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Introduction: Increased Pulse Pressure (PP) and arterial stiffness are both associated with an elevated risk of Cardiovascular Disease (CVD). Raised PP is an independent prognostic marker for CVD not only in adults but also in young normotensive subjects. Normotensive Offspring of Hypertensive Parents (OHP) are more likely to develop future hypertension. Visceral obesity, closely tied to endocrine activity, magnifies susceptibility to hypertension and CVD development in young adults. Thus, understanding the association between visceral fat and PP assumes paramount importance in young adults. Aim: To study the correlation between visceral fat and PP in young offspring of hypertensive and normotensive parents. Materials and Methods: The cross-sectional study was conducted in the Department of Physiology, Government Medical College, Datia, Madhya Pradesh, India for eight months from June 2023 to January 2024 among 140 healthy young participants aged 18-25 years. The subjects were divided into two groups: Group-1 {Offspring of Normotensive Parents (ONP)} and Group-2 offsprings of Hypertensive Parents (OHPs). Body composition parameters and visceral fat levels were measured using a calibrated Karada scan. Detailed information regarding the history of hypertension in the family, alcohol intake, etc., was collected in a pre-defined proforma. Blood pressure measurements of subjects were taken using a standard electronic sphygmomanometer. Statistical analysis of the data was conducted using Statistical Package for Social Sciences (SPSS) Version 28.0 software. For correlational analysis, Pearson correlation test was used and a p-value

Background: Several observational studies have reported the prevalence of cerebral microbleeds (CMBs) and their risk factors in an elderly population. Any information in this regard is currently lacking from India. Aim of this study was to estimate the prevalence, risk factors of CMBs, and association with cognition in an Indian urban population aged 50 years and above. Methods: Household surveys were conducted as part of ongoing Longitudinal Cognition and Aging Research on Population of the National Capital Region (LoCARPoN) study in areas of urban Delhi. Magnetic resonance imaging of the brain was performed in 2599 participants. Using standard neuropsychological battery, mean Z-scores for each domain (memory, executive, information) were derived. Binary and stepwise logistic regression models were used to determine associated risk factors for the presence of CMB and its association with cognitive domains. Results: The prevalence of CMBs was 14.42% (95% confidence interval [CI]: 13.06–15.73). Of these, 203 (7.81%) participants had single CMBs and 172 (6.61%) had multiple microbleeds (≥2). Higher prevalence was observed in older age (60–70 years: odds ratio [OR]: 1.25 [95% CI: 0.93–1.67]; 70–80 years: OR: 2.05 [95% CI: 1.48–2.84]; ≥80 years: OR: 3.27 [95% CI: 1.97–5.44]) compared to individuals in the age group 50–60 years. History of stroke (OR: 2.97 [95% CI: 1.56–5.66]), hypertension (OR: 1.36 [95% CI: 1.05–1.75]), and smoking (OR: 1.43 [95% CI: 1.11–1.85]) was associated with at least one CMB. Multiple CMBs were associated with worse scores in memory and executive domains. Conclusion: Older age, hypertension, history of stroke, and history of smoking emerged as important risk factors for the presence of multiple CMBs. Follow-up study is required to determine implications of CMBs.

Background BMS-986156 is an agonist of the glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) and promotes increased effector T-cell activation. Combined anti-GITR, anti-programmed death-1, anti-cytotoxic T-lymphocyte-associated protein 4 antibodies and radiotherapy improve tumor control in preclinical studies. Herein we describe the results of the safety and efficacy of BMS-986156+ipilimumab or nivolumab with/without stereotactic ablative radiotherapy (SABR) in patients with advanced solid cancers (NCT04021043).Methods This open-label, multigroup, single-center phase I/II study enrolled patients with histologically-confirmed stage IV solid cancers resistant to standard treatments. Group 1 (G1, n=20) received four cycles of ipilimumab (3 mg/kg) plus BMS-986156 (30 mg as dose level 1 (L1) or 100 mg as dose level 2 (L2)), every 3 weeks (Q3W). Group 2 (G2, n=10) received four cycles of ipilimumab (3 mg/kg) plus BMS-986156 (dose as determined in G1, Q3W) with SABR (50 Gy/4 fx or 60–70 Gy/10 fx to liver/lung lesions. Group 3 (G3, n=20) received four cycles of nivolumab (480 mg) plus BMS-986156 (30 mg), every 4 weeks with SABR. Maintenance nivolumab could be given up to 2 years. Tumor responses were assessed every 1–3 months until progression, using immune-related response criteria.Results 50 patients were enrolled between 10/2019 and 12/2021. Patients received a median of 3 (IQR 2–4.25) initial treatment cycles. 100 mg BMS-986156 with ipilimumab was tolerated well. Five discontinued BMS-986156 with ipilimumab due to treatment-related adverse events (TRAEs), with three in G1/L1, one in G1/L2 and one in G2, respectively. 22 patients (44%) experienced Grade 1–3 TRAEs (6, 4, 5, 7 patients for G1/L1, G1/L2, G2, G3). Six (12%) had Grade 3 TRAEs (2, 2, 1, 1 for G1/L1, G1/L2, G2, G3), with elevated alanine aminotransferase (n=3, in G1/L2, G2 and G3) and aspartate aminotransferase (n=2, in G2 and G3) being the most common. There was no Grade 4–5 TRAEs. Overall, 19/39 (48.7%) patients eligible for efficacy analysis had stable disease and 3 (7.7%) achieved a partial response. Out-of-field (abscopal) disease control rate (ACR) and out-of-field (abscopal) response rate (ARR) were 38.5% and 7.7%, respectively, with the highest ACR (50%, 9/18) and ARR (11.1%, 2/18) in G3.Conclusions BMS-986156 was well-tolerated with ipilimumab, nivolumab, with or without SABR. Outcomes were encouraging in this population, as more than half of patients had stable disease/partial response.

Abstract Direct recycling is a novel approach to overcoming the drawbacks of conventional lithium‐ion battery (LIB) recycling processes and has gained considerable attention from the academic and industrial sectors in recent years. The primary objective of directly recycling LIBs is to efficiently recover and restore the active electrode materials and other components in the solid phase while retaining electrochemical performance. This technology's advantages over traditional pyrometallurgy and hydrometallurgy are cost‐effectiveness, energy efficiency, and sustainability, and it preserves the material structure and morphology and can shorten the overall recycling path. This review extensively discusses the advancements in the direct recycling of LIBs, including battery sorting, pretreatment processes, separation of cathode and anode materials, and regeneration and quality enhancement of electrode materials. It encompasses various approaches to successfully regenerate high‐value electrode materials and streamlining the recovery process without compromising their electrochemical properties. Furthermore, we highlight key challenges in direct recycling when scaled from lab to industries in four perspectives: (1) battery design, (2) disassembling, (3) electrode delamination, and (4) commercialization and sustainability. Based on these challenges and changing market trends, a few strategies are discussed to aid direct recycling efforts, such as binders, electrolyte selection, and alternative battery designs; and recent transitions and technological advancements in the battery industry are presented.

Objective: Exposure to tobacco smoke causes numerous health problems in children, and create burden on the population in terms of economy, morbidity and mortality. In order to protect the child from exposure to tobacco smoke in the outdoor environment, sufficient legislative enactments are available in Indian legislation. The objective of the present study is to investigate the fact that in absence of any specific laws stating about protection of children from exposure to tobacco smoke in indoor environment, whether outdoor related legislations are sufficient to protect children from exposureand to explore the scope for enforcement of both state and central laws in improving health of children in India. Study design: The study considered cross-sectional survey data of Demographic and Health Survey Data on India, National Family and Health Survey fourth round (NFHS-4) for the year 2015-16 on Indian children (below age of four). Methods: Both bivariate and multivariate logistic regression models were used to assess the impact of anti-smoking laws on the prevalence of acute respiratory infection (ARI) based on the place of residence, indoor tobacco smoke exposure and age of the child. Results: The results have shown an inclination of ARI among children in association with states having single law, rural area resident, exposure to indoor tobacco smoke and age of the child, both as independent or in combination are quite conspicuous, and are found to be underestimated. The logistic regression also revealed the influence of these factors both as independent and even in interaction with other. Conclusions: Legislative intervention through both at central (or national)and state levels through anti-smoking laws will decrease the indoor tobacco smoke exposure as a result ARI prevalence will also decrease among children in India.

