Phase III randomized trial comparing palliative systemic therapy to best supportive care in advanced esophageal/GEJ cancer.

No study has unequivocally proven that chemotherapy prolongs overall survival (OS) in advanced esophageal cancer. We conducted a Phase III randomized study in first-line advanced unresectable/metastatic esophageal/GEJ cancer. Patients aged 18-70 years, with performance status 0-2, were randomized to best supportive care (BSC) alone, or BSC with weekly paclitaxel 80 mg/m2. BSC comprised, as indicated, education, counselling, radiation, stenting, feeding tube placement, nutritional supplementation, medications like analgesics, and referral to a support group and palliative care. The primary endpoint was OS; secondary endpoints included progression free survival (PFS), response, toxicity, and QoL. Between May 2016-December 2020, we recruited 281 patients: 143 to chemotherapy and 138 to BSC. Histopathology was squamous in 269 (95.7%) patients. Median number of paclitaxel doses was 12 (IQR, 7-23). Median OS was 4.2 months (95% CI, 3.42-5.32) in BSC, and 9.2 months (95% CI, 8.02-10.48) in chemotherapy; HR, 0.49 (95% CI, 0.39-0.64); p < .001. As compared to BSC, chemotherapy increased response (2.9% to 39%), median PFS (2.1 to 4.2 months), 1-year OS (11% to 32%), 2-year OS (0 to 9%), median dysphagia-free survival (2.9 to 14.8 months), and global and esophagus-specific QoL, without significantly increasing all-grade or grade ≥3 toxicities. Using ESMO clinical benefit scale and ASCO Value Framework, palliative chemotherapy scored as having "substantial value." Our study provides the first level 1 evidence that chemotherapy prolongs survival in advanced esophageal/GEJ carcinoma. BSC alone is no longer appropriate. Weekly paclitaxel is an attractive option, especially in LMICs with limited access to immunotherapy.

Longitudinal Assessment of ROX and HACOR Scores to Predict Non-Invasive Ventilation Failure in Patients with SARS-CoV-2 Pneumonia.

Introduction: NIV (Non-invasive ventilation) and HFNC (High Flow nasal cannula) are being used in patients with acute respiratory failure. HACOR score has been exclusively calculated for patients on NIV, on other hand ROX index is being used for patients on HFNC. This is first study where ROX index has been used in patients on NIV to predict failure. Aim of the study: This study investigates the comparative diagnostic performance of HACOR score and ROX index to predict NIV failure. Methods: We performed a retrospective cohort study of non-invasively ventilated COVID-19 patients admitted between 1st April 2020 to 15th June 2021 to ICU of a tertiary care teaching hospital located in Central India. We assessed factors responsible for NIV failure, and whether these scores HACOR/ROX index have discriminative capacity to predict risk of invasive mechanical ventilation. Results: Of the 441 patients included in the current study, 179 (40.5%) recovered, while remaining 262 (59.4%) had NIV failure. On multivariable analysis, ROX index > 4.47 was found protective for NIV-failure (OR 0.15 (95% CI 0.03-0.23; p<0.001). Age > 60 years and SOFA score were other significant independent predictors of NIV-failure. The AUC for prediction of failure rises from 0.84 to 0.94 from day 1 to day 3 for ROX index and from 0.79 to 0.92 for HACOR score in the same period, hence ROX score was non-inferior to HACOR score in current study. DeLong's test for two correlated ROC curves had insignificant difference expect day-1 (D1: 0.03 to 0.08; p=3.191e-05, D2: -0.002 to 0.02; p = 0.2671, D3: -0.003 to 0.04; p= 0.1065). Conclusion: ROX score of 4.47 at day-3 consists of good discriminatory capacity to predict NIV failure. Considering its non-inferiority to HACOR score, the ROX score can be used in patients with acute respiratory failure who are on NIV.

Surveillance of ventilator associated pneumonia in a network of indian hospitals using modified definitions: a pilot study.

Background: Ventilator-associated pneumonia (VAP) is a major cause of morbidity and mortality in patients receiving mechanical ventilation in India. Surveillance of VAP is essential to implement data-based preventive measures. Implementation of ventilator-associated events (VAE) criteria for surveillance has major constraints for low resource settings, which can lead to significant underreporting. Surveillance of VAP using common protocols in a large network of hospitals would give meaningful estimates of the burden of VAP in low resource settings. This study leverages a previously established healthcare-associated infections (HAI) surveillance network to develop and test a modified VAP definition adjusted for Indian settings. Methods: In this observational pilot study, thirteen hospitals from the existing HAI surveillance network were selected for developing and testing a modified VAP definition between February 2021 and April 2023. The criteria used for diagnosing VAP were adapted from the CDC's Pediatric VAP definition and modified to cater to the needs of Indian hospitals. Designated nurses recorded each VAP event in a case report form (CRF) and also collected denominator data. The data was entered into an indigenously developed database for validation and analysis. At the time of data analysis, a questionnaire was sent to sites to get feedback on the performance of the modified VAP definitions. Findings: Out of 133,445 patient days and 40,533 ventilator days, 261 VAP events were recorded, with an overall VAP rate of 6.4 per 1000 ventilator days and a device utilization ratio (DUR) of 0.3. A total of 344 organisms were reported from the VAP events. Of these, Acinetobacter spp (29.6%, 102) was the most frequent, followed by Klebsiella spp (26.7%, 92). Isolates of Acinetobacter spp (98%) and Enterobacterales (85.5%) showed very high resistance against Carbapenem. Colistin resistance was observed in 6% of Enterobacterales and 3.2% of Acinetobacter spp. Interpretation: Data from this pilot study needs to validated in the larger Indian HAI surveillance network so that it can help in wider implementation of this protocol in order to assess its applicability p VAP across India. Funding: This work was supported by a grant received from the Indian Council of Medical Research (code I-1203).

