SARS-CoV-2 vaccine response in CAR T-cell therapy recipients: A systematic review and preliminary observations.

Evolving data suggest that SARS-CoV-2 vaccine responses are blunted in allogeneic hematopoeitic cell transplant (HCT) recipients. Responses to the vaccine in chimeric antigen receptor T-cell (CAR-T) therapy are unknown and are likely to be even more diminished. We manually searched vital databases and identified 5 studies that have so far reported COVID-19 vaccine response in a total of 70 CAR-T recipients. The cumulative humoral response rate across all 5 studies was 31%. However, the results are not generalizable due to non-standardized units of humoral response measurement and a lack of external validation. Heterogeneity existed in studies regarding the timing of vaccination post-CAR-T, intervals between the vaccine doses, platforms of response assessment, vaccine platforms, and pre-vaccine immune status. CAR-T-related factors that independently impact vaccine response to prevent COVID-19 have further been reviewed. We conclude that the results must be interpreted with caution given the limitations of small sample sizes, differences in immunoassays, lack of standard definitions and clinical correlates of SARS-CoV-2 immune response, and lack of cellular responses. Until large-scale, homogenous prospective data become available, these preliminary observations will help transplant and infectious disease clinicians with their decision-making while providing care to this profoundly immunosuppressed cohort of patients.

Development and validation of standard and real patient gallstone library using Fourier transform infra-red spectroscopy.

BACKGROUND: Analysis of the constituents of gallstones using various spectroscopic techniques assists in identification of the pathogenesis of gallstones. In the current study, using Fourier Transform Infra-Red (FTIR) Spectroscopy, a Gallstone Standard Library (GSL) and a Gallstone Real Patients' Library (GRPL) were developed and validated for gallstone composition analysis. METHODS: The study was conducted at the Department of Pathology & Laboratory Medicine, Aga Khan University, Pakistan. Pure standards (cholesterol, calcium carbonate, bilirubin and bile salts) and gallstone specimens were analyzed using FTIR Nicolet iS-5 Spectrometer from Thermo Fisher Scientific, USA. Thermo Scientific™ QCheck™ algorithm, embedded within the OMNIC™ software, was used to identify the unique spectral fingerprint of the patient samples to match with known, standard material. Matching of > 75% was considered acceptable. Validation for accuracy of the library was performed for twenty analyzed gallstones at an international reference lab. RESULTS: Concerted search analysis was performed against the developed GSL consisting of 71 "pure component" spectrum divided into 5 types to generate the library. For the Gallstone Real Patient Library (GRPL), 117 patient samples were analyzed. Ninety-eight gall stones (83.8%) out of 117 stones matched with the developed GSL. Majority stones were mixed stones (95.92%), with cholesterol being the primary component (91.83%). Results of the developed library were 100% in agreement with the reports received from the external reference lab. CONCLUSIONS: The library developed displayed good consistency and can be used for detection of gallstone composition in Pakistan and replace the traditional labor- and time-intensive chemical method of gallstone analysis.

Effect of physical activity and vitamin D compared with vitamin D alone on muscle strength, back flexibility and aerobic activity in patients with chronic kidney disease: A comparative study from Pakistan.

BACKGROUND AND OBJECTIVES: To compare the differences in musculoskeletal health with vitamin D alone in comparison with vitamin D with physical activity (PA) among chronic kidney disease (CKD) patients. METHODS AND STUDY DESIGN: An open labeled, randomized, controlled trial was conducted at two tertiary care centers in Pakistan. Patients with CKD stage 2-4 and vitamin D deficiency (<20 ng/mL) were recruited in the trial. Both the arms were given oral vitamin D (cholecalciferol) drops (4000 IU) once daily for three months. One arm received only vitamin D (VD arm), while the second arm received vitamin D along with PA (VDPA arm). RESULTS: Of the 1,235 CKD stage 2-4 subjects contacted, forty-six subjects were enrolled. Eighteen were assigned to VD arm and twenty-eight were assigned to VDPA arm. Between groups comparison shows that bicep strength increases from 15 to 17 kg. Likewise, back flexibility and aerobic fitness also increased among those who receive vitamin D and physical activity, however these differences were not statistically significant (p>0.05). Sensitivity analysis within group comparison shows rise of bicep strength from 13.8 kg to 15.2 kg in the VD alone arm (p=0.05); however, in the VDPA arm, there is a greater difference of 14.3 kg to 17.2 kg (p<0.001). CONCLUSIONS: Targeted PA among CKD patients has potential to improve bicep strength and back flexibility. However, as the sample size was small, further studies would be required to suggest whether a PA should be included as part of the treatment regimen.

