Antiphospholipid antibodies in patients with acute ischaemic stroke during the COVID-19 pandemic

Background: COVID-19 is associated with arterial thromboembolism, including acute ischaemic stroke (AIS). An association with antiphospholipid antibodies (aPL) has been noted;however, the prevalence of aPL and their clinical relevance in COVID 19-associated AIS are undefined. Aim(s): The aim was to assess the prevalence, subtypes and persistence of aPL in COVID-19- associated AIS. Method(s): We retrospectively reviewed AIS patients consecutively admitted to the Hyperacute Stroke Unit, University College London Hospitals, during local COVID-19 admission waves (18-Mar- 2020 to 31-May- 2020 and 01-Dec- 2020 to 24-Feb- 2021). Electronic patient records were reviewed for relevant study data, including COVID-19 and aPL status (in accordance with international consensus criteria). Result(s): 380 patients with AIS were identified (median age 74 years, range 24-99);35/380 (9.2%) had active/recent COVID-19 infection (median age 79 years, range 37-93). 132/380 patients were further analysed (those <=65 years), including 11/132 with COVID-19- associated- AIS. Overall, 105/132 (79.5% [including 31/32 (97.9%) patients < 50]), were screened for aPL, of which 26/105 (24.8% [including 7/31 (22.6%) patients < 50]) were aPL positive. In patients with AIS that were screened, aPL prevalence was significantly higher in those associated with COVID-19 than those not associated with COVID-19: 10/11 (90.9%) vs. 16/94 (17.0%), p< 0.05 (Fisher's exact test). Within the COVID-19 AIS group, 8/10 aPL positive patients had an isolated lupus anticoagulant (LA);1/10 was double aPL positive. Five of 10 patients with COVID-19- associated AIS underwent repeat aPL assessment: aPL were persistently positive beyond 12 weeks in 1/5, and transient in 4/5. In the non-COVID- 19 AIS group, 7/16 underwent repeat aPL testing, with 4/7 (57.1%) demonstrating persistence. aPL subtypes are shown in Table 1. Conclusion(s): Among AIS patients, aPL, mainly LA, are more frequent in those with COVID-19 infection. Patients with AIS (with or without COVID-19) found to have aPL should be retested for aPL persistence, potentially leading to a diagnosis of antiphospholipid syndrome.

Advances in Patient Care for Preclinical Extracorporeal Life Support

Extracorporeal life support (ECLS) reduces the functional workload requirements of the lungs, heart, or both for days to weeks in patients with reversible life threatening respiratory or cardiac disease. It is estimated that ECLS could have saved close to half of the seriously ill COVID-19 patients for whom mechanical ventilation was not effective if ECLS had been available. Supporting an ECLS patient however requires extensive knowledge and resources, and this is true also in the preclinical space when working with healthy animal models. The most common serious complications in the clinical setting are bleeding and thrombosis, both of which are also seen in preclinical studies performed on healthy sheep. From late 2020 to early 2021, the animal care and clinical laboratory teams made significant advances in supporting preclinical ECLS studies, reducing both mortality and other adverse outcomes significantly by implementing several interventions: 1) improving diagnostic ability to monitor anticoagulation status more accurately with the measurement of activated clotting time (ACT), blood heparin concentration, partial thromboplastin time (PTT), activated partial thromboplastin time (aPTT), plasma free hemoglobin and red blood cell values;2) refining ECLS circuit attachments and optimizing the kennel environment to allow for improved animal comfort while decreasing the risk for canulae or circuit kinking or migration and 3) refining nursing care and monitoring by the inclusion of improved AV system and standardized care protocols. One of the core improvements was supplementing periodic ACT tests with blood heparin concentration. After these refinements, mortality during 7 d in life ECLS studies was reduced from 50% (3/6 animals, study1) to none (0/3 animals, study2) Blood heparin concentration is also beneficial in the management of human patients on ECLS. Facilities performing ECLS studies can benefit from expanding anticoagulation evaluation from simple ACT measurements to a multimodal approach, with blood heparin concentration measurements being especially advantageous. In addition, skilled round-the-clock nursing care of the study animals is vital for success.