Repurposing surgical wards in pandemics - An appraisal of outcomes of COVID-19 patients treated in Orthopaedic wards.

Background: The COVID-19 pandemic resulted in a shift in the way healthcare resources were used. While India faced limited effects in the first COVID wave primarily due to strict lockdown of the county, it was one of the worst affected in the second wave and at one time reported the highest number of daily cases. To address the lack of intensive care units (ICU) beds, the surgical wards of our institute were repurposed to take care of patients requiring supplementary oxygen and other supportive care till either they improved or an ICU bed was available. The medical personnel in charge of the surgical wards were entrusted with the care of patients with support from intensive care support teams (ICST). Aims: We aimed to examine the clinical details of patients admitted in the repurposed orthopaedic wards during the second COVID wave and to evaluate the factors that might affect the clinical outcomes in such patients. Methods: This was a retrospective review of records of patients admitted in the repurposed orthopaedic wards between 16 April 2021 and 20 May 2021. Details related to demography, COVID-19 presentation, COVID-19-related management and clinical course, including transfers to ICUs, and outcomes in terms of either discharge to home or death were recorded. They were analysed using statistical software. Results: One hundred and twenty three patients were treated during the said period. Twenty patients died during treatment, resulting in a mortality rate of 16.3%. Age, gender, RT-PCR status, pre-existing comorbidities, SpO2 at admission, method of supplemental oxygen supply, total leukocyte counts, haemoglobin values, serum C-reactive protein, Lactate dehydrogenase (LDH) and creatinine values had no statistically significant association with death of a patient during treatment. Conclusion: Based on the results, one can state that clinicians of surgical specialities having background knowledge of internal medicine from undergraduate education can manage patients of COVID-19 with support from ICST with reasonable outcomes. In case of future pandemics, surgical wards can be repurposed to tide over exigencies. Additionally, primary care physicians, who are often the first point of contact for patients, can allay their apprehensions adequately in future pandemics, thus preventing widespread panic and burdening of healthcare resources.

Addressing challenges in low-income and middle-income countries through novel radiotherapy research opportunities.

Although radiotherapy continues to evolve as a mainstay of the oncological armamentarium, research and innovation in radiotherapy in low-income and middle-income countries (LMICs) faces challenges. This third Series paper examines the current state of LMIC radiotherapy research and provides new data from a 2022 survey undertaken by the International Atomic Energy Agency and new data on funding. In the context of LMIC-related challenges and impediments, we explore several developments and advances-such as deep phenotyping, real-time targeting, and artificial intelligence-to flag specific opportunities with applicability and relevance for resource-constrained settings. Given the pressing nature of cancer in LMICs, we also highlight some best practices and address the broader need to develop the research workforce of the future. This Series paper thereby serves as a resource for radiation professionals.

Exploring data sources and mathematical approaches for estimating human mobility rates and implications for understanding COVID-19 dynamics: a systematic literature review.

Human mobility, which refers to the movement of people from one location to another, is believed to be one of the key factors shaping the dynamics of the COVID-19 pandemic. There are multiple reasons that can change human mobility patterns, such as fear of an infection, control measures restricting movement, economic opportunities, political instability, etc. Human mobility rates are complex to estimate as they can occur on various time scales, depending on the context and factors driving the movement. For example, short-term movements are influenced by the daily work schedule, whereas long-term trends can be due to seasonal employment opportunities. The goal of the study is to perform literature review to: (i) identify relevant data sources that can be used to estimate human mobility rates at different time scales, (ii) understand the utilization of variety of data to measure human movement trends under different contexts of mobility changes, and (iii) unraveling the associations between human mobility rates and social determinants of health affecting COVID-19 disease dynamics. The systematic review of literature was carried out to collect relevant articles on human mobility. Our study highlights the use of three major sources of mobility data: public transit, mobile phones, and social surveys. The results also provides analysis of the data to estimate mobility metrics from the diverse data sources. All major factors which directly and indirectly influenced human mobility during the COVID-19 spread are explored. Our study recommends that (a) a significant balance between primitive and new estimated mobility parameters need to be maintained, (b) the accuracy and applicability of mobility data sources should be improved, (c) encouraging broader interdisciplinary collaboration in movement-based research is crucial for advancing the study of COVID-19 dynamics among scholars from various disciplines.