Is tocilizumab a potential therapeutic option for refractory unicentric Castleman disease?

Castleman disease is a rare lymphoproliferative disorder with 2 distinctly defined clinical forms. While multicentric Castleman disease (UCD) poses a potential therapeutic challenge, unicentric variant has historically been considered curable with surgical resection. Hence, little is known to guide management of patients with UCD, refractory to surgical resection and combination chemotherapy. We present a case of a patient, negative for HIV and HHV-8, who had an unsuccessful surgical intervention and no response to radiotherapy and chemotherapy. He had severe paraneoplastic pemphigus and was treated with tocilizumab, an anti-interleukin-6 receptor monoclonal antibody that has demonstrated good response rates in multicentric Castleman disease but demonstrated no clinical response despite 2 months of treatment. Our report is the first to describe a lack of response to tocilizumab in the rare setting of refractory UCD and discuss potential for distinct disease biology.

Evaluation of CSF kappa free light chains for the diagnosis of multiple sclerosis (MS): a comparison with oligoclonal bands (OCB) detection via isoelectric focusing (IEF) coupled with immunoblotting.

This study was done to evaluate the diagnostic accuracy of cerebrospinal fluid kappa free light chain (KFLC) for diagnosis of multiple sclerosis, against isoelectrofocusing (IEF) to detect oligoclonal bands (OCB) as gold standard. 64 cases were divided into positive and negative based on the OCB results. Diagnostic accuracy was calculated for the 1 mg/L cut-off. The 1 mg/L cut-off yielded a percent agreement of 86.1% and Cohen's kappa value of 0.8. Youden's index, yielded a cut-off of 0.92 mg/L as optimal (90.3% specificity and 90.9% sensitivity). The analytical time was 3 hours and 55 min for IEF and 25 min for KFLC. The cost of a single OCB test was PKR12 000 (US$68.17) compared with PKR4150 (US$23.58) for KFLC. KFLC proved to be an accurate, cheaper and time-saving alternative and can be performed prior to the contemporary testing.

GRADE-ADOLOPMENT of clinical practice guideline for postmenopausal osteoporosis management-a Pakistani context.

Due to its high prevalence, we aimed to create postmenopausal osteoporosis clinical practice guideline via GRADE-ADOLOPMENT for Pakistan. We recommend a higher dose (2000-4000 IU) of vitamin D for osteoporotic patients who are old, have malabsorption, or are obese. The guideline will help standardize care provision and improve health care outcomes for osteoporosis. PURPOSE: Postmenopausal osteoporosis affects one in every five postmenopausal women in Pakistan. An evidence-based clinical practice guideline (CPG) is needed to standardize care provision to optimize health outcomes. Hence, we aimed to develop CPG for the management of postmenopausal osteoporosis in Pakistan. METHODS: The GRADE-ADOLOPMENT process was used to adopt (as is or with minor changes), exclude (omit), or adapt (modify based on local context) recommendations to the source guideline (SG)-clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis-2020 update from American Association of Clinical Endocrinology (AACE). RESULTS: The SG was "adoloped" to cater to the local context. The SG consisted of 51 recommendations. Forty-five recommendations were adopted as is. Due to unavailability of drugs, 4 recommendations were adopted with minor changes, and one was excluded, while one recommendation was adopted with the inclusion of use of a surrogate FRAX tool specific for Pakistan. One recommendation regarding vitamin D dosage was adapted to recommend a dose of 2000-4000 IU of vitamin D in patients with obesity, malabsorption, and old age. CONCLUSION: The developed Pakistani postmenopausal osteoporosis guideline consists of 50 recommendations. The guideline created recommends a higher dose (2000-4000 IU) of vitamin D for patients who are old, have malabsorption, or are obese, which is an adaptation from the SG by the AACE. This higher dose is justified as lower doses prove to be suboptimal in these groups and should be complemented with baseline vitamin D and calcium levels.

Publication dynamics: what can be done to eliminate barriers to publishing full manuscripts by the postgraduate trainees of a low-middle income country?