Abstract Mental health law in Argentina

This article reviews important issues in relation to mental health in Argentina. In the first place, its situation in the country and the recommendations of the World Health Organization in reference to the fact that, in low-and middle-income countries, more than 75% of people with mental, neurological and substance use dis-orders do not receive any treatment. Human resources in Argentina and its comparison with other countries are reviewed. Emphasis is placed on the need for trained primary care services in mental health and to improve the organization of health systems and services. Reference is also made to the Mental Health Law 26657 enacted in 2010, and the problems that have led to it not yet being fully implemented, the debate about this law, and the current claim of family members for the lack of response to their needs, and therefore the importance of its imple-mentation. Finally, the effects of the COVID pandemic on the mental health of the general population are exposed. Copyright © 2022, Instituto de Investigaciones Medicas. All rights reserved.

[Mental health law in Argentina]

This article reviews important issues in relation to mental health in Argentina. In the first place, its situation in the country and the recommendations of the World Health Organization in reference to the fact that, in low- and middle-income countries, more than 75% of people with mental, neurological and substance use disorders do not receive any treatment. Human resources in Argentina and its comparison with other countries are reviewed. Emphasis is placed on the need for trained primary care services in mental health and to improve the organization of health systems and services. Reference is also made to the Mental Health Law 26657 enacted in 2010, and the problems that have led to it not yet being fully implemented, the debate about this law, and the current claim of family members for the lack of response to their needs, and therefore the importance of its implementation. Finally, the effects of the COVID pandemic on the mental health of the general population are exposed.

CELLULAR IMMUNE RESPONSE TO THE BNT162B2 VACCINE IN LYMPHOMA PATIENTS

Background: In most individuals, protective humoral and cellular immunity develops after two doses of the BNT162b2 Pfizer vaccine. In patients with lymphoma, humoral response is weaker and almost universally abrogated in patients who received anti-CD20 monoclonal antibodies. Whether cellular immune response is also abrogated is unknown. Aims: To determine whether patients with lymphoma develop specific T-cell mediated cellular response to BNT162b2 Pfizer vaccine. Methods: We included patients with lymphoma above the age of 18 years who received two doses of the BNT162b2 Pfizer vaccine and collected clinical and demographics data. T-cell immune response to the vaccine was analysed in patients' blood samples stimulated by spike antigen and quantified by two methods: (1) Interferon-gamma (IFNg)- release assay (IGRA, EuroImmun, Germany)- IFNg was quantified by ELISA (DuoSet, R and D Systems, Minneapolis, Minnesota, USA) and response above 50 pg/ml was considered positive. (2) Flow cytometry- Quantification of the T cell activation markers, CD134+ CD25+CD4+ T-cells was performed (Act-T4 CellTM kit, Cytognos, Spain), and any response above 0 was considered positive. Humoral response was measured by SARS-CoV-2 IgG II Quant (Abbott©) assay. The positive cut-off was set at 50AU/ml. Blood samples were drawn approximately 4 months after the second vaccination. Results: Sixty-nine lymphoma patients, treated with two vaccine doses, were included in this study. Median age was 66 (range: 30-84) and 39 (57%) were males. Sixty-two patients (90%) had non-Hodgkin lymphoma (NHL) including 18 with DLBCL, 26 with follicular lymphoma and 14 with marginal zone lymphoma. Seven (10%) patients had Hodgkin lymphoma. In this cohort, 70% (n=49) of the patients received anti CD20 MoAb, and 35% of them (n=27) were still on anti CD20 treatment. Thirteen patients received bendamustine-based immunochemotherapy. At the time of assessment (median 4.8 months after the 2nd vaccine) anti-spike antibodies were detected in only 42% (N = 29) of patients. In comparison, there was an increase in specific T cell response by any assay (IGRA and Flow) in 49% of patients (n = 34). The correlation between the IGRA and flow data was 0.7 (pearson correlation, P = 0.01). However, no correlation between humoral (qualitative and quantitative) and T cell response was shown, regardless of the assay applied. Cellular response was not corelated with the time elapsing from last immunochemotherapy. In the anti-CD20 MoAb treated cohort, of which 27 patients were still on active treatment at the time of vaccination, only 2 patients (7%) developed a humoral immune response, while cellular immunity was elicited in 52% (N = 15) patients (ELISA assay). In the Bendamustine treated cohort, with a median time from end of treatment to vaccination of 23 months (1-106 months), humoral but not cellular response correlated positively with the time from treatment completion to vaccination (p=0.04). Summary/Conclusion: The rate of cellular and humoral response to two doses of the BNT162b2 Pfizer vaccine in lymphoma patients was found to be significantly abrogated. In this small cohort, 49% of patients developed a cellular response despite a severely abrogated humoral immunity. These findings suggest that vaccine administration should be considered even early after anti CD20 therapy despite the reduced humoral immunity. These findings should be validated in studies with a higher number of patients.

