Evaluation of delays during diagnosis and management of lung cancer in India: A prospective observational study.

OBJECTIVE: The majority of lung cancers are diagnosed at an advanced stage; the reasons for which are variable and unclear. METHODS: Lung cancer patients were evaluated prospectively to quantify various timelines and establish reasons for delays. Timelines were defined as time intervals between symptom onset, first physician visit, first specialist visit, date of diagnosis and treatment. RESULTS: A total 410 patients were included, majority having advanced disease. The median period for a first visit to a physician was 30 days (interquartile range [IQR] 20-90), 50 days (IQR 20-110) for referral to our centre, 23 days (IQR 14-33) to reach diagnosis, and 24 days (IQR 14.5-34) to initiate treatment. Administration ofanti-tuberculosis treatment further delayed referral to specialist centre. Treatment delays were related to performance status, disease stage and treatment type. On multivariate analysis, education and histology affected diagnosis delay and treatment delay. Treatment delay was less in those who received targeted therapy compared to chemotherapy. Various time delays did not affect the overall survival. CONCLUSION: Poor education status and inappropriate anti-tubercular treatment were primary factors associated with longer diagnostic delays. Creating disease awareness and high clinical suspicion are essential to overcome these lacunae in lung cancer care.

To study heterogeneity in SARS-CoV-2 IgG response titre in patients recovered from COVID-19.

The COVID-19 pandemic caused a serious health challenge to the entire mankind. The association between clinical characteristics of disease and formation of neutralizing antibodies have not well studied. A prospective study was conducted for patients recovered from confirmed SARS-CoV-2 infections from 1st August 2020 to 28th February 2021, to study the association between SARS-CoV-2 IgG antibody response titres and clinical characteristics of the disease. A total 92 patients were included in the study. Median age was 52 years; majority were male and middle or old aged.  About 48% patients required hospitalization and 38.3% had moderate CT severity score. Positive SARS-CoV-2-IgG was detected in all patients except one. On comparing the antibody titres among various sub-groups of COVID-19 recovered patients, old age was the only factor associated with statistically significant higher antibody response (28 AU/ml for age<35 years, 53 AU/ml for age group 35-60, and 71 AU/ml for age group >60 years, p=0.01). Severity of infection, worse CT severity scores, need of hospitalization, oxygen or ventilatory support were associated with higher antibody titres but were not statistically significant. There was a strong correlation of antibody titres when analysed for age of study population (Spearman correlation=0.39, p<0.001); whereas a weak correlation (Spearman correlation=0.03, p=0.753) was seen when analysed for CT severity score. Elderly patients had higher antibody titre after recovery from Covid-19 infection. Severity of disease, need of hospitalisation or oxygen/mechanical ventilation did not influence the antibody titre.

TACO produces robust multisample transcriptome assemblies from RNA-seq.

Accurate transcript structure and abundance inference from RNA sequencing (RNA-seq) data is foundational for molecular discovery. Here we present TACO, a computational method to reconstruct a consensus transcriptome from multiple RNA-seq data sets. TACO employs novel change-point detection to demarcate transcript start and end sites, leading to improved reconstruction accuracy compared with other tools in its class. The tool is available at http://tacorna.github.io and can be readily incorporated into RNA-seq analysis workflows.

Association of Environmental Factors, Prevalence of Asthma and Respiratory Morbidity in Mumbai: Need of a Public Health Policy.

OBJECTIVE: To study the association between environmental factors, prevalence of asthma and respiratory morbidity in relation to air quality levels in a mega city. To study modifiable environmental factors in people with diagnosed asthma and increased respiratory morbidity. METHODS: Cross sectional survey of population (N-3233) from 6 localities near air quality stations was done to study prevalence of asthma and respiratory morbidity (n-1006) followed by case control study of environmental factors by air sampling to study biological contamination. RESULTS: Univariate analysis was performed to study effect of various risk factors. Respiratory morbidity was significantly high in areas with high SPM levels. Odd's ratio was 10.3 for wheezing, 9.16 for cough, and 12.6 for breathlessness. Presence of biological contamination of air [bacterial spores] was associated with respiratory morbidity with odds ratio of 2.2 in areas with open drainage system. Pigeon droppings were found to be the source of fungal spores and associated with respiratory symptoms with odds ratio of 1.8. CONCLUSIONS: Respiratory morbidity significantly rises in areas with high particulate matter levels and biological contamination of air. Identification of environmental risk factors in different localities will be useful for undertaking specific mitigation measures at local level as a public health measure.

svclassify: a method to establish benchmark structural variant calls.

