Multidisciplinary Management Strategies for Long COVID: A Narrative Review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of infections to date and has led to a worldwide pandemic. Most patients had a complete recovery from the acute infection, however, a large number of the affected individuals experienced symptoms that persisted more than 3 months after diagnosis. These symptoms most commonly include fatigue, memory difficulties, brain fog, dyspnea, cough, and other less common ones such as headache, chest pain, paresthesias, mood changes, muscle pain, and weakness, skin rashes, and cardiac, endocrine, renal and hepatic manifestations. The treatment of this syndrome remains challenging. A multidisciplinary approach to address combinations of symptoms affecting multiple organ systems has been widely adopted. This narrative review aims to bridge the gap surrounding the broad treatment approaches by providing an overview of multidisciplinary management strategies for the most common long COVID conditions.

The impact of lung transplantation on esophageal motility and inter-relationships with reflux and lung mechanics in patients with restrictive and obstructive respiratory disease.

BACKGROUND: For many patients with lung disease the only proven intervention to improve survival and quality of life is lung transplantation (LTx). Esophageal dysmotility and gastroesophageal reflux (GER) are common in patients with respiratory disease, and often associate with worse prognosis following LTx. Which, if any patients, should be excluded from LTx based on esophageal concerns remains unclear. Our aim was to understand the effect of LTx on esophageal motility diagnosis and examine how this and the other physiological and mechanical factors relate to GER and clearance of boluses swallowed. METHODS: We prospectively recruited 62 patients with restrictive (RLD) and obstructive (OLD) lung disease (aged 33-75 years; 42 men) who underwent high resolution impedance manometry and 24-h pH-impedance before and after LTx. KEY RESULTS: RLD patients with normal motility were more likely to remain normal (p = 0.02), or if having abnormal motility to change to normal (p = 0.07) post-LTx than OLD patients. Esophageal length (EL) was greater in OLD than RLD patients' pre-LTx (p < 0.001), reducing only in OLD patients' post-LTx (p = 0.02). Reduced EL post-LTx associated with greater contractile reserve (r = 0.735; p = 0.01) and increased likelihood of motility normalization (p = 0.10). Clearance of reflux improved (p = 0.01) and associated with increased mean nocturnal baseline impedance (p < 0.001) in RLD but not OLD. Peristaltic breaks and thoraco-abdominal pressure gradient impact both esophageal clearance of reflux and boluses swallowed (p < 0.05). CONCLUSIONS AND INFERENCES: RLD patients are more likely to show improvement in esophageal motility than OLD patients post-LTx. However, the effect on GER is more difficult to predict and requires other GI, anatomical and pulmonary factors to be taken into consideration.

Quality by design engineered, enhanced anticancer activity of temozolomide and resveratrol coloaded NLC and brain targeting via lactoferrin conjugation in treatment of glioblastoma.

The most dangerous type of high-grade astrocytoma is glioblastoma multiforme. The objective of the work was to engineer lactoferrin conjugated temozolomide and resveratrol co-loaded NLC for the treatment of glioblastoma using intranasal delivery for brain targeting. Synergistic activity of temozolomide and resveratrol was determined using combination index method and 1:1 ratio was selected. QbD approach was used to formulate and optimize NLC, with minimum particle size, maximum transmittance and entrapment efficiency using Central Composite Rotable Design (CCRD) method. The optimized LTR-NLC had desired average particle size (209.3 nm), narrow PDI along, high percentage transmittance (>95%) and better entrapment efficiency (95.26% of TEM and 87.59% of RES). From ex-vivo permeation studies it was found that the permeation at 24 h was 77.43 %, and 88.55 % from LTR-NLC and 25.76 % and 31.10% from suspension for resveratrol and temozolomide respectively. In comparison to drug suspension, NLC had nearly 3-fold increase in drug penetration. IC50 value was also significantly better in the groups treated with LTR-NLC. Hence it can be concluded that LTR-NLC may be an effective formulation for the treatment of glioblastoma, according to the findings of this investigation.

Expanded extracorporeal membrane oxygenation bridge to heart and lung transplant candidate selection does not impact outcomes compared to traditional candidate selection criteria.