Postoperative Outcomes After Emergency Surgery in COVID-19 Patients: An Ambispective Matched Cohort Study.

Purpose There is limited data from the Indian subcontinent regarding the surgical outcomes of coronavirus disease (COVID-19) patients. In this observational study, we aimed to evaluate the postoperative outcomes after emergency surgery in COVID-19 patients compared to concurrent age and gender-matched controls. We also sought to analyze the possible predictors of postoperative mortality in COVID-19 patients. Methods This matched cohort study was conducted in a tertiary care teaching hospital in central India, between 1st July 2021 and 30th June 2022. COVID-19-positive patients undergoing emergency surgery under anesthesia were recruited as cases. Age and gender-matched COVID-19-negative patients undergoing a similar nature of surgery in the same period served as concurrent controls. The cases and controls were compared for the 30-day mortality and perioperative complications. Results The COVID-19-positive surgical cohort had a 12.3 times greater 30-day postoperative overall mortality risk as compared to a matched cohort of patients with a negative COVID-19 test. A positive COVID-19 status was associated with more postoperative complications of acute respiratory distress syndrome (ARDS), sepsis, shock, and persistent hyperglycemia. On analysis of predictors of mortality, the presence of preoperative dyspnea, ARDS, American Society of Anesthesiologists Physical Status (ASA-PS) Class IIIE/IVE, increase in sequential organ failure assessment (SOFA) score, Quick SOFA>1, higher creatinine, bilirubin, and lower albumin were observed to be associated with increased mortality. Conclusions Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients undergoing emergency surgery is significantly associated with higher postoperative complications and increased 30-day postoperative mortality.

Immunogenicity and safety of a 14-valent pneumococcal polysaccharide conjugate vaccine (PNEUBEVAX 14™) administered to 6-8 weeks old healthy Indian Infants: A single blind, randomized, active-controlled, Phase-III study.

BACKGROUND: Introduction of pneumococcal conjugate vaccines (PCVs) reduced the number of cases of pneumococcal disease (PD). However, there is an increase in clinical and economic burden of PD from serotypes that are not part of the existing pneumococcal vaccines, particularly impacting pediatric and elder population. In addition, the regions where the PCV is not available, the disease burden remains high. In this study, immunogenicity and safety of the BE's 14-valent PCV (PNEUBEVAX 14™; BE-PCV-14) containing two additional epidemiologically important serotypes (22F and 33F) was evaluated in infants in comparison to licensed vaccine, Prevenar-13 (PCV-13). METHODS: This is a pivotal phase-3 single blind randomized active-controlled study conducted at 12 sites across India in 6-8 weeks old healthy infants at 6-10-14 weeks dosing schedule to assess immunogenic non-inferiority and safety of a candidate BE-PCV-14. In total, 1290 infants were equally randomized to receive either BE-PCV-14 or PCV-13. Solicited local reactions and systemic events, adverse events (AEs), serious AEs (SAEs), and medically attended AEs (MAAEs) were recorded. Immunogenicity was assessed by measuring anti-PnCPS (anti-pneumococcal capsular polysaccharide) IgG concentration and functional antibody titers through opsonophagocytic activity (OPA), one month after completing three dose schedule. Cross protection to serotype 6A offered by serotype 6B was also assessed in this study. FINDINGS: The safety profile of BE-PCV-14 was comparable to PCV-13 vaccine. Majority of reported AEs were mild in nature. No severe or serious AEs were reported in both the treatment groups. For the twelve common serotypes and for the additional serotypes (22F and 33F) in BE-PCV-14, NI criteria was demonstrated as defined by WHO TRS-977. Primary immunogenicity endpoint was met in terms of IgG immune responses for all 14 serotypesof BE-PCV-14. Moreover, a significant proportion of subjects (69%) seroconverted against serotype 6A, even though this antigen was not present in BE-PCV-14. This indicates that serotype 6B of BE-PCV-14 cross protects serotype 6A. BE-PCV-14 also elicited comparable serotype specific functional OPA immune responses to all the serotypes common to PCV-13. INTERPRETATIONS: BE-PCV-14 was found to be safe and induced robust and functional serotype specific immune responses to all 14 serotypes. It also elicited cross protective immune response against serotype 6B.These findings suggest that BE-PCV-14 can be safely administered to infants and achieve protection against pneumococcal disease caused by serotypes covered in the vaccine. The study was prospectively registered with clinical trial registry of India - CTRI/2020/02/023129.

Mutations make pandemics worse or better: modeling SARS-CoV-2 variants and imperfect vaccination.