Cellular immune responses to BNT162b2 mrna covid-19 vaccine in patients with chronic lymphocytic leukemia

Background: Patients with chronic lymphocytic leukemia (CLL) are known to have a suboptimal immune response of both humoral and cellular arms. Recently, a BNT162b2 mRNA COVID-19 vaccine was introduced with a high efficacy of 95% in immunocompetent individuals. Approximately half of the patients with CLL fail to mount a humoral response to the vaccine, as detected by anti-spike antibodies. Currently, there is no data available regarding T-cell immune responses following the vaccine of these patients. Aim of the study: To investigate T-cell response determined by interferon gamma (IFNγ) secretion in patients with CLL following BNT162b mRNA Covid-19 vaccine, in comparison with serologic response. Methods: CLL patients from 3 medical centers in Israel were included in the study. All patients received two 30-μg doses of BNT162b2 vaccine (Pfizer), administered intramuscularly 3 weeks apart. For evaluation of SARS-CoV-2 Spike-specific T-cell responses, blood samples were stimulated ex-vivo with Spike protein and secreted IFNγ was quantified (ELISA DuoSet, R&D Systems, Minneapolis, Minnesota, USA). T-cell immune response was considered to be positive for values above 25 pg/ml of Spike-specific response. T-cell subpopulations were characterized by flow cytometry (CD3, CD4, CD8). Anti-spike antibody tests were performed using the Architect AdviseDx SARS-CoV-2 IgG II (Abbot, Lake Forest, Illinois, USA). Statistical analysis was performed using Mann-Whitney test for continuous variables while the Wald Chi-square test was used for comparing categorical variables. Results: 83 patients with CLL were tested for T-cell response. Blood samples were collected after a median time of 139 days post administration of the second dose of vaccine (IQ range 134-152). Out of 83 patients, 68 were eligible for the analysis (with positive internal control). Median age of the cohort was 68 years (56-72);and 44 (65%) were males. 19 (28%) patients were treatment-naïve, most of whom were Binet stage A or B. 31 (46%) patients were on therapy: 17 with a BTK-inhibitor, and 13 with a venetoclax-based regimen. 29 (42%) patients were previously treated with anti-CD20, 13 of whom in the 12 months period prior to vaccination. T cell immune response to the vaccine was evident in 22 (32%) patients. CIRS Score>6 and specifically hypertension were statistically significantly associated with a lower T-cell response (univariate analysis, p-value<0.05). Variables that were associated with the development of T-cell response were presence of del(13q), IgM ≥ 40 mg/dL, and IgA ≥ 80 mg/dL (p-value 0.05-0.1). There was no significant difference with regards to age, gender, other CLL-specific prognostic markers, treatment, and T-cell subpopulation distribution according to flow cytometry (Table 1). The presence of T-cell response highly correlated with both the detection of anti-spike IgG antibodies following the second dose (p=0.0239) and at the time of T-cell testing (n=66, p=0.048, Table 2). While 50% of patients who tested positive for anti-spike IgG antibodies also developed positive T-cell response, only 17% of patients who did not develop T-cell response, tested positive for antispike antibodies. Importantly, 24% of the patients who tested negative for anti-spike IgG antibodies, developed positive T cell response. Moreover, the level of the T-cell response (log transformed) correlated linearly with (log transformed) anti-spike IgG titer (adjusted r=0.26 and p =0.026 according to Pearson correlation, Figure 1). Conclusion: We show that cellular immune response to the BNT162b2 mRNA COVID-19 vaccine, is blunted in most CLL patients and that there is a correlation between T-cell response and serologic response to the vaccine. These results need to be validated in a larger cohort.