Purpose: Adherence to glaucoma medical therapy is a key factor in achieving target intraocular pressure to prevent glaucoma progression. To determine factors affecting medication adherence in glaucoma patients in an urban population belonging to poor socioeconomic status. Methods: A cross-sectional study was conducted on 200 patients attending glaucoma services in a tertiary referral hospital of North India. Adherence to medication was determined subjectively by questionnaire and objectively by counting the number of used bottles at the end of a month or during refill, whichever was earlier. Patient-related parameters in adherence toward glaucoma medication were studied based on demography, knowledge, attitudes, and practices (KAP). The statistical techniques of bivariate and multivariate logistic regression were adopted to test the objective. Results: The population was statistically homogeneous based on gender and income in both groups. A large proportion of patients had bilateral disease (87%) and were on two or more medications (62.5%). Adherence to glaucoma medical therapy was seen in 68% of patients, with knowledge about glaucoma present in 58% of patients. Deterrents to drug adherence were identified as forgetfulness (71%), unavailability of drugs (19%) or funds to purchase the same (26%), polypharmacy (21%), and side effects (5%). Dependence on an escort by 44% and dependence on hospital supply of medications by 60% emerged as the contextual factors requiring scrutiny while prescribing lifelong glaucoma medications. Disease misconceptions (53%) were prevalent and drug instillation practices were unsatisfactory (57%). Conclusion: The study offers insight into patients' perspectives regarding the lifetime use of antiglaucoma medications and focuses on key issues linked to drug nonadherence.

Introduction: Despite the advancements in technique and technology, urethrocutaneous fistula (UCF) formation continues to be the most common complication after hypospadias repair. Objective: The objective of the current synthesis is to define the indications of PATIO technique for UCF repair. Materials and Methods: The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Scopus, Ovid, Embase, Web of Science, and Google Scholar were interrogated for studies presenting primary data upon UCF repair by the PATIO technique. Data analysis was performed on MedCalc and R software. Results: Eighteen studies were identified relevant to the current context: inversion of UCF tract has been described in 13 and ligation in 5. There were 2 duplications (abstract and manuscript). The overall success for PATIO is 88.2% (314/356). The success rate was variable between classic PATIO (inversion at 87.2%), ligation-inversion at 86.9%, and ligation alone at 88.9%. The success rate was not improvised upon by supplementing inversion of UCF tract with ligation (p = 0.957) or addition of a waterproofing layer (p = 0.622). PATIO has been used for single or multiple UCFs post hypospadias repair, genital piercing, and genitoplasty in cis- or transgender population for UCF up to 5 mm in size. The success rates were best for UCF

Abstract Objective Health economic comparisons of various therapies are often based on health-related quality of life (HRQOL) using EQ-5D questionnaires within the framework of clinical trials. This real-world study prospectively evaluates the patient reported outcomes (PROs)-based HRQOL of head-and-neck (H&N) cancer patients undergoing modern radiotherapy (RT) to reflect PRO trajectories. Methods All H&N cancer patients treated in our clinic between July 2019 and December 2020 who completed the self-reported validated EQ-5D-5L questionnaire (health state index (HI) and Visual Analog Scale (VAS)) at baseline, end of radiotherapy, and at each respective follow up (FU) were included. Descriptive analysis of clinical and sociodemographic data, the frequency and level of each dimension was conducted. To assess the significance of therapy-induced HRQOL changes within and between the group, a distribution-based approach was used. Results Altogether, 366 participants completed a total of 565 questionnaires. For the whole cohort, HI at baseline was 0.804 (±0.208), 0.830 (±0.162) at RT completion, 0.812 (±0.205) at the first follow-up, and 0.769 (±0.224) at the second follow-up. The respective VAS values were 62.06 (±23,94), 66.73 (±82.20), 63.30 (±22.74), and 65.48 (±23.39). Females showed significantly lower HI values compared to males, but only at baseline (p = 0.034). Significantly lower HI values were also seen in patients with definitive RT as compared to adjuvant RT at baseline (p = 0.023), the second follow-up (p = 0.047), and the third follow-up (p = 0.010). As compared to outpatients, inpatients had significantly lower HI values at RT completion (p = 0.017), the second follow-up (p = 0.007), and the third follow-up (p = 0.031). Subgroup analyses by age (

Abstract Background Currently, due to synergy enhancement of anti‐tumor effects and potent stimulation of abscopal effects, combination therapy with irradiation and programmed cell death protein 1/programmed death‐ligand 1 (PD‐1/PD‐L1) immune checkpoint inhibition (immuno‐radiotherapy, iRT) has revolutionized the therapeutic guidelines. It has been demonstrated that tumor‐draining lymph nodes (TDLN) are essential for effective antitumor immunity induced by radiotherapy, immunotherapy, or iRT. Given that the function of TDLN in iRT remains unclear, this study aimed to investigate the function and mechanism of TDLN in iRT‐induced abscopal effects. Methods The function of TDLN was evaluated using unilateral or bilateral MC38 and B16F10 subcutaneous tumor models with or without indicated TDLN. The flow cytometry, multiple immunofluorescence analysis, and NanoString analysis were utilized to detect the composition and function of the immune cells in the primary and abscopal tumor microenvironment. Additionally, we tempted to interrogate the possible mechanisms via RNA‐sequencing of tumor‐infiltrating lymphocytes and TDLN. Results TDLN deficiency impaired the control of tumor growth by monotherapy. Bilateral TDLN removal rather than unilateral TDLN removal substantially curtailed iRT‐stimulated anti‐tumor and abscopal effects. Furthermore, in the absence of TDLN, the infiltration of CD45+ and CD8+ T cells was substantially reduced in both primary and abscopal tumors, and the anti‐tumor function of CD8+ T cells was attenuated as well. Additionally, the polarization of tumor‐associated macrophages in primary and abscopal tumors were found to be dependent on intact bilateral TDLN. RNA‐sequencing data indicated that impaired infiltration and anti‐tumor effects of immune cells partially attributed to the altered secretion of components from the tumor microenvironment. Conclusions TDLN play a critical role in iRT by promoting the infiltration of CD8+ T cells and maintaining the M1/M2 macrophage ratio.

Abstract As the NRG GI006 and PROTECT trials seek to confirm results of the first randomized trial supporting the utility of proton beam therapy for esophageal cancer, several outstanding questions are discussed in this review. First, the applicability/extrapolation of the existing randomized trial is mentioned. This includes a potentially larger benefit of PBT at non‐high‐volume centers with less surgical expertise, along with the emerging use of active scanning PBT approaches that could further improve toxicity profiles. Patient selection for PBT is then discussed, including differential utility for patients based on the degree of baseline comorbidities, the extent/location of disease, and the surgical case volume at the treating institution. PBT in the setting of emerging techniques, such as minimally invasive esophagectomy, is also mentioned. Next, costs of PBT and insurance coverage hurdles are described, especially regarding pre‐specified agreements between providers/institutions and payors, the need for cost‐effectiveness analyses for PBT in this population, and effects of the new radiation oncology alternative payment model. Finally, immunotherapy has now become a standard option for esophageal cancer (resected or unresected/recurrent/metastatic cases). Therefore, in the context of immunotherapy for these patients, revisiting the role of radiation dose‐escalation and elective nodal irradiation may be required.