OBJECTIVES: This study aimed to determine the publication rate of free paper abstracts presented by the postgraduate (PG) trainees and determine the reasons for non-publication. A mixed methods study was conducted. PG trainees presenting free papers at the at the Pakistan Society of Chemical Pathologist conferences from 2012 to 2018 were included. Three databases were searched to identify if the abstracts were published or not. The PG trainee authors of abstracts not published as full manuscript, were surveyed to determine the barriers and challenges in publishing a manuscript. RESULTS: The average rate of full manuscript publication was 51.8% (n = 93/177) for the abstracts presented by the PG trainees. Publication rate was higher for oral (n = 73/119, 61.3%) compared to poster presentation (n = 20/58, 34.5%). Most of the manuscripts were published after two years of abstract presentation. The survey showed that the main challenges to publishing an abstract were lack of time, limited scientific writing or submission skills, lack of funding for publication fee, and negative or statistically non-significant results. This reflects a need to arrange workshops/symposia for the PG trainees of low-middle income country (LMIC) to enhance their writing and time management skills and improve the full manuscript publication rate from LMICs.

Development of a virtual classroom for pre-analytical phase of laboratory medicine for undergraduate medical students using the Delphi technique.

BACKGROUND: Amongst the pre-analytical, analytical, and post-analytical phase of laboratory testing, pre-analytical phase is the most error-prone. Knowledge gaps in understanding of pre-analytical factors are identified in the clinical years amongst undergraduate students due to lack of formal teaching modules on the pre-analytical phase. This study was conducted to seek experts' consensus in Clinical Chemistry on learning objectives and contents using the Delphi technique with an aim to develop an asynchronous virtual classroom for teaching pre-analytical factors of laboratory testing. METHODS: A mixed method study was conducted at the Aga Khan University. A questionnaire comprising of 16 learning objectives and their associated triggers was developed on Google Docs for developing the case vignettes. A four-point Likert Scale, which included strongly agree, agree, disagree and strongly disagree, was utilized for the learning objectives. An open-ended question was included for experts to suggest new items for inclusion. A cut off of at least 75% agreement was set to establish consensus on each item. A total of 17 Chemical Pathology faculty from 13 institutions across Pakistan were invited to participate in the first round of Delphi. Similar method of response was used in round two to establish consensus on the newly identified items suggested by the faculty in round 1. Later, the agreed-upon objectives and triggers were used to develop interactive scenarios over Moodle to concurrently test and teach medical students in a nonchalant manner. RESULTS: A total of 17 responses were received in Round 1 of the Delphi process (response rate = 100%), while 12 responses were received in Round 2 (response rate = 71%). In round 1, all 16 learning objectives reached the required consensus (≥ 75%) with no additional learning objectives suggested by the experts. Out of 75 triggers in round 1, 61 (81.3%) reached the consensus to be included while 39 were additionally suggested. In 2nd round, 17 out of 39 newly suggested triggers met the desired consensus. 14 triggers did not reach the consensus after two rounds, and were therefore eliminated. The virtual classroom developed using the agreed-upon learning objectives and triggers consisted of 20 items with a total score of 31 marks. The questions included multiple choice questions, fill in the blanks, drag and drop sequences and read-and-answer comprehensions. Specific learning points were included after each item and graphs and pictures were included for a vibrant experience. CONCLUSION: We developed an effective and interactive virtual session with expert consensus on the pre-analytical phase of laboratory testing for undergraduate medical students which can be used for medical technologist, graduate students and fellows in Chemical Pathology.

State of the CAR-T: Risk of Infections with Chimeric Antigen Receptor T-Cell Therapy and Determinants of SARS-CoV-2 Vaccine Responses.