Extracorporeal membrane oxygenation is used as a bridge to transplant (ECMO-BTT) in selected patients. The objective of this study was to determine whether 1-year post-transplant and post-ECMO survival are impacted by traditional compared to expanded selection criteria. We performed a retrospective study of patients >17 years who received ECMO as bridge to transplant (BTT) or bridge to transplant decision for lung or combined heart and lung transplantation at the Mayo Clinic Florida and Rochester. Institutional protocol excludes patients >55 years, maintained on steroids, unable to participate in physical therapy, with body mass index >30 or <18.5 kg/m2, non-pulmonary end-organ dysfunction, or unmanageable infections from ECMO-BTT. For this study, adherence to this protocol was considered traditional whereas exceptions to the protocol were considered expanded selection criteria. A total of 45 patients received ECMO as bridge therapy. Out of those 29 patients (64%) received ECMO as bridge to transplant and 16 patients (36%) as bridge to transplant decision. The traditional criteria cohort consisted of 15 (33%) patients and expanded criteria cohort consisted of 30 (67%) patients. In the traditional cohort, 9 (60%) of 15 patients were successfully transplanted compared to 16 (53%) of 30 patients in the expanded criteria cohort. No difference in being delisted or dying on the waitlist (OR: 0.58, CI: 0.13-2.58), surviving to 1-year post-transplant (OR: 0.53, CI: 0.03-9.71) or 1-year post-ECMO (OR: 0.77, CI: 0.0.23-2.56) was observed between the traditional criteria and expanded criteria cohorts. At our institution, we did not see differences in odds of 1-year post-transplant and post-ECMO survival between those who met traditional criteria compared to those who did not. Multicenter, prospective studies are needed to evaluate the impact of ECMO-BTT selection criteria.

Effect of vinpocetine alone and in combination with enalapril in experimental model of diabetic cardiomyopathy in rats: possible involvement of PDE-1/TGF-ß/ Smad 2/3 signalling pathways.

OBJECTIVE: Diabetic cardiomyopathy (DC) is one of the severe secondary complications of diabetes mellitus in humans. Vinpocetine is an alkaloid having pleiotropic pharmacological effects. The present study is designed to investigate the effect of vinpocetine in DC in rats. METHODS: Rats were fed a high-fat diet for nine weeks along with single dose of streptozotocin after the second week to induce DC. The haemodynamic evaluation was performed to assess the functional status of rats using the Biopac system. Cardiac echocardiography, biochemical, oxidative stress parameters and inflammatory cytokine level were analysed in addition to haematoxylin-eosin and Masson's trichome staining to study histological changes, cardiomyocyte diameter and fibrosis, respectively. Phosphodiesterase-1 (PDE-1), transforming growth factor-ß (TGF-ß) and p-Smad 2/3 expression in cardiac tissues were quantified using western blot/RT-PCR. KEY FINDING: Vinpocetine treatment and its combination with enalapril decreased the glucose levels compared to diabetic rats. Vinpocetine improved the echocardiographic parameters and cardiac functional status of rats. Vinpocetine decreased the cardiac biochemical parameters, oxidative stress, inflammatory cytokine levels, cardiomyocyte diameter and fibrosis in rats. Interestingly, expressions of PDE-1, TGF-ß and p-Smad 2/3 were ameliorated by vinpocetine alone and in combination with enalapril. CONCLUSIONS: Vinpocetine is a well-known inhibitor of PDE-1 and the protective effect of vinpocetine in DC is exerted by inhibition of PDE-1 and subsequent inhibition of the expression of TGF-ß/Smad 2/3.

Coronavirus Disease 2019 Causing Infection of Transplanted Lung Allograft: A Pitfall of Prolonged Shedding of Severe Acute Respiratory Syndrome Coronavirus-2 Pretransplant.

Coronavirus disease 2019 (COVID-19) pandemic has led to considerable morbidity and mortality across the world. Lung transplant is a viable option for a few with COVID-19-related lung disease. Whom and when to transplant has been the major question impacting the transplant community given the novelty of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We describe a pitfall of presumed prolonged shedding of SARS-CoV-2 in a patient with COVID-19 associated acute respiratory distress syndrome leading to COVID-19 pneumonia after lung transplant. This raises concerns that replication-competent SARS-CoV-2 virus can persist for months post-infection and can lead to re-infection of grafts in the future.