The role of Sn doping on the structural, magnetic and power loss properties of Li0.5+0.5xSnxFe2.5-1.5xO4 ferrites (x = 0.0 to 0.20 in step of 0.05) + 0.5 wt % Bi2O3, prepared by solid state technique, has been investigated. X-ray diffraction reveals that Sn ions doped in lithium ferrite up to small concentration. Surface morphology recorded by SEM micrographs illustrates uniform, well connected grain growth in all samples. A small concentration of Sn doping in lithium ferrite improves the grain growth and densification. Magnetic parameters have been evaluated by M − H curves measured at room temperature by VSM. Saturation magnetization was found to be decreasing with Sn concentration in Li0.5+0.5xSnxFe2.5-1.5xO4 ferrites. In view of applicability of prepared samples for power devices, the magnetic permeability (μ* = μ′-jμ'′) has been recorded in the frequency range of 1 MHz–103 MHz at room temperature. Further, Power loss response has also been recorded in presence of magnetic induction (B = 10 mT) in frequency range of 50 kHz to 3 MHz. It was depicted a significant reduction in power loss in Sn = 0.05 doped lithium ferrite sample. Reduction in power loss with Sn doping makes it suitable for power applications.

Anticancer immunotherapies, such as immune checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T cells, have improved outcomes for patients with a variety of malignancies. However, most patients either do not initially respond or do not exhibit durable responses due to primary or adaptive/acquired immune resistance mechanisms of the tumor microenvironment. These suppressive programs are myriad, different between patients with ostensibly the same cancer type, and can harness multiple cell types to reinforce their stability. Consequently, the overall benefit of monotherapies remains limited. Cutting-edge technologies now allow for extensive tumor profiling, which can be used to define tumor cell intrinsic and extrinsic pathways of primary and/or acquired immune resistance, herein referred to as features or feature sets of immune resistance to current therapies. We propose that cancers can be characterized by immune resistance archetypes, comprised of five feature sets encompassing known immune resistance mechanisms. Archetypes of resistance may inform new therapeutic strategies that concurrently address multiple cell axes and/or suppressive mechanisms, and clinicians may consequently be able to prioritize targeted therapy combinations for individual patients to improve overall efficacy and outcomes.

Purpose: In patients treated with chemoradiation for esophageal cancer (EC), randomized trial data demonstrate that proton beam therapy (PBT) reduces toxicities and postoperative complications (POCs) compared with intensity-modulated radiation therapy (IMRT). However, whether radiation therapy modality affects postoperative health care resource utilization remains unknown. Materials and Methods: We examined 287 patients with EC who received chemoradiation (prescribed 50.4 Gy/GyE) followed by esophagectomy, including a real-world observational cohort of 237 consecutive patients treated from 2007 to 2013 with PBT (n = 81) versus IMRT (n = 156); and an independent, contemporary comparison cohort of 50 patients from a randomized trial treated from 2012 to 2019 with PBT (n = 21) versus IMRT (n = 29). Postoperative complications were abstracted from medical records. Health care charges were obtained from institutional claims and adjusted for inflation (2021 dollars). Charge differences (Δ = $PBT − $IMRT) were compared by treatment using adjusted generalized linear models with the gamma distribution. Results: Baseline PBT versus IMRT characteristics were not significantly different. In the observational cohort, during the neoadjuvant chemoradiation phase, health care charges were higher for PBT versus IMRT (Δ =+ $71,959; 95% confidence interval [CI], $62,274–$82,138; P < .001). There was no difference in surgical charges (Δ =−$2234; 95% CI, −$6003 to $1695; P = .26). However, during postoperative hospitalization following esophagectomy, health care charges were lower for PBT versus IMRT (Δ = −$25,115; 95% CI, −$37,625 to −$9776; P = .003). In the comparison cohort, findings were analogous: Charges were higher for PBT versus IMRT during chemoradiation (Δ =+$61,818; 95% CI, $49,435–$75,069; P < .001), not different for surgery (Δ = −$4784; 95% CI, −$6439 to $3487; P = .25), and lower for PBT postoperatively (Δ = −$27,048; 95% CI, −$41,974 to −$5300; P = .02). Lower postoperative charges for PBT were especially seen among patients with any POCs in the contemporary comparison (Δ =−$176,448; 95% CI, −$209,782 to −$78,813; P = .02). Conclusion: Higher up-front chemoradiation resource utilization for PBT in patients with EC was partially offset postoperatively, moderated by reduction in POC risks. Results extend existing clinical evidence of toxicity reduction with PBT.

Abstract Background Radiotherapy using the deep inspiration breath-hold (DIBH) technique compared with free breathing (FB) can achieve substantial reduction of heart and lung doses in left-sided breast cancer cases. The anatomical organ movement in deep inspiration also cause unintended exposure of locoregional lymph nodes to the irradiation field. Methods From 2017–2020, 148 patients with left-sided breast cancer underwent breast conserving surgery (BCS) or mastectomy (ME) with axillary lymph node staging, followed by adjuvant irradiation in DIBH technique. Neoadjuvant or adjuvant systemic therapy was administered depending on hormone receptor and HER2-status. CT scans in FB and DIBH position with individual coaching and determination of the breathing amplitude during the radiation planning CT were performed for all patients. Intrafractional 3D position monitoring of the patient surface in deep inspiration and gating was performed using Sentinel and Catalyst HD 3D surface scanning systems (C-RAD, Catalyst, C-RAD AB, Uppsala, Sweden). Three-dimensional treatment planning was performed using standard tangential treatment portals (6 or 18 MV). The delineation of ipsilateral locoregional lymph nodes was done on the FB and the DIBH CT-scan according to the RTOG recommendations. Results The mean doses (Dmean) in axillary lymph node (AL) level I, II and III in DIBH were 32.28 Gy (range 2.87–51.7), 20.1 Gy (range 0.44–53.84) and 3.84 Gy (range 0.25–39.23) vs. 34.93 Gy (range 10.52–50.40), 16.40 Gy (range 0.38–52.40) and 3.06 Gy (range 0.21–40.48) in FB (p

Metabolism is central to energy generation and cell signaling in all life forms. Cancer cells rely heavily on glucose metabolism wherein glucose is primarily converted to lactate even in adequate oxygen conditions, a process famously known as “the Warburg effect.” In addition to cancer cells, Warburg effect was found to be operational in other cell types, including actively proliferating immune cells. According to current dogma, pyruvate is the end product of glycolysis that is converted into lactate in normal cells, particularly under hypoxic conditions. However, several recent observations suggest that the final product of glycolysis may be lactate, which is produced irrespective of oxygen concentrations. Traditionally, glucose-derived lactate can have three fates: it can be used as a fuel in the TCA cycle or lipid synthesis; it can be converted back into pyruvate in the cytosol that feeds into the mitochondrial TCA; or, at very high concentrations, accumulated lactate in the cytosol may be released from cells that act as an oncometabolite. In immune cells as well, glucose-derived lactate seems to play a major role in metabolism and cell signaling. However, immune cells are much more sensitive to lactate concentrations, as higher lactate levels have been found to inhibit immune cell function. Thus, tumor cell-derived lactate may serve as a major player in deciding the response and resistance to immune cell-directed therapies. In the current review, we will provide a comprehensive overview of the glycolytic process in eukaryotic cells with a special focus on the fate of pyruvate and lactate in tumor and immune cells. We will also review the evidence supporting the idea that lactate, not pyruvate, is the end product of glycolysis. In addition, we will discuss the impact of glucose-lactate-mediated cross-talk between tumor and immune cells on the therapeutic outcomes after immunotherapy.