Chimeric antigen receptor T cell (CAR-T) therapy has shown unprecedented response rates in patients with relapsed/refractory (R/R) hematologic malignancies. Although CAR-T therapy gives hope to heavily pretreated patients, the rapid commercialization and cumulative immunosuppression of this therapy predispose patients to infections for a prolonged period. CAR-T therapy poses distinctive short- and long-term toxicities and infection risks among patients who receive CAR T-cells after multiple prior treatments, often including hematopoietic cell transplantation. The acute toxicities include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. The long-term B cell depletion, hypogammaglobulinemia, and cytopenia further predispose patients to severe infections and abrogate the remission success achieved by the living drug. These on-target-off-tumor toxicities deplete B-cells across the entire lineage and further diminish immune responses to vaccines. Early observational data suggest that patients with hematologic malignancies may not mount adequate humoral and cellular responses to SARS-CoV-2 vaccines. In this review, we summarize the immune compromising factors indigenous to CAR-T recipients. We discuss the immunogenic potential of different SARS-CoV-2 vaccines for CAR-T recipients based on the differences in vaccine manufacturing platforms. Given the lack of data related to the safety and efficacy of SARS-CoV-2 vaccines in this distinctively immunosuppressed cohort, we summarize the infection risks associated with Food and Drug Administration-approved CAR-T constructs and the potential determinants of vaccine responses. The review further highlights the potential need for booster vaccine dosing and the promise for heterologous prime-boosting and other novel vaccine strategies in CAR-T recipients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Role of Gut Microbiome in COVID-19: An Insight Into Pathogenesis and Therapeutic Potential.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in an unprecedented global crisis. Although primarily a respiratory illness, dysregulated immune responses may lead to multi-organ dysfunction. Prior data showed that the resident microbial communities of gastrointestinal and respiratory tracts act as modulators of local and systemic inflammatory activity (the gut-lung axis). Evolving evidence now signals an alteration in the gut microbiome, brought upon either by cytokines from the infected respiratory tract or from direct infection of the gut, or both. Dysbiosis leads to a "leaky gut". The intestinal permeability then allows access to bacterial products and toxins into the circulatory system and further exacerbates the systemic inflammatory response. In this review, we discuss the available data related to the role of the gut microbiome in the development and progression of COVID-19. We provide mechanistic insights into early data with a focus on immunological crosstalk and the microbiome's potential as a biomarker and therapeutic target.

Ups and Downs of COVID-19: Can We Predict the Future? Local Analysis with Google Trends for Forecasting the Burden of COVID-19 in Pakistan.

BACKGROUND: We aim to study the utility of Google Trends search history data for demonstrating if a correlation may exist between web-based information and actual coronavirus disease 2019 (COVID-19) cases, as well as if such data can be used to forecast patterns of disease spikes. PATIENTS & METHODS: Weekly data of COVID-19 cases in Pakistan was retrieved from online COVID-19 data banks for a period of 60 weeks. Search history related to COVID-19, coronavirus and the most common symptoms of disease was retrieved from Google Trends during the same period. Statistical analysis was performed to analyze the correlation between the two data sets. Search terms were adjusted for time-lag over weeks, to find the highest cross-correlation for each of the search terms. RESULTS: Search terms of 'fever' and 'cough' were the most commonly searched online, followed by coronavirus and COVID. The highest peak correlations with the weekly case series, with a 1-week backlog, was noted for loss of smell and loss of taste. The combined model yielded a modest performance for forecasting positive cases. The linear regression model revealed loss of smell (adjusted R2 of 0.7) with significant 1-week, 2-week and 3-week lagged time series, as the best predictor of weekly positive case counts. CONCLUSIONS: Our local analysis of Pakistan-based data seemingly confirms that Google trends can be used as an important tool for anticipating and predicting pandemic patterns and pre-hand preparedness in such unprecedented pandemic crisis.

Herpetic optic perineuritis presenting as classic abducens nerve palsy.

Optic perineuritis is a rare manifestation of herpes zoster ophthalmicus (HZO). Relative afferent pupillary defect (RAPD) is an important early clue to an impending nerve involvement, and robust clinical examination allows early detection of such rare metachronous manifestation of cutaneous HZ and institution of timely management for such sight-threatening conditions.

Small Centers with Big Ventures: Autologous Stem Cell Transplantation Survival Data

We present the first-ever autologous stem cell transplantation (ASCT) outcome data from a secondary-care healthcare facility. Albeit exact details of patient and disease characteristics and co-morbidity scores for all patients are not available, the engraftment and survival data is very similar to those published from large tertiary-care cancer centres, both regionally and internationally. Transplant Related Mortality (TRM) of 3.1% is within the expected range and includes a patient who died of acute drug reaction (ADR) during conditioning chemotherapy, prior to the ASCT. Furthermore, cyclophosphamide mobilization chemotherapy is given in the outpatient setting. This study is important in terms of healthcare resource optimization as well as patients' convenience and highlights that ASCT can be performed in a safe and effective manner with comparable survival rates even at a DGH, provided the centre stays abreast with the recent developments and can offer its patients with standard of care treatment of the era.