Association of Neutralizing Antispike Monoclonal Antibody Treatment With Coronavirus Disease 2019 Hospitalization and Assessment of the Monoclonal Antibody Screening Score.

Objective: To test the hypothesis that the Monoclonal Antibody Screening Score performs consistently better in identifying the need for monoclonal antibody infusion throughout each "wave" of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant predominance during the coronavirus disease 2019 (COVID-19) pandemic and that the infusion of contemporary monoclonal antibody treatments is associated with a lower risk of hospitalization. Patients and Methods: In this retrospective cohort study, we evaluated the efficacy of monoclonal antibody treatment compared with that of no monoclonal antibody treatment in symptomatic adults who tested positive for SARS-CoV-2 regardless of their risk factors for disease progression or vaccination status during different periods of SARS-CoV-2 variant predominance. The primary outcome was hospitalization within 28 days after COVID-19 diagnosis. The study was conducted on patients with a diagnosis of COVID-19 from November 19, 2020, through May 12, 2022. Results: Of the included 118,936 eligible patients, hospitalization within 28 days of COVID-19 diagnosis occurred in 2.52% (456/18,090) of patients who received monoclonal antibody treatment and 6.98% (7,037/100,846) of patients who did not. Treatment with monoclonal antibody therapies was associated with a lower risk of hospitalization when using stratified data analytics, propensity scoring, and regression and machine learning models with and without adjustments for putative confounding variables, such as advanced age and coexisting medical conditions (eg, relative risk, 0.15; 95% CI, 0.14-0.17). Conclusion: Among patients with mild to moderate COVID-19, including those who have been vaccinated, monoclonal antibody treatment was associated with a lower risk of hospital admission during each wave of the COVID-19 pandemic.

Fat fighting liraglutide based nano-formulation to reverse obesity: Design, development and animal trials.

Obesity is a metabolic disease, which is one of the major causes of morbidity and mortality, where therapeutic options are limited. Treatment of obesity is necessary as it is associated with fatal complications like diabetes mellitus, cardiovascular disease, non-alcoholic fatty liver disease, osteoarthritis, and many more. Liraglutide (Lir), a synthetic analogue of Glucagon-like Peptide-1 (GLP-1), is the FDA approved anti-obesity drug, however, its major limitation is its clinical application which needs frequent parenteral injections. To address the issue of regular injection, we have synthesized a fat fighting oral nano-formulation of liraglutide with a sustained release feature, which was evaluated against high fat diet (HFD) induced obesity in mice. Experimental obesity was induced in mice by feeding HFD for 26 weeks. Lir nanoparticles (NP) were fabricated with chitosan via ion-gelation technique and were coated with Eudragit@S100 to protect the drug in harsh gastric conditions. Physiochemical characterization of Eu-Lir-Cs-NP demonstrated a small particle size of 253.1 ± 1.21 nm with âˆ¼ 9.74 % loading and âˆ¼ 72.11 % encapsulation efficiency of the drug. In-vitro studies showed successful cellular uptake of NP in Caco-2 cells and were stable in various enteric fluid pH conditions. Eudragit@S100 coated chitosan NP were able to protect the drug from harsh gastric pH conditions with more than âˆ¼ 74% of recovery. Treatment of two weeks of liraglutide Eu-Lir-Cs-NP (0.1, 0.2 and 0.4 mg/kg, orally; twice daily) moderately reduces obesity in mice as evidenced by a reduction in the body weight, blood glucose, serum total cholesterol, serum triglyceride, serum resistin and serum insulin level of mice. In addition, significant reduction of liver weight, abdominal white adipose tissue, and hepatic oxidative stress were noted. Our results suggest that chitosan-based NP of liraglutide can be an effective and convenient formulation for the management of obesity.

Survival Outcomes of Lung Transplant Recipients From Donors With Abnormal Kidney Function.