Background: Isolated Systolic Hypertension (ISH) and Isolated Diastolic Hypertension (IDH) are often the ignored forms of hypertension and are determinants of future cardiac and neurological events and contribute to mortality. However, the nationally representative estimates of both these forms of hypertension remain unknown from India. Aim: To estimate the ISH and IDH from a nationally representative survey of India. Material and Methods: The present study used data from 7,23,181 people (15–54 years), recorded during the fourth round (2015–2016) of the National Family Health Survey (NFHS), India. The prevalence of ISH and IDH was calculated for state comparison, while multilevel logistic regression analysis was done to assess the correlates of both types of hypertension. Results: The prevalence of ISH and IDH was found to be 1.2% (95% CI 1.0–1.4) and 5.7% (95% CI 5.2–6.2), respectively. The prevalence of both ISH and IDH increased with age, with a more significant increase in systolic pressure towards the higher age. Northeastern states of India (Assam, Meghalaya, and Arunachal Pradesh) had the highest prevalence of both forms of hypertension. On multilevel logistic regression, male gender, increasing age groups (highest odds ratio (OR) being in 45–49 year age group), alcohol, and diabetes positively predicted both ISH and IDH. Urban residence, literacy, and tobacco were positive predictors of IDH, whereas urban residence, smoking, and literacy negatively predicted ISH. Conclusion: ISH and IDH have a significant presence among the population of India. This data provides insights to formulate strategies at the primary and primordial prevention levels.

Aim: A study was conducted to explore the characteristics of the videos on pediatric inguinal hernia repair on YouTube and compare the most popular videos (MPV) with the least popular ones in terms of educative value vis-a-vis their popularity. Materials and Methods: The term “Pediatric inguinal hernia repair” was searched for on YouTube on August 15, 2021, with the filter set to “view rate.” Pertinent data were collected from the 50 MPV and the 50 least popular videos (LPV) and then compared. The h-index and affiliation of the surgeon were obtained from the Scopus database, and their affiliation was further categorized as academic or nonacademic. Results: One hundred and seventy-five videos were found with median views of MPV: LPV being 9270 (interquartile range [IQR] – 12099):127 (IQR – 194), respectively (P < 0.0001). Most of the videos in the MPV and LPV groups were uploaded from the United States of America (USA) (MPV – 17 and LPV – 13) and India (MPV – 15 and LPV – 15). The MPV were on YouTube for a median duration of 3.1 (IQR – 5.5) years as compared to 1.2 (IQR – 2.3) years for the LPV (P < 0.0001). Ninety-two surgeons were identified. The median h-index of the surgeons of MPV was 3 (IQR – 12) in comparison to 1 (IQR – 10) of LPV (P = 0.13). The ratio of academic versus nonacademic affiliation among MPV and LPV was almost equal in both the groups. Conclusions: On either end of the spectrum of popularity, the majority of the pediatric inguinal hernia videos on YouTube were surgical videos uploaded from the USA and India. The educative value of these videos was found to be low and widely dispersed. Surgeons from both academic and nonacademic affiliations had contributed similarly.

Abstract Background Re-irradiation (re-RT) is a technically challenging task for which few standardized approaches exist. This is in part due to the lack of a common platform to assess dose tolerance in relation to toxicity in the re-RT setting. To better address this knowledge gap and provide new tools for studying and developing thresholds for re-RT, we developed a novel algorithm that allows for anatomically accurate three-dimensional mapping of composite biological effective dose (BED) distributions from nominal doses (Gy). Methods The algorithm was designed to automatically convert nominal dose from prior treatment plans to corresponding BED value maps (voxel size 2.5 mm3 and α/β of 3 for normal tissue, BED3). Following the conversion of each plan to a BED3 dose distribution, deformable registration was used to create a summed composite re-irradiation BED3 plan for each patient who received two treatments. A proof-of-principle analysis was performed on 38 re-irradiation cases of initial stereotactic ablative radiotherapy (SABR) followed by either re-SABR or chemoradiation for isolated locoregional recurrence of early-stage non-small cell lung cancer. Results Evaluation of the algorithm-generated maps revealed appropriate conversion of physical dose to BED at each voxel. Of 14 patients receiving repeat SABR, there was one case each of grade 3 chest wall pain (7%), pneumonitis (7%), and dyspnea (7%). Of 24 patients undergoing repeat fractionated radiotherapy, grade 3 events were limited to two cases each of pneumonitis and dyspnea (8%). Composite BED3 dosimetry for each patient who experienced grade 2–3 events is provided and may help guide development of precise cumulative dose thresholds for organs at risk in the re-RT setting. Conclusions This novel algorithm successfully created a voxel-by-voxel composite treatment plan using BED values. This approach may be used to more precisely examine dosimetric predictors of toxicities and to establish more accurate normal tissue constraints for re-irradiation.

A team of 10 personnel from a mountaineering team has undertaken an expedition to Mt Menthosa at an altitude of 21138 ft. in October 2018. After scaling the peak and in the following days during descent, the three members of the team had developed cold injuries. They were given first aid during descent. Later, they were diagnosed as cases of frostbite. All three personnel were evacuated to a Military Hospital, Delhi, India and were treated with oral vasodilators, antiplatelet drugs, analgesics, and hyperbaric oxygen therapy (HBO2T) was administered at a Recompression chamber at Delhi for 1 week. These personnel were thereafter referred to INHS Asvini for further management and continuation of HBO2T. After 30 sessions of HBO2T administration at this hospital, there was a significant improvement in the wounds of all three personnel with minimal surgical intervention and no major amputation. The treatment of frostbite includes treating hypothermia before thawing of cold injury, nonsteroidal anti-inflammatory drugs, antibiotics, tissue plasminogen activators and iloprost, a potent vasodilator which is used in severe cases. Planning of surgery is vital with the goal of obtaining the best functional outcome. Premature amputation increases morbidity and is likely to lead to poor subsequent function. This article aims to discuss the advantages of HBO2T administration as an adjuvant therapy in the management of frostbite cases along with wound care management.

We quantified and investigated multimodal brain MRI measures in the LoCARPoN Study due to lack of normative data among Indians. A total of 401 participants (aged 50–88 years) without stroke or dementia completed MRI investigation. We assessed 31 brain measures in total using four brain MRI modalities, including macrostructural (global & lobar volumes, white matter hyperintensities [WMHs]), microstructural (global and tract-specific white matter fractional anisotropy [WM-FA] and mean diffusivity [MD]) and perfusion measures (global and lobar cerebral blood flow [CBF]). The absolute brain volumes of males were significantly larger than those of females, but such differences were relatively small (

Abstract Background About 50 000 new cases of cancer in the United States are attributed to obesity. The adverse effects of obesity on breast cancer may be most profound when affecting the early development; that is, in the womb of a pregnant obese mother. Maternal obesity has several long‐lasting adverse health effects on the offspring, including increasing offspring's breast cancer risk and mortality. Gut microbiota is a player in obesity as well as may impact breast carcinogenesis. Gut microbiota is established early in life and the microbial composition of an infant's gut becomes permanently dysregulated because of maternal obesity. Metabolites from the microbiota, especially short chain fatty acids (SCFAs), play a critical role in mediating the effect of gut bacteria on multiple biological functions, such as immune system, including tumor immune responses. Recent Findings Maternal obesity can pre‐program daughter's breast cancer to be more aggressive, less responsive to treatments and consequently more likely to cause breast cancer related death. Maternal obesity may also induce poor response to immune checkpoint inhibitor (ICB) therapy through increased abundance of inflammation associated microbiome and decreased abundance of bacteria that are linked to production of SCFAs. Dietary interventions that increase the abundance of bacteria producing SCFAs potentially reverses offspring's resistance to breast cancer therapy. Conclusion Since immunotherapies have emerged as highly effective treatments for many cancers, albeit there is an urgent need to enlarge the patient population who will be responsive to these treatments. One of the factors which may cause ICB refractoriness could be maternal obesity, based on its effects on the microbiota markers of ICB therapy response among the offspring. Since about 40% of children are born to obese mothers in the Western societies, it is important to determine if maternal obesity impairs offspring's response to cancer immunotherapies.

