scheme A plus B vaccine effectiveness against COVID-19-related hospital admission during beta wave was 62% [95% CI 42-76] and during delta wave was 67% [62-71], and vaccine effectiveness against COVID-19-related death during beta wave was 86% [57-100] and during delta wave was 82% [74-89]). INTERPRETATION: The single-dose Ad26.COV2.S vaccine shows effectiveness against severe COVID-19 disease and COVID-19-related death after vaccination, and against both beta and delta variants, providing real-world evidence for its use globally. FUNDING: National Treasury of South Africa, the National Department of Health, Solidarity Response Fund NPC, The Michael & Susan Dell Foundation, The Elma Vaccines and Immunization Foundation, and the Bill & Melinda Gates Foundation.

Allergic reactions to the Ad26.COV2.S Vaccine in South Africa

Background The Janssen-Ad26.COV2.S vaccine is authorised for use in several countries with over 30 million doses administered. Mild and severe allergic adverse events following immunisation(AEFI) have been reported. The aim of this report is to detail allergic reactions reported during the Sisonke phase 3B study in South Africa. Methods A single-dose of the Ad26.COV2.S vaccine was administered to 477234 South African Healthcare Workers between 17 February and 17 May 2021. Monitoring of adverse events used a combination of passive reporting and active case finding. Telephonic contact was attempted for all adverse events reported as “allergy”. Anaphylaxis adjudication was performed using the Brighton Collaboration (BCC) and NIAID case definitions. Results Only 251(0.052%) patients reported any allergic-type reaction(less than 1 in 2000), with four cases of adjudicated anaphylaxis (BCC level 1, n=3)(prevalence of 8.4 per million doses). All anaphylaxis cases had a prior history of drug or vaccine-associated anaphylaxis. Cutaneous allergic reactions were the commonest non-anaphylatic reactions and included: self-limiting, transient/localised rashes requiring no healthcare contact(n=92);or isolated urticaria and/or angioedema[n=70 median onset 48(IQR 11.5-120) hours post vaccination] that necessitated healthcare contact(81%), antihistamine(63%), and/or systemic/topical corticosteroid(16%). All immediate (including adjudicated anaphylaxis) and the majority of delayed AEFI(65/69) cases resolved completely. Conclusions Allergic AEFI are rare following a single-dose of Ad26.COV with complete resolution in all cases of anaphylaxis. Though rare, isolated, delayed onset urticaria and/or angioedema was the commonest allergic AEFI requiring treatment, with nearly half occurring in participants without known atopic disease.

The evolution of clot strength in critically-ill COVID-19 patients: a prospective observational thromboelastography study.

BACKGROUND: Few studies detail the evolution of COVID-19 associated coagulopathy. We performed serial thromboelastography (TEG) and laboratory coagulation studies in 40 critically-ill, mechanically ventilated COVID-19 patients over a 14-day period and analysed differences between 30-day survivors and non-survivors. METHODS: Single-center prospective, observational study including 40 patients with severe COVID-19 pneumonia admitted to the intensive care unit (ICU) for mechanical ventilation. TEG analysis was performed on days 1, 7 and 14 of ICU admission and laboratory coagulation studies were performed on days 1 and 14. Coagulation variables were evaluated for change over the 14-day observation period. Differences between survivors and non-survivors at 30-days were analysed and compared. RESULTS: On admission, TEG maximum amplitude (MA) with heparinase correction was above the upper limit of the reference range in 32 (80%) patients while 33 (82.5%) presented with absent clot lysis at 30 min. The functional fibrinogen MA was also elevated above the upper limit of the reference range in 37 (92.5%) patients. All patients had elevated D-dimer and fibrinogen levels, mildly prolonged prothrombin times (PT), normal platelet counts and normal activated partial thromboplastin times (aPTT). The heparinase MA decreased significantly with time and normalised after 14 days (p = < 0.001) while the increased fibrin contribution to clot strength persisted with time (p = 0.113). No significant differences in TEG analysis were noted between 30-day survivors and non-survivors at all time points. No patients developed disseminated intravascular coagulopathy (DIC) after 14-days, however thrombosis and bleeding were each reported in 3 (7.5%) patients. CONCLUSION: Critically-ill patients with COVID-19 present in a hypercoagulable state characterised by an increased clot strength. This state normalises after 14 days despite a persistently increased fibrin contribution to clot strength. We were unable to demonstrate any significant differences in TEG parameters between 30-day survivors and non-survivors at all time points.