COVID-19 is a respiratory disease triggered by an RNA virus inclined to mutations. Since December 2020, variants of COVID-19 (especially Delta and Omicron) continuously appeared with different characteristics that influenced death and transmissibility emerged around the world. To address the novel dynamics of the disease, we propose and analyze a dynamical model of two strains, namely native and mutant, transmission dynamics with mutation and imperfect vaccination. It is also assumed that the recuperated individuals from the native strain can be infected with mutant strain through the direct contact with individual or contaminated surfaces or aerosols. We compute the basic reproduction number, R 0 , which is the maximum of the basic reproduction numbers of native and mutant strains. We prove the nonexistence of backward bifurcation using the center manifold theory, and global stability of disease-free equilibrium when R 0 < 1 , that is, vaccine is effective enough to eliminate the native and mutant strains even if it cannot provide full protection. Hopf bifurcation appears when the endemic equilibrium loses its stability. An intermediate mutation rate ν 1 leads to oscillations. When ν 1 increases over a threshold, the system regains its stability and exhibits an interesting dynamics called endemic bubble. An analytical expression for vaccine-induced herd immunity is derived. The epidemiological implication of the herd immunity threshold is that the disease may effectively be eradicated if the minimum herd immunity threshold is attained in the community. Furthermore, the model is parameterized using the Indian data of the cumulative number of confirmed cases and deaths of COVID-19 from March 1 to September 27 in 2021, using MCMC method. The cumulative cases and deaths can be reduced by increasing the vaccine efficacies to both native and mutant strains. We observe that by considering the vaccine efficacy against native strain as 90%, both cumulative cases and deaths would be reduced by 0.40%. It is concluded that increasing immunity against mutant strain is more influential than the vaccine efficacy against it in controlling the total cases. Our study demonstrates that the COVID-19 pandemic may be worse due to the occurrence of oscillations for certain mutation rates (i.e., outbreaks will occur repeatedly) but better due to stability at a lower infection level with a larger mutation rate. We perform sensitivity analysis using the Latin Hypercube Sampling methodology and partial rank correlation coefficients to illustrate the impact of parameters on the basic reproduction number, the number of cumulative cases and deaths, which ultimately sheds light on disease mitigation.

SALTT study: A retrospective analysis of 111 SAlivary gland tumors of Lung and Tracheobronchial Tree.

INTRODUCTION: Primary pulmonary salivary gland-type tumours (PPSGT) are rare lung neoplasms arising from submucosal seromucinous glands in the central airway. METHODS AND RESULTS: We retrospectively analysed the clinicopathological features of 111 PPSGTs diagnosed at our institute between 2003 and 2021. The mean age at diagnosis was 43.8 years(range 6-78 years) and a male-to-female ratio of 2:1. On imaging, 92 % of cases had centrally located tumours and 37.3 % were early stage. The histopathological types included 70 cases (63 %) of mucoepidermoid carcinoma (MEC), 31 cases (27.7 %) of adenoid cystic carcinoma (ADCC), two cases of myoepithelial carcinoma, one case each of acinic cell carcinoma (ACC), clear cell carcinoma (CCC), epithelial myoepithelial carcinoma (EMC) and 5 others [including adenocarcinoma of minor salivary gland origin(n = 3), carcinoma with sebaceous differentiation(n = 1) and poorly differentiated carcinoma of salivary gland type(n = 1)]. The size of the tumours found in the resection specimens ranged from 1 cm to 13 cm, with an average size of 4.9 cm. High-risk attributes such as lymphovascular invasion (LVI), perineural invasion (PNI), pleural involvement, positive resection margins, and nodal metastasis were identified in 15.3 %, 15.3 %, 13.6 %,15.2 % and 6.7 % of cases, respectively. These attributes were found to be more frequent in ADCC than in MEC. Surgery was the main treatment modality [68/84 (80 %) cases]. ADCC cases had more recurrence and distant metastasis than MEC cases. The 3- year overall-survival (OS) and recurrence-free survival(RFS) were better in patients with age lesser than 60 years(p-value <0.0001), low pT stage (p-value 0.00038) and lower grade of MEC(p-value-0.0067). CONCLUSION: It is crucial to have an acquaintance with the morphologic spectrum and immunophenotypic characteristics of PPSGT to recognize them in this unusual location. In tandem, it is crucial to differentiate them from conventional primary non-small cell lung carcinoma, as the management protocols and prognostic implications differ significantly.

Volumetric and geometric changes in the parotid glands and target volume during image-guided radiotherapy for locally advanced oropharyngeal cancers.