Abstract The efficacy of immunotherapy for advanced non‐small cell lung cancer (NSCLC) remains unsatisfactory, as the majority of patients either do not experience an objective response or acquire secondary resistance. As a result, several methods to enhance the systemic efficacy of immunotherapy have been investigated, including a large area of active research by combining immunotherapy with radiation therapy (RT). Given the rapidly burgeoning concept of combining immunotherapy and RT for increasing therapeutic benefit, we review the progress in this field thus far and explore further avenues for enhancing this combination. This review commences with a discussion of the only two existing randomized trials (and a pooled analysis) showing that the addition of RT to immunotherapy improves the abscopal response rate, progression‐free survival, and overall survival in metastatic NSCLC patients. We then discussed factors and biomarkers that may be associated with a proportionally greater benefit to additional RT, such as low programmed cell death protein ligand 1 (PD‐L1) status, tumor mutational burden (TMB), and patient's immune function. Next, the implementation of RT to overcome immunotherapy resistance is discussed, including a mechanistic discussion and methods with which these mechanisms could be exploited. Lastly, the emerging role of low‐dose RT is discussed, which may help to overcome inhibitory signals in the tumor stroma that limit T‐cell infiltration. Taken together, given the current state of this rapidly expanding realm, these futuristic strategies may be reflected upon to further enhance the efficacy of immunotherapy for a wider group of patients.

Abstract Urinary tract infections (UTI) are the most common infectious diseases in the world. It is becoming increasingly tough to treat because of emergence of antibiotic resistance. So, there is an exigency to develop novel anti-virulence therapeutics to combat multi-drug resistance pathogenic strains. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) discovery has revolutionized the gene editing technology for targeted approach. The greatest obstacle for CRISPR/Cas9 is cargo delivery systems and both viral and plasmid methods have disadvantages. Here, we report a highly efficient novel CRISPR based gene editing strategy, CRISPR-dots for targeting virulence factor Fimbrial Adhesion (papG gene), the bacterial adhesion molecule. Carbon quantum dots (CQD) were used as a delivery vehicle for Cas9 and gRNA into CFT073, a UPEC strain. CQDs were covalently conjugated to cas9 and papG-targeted guide RNA (gRNA) forming a nanocomplex CRISPR-dots (Cri-dots) as confirmed by DLS and transmission electron microscopy. Cri-dots-papG significantly targeted papG as demonstrated by decrease in the expression of papG.Further papG deficient UPEC had significantly reduced adherence ability and biofilm forming ability as demonstrated by fluorescence microscopy and scanning electron microscopy. Also, papG deficient UPEC had reduced virulence as shown by significantly increased survival of Caenorhabditis elegans (C. elegans) worms compared to UPEC. Our findings suggest that targeting of papG gene using Cri-dots nanocomplexes significantly reduced the pathogenicity of UPEC. Thus, Cri-dots nanocomplex offer a novel anti-bacterial strategy against multi-drug resistant UPEC.

Acute kidney injury (AKI) is a serious complication of rhabdomyolysis that significantly impacts survival. Myoglobin released from the damaged muscle accumulates in the kidney, causing heme iron-mediated oxidative stress, tubular cell death, and inflammation. In response to injury, myeloid cells, specifically neutrophils and macrophages, infiltrate the kidneys, and mediate response to injury. Ferritin, comprised of ferritin light chain and ferritin heavy chain (FtH), is vital for intracellular iron handling. Given the dominant role of macrophages and heme-iron burden in the pathogenesis of rhabdomyolysis, we studied the functional role of myeloid FtH in rhabdomyolysis-induced AKI and subsequent fibrosis. Using two models of rhabdomyolysis induced AKI, we found that during the acute phase, myeloid FtH deletion did not impact rhabdomyolysis-induced kidney injury, cell death or cell proliferation, suggesting that tubular heme burden is the dominant injury mechanism. We also determined that, while the kidney architecture was markedly improved after 28 days, tubular casts persisted in the kidneys, suggesting sustained damage or incomplete recovery. We further showed that rhabdomyolysis resulted in an abundance of disparate intra-renal immune cell populations, such that myeloid populations dominated during the acute phase and lymphoid populations dominated in the chronic phase. Fibrotic remodeling was induced in both genotypes at 7 days post-injury but continued to progress only in wild-type mice. This was accompanied by an increase in expression of pro-fibrogenic and immunomodulatory proteins, such as transforming growth factor-β, S100A8, and tumor necrosis factor-α. Taken together, we found that while the initial injury response to heme burden was similar, myeloid FtH deficiency was associated with lesser interstitial fibrosis. Future studies are warranted to determine whether this differential fibrotic remodeling will render these animals more susceptible to a second AKI insult or progress to chronic kidney disease at an accelerated pace.

Abstract Background Phase 3 oncologic randomized clinical trials (RCTs) can lead to Food and Drug Administration (FDA) approvals. In this study, we aim to identify trial-related factors associated with trials leading to subsequent FDA drug approvals. Methods We performed a database query through the ClinicalTrials.gov registry to search for oncologic phase 3 RCTs on February 2020. We screened all trials for therapeutic, cancer-specific, phase 3, randomized, multi-arm trials. We then identified whether a trial was used for subsequent FDA drug approval through screening of FDA approval announcements. Results In total, 790 trials were included in our study, with 225 trials (28.4%) generating data that were subsequently used for FDA approvals. Of the 225 FDA approvals identified, 65 (28.9%) were based on trials assessing overall survival (OS) as a primary endpoint (PEP), two (0.9%) were based on trials with a quality of life (QoL) PEP, and 158 approvals (70.2%) were based on trials with other PEP (P = 0.01). FDA approvals were more common among industry funded-trials (219, 97.3%; P

Purpose: Proton beam therapy (PBT) is associated with less toxicity relative to conventional photon radiotherapy for head-and-neck cancer (HNC). Upfront delivery costs are greater, but PBT can provide superior long-term value by minimizing treatmentrelated complications. Cost-effectiveness models (CEMs) estimate the relative value of novel technologies (such as PBT) as compared with the established standard of care. However, the uncertainties of CEMs can limit interpretation and applicability. This review serves to (1) assess the methodology and quality of pertinent CEMs in the existing literature, (2) evaluate their suitability for guiding clinical and economic strategies, and (3) discuss areas for improvement among future analyses. Materials and Methods: PubMed was queried for CEMs specific to PBT for HNC. General characteristics, modeling information, and methodological approaches were extracted for each identified study. Reporting quality was assessed via the Consolidated Health Economic Evaluation Reporting Standards 24-item checklist, whereas methodologic quality was evaluated via the Philips checklist. The Cooper evidence hierarchy scale was employed to analyze parameter inputs referenced within each model. Results: At the time of study, only 4 formal CEMs specific to PBT for HNC had been published (2005, 2013, 2018, 2020). The parameter inputs among these various Markov cohort models generally referenced older literature, excluding many clinically relevant complications and applying numerous hypothetical assumptions for toxicity states, incorporating inputs from theoretical complication-probability models because of limited availability of direct clinical evidence. Case numbers among study cohorts were low, and the structural design of some models inadequately reflected the natural history of HNC. Furthermore, cost inputs were incomplete and referenced historic figures. Conclusion: Contemporary CEMs are needed to incorporate modern estimates for toxicity risks and costs associated with PBT delivery, to provide a more accurate estimate of value, and to improve their clinical applicability with respect to PBT for HNC.

The crystallization of peptides offers a sustainable and inexpensive alternative to the purification process. In this study, diglycine was crystallised in porous silica, showing the porous templates’ positive yet discriminating effect. The diglycine induction time was reduced by five-fold and three-fold upon crystallising in the presence of silica with pore sizes of 6 nm and 10 nm, respectively. The diglycine induction time had a direct relationship with the silica pore size. The stable form (α-form) of diglycine was crystallised in the presence of porous silica, with the diglycine crystals obtained associated with the silica particles. Further, we studied the mechanical properties of diglycine tablets for their tabletability, compactability, and compressibility. The mechanical properties of the diglycine tablets were similar to those of pure MCC, even with the presence of diglycine crystals in the tablets. The diffusion studies of the tablets using the dialysis membrane presented an extended release of diglycine through the dialysis membrane, confirming that the peptide crystal can be used for oral formulation. Hence, the crystallization of peptides preserved their mechanical and pharmacological properties. More data on different peptides can help us produce oral formulation peptides faster than usual.