BACKGROUND: Recovering lungs with pulmonary edema due to abnormal kidney function is considered one of the expanded selection criteria for lung transplant. The aim of this study is to assess lung transplant recipients' survival from donors with abnormal kidney function and to determine differences in lung recovery rates from donors with and donors without abnormal kidney function. METHODS: We reviewed the United Network for Organ Sharing registry for first-time adult lung transplant donors and recipients from June 2005 to March 2017. Donor kidney function was categorized into three groups based on estimated glomerular filtration rate: group I, greater than 60 mL/min; group II, 15 to 59 mL/min; and group III, less than 15 mL/min. Recipient survival was stratified based on estimated glomerular filtration rate using Kaplan-Meier. A multivariate Cox Regression model with known risk factors that affect survival was used to compare survival among groups. Comparison of lung recovery among the three groups was also performed. RESULTS: Lung recovery rates were 29.7% (15,670 of 52,747), 19.4% (3879 of 20,040), and 18.1% (704 of 3898) for groups I, II, and III, respectively. The 1-, 3-, and 5-year recipient survival rates were 86.2%, 69.2%, and 55.7% for group I; 84.9%, 66.9%, and 53.8% for group II; and 85.5%, 65.3%, and 50.3% for group III, respectively (adjusted P = .25; multivariate Cox regression method). When group I was used as reference, the adjusted hazard ratio for group II was 1.04 (95% CI, 0.98-1.10) and for group III, it was 1.08 (95% CI, 0.96-1.23), after adjusting with the multivariate Cox regression model. CONCLUSIONS: There was no significant difference in lung recipient survival. The lung recovery rate from donors with abnormal kidney function was lower compared with that of donors with normal kidney function.

Differential effect of basal vitamin D status in monocrotaline induced pulmonary arterial hypertension in normal and vitamin D deficient rats: Possible involvement of eNOS/TGF-ß/α-SMA signaling pathways.

Vitamin D deficiency is common and linked to poor prognosis in pulmonary arterial hypertension (PAH). We investigated the differential effect of basal vitamin D levels in monocrotaline (MCT) induced PAH in normal and vitamin D deficient (VDD) rats. Rats were fed a VDD diet and exposed to filtered fluorescent light to deplete vitamin D. Normal rats were pretreated with vitamin D 100 IU/d and treated with vitamin D 100 and 200 IU/d, while VDD rats received vitamin D 100 IU/d. Vitamin D receptor (VDR) silencing was done in human umbilical vein endothelial cells (HUVECs) using VDR siRNA. Calcitriol (50 nM/mL) was added to human pulmonary artery smooth muscle cells (HPASMCs) and HUVECs before and after the exposure to TGF-ß (10 ng/mL). Vitamin D 100 IU/d pretreatment in normal rats up-regulated the expression of eNOS and inhibited endothelial to mesenchymal transition significantly and maximally. Vitamin D 100 IU/d treatment in VDD rats was comparable to vitamin D 200 IU/d treated normal rats. These effects were significantly attenuated by L-NAME (20 mg/kg), a potent eNOS inhibitor. Exposure to TGF- ß significantly reduced the expression of eNOS and increased the mesenchymal marker expression in normal and VDR-silenced HUVECs and HPASMCs, which were averted by treatment and maximally inhibited by pretreatment with calcitriol (50 nM). To conclude, this study provided novel evidence suggesting the beneficial role of higher basal vitamin D levels, which are inversely linked with PAH severity.

Association between SARS-CoV-2 infection and de novo HLA donor specific antibody production in lung transplant recipients: Single-center study.

The COVID-19 pandemic has led to significant morbidity and mortality in lung transplant recipients. Respiratory viral infections may be associated with de-novo HLA donor-specific antibody production and impact lung transplant outcome. Since one of the immunomodulation strategies post-SARS-CoV-2 infection in lung transplant recipients include decreasing or holding anti-metabolites, concerns have been raised for higher incidence of de-novo HLA donor specific antibody production in lung transplant recipients. We performed a retrospective chart review of 24 consecutive lung transplant recipients diagnosed with COVID-19 to investigate this concern. We observed no significant differences in the CPRA or MFI levels of HLA class I and II antibodies pre- COVID-19 compared to 1 and 6 months post-COVID-19 diagnosis in 11/24 (45.8 %) LTR (p = 0.98 and p = 0.63 respectively). HLA class I and II DSA were detected in 5/24 LTR pre-COVID-19 diagnosis and persisted with no significant differences in the median MFI levels at 1 and 6 months post-COVID-19 diagnosis (p = 0.89). De-novo HLA class I and II DSA were detected in 1/24 (4.2 %) LTR at one month post-COVID-19 diagnosis and persisted with no significant differences in the median MFI levels at 1 and 6 months post-COVID-19 diagnosis (p = 0.54). Our results suggest that there was no significant association between SARS-CoV-2 infection and immunomodulation on pre-existing or de novo HLA donor specific antibodies.