Remdesivir and Tocilizumab for the Treatment of Severe COVID-19 in a Community Hospital: A Retrospective Cohort Study

Background. Growing evidence supports the use of remdesivir and tocilizumab for the treatment of hospitalized patients with severe COVID-19. The purpose of this study was to evaluate the use of remdesivir and tocilizumab for the treatment of severe COVID-19 in a community hospital setting. Methods. We used a de-identified dataset of hospitalized adults with severe COVID-19 according to the National Institutes of Health definition (SpO2 < 94% on room air, a PaO2/FiO2 < 300 mm Hg, respiratory frequency > 30/min, or lung infiltrates > 50%) admitted to our community hospital located in Evanston Illinois, between March 1, 2020, and March 1, 2021. We performed a Cox proportional hazards regression model to examine the relationship between the use of remdesivir and tocilizumab and inpatient mortality. To minimize confounders, we adjusted for age, qSOFA score, noninvasive positive-pressure ventilation, invasive mechanical ventilation, and steroids, forcing these variables into the model. We implemented a sensitivity analysis calculating the E-value (with the lower confidence limit) for the obtained point estimates to assess the potential effect of unmeasured confounding. Figure 1. Kaplan-Meier survival curves for in-hospital death among patients treated with and without steroids The hazard ratio was derived from a bivariable Cox regression model. The survival curves were compared with a log-rank test, where a two-sided P value of less than 0.05 was considered statistically significant. Figure 2. Kaplan-Meier survival curves for in-hospital death among patients treated with and without remdesivir The hazard ratio was derived from a bivariable Cox regression model. The survival curves were compared with a log-rank test, where a two-sided P value of less than 0.05 was considered statistically significant. Results. A total of 549 patients were included. The median age was 69 years (interquartile range, 59 - 80 years), 333 (59.6%) were male, 231 were White (41.3%), and 235 (42%) were admitted from long-term care facilities. 394 (70.5%) received steroids, 192 (34.3%) received remdesivir, and 49 (8.8%) received tocilizumab. By the cutoff date for data analysis, 389 (69.6%) patients survived, and 170 (30.4%) had died. The bivariable Cox regression models showed decreased hazard of in-hospital death associated with the administration of steroids (Figure 1), remdesivir (Figure 2), and tocilizumab (Figure 3). This association persisted in the multivariable Cox regression controlling for other predictors (Figure 4). The E value for the multivariable Cox regression point estimates and the lower confidence intervals are shown in Table 1. The hazard ratio was derived from a bivariable Cox regression model. The survival curves were compared with a log-rank test, where a two-sided P value of less than 0.05 was considered statistically significant. The hazard ratios were derived from a multivariable Cox regression model adjusting for age as a continuous variable, qSOFA score, noninvasive positive-pressure ventilation, and invasive mechanical ventilation. Table 1. Sensitivity analysis of unmeasured confounding using E-values CI, confidence interval. Point estimate from multivariable Cox regression model. The E value is defined as the minimum strength of association on the risk ratio scale that an unmeasured confounder would need to have with both the exposure and the outcome, conditional on the measured covariates, to explain away a specific exposure-outcome association fully: i.e., a confounder not included in the multivariable Cox regression model associated with remdesivir or tocilizumab use and in-hospital death in patients with severe COVID-19 by a hazard ratio of 1.64-fold or 1.54-fold each, respectively, could explain away the lower confidence limit, but weaker confounding could not. Conclusion. For patients with severe COVID-19 admitted to our community hospital, the use of steroids, remdesivir, and tocilizumab were significantly associated with a slower progression to in-hospital death while controlling for other predictors included in the models.