Introduction: Once a submarine dives, the captive atmosphere inside keeps changing due to release of various pollutant gases. The gases are produced by machinery, cooking, human, paints, batteries, cooking etc. The study was envisaged to measure these gaseous pollutants on surface and in prolonged dive onboard EKM and SSK class submarines. Methods and Material: Detector tubes and pumps were used to measure the concentration of twenty gaseous pollutants in harbour on surface & during sailing in dived condition. In harbour, readings were taken early morning and before secure in the evening. During sailing readings were taken on surface, just after diving and thereafter every four hrs. The readings were recorded in excel sheet and correlated with activities on board at time of taking reading. Results: Only Ammonia and Hydrogen Sulphide were detected at the beginning of the day in harbour, however by the end of the day all other gases were detected except Mercury, Oil mist, Nitrogen Dioxide, Ozone & Arsine. At Sea none of the gases were detected at the beginning of sailing. At 12h post dive all gases were detected except Mercury, Oil mist, Nitrogen Dioxide, Ozone, Halogenated Hydrocarbons & Arsine. Recommendations and Conclusion: The gas concentration values obtained by using detector tubes and pumps were found to be within recommended Permitted Exposure Levels (PEL) for human for continuous exposure. No gas was found to be above the recommended PEL. There was no significant difference in the gas concentration levels in the EKM & SSK Class submarines. Pump and detector tube is a convenient, reasonably accurate and efficient method to measure gaseous pollutants on board Submarines.

Abstract Background Shannon’s index is one of the measures of biodiversity, which is intended to quantify both richness and evenness of the species/individuals in the ecosystem or community. However, application of Shannon’s index in the field of substance use among the street children has not been done till date. Methods This paper is concerned with methods of estimating Shannon’s diversity index (SDI), which can be used to capture the variation in the population due to certain characteristics. Under the consideration that the probability of abundance, based on certain characteristics in the population, is a random phenomenon, we derive a Bayesian estimate in connection with Shannon’s information measure and their properties (mean and variance), by using a probability matching prior, through simulation and compared it with those of the classical estimates of Shannon. The theoretical framework has been applied to the primary survey data of substance use among the street children in Delhi, collected during 2015. The measure of diversity was estimated across different age profiles and districts. Results The results unrevealing the diversity estimate for street children corresponding to each region of Delhi, under both the classical and Bayesian paradigms. Although the estimates were close to one another, a striking difference was noted in the age profile of children. Conclusions The Bayesian methodology provided evidence for a greater likelihood of finding substance-using street children, belonging to the lower age group (7-10, maximum Bayesian entropy-3.73), followed by the middle (11-14) and upper age group (15-18). Moreover, the estimated variance under the Bayesian paradigm was lesser than that of the classical estimate. There is ample scope for further refinement in these estimates, by considering more covariates that may have a possible role in initiating substance use among street children in developing countries like India.

The bidirectional stiffness grading of orthopaedic plate has been investigated for internal fixation of transverse fracture in tibia bone. Highly porous cellular materials made of two types of cubic unit cells were designed. Their effective mechanical properties (elastic moduli and yield strengths) were computationally evaluated using finite element analysis. The Gibson-Ashby model was derived for elastic moduli and yield strengths of the cellular geometries. The modified cellular structure provided the desired minimum stiffness within the selected strut sizes. The developed structures were mapped to seven zones of the orthopaedic plate assigning the bidirectional stiffness grading (longitudinal direction). The effect of functional grading on mechanical stimulation through three stages of healing was studied. The results indicated less stress shielding and improvement in uniformity of distribution of equivalent stress around the newly formed bone. Thus, a functionally designed plate will offer a way to dynamically load the healing tissues by encouraging the patient for a regular walk and exercise. Hence, the generated mechanical signal will significantly help mechanically stimulated bone formation and remodeling in the fractured zone.

Multidrug products enable more effective therapies and simpler administration regimens, provided that a stable formulation is prepared, with the desired composition. In this view, solid solutions have the advantage of combining the stability of a single crystalline phase with the potential of stoichiometry variation of a mixture. Here a drug–prodrug solid solution of cortisone and cortisol (hydrocortisone) is described. Despite the structural differences of the two components, the new phase is obtained both from solution and by supercritical CO2 assisted spray drying. In particular, to enter the solid solution, hydrocortisone must violate Etter's rules for hydrogen bonding. As a result, its dissolution rate is almost doubled.

The current research endeavor, explores the thermal, mechanical, and degradation behavior of alkaline treated banana fibers reinforced polypropylene composites. Composites incorporating BF (20% w: w) treated with NaOH (5% w: v) aqueous solution were developed using extrusion-injection molding processes. After chemical treatment, the tensile, flexural and impact strength of the composite increases by 3.8%, 5.17%, and 11.50%, respectively. Scanning electron microscope (SEM) observations of tested specimens confirm the fiber pull out and fiber fracture as the main reasons for failure of developed composites under tensile and impact loading. The specimens were exposed to two different environments, water immersion and soil burial for 5 weeks for the degradation studies. The degradation behavior of composites was measured in terms of variation in weight and mechanical properties (tensile, flexural, and impact). The maximum degradation in mechanical properties was observed for the composites buried under soil. The composite lost 7.69%, 12.06%, and 3.27% of tensile, flexural, and impact strength, respectively.

Abstract Purpose To analyze management and outcomes following (chemo)radiation therapy in patients with cervical lymph node metastases from an unknown primary site (CCUP) in a large single-center cohort. Methods Between 2008 and 2019, 58 patients with CCUP were treated with (chemo)radiation therapy at the University of Freiburg Medical Center and were included in this analysis. Overall survival (OS), locoregional progression-free survival (PFS) and distant metastasis-free survival (DMFS) were calculated using the Kaplan-Meier method. The use of diagnostic procedures and their impact on oncological outcomes was analyzed by Cox regression, and treatment-related toxicities were quantified. Results Median follow-up was 29.9 months (range 4.6–121.9). Twenty-one patients (36.2%) received definitive RT, 35 (60.3%) underwent adjuvant RT, and 2 (3.4%) were treated for oligometastatic disease. Concurrent chemotherapy was prescribed in 40 patients (69.0%). 89.6% of patients completed the prescribed RT, and 65.0% completed the prescribed simultaneous chemotherapy. Locoregional recurrence was observed in 7 patients (12.1%) and distant metastases in 13 cases (22.4%). OS was 81,1, 64.9% and 56,6% after 1, 3 and 5 years, respectively. Univariate analysis of age, gender, extracapsular spread, tumor grading, neck dissection, diagnostic utilization of 18F-fluorodeoxyglucose positron-emission tomography and concomitant chemotherapy showed no effect on OS (p > 0.05 for all), while smoking was significantly associated with decreased survival (p

Leptospirosis can be found in virtually all tropical and temperate areas of the world and is presumed to be the widely spread zoonotic infection in the world. Because of the variety of clinical symptoms seen in the symptomatic cases, leptospirosis at its onset is often misdiagnosed as aseptic meningitis, influenza, hepatic disease or fever (pyrexia) of unknown origin. The disease has been widely spread, ranging from subclinical infection to a severe syndrome of multiorgan infection with high mortality. It is an occupational hazard for people who work outdoors or with animals, such as rice and sugar-cane field workers, farmers, sewer workers, veterinarians, dairy workers, and military personnel. Various diagnostic methods have been developed for the diagnosis of leptospirosis that includes direct examination; serology and molecular based techniques, but have various shortcomings, so there is a need to develop an effective surveillance system to monitor the trends of disease to control this life-threatening zoonosis. Now a day’s biosensor based technology becomes an excellent platform in the field of diagnostics due to their better sensitivity and specificity. So different types of biosensors such as enzyme-based, tissue-based, immunosensor, DNA biosensors, thermal and piezoelectric biosensors have been discussed here to highlight their indispensable applications in different fields. In this review, we will examine the current utilization of functionalized detection methods with other synthetic mixes for the development of biosensor prompting to the location of particular analytes with low discovery cut-off and quick reaction.