BACKGROUND: The human genome contains variants ranging in size from small single nucleotide polymorphisms (SNPs) to large structural variants (SVs). High-quality benchmark small variant calls for the pilot National Institute of Standards and Technology (NIST) Reference Material (NA12878) have been developed by the Genome in a Bottle Consortium, but no similar high-quality benchmark SV calls exist for this genome. Since SV callers output highly discordant results, we developed methods to combine multiple forms of evidence from multiple sequencing technologies to classify candidate SVs into likely true or false positives. Our method (svclassify) calculates annotations from one or more aligned bam files from many high-throughput sequencing technologies, and then builds a one-class model using these annotations to classify candidate SVs as likely true or false positives. RESULTS: We first used pedigree analysis to develop a set of high-confidence breakpoint-resolved large deletions. We then used svclassify to cluster and classify these deletions as well as a set of high-confidence deletions from the 1000 Genomes Project and a set of breakpoint-resolved complex insertions from Spiral Genetics. We find that likely SVs cluster separately from likely non-SVs based on our annotations, and that the SVs cluster into different types of deletions. We then developed a supervised one-class classification method that uses a training set of random non-SV regions to determine whether candidate SVs have abnormal annotations different from most of the genome. To test this classification method, we use our pedigree-based breakpoint-resolved SVs, SVs validated by the 1000 Genomes Project, and assembly-based breakpoint-resolved insertions, along with semi-automated visualization using svviz. CONCLUSIONS: We find that candidate SVs with high scores from multiple technologies have high concordance with PCR validation and an orthogonal consensus method MetaSV (99.7 % concordant), and candidate SVs with low scores are questionable. We distribute a set of 2676 high-confidence deletions and 68 high-confidence insertions with high svclassify scores from these call sets for benchmarking SV callers. We expect these methods to be particularly useful for establishing high-confidence SV calls for benchmark samples that have been characterized by multiple technologies.

Vascular calcification in chronic kidney disease associated with pathogenic variants in ABCC6.

Vascular calcification is prevalent in chronic kidney disease (CKD). Genetic causes of CKD account for 10-20% of adult-onset disease. Vascular calcification is thought to be one of the most important risk factors for increased cardiovascular morbidity and mortality in CKD patients and is detectable in 80% of patients with end stage kidney disease (ESKD). Despite the high prevalence of vascular calcification in CKD, no single gene cause has been described. We hypothesized that variants in vascular calcification genes may contribute to disease pathogenesis in CKD, particularly in families who exhibit a predominant vascular calcification phenotype. We developed a list of eight genes that are hypothesized to play a role in vascular calcification due to their involvement in the ectopic calcification pathway: ABCC6, ALPL, ANK1, ENPP1, NT5E, SLC29A1, SLC20A2, and S100A12. With this, we assessed exome data from 77 CKD patients, who remained unsolved following evaluation for all known monogenic causes of CKD. We also analyzed an independent cohort (Ontario Neurodegenerative Disease Research Initiative (ONDRI), n = 520) who were screened for variants in ABCC6 and compared this to a control cohort of healthy adults (n = 52). We identified two CKD families with heterozygous pathogenic variants (R1141X and A667fs) in ABCC6. We identified 10 participants from the ONDRI cohort with heterozygous pathogenic or likely pathogenic variant in ABCC6. Replication in a healthy control cohort did not reveal any variants. Our study provides preliminary data supporting the hypothesis that ABCC6 may play a role in vascular calcification in CKD. By screening CKD patients for genetic causes early in the diagnostic pathway, patients with genetic causes associated with vascular calcification can potentially be preventatively treated with new therapeutics with aims to decrease mortality.

Transplanting the highly sensitized patient: trials and tribulations.