PURPOSE: This study aimed to evaluate the volumetric and geometric changes in the parotid glands and target volume during image-guided radiotherapy (IGRT) for locally advanced oropharyngeal cancers. MATERIALS AND METHODS: Twenty patients receiving radiotherapy using IGRT at a dose of 70 Gy/35 fractions/7 weeks for locally advanced oropharyngeal cancers were accrued. Radiotherapy planning computed tomography (CT) scans were performed at pre-radiotherapy (RT), 20, 40, and 60 Gy for each patient. Volume changes in target and parotids along with shifts of parotids were assessed with respect to pre-RT scan after co-registration. In study scans, GTVp and GTVn were recontoured as per particular CT. CTV and PTV were copied from planning CT to study CT. CTV was edited from anatomical barriers, and PTV was edited only from the skin in the study CT. The parotids were recontoured on each study scan. The center of mass (COM) of C2 vertebral body was considered as the reference to evaluate its shifts. RESULTS: There was a statistically significant percentage regression of ipsilateral and contralateral parotid mean volumes at the rate of 0.85%/0.207 cc and 0.98%/0.26 cc per day, respectively. We observed the mean medial shift of center of mass of ipsilateral parotid of 2.23 mm (p = 0.011) and contralateral parotid of 2.67 mm (p = 0.069) at the end of 60 Gy. GTVp (mean) reduced from 41.87 cc at 0 Gy to 31.13 cc (25.65%) at 60 Gy (p = 0.003), while GTVn (mean) reduced from 19.98 cc at 0 Gy to 10.79 cc (45.99%) at 60 Gy (p = 0.003). There was a statistically significant reduction in CTV and PTV volumes at 60 Gy. CONCLUSION: Statistically significant volumetric and geometric changes occurred during intensity-modulated radiation (IMRT), which were most prominent after 40 Gy and were maximum at 60 Gy. There was a medial shift of parotid glands toward the high-dose region. This study can be useful to devise an adaptive radiotherapy strategy.

Clinical Implementation of "Plan of the Day" Strategy in Definitive Radiation Therapy of Cervical Cancer: Online Adaptation to Address the Challenge of Organ Filling Reproducibility.

PURPOSE: Definitive pelvic intensity modulated radiation therapy (IMRT) in cervical cancer is susceptible to geographic miss due to daily positional and volumetric variations in target and organs at risk. Hence, despite evidence of reduced acute and late treatment-related toxicities, implementation of image-guided IMRT (IG-IMRT) with a reasonable safety margin to encompass organ motion is challenging. METHODS AND MATERIALS: In this prospective, nonrandomized phase 2 study, patients with cervical cancer International Federation of Gynecology and Obstetrics (2009) stage IB2-IIIB between the ages of 18 and 65 years were treated with definitive pelvic chemoradiotherapy with a prespecified organ (bladder and rectum) filling protocol. Reproducibility of organ filling was assessed along with the implementation of daily comprehensive adaptive image-guided radiotherapy (IGRT), with a library of 3 IMRT (volumetric modulated arc therapy) plans with incremental expansions of clinical target volume (CTV) to planning target volume (PTV) (primary) margins (small, 0.7 cm; adequate, 1 cm; and large, 1.5 cm) and a backup motion robust 3-dimensional conformal radiotherapy plan; the appropriate plan is chosen based on pretreatment cone beam computed tomography (CBCT) ("plan of the day" approach). RESULTS: Fifty patients with a median age of 49 years (IQR, 45-56 years) received definitive radiation therapy (45-46 Gy in 23-25 fractions to pelvis, with simultaneous integrated boost to gross nodes in 15 patients) with the aforementioned IGRT protocol. In the analysis of 1171 CBCT images (in 1184 treatment sessions), the mean planning computed tomography (CT) and CBCT bladder volumes were 417 and 373 cc, respectively. Significant interfractional variation in bladder volume was noted with a mean absolute dispersion of 29.5% with respect to planning CT; significant influential random factors were postchemotherapy sessions (P ≤ .001), pre-CBCT protocol duration (P = .001), and grades of chemotherapy induced nausea vomiting (P = .001). Significantly higher variation in bladder filling was noted in patients with older age (P = .014) and larger planning CT bladder volume (P ≤ .001). Time trend analysis of fraction-wise bladder volume revealed an absolute systemic reduction of 16.3% in bladder volume means from the first to the fifth week. Variation in rectal diameter was much less pronounced, with 19.2% mean dispersion and without any significant factors affecting it. Although in 19% and 2% of sessions large IMRT PTV and 3-dimensional conformal radiotherapy were necessary to cover the primary target, respectively, reduction in treated volume was possible in 43% of sessions with small PTV selection instead of standard adequate PTV (36% sessions). Plan of the day selection had a moderate to strong correlation with nonabsolute dispersion of bladder filling (Spearman ρ =0.4; P = .001) and a weak (but significant) correlation with grades of acute toxicities. The planned protocol was well tolerated with no radiation-induced local grade 3 toxicity. CONCLUSIONS: Interfractional variation in organ filling (especially bladder) is inevitable despite fixed pretreatment protocol in definitive settings (intact cervix). Despite the logistical challenges, adaptive IGRT in the form of plan of the day based on incremental CTV-to-PTV margins is a relatively simple and feasible strategy to minimize geometric uncertainties in radical IG-IMRT of cervical cancer.

Intensity-Modulated Radiation Therapy Alone Versus Intensity-Modulated Radiation Therapy and Brachytherapy for Early-Stage Oropharyngeal Cancers: Results From a Randomized Controlled Trial.