Purpose: Metaplastic breast cancer (MBC) is a rare, aggressive variant of breast cancer that has been associated with poor clinical outcomes, as has triple-negative breast (TNBC) cancer. Limited studies compare the clinical characteristics and prognosis of MBC to TNBC. This study uses a large, contemporary US cancer database to compare clinical characteristics and survival outcomes for patients with MBC to those with TNBC. Methods: The National Cancer Database was queried for women with cT1-4N1-3M0 MBC or TNBC diagnosed between 2004 and 2013 and treated with definitive surgery. Chi-squared analysis was performed to determine differences between the cohorts. Kaplan-Meier curves compared overall survival (OS), and Cox regression determined patient factors associated with OS. Results: Altogether, 55,847 patients met the inclusion criteria; 50,705 (90.8%) had TNBC and 5,142 (9.2%) had MBC. Most patients had no comorbid conditions (82%), N0 disease (71%), poorly differentiated histology (77%), received chemotherapy (87%), and received radiation therapy (60%). Amongst all patients, patients with TNBC disease were observed to have greater OS than those with MBC (5-year OS 72.0% vs 55.8%, p

PurposeDosimetric parameters (e.g., mean lung dose (MLD), V20, and V5) can predict radiation pneumonitis (RP). Constraints thereof were formulated before the era of combined immune checkpoint inhibitors (ICIs) and radiotherapy, which could amplify the RP risk. Dosimetric predictors of acute RP (aRP) in the context of ICIs are urgently needed because no data exist thus far.Methods and MaterialsAll included patients underwent thoracic intensity-modulated radiotherapy, previously received ICIs, and followed-up at least once. Logistic regression models examined predictors of aRP (including a priori evaluation of MLD, V20, and V5), and their discriminative capacity was assessed by receiver operating characteristic analysis.ResultsMedian follow-up of the 40 patients was 5.3 months. Cancers were lung (80%) or esophageal (20%). ICIs were PD-1 (85%) or PD-L1 (15%) inhibitors (median 4 cycles). Patients underwent definitive (n=19), consolidative (n=14), or palliative (n=7) radiotherapy; the median equivalent dose in 2 Gy fractions (EQD2) was 60 Gy (IQR, 51.8-64 Gy). Grades 1-5 aRP occurred in 25%, 17.5%, 15%, 2.5%, and 5%, respectively. The only variables associated with any-grade aRP were V20 (p=0.014) and MLD (p=0.026), and only V20 with grade ≥2 aRP (p=0.035). Neither the number of prior ICI cycles nor the delivery of concurrent systemic therapy significantly associated with aRP risk. Graphs were constructed showing the incrementally increasing risk of aRP based on V20 and MLD (continuous variables).ConclusionsThis is the first study illustrating that V20 and MLD may impact aRP in the setting of prior ICIs. However, these data should not be extrapolated to patients without pre-radiotherapy receipt of prior ICIs, or to evaluate the risk of chronic pulmonary effects. If these results are validated by larger studies with more homogeneous populations, the commonly accepted V20/MLD dose constraints could require revision if utilized in the setting of ICIs.

ABSTRACT: OBJECTIVE: This phase I trial (NCT01912625) evaluated the safety and pharmacokinetics of definitive concurrent chemoradiotherapy (cCRT) and the radiosensitizer trametinib (MEK1/2 inhibitor) for KRAS-mutated nonmetastatic non-small cell lung cancer (NSCLC). METHODS: Patients received cCRT (carboplatin/paclitaxel and 60 Gy/30 fractions radiotherapy); oral trametinib (7 days/week) commenced on day 1 and completed on the final day of radiotherapy. Dose-finding of trametinib was done using the time-to-event continual reassessment method (TiTE-CRM); dose levels were 0.5mg (level -1), 1mg (initial, level 1), 1.5mg (level 2), and 2mg (level 3). Progression-free (PFS) and overall survival (OS) times were also recorded. RESULTS: Fifteen patients (stage III, variety of KRAS mutations) were treated, with 1/5/4/5 at dose levels -1/1/2/3, respectively. Five patients received dose reductions (n=2, levels 2 and 3; n=1, level 1). Twelve patients completed the full cCRT course. One patient (following 12d trametinib) was taken off protocol for an unrelated/unresolved grade 1 event and later experienced grade 5 sepsis/respiratory failure. There was one grade 4 retinal detachment; grade 3 events included skin rash (n=2) and ventricular dysfunction, pneumonitis, pain, fatigue, and diarrhea (n=1 each). The final dose selected by the TiTE-CRM of trametinib was 1.5 mg. Pharmacokinetic profiles were elucidated and extensively described. At median follow-up of 70 months, median PFS was 11 months and median OS was 38 months. CONCLUSIONS: The MTD for trametinib when combined with cCRT is 1.5 mg, with encouraging preliminary outcomes. This combination merits further study to combine with consolidation durvalumab in non-metastatic KRAS mutant NSCLC.

Radiation-induced lung injury (RILI) is a form of radiation damage to normal lung tissue caused by radiotherapy (RT) for thoracic cancers, which is most commonly comprised of radiation pneumonitis (RP) and radiation pulmonary fibrosis (RPF). Moreover, with the widespread utilization of immunotherapies such as immune checkpoint inhibitors as first- and second-line treatments for various cancers, the incidence of immunotherapy-related lung injury (IRLI), a severe immune-related adverse event (irAE), has rapidly increased. To date, we know relatively little about the underlying mechanisms and signaling pathways of these complications. A better understanding of the signaling pathways may facilitate the prevention of lung injury and exploration of potential therapeutic targets. Therefore, this review provides an overview of the signaling pathways of RILI and IRLI and focuses on their crosstalk in diverse signaling pathways as well as on possible mechanisms of adverse events resulting from combined radiotherapy and immunotherapy. Furthermore, this review proposes potential therapeutic targets and avenues of further research based on signaling pathways. Many new studies on pyroptosis have renewed appreciation for the value and importance of pyroptosis in lung injury. Therefore, the authors posit that pyroptosis may be the common downstream pathway of RILI and IRLI; discussion is also conducted regarding further perspectives on pyroptosis as a crucial signaling pathway in lung injury treatment.

Despite multiple therapeutic approaches, the presence of liver metastases carries a guarded prognosis, urgently necessitating further clinical and scientific research to develop curative interventions. The liver is an immunoprivileged organ that suppresses the effectiveness of immunotherapies in patients with hepatic metastases. Cancer immunotherapies have been successfully bolstered by low-dose radiotherapy (LDRT), which is capable of reprogramming the tumor microenvironment (TME) from an immunosuppressive to an immunostimulatory one. Likewise, LDRT may be able to revoke the immune privilege enjoyed by the liver, permitting successful immunotherapies there. Here, we first review challenges that face the treatment of liver metastases. We next outline emerging preclinical and clinical evidence supporting enhanced systemic tumor control of LDRT in the context of cancer immunotherapy. Finally, we will discuss the rationale of combining liver-directed LDRT with immunostimulatory strategies to overcome immune resistance and achieve better clinical response. This notion is supported by a recent case study in which a patient who had progressed following T cell therapy experienced a complete response after LDRT to the liver.