PURPOSE OF REVIEW: Humoral sensitization to antigens of the human leukocyte antigen and ABO systems remains one of the largest barriers to further expansion in renal transplantation. This barrier translates into prolonged waiting time and a greater likelihood of death. The number of highly sensitized patients on the renal transplant waiting list continues to increase. This review focuses on the options available to these patients and speculates on future directions for incompatible transplantation. RECENT FINDINGS: Desensitization protocols (to remove antibodies), kidney-paired donation (to circumvent antibodies) or a hybrid technique involving a combination of both have broadened the access to transplantation for patients disadvantaged by immunologic barriers. However, the risk of antibody-mediated rejection may be increased and warrants caution. Technical advances in antibody characterization using sensitive bead immunoassays and the C1q assay and therapeutic modalities such as complement inhibitors and proteasome inhibitors have been used to avoid or confront these antibody incompatibilities. SUMMARY: A growing body of knowledge and literature indicates that these diagnostic and therapeutic modalities can facilitate a safer and more successful treatment course for these difficult-to-treat patients. Rigorous investigations into newer interventions will help in broadening the options for these patients and also expand the living donor pool.

Five Versus 10 Pharyngeal Sprays of 10% Lignocaine for Topical Anesthesia During Flexible Bronchoscopy: A Multicenter, Randomized Controlled Trial.

BACKGROUND: Ensuring adequate patient comfort is crucial during bronchoscopy. Although lidocaine spray is recommended for topical pharyngeal anesthesia, the optimum dose of sprays is unclear. We compared 5 versus 10 sprays of 10% lidocaine for topical anesthesia during bronchoscopy. METHODS: In this investigator-initiated, prospective, multicenter, randomized clinical trial, subjects were randomized to receive 5 (group A) or 10 sprays (group B) of 10% lidocaine. The primary objective was to compare the operator-rated overall procedure satisfaction between the groups. RESULTS: Two hundred eighty-four subjects were randomized (143 group A and 141 group B). The operator-rated overall procedure satisfaction, VAS [mean (SD)] was similar between the groups [group A, 74.1 (19.9) and group B, 74.3 (18.5), P =0.93]. The VAS scores of patient-rated cough [group A, 32.5 (22.9) and group B, 32.3 (22.2), P =0.93], and operator-rated cough [group A, 29.8 (22.3) and group B, 26.9 (21.5), P =0.26] were also similar. The time to reach vocal cords, overall procedure duration, mean doses of sedatives, the proportion of subjects willing to return for a repeat procedure (if required), and complications were not significantly different. Subjects in group A received significantly less cumulative lidocaine (mg) [group A, 293.9 (11.6) and group B, 343.5 (10.6), P <0.001]. CONCLUSION: During bronchoscopy, topical anesthesia with 5 sprays of 10% lidocaine is preferred as it is associated with a similar operator-rated overall procedure satisfaction at a lower cumulative lidocaine dose compared with 10 sprays.

Lung cancer in Asian Indian females: Identification of disease-specific characteristics and outcome measures over a 12-year period.

Aim: Globally, the incidence of lung cancer amongst women appears to be increasing. We aimed to compare the socio-epidemiological and clinical characteristics of lung cancer amongst men and women from a large cohort at a tertiary care hospital in Northern India. Methods: Records of patients diagnosed with lung cancer between January 2008 and March 2020 were reviewed. Baseline epidemiological data, clinical characteristics, histologic profiles, treatment administered, and survival were compared between males and females. Results: A total of 2054 male and 438 female patients were included in analysis. Compared to males, female patients were younger [median age, 56 vs. 60 years, P < 0.001)], less likely to be working, less educated beyond secondary level and less likely to be smokers (29.1% vs. 84.9%, P < 0.0001). No difference in baseline performance status was observed. Females were more frequently diagnosed with adenocarcinoma (54.2% vs. 30.2%, P = <0.0001), stage IV disease (70.8% vs. 63%, P = 0.001), and had higher rate of EGFR mutation (37.2% vs. 21.5%, P < 0.0001). There was no difference in the proportion of females receiving cancer-specific therapy. Multivariate Cox proportional hazards model revealed higher progression-free survival [median 9.17 vs. 7.23 months; P = 0.007] and overall survival [median 13.80 vs. 9.10 months respectively, P = 0.001] amongst females compared to males. Conclusion: Amongst a large cohort of lung cancer, females demonstrated several distinct and characteristic demographics as well as disease-related features, especially better survival outcomes.