PURPOSE: The objective of this study was to compare clinical outcomes of intensity-modulated radiation therapy (IMRT) alone versus IMRT + brachytherapy (BT) in patients with T1-T2N0M0 oropharyngeal squamous cell cancers (OPSCC). METHODS AND MATERIALS: This open-label randomized controlled trial was conducted at Tata Memorial Hospital, Mumbai, India. Patients with stage I and II OPSCC were considered for IMRT to a dose of 50 Gy/25 fractions/5 weeks in phase I followed by randomization (1:1) to further treatment with IMRT (20 Gy/10 fractions/2 weeks) or BT (192Ir high dose rate, 21 Gy/7 fractions/2 fractions per day). The primary endpoint of the trial was the reduction in xerostomia at 6 months evaluated using 99mTc salivary scintigraphy. Severe salivary toxicity (xerostomia) was defined as posttreatment salivary excretion fraction ratio <45%. Secondary endpoints were local control, disease-free survival, and overall survival. RESULTS: Between November 2010 and February 2020, 90 patients were randomized to IMRT (n = 46) alone or IMRT + BT (n = 44). Eleven patients (8 residual/recurrent disease, 2 lost to follow-up, 1 second primary) in the IMRT arm and 9 patients (8 residual/recurrence, 1 lost to follow-up) in the BT arm were not evaluable at 6 months for the primary endpoint. At 6 months, xerostomia rates using salivary scintigraphy were 14% (5/35: 95% CI, 5%-30%) in the BT arm while it was seen in 44% (14/32: 95% CI, 26%-62%) in the IMRT arm (P = .008). Physician-rated Radiation Therapy Oncology Group grade ≥2 xerostomia at any time point was observed in 30% of patients (9/30) in the IMRT arm and 6.7% (2/30) in the BT arm (P = .02). At a median follow-up of 42.5 months, the 3-year local control in the IMRT arm was 56.4% (95% CI, 43%-73%) while it was 66.2% (95% CI, 53%-82%) in the BT arm (P = .24). CONCLUSIONS: The addition of BT to IMRT for T1-T2N0M0 OPSCC results in a significant reduction in xerostomia. This strongly supports the addition of BT to IMRT in suitable cases.

Protein tyrosine phosphatase 1B is a regulator of alpha-actinin4 in the glomerular podocyte.

Glomerular podocytes are instrumental for the barrier function of the kidney, and podocyte injury contributes to proteinuria and the deterioration of renal function. Protein tyrosine phosphatase 1B (PTP1B) is an established metabolic regulator, and the inactivation of this phosphatase mitigates podocyte injury. However, there is a paucity of data regarding the substrates that mediate PTP1B actions in podocytes. This study aims to uncover novel substrates of PTP1B in podocytes and validate a leading candidate. To this end, using substrate-trapping and mass spectroscopy, we identified putative substrates of this phosphatase and investigated the actin cross-linking cytoskeletal protein alpha-actinin4. PTP1B and alpha-actinin4 co-localized in murine and human glomeruli and transiently transfected E11 podocyte cells. Additionally, podocyte PTP1B deficiency in vivo and culture was associated with elevated tyrosine phosphorylation of alpha-actinin4. Conversely, reconstitution of the knockdown cells with PTP1B attenuated alpha-actinin4 tyrosine phosphorylation. We demonstrated co-association between alpha-actinin4 and the PTP1B substrate-trapping mutant, which was enhanced upon insulin stimulation and disrupted by vanadate, consistent with an enzyme-substrate interaction. Moreover, we identified alpha-actinin4 tandem tyrosine residues 486/487 as mediators of its interaction with PTP1B. Furthermore, knockdown studies in E11 cells suggest that PTP1B and alpha-actinin4 are modulators of podocyte motility. These observations indicate that PTP1B and alpha-actinin4 are likely interacting partners in a signaling node that modulates podocyte function. Targeting PTP1B and plausibly this one of its substrates may represent a new therapeutic approach for podocyte injury that warrants additional investigation.

miRNAs as biomarkers of therapeutic response to HER2-targeted treatment in breast cancer: A systematic review.

Breast cancer is the most common type of lethal cancer in women globally. Women have a 1 in 8 chance of developing breast cancer in their lifetime. Among the four primary molecular subtypes (luminal A, luminal B, HER2+, and triple-negative), HER2+ accounts for 20-25 % of all breast cancer and is rather aggressive. Although the treatment outcome of HER2+ breast cancer patients has been significantly improved with anti-HER2 agents, primary and acquired drug resistance present substantial clinical issues, limiting the benefits of HER2-targeted treatment. MicroRNAs (miRNAs) play a central role in regulating acquired drug resistance. miRNA are single-stranded, non-coding RNAs of around 20-25 nucleotides, known for essential roles in regulating gene expression at the post-transcriptional level. Increasing evidence has demonstrated that miRNA-mediated alteration of gene expression is associated with tumorigenesis, metastasis, and tumor response to treatment. Comprehensive knowledge of miRNAs as potential markers of drug response can help provide valuable guidance for treatment prognosis and personalized medicine for breast cancer patients.