Clinical and laboratory profiles of the SARS-CoV-2 Delta variant compared with pre-Delta variants.

OBJECTIVES: The emergence of SARS-CoV-2 variants of concern has led to significant phenotypical changes in transmissibility, virulence, and public health measures. Our study used clinical data to compare characteristics between a Delta variant wave and a pre-Delta variant wave of hospitalized patients. METHODS: This single-center retrospective study defined a wave as an increasing number of COVID-19 hospitalizations, which peaked and later decreased. Data from the United States Department of Health and Human Services were used to identify the waves' primary variant. Wave 1 (August 8, 2020-April 1, 2021) was characterized by heterogeneous variants, whereas Wave 2 (June 26, 2021-October 18, 2021) was predominantly the Delta variant. Descriptive statistics, regression techniques, and machine learning approaches supported the comparisons between waves. RESULTS: From the cohort (N = 1318), Wave 2 patients (n = 665) were more likely to be younger, have fewer comorbidities, require more care in the intensive care unit, and show an inflammatory profile with higher C-reactive protein, lactate dehydrogenase, ferritin, fibrinogen, prothrombin time, activated thromboplastin time, and international normalized ratio compared with Wave 1 patients (n = 653). The gradient boosting model showed an area under the receiver operating characteristic curve of 0.854 (sensitivity 86.4%; specificity 61.5%; positive predictive value 73.8%; negative predictive value 78.3%). CONCLUSION: Clinical and laboratory characteristics can be used to estimate the COVID-19 variant regardless of genomic testing availability. This finding has implications for variant-driven treatment protocols and further research.

Multidisciplinary Approach for Lung Transplantation due to COVID-19.

Coronavirus disease 2019 (COVID-19), a novel etiology of end-stage lung disease, has resulted in major disruptions to the process of health care delivery worldwide. These disruptions have led to team-based innovations globally, resulting in a broad range of new processes in cardiopulmonary perioperative management. A key intersection of multidisciplinary teamwork and COVID-19 is found in lung transplantation, in which diverse teams collaborate throughout the perioperative period to achieve optimal outcomes. In this article, we describe the multidisciplinary approach taken by Mayo clinic in Florida to manage patients with COVID-19 presenting for lung transplantation.

Low antispike antibody levels correlate with poor outcomes in COVID-19 breakthrough hospitalizations.

BACKGROUND: While COVID-19 immunization programs attempted to reach targeted rates, cases rose significantly since the emergence of the delta variant. This retrospective cohort study describes the correlation between antispike antibodies and outcomes of hospitalized, breakthrough cases during the delta variant surge. METHODS: All patients with positive SARS-CoV-2 polymerase chain reaction hospitalized at Mayo Clinic Florida from 19 June 2021 to 11 November 2021 were considered for analysis. Cases were analyzed by vaccination status. Breakthrough cases were then analyzed by low and high antibody titers against SARS-CoV-2 spike protein, with a cut-off value of ≥132 U/ml. Outcomes included hospital length of stay (LOS), need for intensive care unit (ICU), mechanical ventilation, and mortality. We used 1:1 nearest neighbor propensity score matching without replacement to assess for confounders. RESULTS: Among 627 hospitalized patients with COVID-19, vaccine breakthrough cases were older with more comorbidities compared to unvaccinated. After propensity score matching, the unvaccinated patients had higher mortality (27 [28.4%] vs. 12 [12.6%], p = 0.002) and LOS (7 [1.0-57.0] vs. 5 [1.0-31.0] days, p = 0.011). In breakthrough cases, low-titer patients were more likely to be solid organ transplant recipients (16 [34.0%] vs. 9 [12.3%], p = 0.006), with higher need for ICU care (24 [51.1%] vs. 22 [11.0%], p = 0.034), longer hospital LOS (median 6 vs. 5 days, p = 0.013), and higher mortality (10 [21.3%] vs. 5 [6.8%], p = 0.025) than high-titer patients. CONCLUSIONS: Hospitalized breakthrough cases were more likely to have underlying risk factors than unvaccinated patients. Low-spike antibody titers may serve as an indicator for poor prognosis in breakthrough cases admitted to the hospital.