Guidelines for endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA): Joint Indian Chest Society (ICS)/Indian Association for Bronchology (IAB) recommendations.

Over the past decade, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has become an indispensable tool in the diagnostic armamentarium of the pulmonologist. As the expertise with EBUS-TBNA has evolved and several innovations have occurred, the indications for its use have expanded. However, several aspects of EBUS-TBNA are still not standardized. Hence, evidence-based guidelines are needed to optimize the diagnostic yield and safety of EBUS-TBNA. For this purpose, a working group of experts from India was constituted. A detailed and systematic search was performed to extract relevant literature pertaining to various aspects of EBUS-TBNA. The modified GRADE system was used for evaluating the level of evidence and assigning the strength of recommendations. The final recommendations were framed with the consensus of the working group after several rounds of online discussions and a two-day in-person meeting. These guidelines provide evidence-based recommendations encompassing indications of EBUS-TBNA, pre-procedure evaluation, sedation and anesthesia, technical and procedural aspects, sample processing, EBUS-TBNA in special situations, and training for EBUS-TBNA.

A rare primary tracheal tumor.

A 20-year-old male without any prior comorbidities presented with 6-month history of hemoptysis as the sole symptom. Clinico-radiological profile and bronchoscopy were suggestive of a tracheal mass. This clinico-pathologic conference discusses the differential diagnoses of primary tumors of the trachea and their management options.

Combined diffuse alveolar hemorrhage and venous thrombosis in a patient with granulomatosis with polyangiitis: Case report and systematic review of literature.

Antineutrophil cytoplasmic antibody-associated vasculitis has associations with both thrombosis and diffuse alveolar hemorrhage (DAH). Management of patients having coexistence of both thrombotic and hemorrhagic manifestations is challenging. Thrombotic conditions require anticoagulation, which can theoretically increase the risk of bleeding and thereby worsen DAH. In this review, we highlight the management of a patient of granulomatosis with polyangiitis with DAH who developed deep vein thrombosis. A systematic review of the literature was also performed summarizing and discussing the issues pertaining to the management of such patients.

Radiographic Outcomes following K-Wire Augmentation of Dorsal Spanning Plate Fixation for Intra-Articular Fractures of the Distal Radius.

Background Restoration of articular surface alignment is critical in treating intra-articular distal radius fractures. Dorsal spanning plate fixation functions as an internal distraction mechanism and can be advantageous in the setting of highly comminuted fracture patterns, polytrauma patients, and patients with radiocarpal instability. The addition of K-wires to support articular surface reduction potentially augments fracture repair stability. Questions/Purposes We examined the radiographic outcomes and maintenance of reduction in patients with comminuted intra-articular distal radius fractures treated with K-wire fixation of articular fragments followed by dorsal spanning plate application. Patients and Methods We reviewed 35 consecutive patients with complex intra-articular distal radius fractures treated with dorsal spanning plate and K-wire fixation between April 2016 and October 2019. AO classification was recorded: B1 (3), B3 (2), C2 (2), C3 (28). A two-tailed paired t -test was used to compare findings immediately post-dorsal spanning plate surgery and at final follow-up after dorsal spanning plate removal. Results Mean patient age was 43.3 years (19-78 years). Mean follow-up was 7.8 months (SD 4.3 months) from surgery and 2.5 months from pin removal (SD 2.6 months). All patients achieved radiographic union. Radial height (mean interval change (MIC) 0.2 mm, SD 2.2, p = 0.63), articular step-off (MIC 0.1 mm, SD 0.6 mm, p = 0.88), and radial inclination (MIC -1.1 degrees, SD 3.7 degrees, p = 0.10) did not change from post-surgery to final follow-up. Ulnar variance (MIC -0.9 mm, SD 2.0 mm, p = 0.02) and volar tilt (MIC -1.5 degrees, SD 4.4 degrees, p = 0.05) were found to have decreased. Conclusion Dorsal spanning plate augmented with K-wire fixation for comminuted intra-articular distal radius fractures in polytrauma patients allows for immediate weightbearing and maintains articular surface alignment at radiographic union and may provide better articular restoration than treatment with dorsal spanning plate alone. Level of Evidence This is a Level IV , therapeutic study.