Osteoporosis in Renal Disease.

Introduction: Osteoporosis is a disorder characterized by decreased bone mass and skeletal fragility with increased fracture risk. Chronic kidney disease presents with wide range of bone metabolic disorders, including osteoporosis. Osteoporosis prevalence is high in early stages of CKD; whereas in late stages, it coexists with renal osteodystrophy. Risk factors: Risk factors for osteoporosis include advancing age, low bone mineral density (BMD), glucocorticoid therapy, smoking, alcohol intake, etc. Diagnosis: The diagnosis of osteoporosis in renal disease is made after assessment of BMD, in addition to exclusion of chronic kidney disease-mineral bone disorder (CKD-MBD), eliciting history of prior fragility fractures and relevant laboratory investigations. Management: The treatment of osteoporosis varies with the different stages of CKD, with management in stages 1-3 being similar to the general population. Special emphasis must be laid on prevention of fractures as well.

A prospective study evaluating the effect of a "Diagnostic Stewardship Care-Bundle" for automated blood culture diagnostics.

OBJECTIVES: We prospectively implemented a diagnostic stewardship care-bundle checklist, 'Sepsis-48 DSB', with the aim of reducing intervening duration of key steps of automated blood culture diagnostics (aBCD). METHODS: Sepsis-48 DSB was implemented for automated blood culture bottles (BCBs) received from adult intensive care units (AICUs) during the intervention period (P2; July 2020-June 2021) and intervening durations were compared with those during the retrospective, pre-intervention period (P1; March-June 2020). During both periods, provisional blood culture reports (pBCR) were issued wherein direct microbial identification (dID) was performed in BCBs with Gram-negatives by directly inoculating conventional biochemical tests and direct antimicrobial susceptibility testing (dAST) using EUCAST RAST method. The results were compared with the standard of care (SoC) method (i.e. full incubation followed by identification and AST by VITEKⓇ-2 Compact). RESULTS: During P2, significant reductions in loading time (LT; median: 63.5 vs. 32 minutes, P < 0.001), time to dID+dAST performance (TTD; 186 vs. 115 minutes, P = 0.0018) and an increase in compliance to bundle targets (LT ≤45: 44% vs. 66%, P = 0.006 and TTD ≤120: 34% vs. 51.7%, P = 0.03) were observed. Using dID+dAST method, results were read 694 minutes earlier than SoC method. Of 176 pBCR, 165 (94%) were concordant with SoC in microbial identification of species. Categorical agreement for any drug-bug combination was 92.7% (1079/1164) and corresponding major, very major, and minor error rates were 8.8% (19/216), 4.9% (45/921), and 1.8% (21/1164), respectively. CONCLUSION: The 'diagnostic stewardship care-bundle' strategy was successfully implemented with considerable diagnostic accuracy leading to significant reductions in duration of targeted steps of aBCD.

Response assessment of post-treatment head and neck cancers to determine further management using NI-RADS (Neck Imaging Reporting and Data System): a subgroup analysis of a randomized controlled trial.

Objective: Interpreting complex post-treatment changes in head and neck cancer (HNC) is challenging with further added perplexity due to variable interobserver interpretation and hence evolved the NI-RADS lexicon. We evaluated the accuracy of NI-RADS in predicting disease status on 1st post-treatment follow-up CECT in a homogenous cohort of those who received only chemoradiation. Methods: Retrospective analysis of imaging was done for LASHNC patients who received radical chemoradiation in an open-label, investigator-initiated, phase 3 randomized trial (2012-2018) randomly assigned to either radical radiotherapy with concurrent weekly cisplatin (CRT) or CRT with the same schedule plus weekly nimotuzumab (NCRT). 536 patients were accrued, and 74 patients who did not undergo PET/CECT after 8 weeks post-CRT were excluded. After assessing 462 patients for eligibility to allocate NI-RADS at primary and node sites, 435 cases fell in the Primary disease cohort and 412 cases in the Node disease cohort. We evaluated sensitivity, disease prevalence, the positive and negative predictive value of the NI-RADS lexicon, and accuracy, which were expressed as percentages. We also prepared flow charts to determine concordance with allocated NI-RADS category and established accuracy with which it can identify disease status. Results: Out of 435 primary disease cohort, 92%, 55%, 48%,70% were concordant and had 100%, 72%, 70%, 82% accuracy in NI-RADS1 (n=12), NI-RADS2 (n=261), NIRADS3 (n=105), and NI-RADS 4 (n=60) respectively. Out of 412 nodes disease cohort, 95%, 90%, 48%, 70%were concordant and had 92%, 97%, 90%, 67% accuracy in NI-RADS1 (n=57), NI-RADS2 (n=255), NI-RADS3 (n=105) and NI-RADS4 (n=60) respectively. % concordance of PET/CT and CECT across all primary and node disease cohorts revealed that PET/CT was 91% concordant in primary NI-RADS2 as compared to 55% concordance of CECT whereas concordance of CECT was better with 57% in primary NI-RADS3 cohort as compared to PET/CT concordance of 41%. Conclusion: The accuracy with which the NI-RADS lexicon performed in our study at node sites was better than that at the primary site. There is a great scope of research to understand if CECT performs better over clinical disease status in NI-RADS 3 and 4 categories. Further research should be carried out to understand if PET/CECT can be used for close interval follow-up in stage III/IV NI-RADS 2 cases.