1502O OncoYoung program: A multidisciplinary program for young cancer patients

Background: Young cancer patients (YCP) face unique obstacles and unmet needs as treatment-induced endocrine disorders, late-term complications and psychosocial perspectives. Currently there are no formal programs to comprehensively address these unmet needs but rather scarce disease-oriented services. We hypothesize that proactive intervention of broadly-designated support for YCP will optimize their coping with the disease and side effects, improve quality of life (QOL) and yield better fertility preservation rate. We aimed to assess the implementation of an “oncoyoung program” using a predefined protocol of patient triage to fertility preservation (FP), supportive care and psychosocial support on patients’ satisfaction rate. Methods: “Oncoyoung” program (for patients <45 years) was launched at our institution in mid-2019 staffed with physician, coordinating nurse, social worker, psychologist, physical therapist, dietician and a multidisciplinary comprehensive umbrella of services. Patient council comprised of young patients or survivors’ representatives was established to tailor program outlines with the program staff. Patient were asked to evaluate the service. We prospectively evaluated the program outcomes. Results: In the first year (2020) 321 patients (median age 37y) visited the program, mostly females (69%). Common diagnoses were breast, gastrointestinal, cervical and hematological cancers. The majority had non-metastatic disease. Of the cohort, 30% had more than one visit. 89% of patients were offered FP (74% successfully performed), which exceeded historical cohorts. Following triage 72% of patients were referred to additional services, and 61% to psychosocial support. During COVID-19 pandemic physiotherapy and psychosocial support were substantially converted into virtual sessions that were considered successful by the patients. Satisfaction rate reached 95% and 83% indicated an improvement in their QOL following the program intervention. Conclusions: With young adults, treating cancer is only part of the equation. Dedicated comprehensive programs aiming at actively intensifying the supportive care paradigm for young cancer patients carries high potential to improve cancer care. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Medical care disruptions during the first six months of the COVID-19 pandemic: the experience of older breast cancer survivors.

PURPOSE: Older cancer survivors required medical care during the COVID-19 pandemic, but there are limited data on medical care in this age group. METHODS: We evaluated care disruptions in a longitudinal cohort of non-metastatic breast cancer survivors aged 60-98 from five US regions (n = 321). Survivors completed a web-based or telephone survey from May 27, 2020 to September 11, 2020. Care disruptions included interruptions in seeing or speaking to doctors, receiving medical treatment or supportive therapies, or filling prescriptions since the pandemic began. Logistic regression models evaluated associations between care disruptions and education, medical, psychosocial, and COVID-19-related factors. Multivariate models included age, county COVID-19 death rates, comorbidity, and post-diagnosis time. RESULTS: There was a high response rate (n = 262, 81.6%). Survivors were 32.2 months post-diagnosis (SD 17.5, range 4-73). Nearly half (48%) reported a medical disruption. The unadjusted odds of care disruptions were higher with each year of education (OR 1.22, 95% CI 1.08-1.37, p = < 0.001) and increased depression by CES-D score (OR 1.04, CI 1.003-1.08, p = 0.033) while increased tangible support decreased the odds of disruptions (OR 0.99, 95% CI 0.97-0.99, p = 0.012). There was a trend between disruptions and comorbidities (unadjusted OR 1.13 per comorbidity, 95% CI 0.99-1.29, p = 0.07). Adjusting for covariates, higher education years (OR1.23, 95% CI 1.09-1.39, p = 0.001) and tangible social support (OR 0.98 95% CI 0.97-1.00, p = 0.006) remained significantly associated with having care disruptions. CONCLUSION: Older breast cancer survivors reported high rates of medical care disruptions during the COVID-19 pandemic and psychosocial factors were associated with care disruptions. CLINICALTRIALS. GOV IDENTIFIER: NCT03451383.