Impact of various hematological and biochemical parameters on mortality in coronavirus disease 2019 (COVID-19): A single-center study from North India.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), which causes coronavirus disease 2019 (COVID-19), has rapidly evolved into a pandemic, affecting more than 90 million people and more than 1.9 million deaths worldwide. Despite extensive study, the prognostic role of various hematological and biochemical parameters remains unclear. Methods: This study was carried out at a COVID care facility in Delhi. The demographic and clinical information, laboratory parameters (hematological, biochemical, and inflammatory), and the treatment of admitted COVID-19 patients during first wave were collected from electronic medical records and were subsequently analyzed. Results: Between March 2020 and November 2020, a total of 5574 patients were admitted to hospital due to COVID-19. Majority (77.2%) were male and had a mean (standard deviation [SD]) age of 38.9 (14.9) years. The mean (SD) duration of hospital stay was significantly higher in nonsurvivors. Out of the entire cohort, 8.7% of the patients had comorbidities, whereas 47.1% of the patients were asymptomatic at presentation. Compared to the survivors, the nonsurvivors had a significantly higher proportion of comorbidities and were more likely to be symptomatic. Patients who died during hospital stay had significantly higher relative neutrophil percent and neutrophil-lymphocyte ratio and lower lymphocyte percent. The patients who died had significantly higher levels of ferritin, D-dimer, and fibrinogen. Conclusions: Analysis of various hematological and inflammatory parameters can provide useful prognostic information among COVID-19-affected patients. It can also help in identifying patients who merit aggressive institutional care and thereby potentially mitigate the mortality.

Clinical profile of small-cell lung cancer in North India: A 12-year analysis from a tertiary care center.

Introduction: The small cell variant is a relatively uncommon but aggressive form of lung cancer. The present study aims to analyse the clinical characteristics, treatment outcomes and prognostic factors of an ambispectively enrolled large cohort of small cell lung cancer (SCLC) in the Indian population over a decade-long period. Materials and Methods: All patients diagnosed with SCLC between 2008 and 2020 at a tertiary care lung cancer clinic were included. The clinical details, demographics, details of investigations, treatment and survival outcomes were recorded and analysed. Results: A total of 361 patients were included. The majority were males (86.4%) with a mean (SD) age of 57.3 (12.3) years. Further, 34.9% were current smokers, with the median smoking index being 520 (interquartile range [IQR]: 260-1000). The majority had good performance status, that is, the Eastern Cooperative Oncology Group scale (ECOG) 0 or 1 (65%), and Karnofsky Performance Scale (KPS) ≥70 (85.9%). Also, 73.3% had extensive stage disease. The median time from symptom onset to definitive diagnosis was 91 days. Treatment details were available for 179 patients: chemotherapy only (n = 128), combined chemo-radiotherapy (n = 41) and radiotherapy only (n = 10). The median (IQR) progression-free survival (PFS) was 182 (94 to 306) days and the median (IQR) overall survival (OS) was 205 (94 to 429) days. On univariate analysis, factors that significantly affected survival included smoking index and performance status. However, on multivariate analysis, only the performance status significantly affected PFS, whereas none of these factors were significant for OS. Conclusions: SCLC predominantly affects males with a heavy smoking index. The diagnosis is usually made late; survival remains poor and is predominantly affected by the performance status.

Utility of Elastography for Differentiating Malignant and Benign Lymph Nodes During EBUS-TBNA: A Systematic Review and Meta-analysis.