Pegylated Filgrastim Versus Filgrastim for Stem Cell Mobilization in Multiple Myeloma After Novel Agent Induction.

BACKGROUND: The current standard of care for transplant-eligible myeloma patients is novel agent-based induction, followed by high-dose chemotherapy and autologous stem cell rescue. Chemo-mobilization of peripheral blood CD34+ stem cells (PBSCs) with pegylated filgrastim (pegfilgrastim), a sustained-duration formulation of filgrastim, has been used as an alternative to filgrastim in several studies involving heterogeneous cohorts of lymphoma and multiple myeloma (MM) patients and shown to be equivalent in PBSC yield and cost-effectiveness. The present study focused on the efficacy of pegfilgrastim in PBSC mobilization compared with filgrastim exclusively after novel agent-based induction in a homogeneous group of MM patients. PATIENTS AND METHODS: We analyzed the data from 89 patients with MM treated at 2 transplant centers in Singapore who had received novel agent-based induction chemotherapy, PBSC mobilization with vinorelbine/cyclophosphamide, high-dose melphalan conditioning, and autologous stem cell rescue. Of the 89 patients, 61 were included in the pegfilgrastim group and 28 in the filgrastim group, with a similar median age and disease characteristics. PBSC harvesting was performed at a similar median time of 9.51 ± 0.84 days for both, and the peak peripheral blood CD34+ stem cell count was 19.90 × 106/kg for pegfilgrastim and 32.50 × 106/kg for filgrastim (95% confidence interval, -4.36 to 0.70 × 106/kg). RESULTS: No significant difference was found in the median PBSC collection between the 2 groups (pegfilgrastim, 7.90 × 106/kg vs. filgrastim, 10.10 × 106/kg; P = .16). CONCLUSION: The present study has demonstrated that a single dose of pegfilgrastim is comparable to filgrastim in terms of the timing and efficacy of PBSC harvest and could potentially spare the patient 6 days of filgrastim injections. In addition, ours is the first study to compare these growth factors using vinorelbine/cyclophosphamide as mobilization chemotherapy.

Balancing standardized testing with personalized training in surgery.

Students pursuing a medical career in the US are subject to standardized testing at regular intervals. These standardized tests not only quantify the milestones students have already achieved, but also define the path for future achievements. The purpose of these examinations is to help students become self-directed, lifelong learners - an essential attribute of a medical professional. However, whether preparing for these examinations actually makes students such disciplined learners needs to be examined. Especially during residency training with its limited time and unpredictable exposure, trainees must learn in the most efficient way for their learning styles, and thus develop attributes that will be helpful to them in their medical career. In this review, we propose that a personalized, learner-centered approach tailored to residents' educational needs and preferences can not only fulfill learning interests and objectives but also serve as a time-efficient and cost-effective approach for graduate medical education.

Development and Pilot Testing of an Objective Structured Clinical Examination for Obstructive Sleep Apnea.

Objective Our aim was (1) to develop an objective structured clinical examination (OSCE) for obstructive sleep apnea (OSA) and (2) to test the reliability and evaluate the feasibility of this OSCE while assessing residents' clinical skills in multiple core competencies via the standardized patient methodology. Study Design Development of assessment tool. Setting Johns Hopkins Medicine Simulation Center. Subjects and Methods Residents of the Department of Otolaryngology-Head and Neck Surgery at The Johns Hopkins University School of Medicine were invited to participate. A 2-station OSCE was developed. The first station used a standardized patient, and the encounter was videotaped for later evaluation by medical faculty not familiar with the participants being tested. The second was a computer-based station developed per a modified Delphi technique, based on feedback from otolaryngology and sleep medicine faculty involved in the care of patients with OSA. Checklists were developed for each station to standardize the evaluation of each trainee's performance. Results The OSCE that we developed is a feasible tool for assessing residents' performance and skills to diagnose and manage a patient with OSA. Internal consistency, as assessed by Krippendorff's alpha, was 0.699 for station 1 and 0.95 for station 2. Conclusion This OSCE was found to be feasible for assessment of clinical competency in OSA. Our model provides targeted assessment of multiple competencies and opportunity to improve clinical knowledge and skills.