Coronavirus Disease 2019 Vaccine-Breakthrough Infections Requiring Hospitalization in Mayo Clinic Florida Through August 2021.

We characterized coronavirus disease 2019 (COVID-19) breakthrough cases admitted to a single center in Florida. With the emergence of delta variant, an increased number of hospitalizations was seen due to breakthrough infections. These patients were older and more likely to have comorbidities. Preventive measures should be maintained even after vaccination.

Treatment of maternal depression in low-income women: A feasibility study from Kilifi, Kenya.

AIMS OF THE STUDY: To test the feasibility and acceptability of a group psychosocial intervention called Learning Through Play (LTP) plus Culturally adapted Cognitive Behaviour Therapy (CaCBT) for depressed Kenyan mothers with children aged 0-36 months. METHODS USED TO CONDUCT THE STUDY: This study was a single-arm mixed methods feasibility study to test an integrated parenting intervention for postnatal depression in a low-income rural area of Fumbini village in Kilifi District of Kenya. Women between the ages of 18 and 45 years with children up to 3 years were screened for depression using the Patient Health Questionnaire (PHQ-9). Those scoring above 10 on PHQ-9 were interviewed using the Revised Clinical Interview Schedule (CIS-R) to confirm the diagnosis of depression. Assessments were carried out at baseline and at the end of the intervention (3 months), followed by qualitative interviews with 12 women. Qualitative interviews were analysed using thematic analysis from a socio-constructionist theoretical lens. RESULTS OF THE STUDY: The LTP Plus was both feasible and acceptable with high satisfaction among the participants. Qualitative results showed that the women perceived the intervention as beneficial in reducing the symptoms of depression, coping with stress and negative emotions. The results also indicated a reduction in scores on PHQ-9, GAD-7 with an increase in perceived social support, health-related quality of life and an improvement in mothers' knowledge about child development at the end of the intervention. CONCLUSIONS DRAWN FROM THE STUDY AND CLINICAL IMPLICATIONS: This study represents the first feasibility research on integrated parenting intervention in Kenya. The results indicated that culturally adapted LTP plus CaCBT is feasible and acceptable in a low-income setting of Kenya. There is now a need to study the clinical and cost-effectiveness of LTP plus CaCBT in an appropriately powered larger randomised control trial, with a longer follow-up period.

An integrated parenting intervention for maternal depression and child development in a low-resource setting: Cluster randomized controlled trial.

BACKGROUND: Rates of depression among Pakistani mothers are high, leading to poor developmental outcomes in their children. This study tested the effectiveness of a manualized integrated parenting program; Learning through Play Plus (LTP+) for maternal depression in Karachi, Pakistan. METHODS: A cluster randomized control trial conducted from January 2014 to December 2015 across 120 villages in Karachi. A total of 774 depressed mothers aged 18-44 years with children aged 0-30 months old, were included. Villages were randomized to receive LTP+ added to treatment as usual (TAU) or TAU alone. Primary outcomes were severity of maternal depression at 3 and 6 months measured by the Edinburgh Postnatal Depression Scale and child socio-emotional development at 6 months measured by the Ages and Stages Questionnaire (ASQ). Secondary outcomes included maternal anxiety, quality of life, social support, parenting competence, and knowledge about child development. RESULTS: Mothers in the LTP+ group reported significantly lower depression scores compared to those in the TAU group (6.6 vs. 13.8, effect size [ES]: -7.2; 95% confidence interval [CI]: -8.2, -6.1) at 3 and 6 months (7.2 vs. 12.00; ES: -4.6; 95% CI: -5.9, -3.4). Child socio-emotional development at 6 months was significantly better in the LTP+ group on all domains of the ASQ. There were also statistically significant improvements on all secondary outcomes at 3- and 6-month follow-up. CONCLUSION: In low-resource settings like Pakistan, low-cost integrated parenting interventions delivered by lay health workers can provide effective treatment for depressed mothers, leading to improvements in child development.