BACKGROUND: Ultrasound elastography noninvasively estimates tissue hardness. Studies have evaluated elastography for differentiating malignant from benign lymph nodes during endobronchial ultrasound-guided transbronchial needle aspiration. Several methods of performing elastography are described with variable diagnostic accuracy. METHODS: The aim of this study was to evaluate endobronchial ultrasound-guided elastography in differentiating malignant from benign mediastinal lymphadenopathy. We performed a systematic search of the PubMed and Embase databases to extract the relevant studies. A diagnostic accuracy meta-analysis was carried out to calculate the pooled sensitivity and specificity [with 95% confidence intervals (CIs)], and positive and negative likelihood ratios of elastography. RESULTS: After a systematic search, 20 studies (1600 patients, 2712 nodes) were selected. The pooled sensitivity and specificity of elastography were 0.90 (95% CI, 0.84-0.94) and 0.79 (95% CI, 0.73-0.84), respectively. The summary receiver operating curve demonstrated an area under the curve for elastography of 0.90 (0.88-0.93). The positive and negative likelihood ratios and the diagnostic odds ratio were 4.3 (95% CI, 3.3-5.5), 0.12 (95% CI, 0.07-0.20), and 35 (95% CI, 19-63), respectively. Of the most commonly described methods, the color classification method (type 3 malignant vs. type 1 benign) demonstrated the highest area under the curve of 0.91 (0.88-0.93). There was significant heterogeneity and publication bias. Subgroup analyses indicated no significant difference between the sensitivity and specificity of quantitative and qualitative elastography methods. CONCLUSIONS: Ultrasound elastography is useful in differentiating malignant and benign lymph nodes during endobronchial ultrasound-guided transbronchial needle aspiration. However, elastography does not replace the requirement of lymph node aspiration.

Prognostic factors for treatment response and survival outcomes after first-line management of Stage 4 non-small cell lung cancer: A real-world Indian perspective.

Background: Indian data on treatment outcomes and survival in advanced non-small cell lung cancer (NSCLC) remain scarce. Materials and Methods: A retrospective review of 537 advanced NSCLC patients treated at a tertiary care facility in North India from January 2008 to March 2018 was done to assess treatment response and survival in terms of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: Median age of enrolled patients was 60 years (range: 26-89 years). The majority were males (78.2%) and smokers (66.5%). Adenocarcinoma (51.2%) was the most common pathological type. Most patients had good performance status (PS) (the Eastern Cooperative Oncology Group [ECOG] 0 or 1 in 55.7%) and received conventional chemotherapy (86.6%). ORR and DCR after 3-4 months of first-line treatment were 55.2% and 71.75%, respectively (n = 223). Never smokers had better ORR as well as DCR compared to chronic smokers whereas treatment with tyrosine kinase inhibitors achieved significantly better ORR, and patients with good PS had better DCR compared to those with poor PS. Median PFS (n = 455) was 7.0 months (95% confidence interval [CI]: 3.7-14.0) and median OS was 11.7 months (95% CI: 5.5-29.9 months). Good PS and nonsmoking status were independent predictors of better PFS on multivariate analysis. For OS, good PS, nonsmoking behavior, and treatment with epidermal growth factor receptor inhibitors were independent predictors. Conclusion: In advanced NSCLC, never-smokers, and patients with good baseline ECOG have favorable treatment and survival outcomes. Treatment with targeted therapy results in better ORR and OS but did not affect PFS.

A Delphi consensus statement for the management of post-COVID interstitial lung disease.

INTRODUCTION: As millions of people worldwide recover from COVID-19, a substantial proportion continue to have persistent symptoms, pulmonary function abnormalities, and radiological findings suggestive of post-COVID interstitial lung disease (ILD). To date, there is limited scientific evidence on the management of post-COVID ILD, necessitating a consensus-based approach. AREAS COVERED: A panel of experts in pulmonology and thoracic radiology was constituted. Key questions regarding the management of post-COVID ILD were identified. A search was performed on PubMed and EMBASE and updated till 1 March 2022. The relevant literature regarding the epidemiology, pathophysiology, diagnosis and treatment of post-COVID ILD was summarized. Subsequently, suggestions regarding the management of these patients were framed, and a consensus was obtained using the Delphi approach. Those suggestions which were approved by over 80% of the panelists were accepted. The final document was approved by all panel members. EXPERT OPINION: Dedicated facilities should be established for the care of patients with post-COVID ILD. Symptom screening, pulmonary function testing, and thoracic imaging have a role in the diagnosis. The pharmacologic and non-pharmacologic options for the management of post-COVID ILD are discussed. Further research into the pathophysiology and management of post-COVID ILD will improve our understanding of this condition.

A young immunocompetent female with anterior mediastinal mass.

A 23-year-old female presented with 3 months of central chest pain and fever. Clinico-radiological investigations were consistent with an anterior mediastinal mass. This clinicopathologic conference discusses the differential diagnoses of such a presentation and their management options.