Examining the effect of perceived fatigability on cognitive function abilities in older adults with MCI

Background Chronic fatigue with cognitive and daily functioning decline is a major public health concern in older adults. The association between fatigue and neurodegenerative conditions (e.g., multiple sclerosis) has been studied for many years. But, it is not known the relationship between Alzheimer's pathology and perceived fatigability, a phenotype characterized by the relationship between an individual's perceived fatigue and the activity level with which the fatigue is associated. We examined the role of fatigability on the link between cognitive function and cognitive function abilities and the effect of sleep on this indirect link in older adults with mild cognitive impairment (MCI). Methods Adults age > 55 years who met the ADNI criteria for MCI were included. Depression assessed by the DSM-V criteria and a GDS>5 was exclusionary. We conducted the study with the PROMIS Cognitive Function-Abilities (CogAb), Sleep Disturbances (SD), Sleep-related Impairment (SRI), and the Neuro-QOL Cognitive Function (CogF) and Fatigue, including Fatigue symptom score (item1-3&7) and Fatigability score (item4-6&8). Linear regression models were fit to Fatigue and Fatigability included sleep outcomes and their interaction as predictors. Mediation models were fit to assess whether fatigability mediated the effect of CogF on CogAb. Results Before the COVID pandemic, 36 subjects were recruited, with the mean age= 68.8 ±9.3, 58.3% female, 78% white, and 15.2% Hispanic. The results revealed that CogF predicted CogAb (b= 0.78, t(34)=4.83, p<0.001). Analysis of the indirect effects showed CogF predicted Fatigability (b=-0.29, t(34)=-3.09, p<0.005), Fatigability predicted CogAb (b= -0.99, t(33)=-4.03, p<0.001), CogF predicted CogAb (b=0.49, t(33)=3.25, p<0.01). The indirect effect of CogF on CogAb mediated through fatigability was significant (95%CI=0.08, 0.44), even after controlling for age and education, and fatigue symptom score. Fatigability was associated with SRI (beta=0.642, t=4.73, p<0.001) but not SD (P>0.05) after controlling for age. SRI had no direct effect on CogAb. Conclusions Perceived fatigability partially mediated the link between CogF and CogAb and sleep outcomes had no significant impact on this indirect link. The results suggested that fatigability could be a biological construct of Alzheimer's pathology, independent from sleep and depression.

Medical Care Disruptions During the First Six-Months of the COVID19 Pandemic: The Experience of Older Breast Cancer Survivors.

PurposeOlder cancer survivors required medical care during the COVID-19 pandemic despite infection risks, but there are limited data on medical care in this age group. METHODS: We evaluated care disruptions in a longitudinal cohort of non-metastatic breast cancer survivors ages 60-98 from five US regions (n=321). Survivors completed a web-based or telephone survey from May 27, 2020 to September 11, 2020. Care disruptions included self-reported interruptions in ability to see doctors, receive treatment or supportive therapies, or fill prescriptions. Logistic regression models evaluated bivariate and multivariate associations between care disruptions and education, medical, psychosocial and COVID-19-related factors. Multivariate models included age, county COVID-19 rates, comorbidity and post-diagnosis time. RESULTS: There was a high response rate (n=262, 81.6%). Survivors were 32.2 months post-diagnosis (SD 17.5, range 4-73). Nearly half (48%) reported a medical disruption. The unadjusted odds of care disruptions were significantly higher with more education (OR 1.23 per one-year increase, 95% CI 1.09-1.39, p =0.001) and greater depression (OR 1.04 per one-point increase in CES-D score, CI 1.003-1.08, p=0.033); tangible support decreased the odds of disruptions (OR 0.99, 95% CI 0.97-0.99 per one-point increase, p=0.012). There was a trend for associations between disruptions and comorbidity (unadjusted OR 1.13 per 1 added comorbidity, 95% CI 0.99-1.29, p=0.07). Adjusting for covariates, only higher education (p=0.001) and tangible social support (p=0.006) remained significantly associated with having care disruptions. CONCLUSIONS: Older breast cancer survivors reported high rates of medical care disruptions during the COVID-19 pandemic and psychosocial factors were associated with care disruptions.