PurposeThis retrospective observational study examined patients who experienced radiotherapy (RT) interruption during the Wuhan lockdown for the novel coronavirus disease 2019 (COVID-19) pandemic.Materials and MethodsThe data of all patients whose RT was interrupted during the Wuhan lockdown from January 23 to April 8, 2020 were collected. Patient-, cancer-, and treatment-related characteristics were analyzed, along with interruption time, disease progression type, and survival status. The methods employed in order to compensate for RT interruption were also described.ResultsThere were altogether 129 cancer patients whose RT was interrupted. Nineteen (14.7%) patients experienced a total interruption time of at most 7 days; the interruption time was 8–14 days for 27 (20.9%) patients, and 15 or more days for 47 (36.4%) patients. The remaining 36 (27.9%) patients did not come back to our hospital for further RT. We first describe our experience with re-immobilization and/or re-planning (n = 17) as well as dose compensation/adjustment. Of the 40 definitive radiotherapy patients, 37 had squamous cell carcinoma of nasopharyngeal, lung, or cervical origin. Most patients (85/93, 91.4%) were followed up for more than one year. Among the 40 patients who received definitive radiotherapy, nine patients experienced disease progression and five patients died. Three of the seven (42.9%) patients who did not finish radiotherapy after interruption died, as compared to only two of the 33 (6.1%) patients who completed radiotherapy. EQD2 (equivalent dose in 2 Gy fractions) at the time point of RT interruption was calculated. Five of the six patients (83.3%) who received EQD2 ≤10 Gy suffered from disease progression, compared with four of the 34 (11.8%) patients who received EQD2 >10 Gy. For the seven definitive radiotherapy cases who did not finish radiotherapy, three received systemic anti-cancer treatments and three died (all of whom did not receive further systemic therapies).ConclusionsThis study provides the longest follow-up for the outcomes of RT interruption during COVID-19 pandemic to date. It cannot imply causation but implies that completing RT is important, along with the utility of having patients remain on systemic therapies if RT is to be interrupted.

Introduction: Lung metastasis is usually associated with poor outcomes in cancer patients. This study was performed to characterize and analyze the population of patients with de novo (synchronous) lung metastases using the Surveillance, Epidemiology and End Results (SEER) database.Materials and Methods: Baseline characteristics of lung metastasis patients were obtained from SEER case listings. Incidence rates and counts of synchronous lung metastasis were also obtained using the SEER*Stat software. Survival outcomes were analyzed using univariate and multivariable Cox regressions, controlling for confounders. An alpha threshold of 0.05 was used for statistical significance and p-values were subject to correction for multiple comparisons.Results: The age-adjusted incidence rate of synchronous lung metastasis was 17.92 per 100,000 between 2010 and 2015. Synchronous lung metastases most commonly arose from primary lung cancers, colorectal cancers, kidney cancers, pancreatic cancers and breast cancers. During this time period, 4% of all cancer cases presented with synchronous lung metastasis. The percentage of patients presenting with synchronous lung metastasis ranged from 0.5% of all prostate cancers to 13% of all primary lung cancers. The percentage of all cancer cases presenting with synchronous lung metastasis increased over time. De novo metastatic patients with lung metastases had worse overall survival [hazard ratio = 1.22 (1.21–1.23), p < 0.001] compared to those with only extrapulmonary metastases, controlling for potential confounders.Conclusions: Synchronous lung metastasis occurs frequently and is an independent predictors of poor patient outcomes. As treatment for lung metastases becomes more complicated, patients with synchronous lung metastasis represent a high-risk population.

Introduction: A few personnel feel more tired staying and working inside submarine, as compared to ashore/outdoor spaces, or even onboard afloat platforms (ships). The microclimate onboard underwater platforms play a vital role in determining the respiratory physiology parameters of personnel onboard. There exists a felt need for deeper evidence in this regard. Aims and Objectives: This study is an effort to analyze if there exists any relationship between concentrations of respiratory gases (such as oxygen and carbon dioxide) and other parameters of submarine microclimate, on the respiratory physiology parameters (such as respiratory rate [RR] and SpO2) of personnel onboard underwater platforms. The difference in concentrations of oxygen and carbon dioxide in exhaled air of personnel both inside and outside submarine was also studied. Any difference between smokers and nonsmokers regarding this parameter was also evaluated. Materials and Methods: The study was carried out on thirty healthy volunteers posted onboard a submarine. Concentrations of oxygen and carbon dioxide in the atmosphere, as also the exhaled air, were measured using a digital gas analyzer. Humidity, temperature, and oxygen saturation were measured using digital meters. The values both inside and outside were recorded and compared. Results: There was a statistically significant difference in the temperature, humidity, and level of CO2 inside and outside the submarine. There was no statistically significant difference in level of oxygen in atmosphere, oxygen and carbon dioxide in exhaled air, RR, and SPO2 level inside and outside the submarine. Conclusion: The corrected effective temperature inside a submarine is to be measured periodically and maintained in the comfort zone. The level of CO2 should be maintained close to environmental levels.

Polycystic ovary syndrome (PCOS) is one of the most common heterogeneous conditions of the endocrine reproductive system in women of childbearing age. Hyperandrogenism and oligomenorrhea are the two core characteristics of PCOS, a complicated and multifaceted illness. The condition is also linked to several major side effects, which include type 2 diabetes, early atherosclerosis, infertility, and endometrial cancer. There are few facts and statistics available on PCOS prevalence internationally due to the significant degree of geographic and ethnic variance and inconsistency caused by different diagnosis standards. Limited (n = 179) explorations have been made in the context of the prevalence of this complicated illness so far, and out of these, only 55 studies have discussed its association with race and/or ethnicity. However, those studies remain restricted due to the small sample size, biased selection, and the lack of comparative studies. Variations in PCOS prevalence frequency also arise due to different diagnostic criteria, as well as racial and ethnic differences, associated lifestyle factors, and subsequent illnesses that affect the accuracy of the diagnosis. The main objective behind this systematic review is to provide comprehensive epidemiological data on PCOS that is organized geographically. This evidence-based study also provides an overview of the clinical management of PCOS to instigate further research on this complex endocrinological condition and the subsequent development of preventive treatment strategies.

Radiation therapy (RT) is emerging as an interventional modality in the cancer-immunity cycle, augmenting the activation of an adaptive immune response against tumors. RT, particularly in combination with immunotherapy, can enhance immune memory effects and shape the tumor-directed T-cell populations. However, a single cycle of RT delivered to a limited number of polymetastatic lesions is rarely sufficient to achieve systemic control. We hypothesize that several rounds of RT, akin to several rounds of immunotherapeutic drugs, is likely to provide greater clinical benefit to patients with metastatic disease. We propose that the repeated exposure to tumor antigens released by “pulsed-RT” (i.e., treating 2-4 tumor lesions with 3 irradiation cycles given one month apart) may amplify the adaptive immune response by expanding the tumor-specific T-cell receptor repertoire, the production of high-affinity tumor antibodies, and the generation of memory lymphocytes and thereby improve immune control of systemic disease.

Abstract Background Preclinical evidence suggests that low-dose radiation may overcome the inhibitory effects of the tumor stroma and improve a tumor’s response to immunotherapy, when combined with high-dose radiation to another tumor. The aim of this study was to evaluate tumor responses to this combination in a clinical setting. Methods A post-hoc analysis of 3 ongoing immunoradiation trials was performed. Twenty-six (of 155) patients received low-dose radiation (1–20 Gy total), either as scatter from high-dose radiation or from intentional treatment of a second isocenter with low-dose radiation, were evaluated for response. The low-dose lesions were compared to lesions that received no radiation (

Plaque brachytherapy is a well-accepted modality to manage selected cases of ocular melanoma. Although this modality provides validated oncologic and quality of life benefits, severe complications and adverse events can occur. This article reviews complications and adverse events of plaque brachytherapy, including scleral necrosis, strabismus, cataract, glaucoma, and retinopathies as well as management of these conditions. For practicing oncologists and ophthalmologists, these complications are important to understand, identify, and treat. Additionally, an understanding of common complications of brachytherapy should influence the decision of pursuing it as a treatment option.