Malaria outbreak along the India-Bhutan border town of Saralpara, Assam, India.

BACKGROUND & OBJECTIVES: A remarkable progress is being made in the South-East Asia region in reducing the burden of malaria. While all countries are committed to malaria elimination, continued transmission at and across international borders poses a threat to achieving this goal. METHODS: We investigated an outbreak of malaria in the India-Bhutan border area in a district of Assam state, India. A line listing of cases occurring during the outbreak period was made and a house-to-house survey was carried out to identify additional cases in the community. Entomological investigation consisted of light trap collection of vectors. Patients and health workers were interviewed to obtain information on the possible mode of transmission and ongoing inter-country collaboration across the border. RESULTS: Between October 21 to November 18 2022, 37 cases of malaria (all Plasmodium vivax), were diagnosed in Saralpara area of Kokrajhar district of Assam, bordering Bhutan. Of these four were diagnosed in Sarpang hospital, Bhutan. Median age was 20 years (range 3 to 70 years). Male to female ratio was 1:1.2. In addition, 6 individuals with asymptomatic malaria were detected in the community through an active case finding campaign. No cases were however reported on Bhutan side of the border. Anopheles culicifacies and An. annularis were identified from light trap collection. Saralpara is a remote and forested area where most of the residents are poor and engaged predominantly in farming activities. Being a harvesting season, they tend to stay overnight to protect their harvest from elephants. The health authorities in India and Bhutan exchanged information regularly at district-to-district level on the outbreak including through available and easy modes such as WhatsApp, telephone as well as electronic mail and collaborated in coherently implementing preventive measures on both sides and in managing the cases. INTERPRETATION & CONCLUSION: The outbreak of malaria in Saralpara demonstrates the risk of malaria outbreak in remote and forested areas, with possibility of spill over to the other side of the border. The fact that two countries had excellent inter-country cross-border collaboration and prior commitment thereby preventing further transmission of malaria to Bhutan can serve as a best practice for cross-border control of malaria and other communicable diseases.

Transitioning India to advanced image based adaptive brachytherapy: a national impact analysis of upgrading National Cancer Grid cervix cancer guidelines.

Background: High-dose-rate image guided brachytherapy (IGBT) for cervical cancer leads to improved local control and reduced toxicity and is a critical component of treatment. However, transition to IGBT requires capacity upscaling. An institutional activity mapping and national impact analysis of such a transition were undertaken to understand feasibility. Methods: Between September 2020 and March 2021, activity mapping was conducted in a high-volume centre that triaged cervical cancer patients for brachytherapy into four workflows; A: two-dimensional (2D) X-Ray point A-based intracavitary brachytherapy, B: CT point A-based intracavitary brachytherapy, C: MRI/CT-volume based intracavitary brachytherapy, D: MRI/CT volume-based intracavitary +/- interstitial brachytherapy. Clinical process time mapping was performed, and case scenarios for transition were modelled at the institutional and national levels based on available incidence and infrastructure levels. Treatment capacity changes were calculated, and potential strategies for workflow reorganisation were proposed. Findings: Eighty-four patients were included in the study. The total time taken for the workflows A, B, C, and D were 176 min (57-208), 224 min (74-260), 267 min (101-302), and 348 min (232-383), respectively. The transition from workflow A to D through sequential steps led to 35%, 49%, and 64% loss of treatment capacity in the index institution. Solutions such as 10-hour or 12-hour overlapping shifts increased treatment capacity by 25% and 50% and performing single implants and delivering multiple fractions increased capacity by 100%. Twenty-three Indian states and Union Territories are predicted to be able to transition to advanced workflows. For four Indian states, it may be detrimental considering the current infrastructure level, and eight Indian states lacked brachytherapy access. Further financial investment is required in the latter 12 states for transition to advanced workflows. Interpretation: Our study demonstrates that unplanned transition to IGBT can lead to treatment capacity loss and increase in waiting lists to access treatment. The proposed solutions of workflow reorganisation, using strategies such as single brachytherapy applicator implant and delivering multiple treatment fractions can improve access to treatment for women with cervix cancer in resource-strained and high patient-volume settings. We recommend state-wise solutions for the upscale from conventional 2D workflows to IGBT, subject to the availability of skilled personnel, infrastructure and training. Financial investments may be needed in some states to achieve this goal. Funding: International Atomic Energy Agency (IAEA) supported the salary of VH through project E33042 that focussed on implementation strategies of image guided brachytherapy.