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Background: With near universal use of internet by college students, there is propensity for internet addiction (IA) among them. This study aimed to estimate the prevalence and predict the factors for internet addiction among college students in Jodhpur, Rajasthan, India, and qualitatively explore the factors associated with internet addiction. Materials and Methods: Explanatory sequential (QUAN-QUAL) mixed-methods design was used. A cross-sectional questionnaire-based survey was conducted among three streams of undergraduate colleges (health, engineering, and others). Survey instruments included Young’s internet addiction test (IAT), Pittsburgh Sleep Quality Index (PSQI), and Depression, Anxiety, and Stress Scale-21 (DASS-21) Items. Focus group discussions (FGDs) and in-depth interviews (IDIs) among the students with mild-to-moderate levels of addiction were conducted to understand the reasons for excessive internet use. Results: The prevalence of internet addiction (IA) among the college students was 51% and the rates for mild, moderate, and severe addiction were 31.8%, 18.5%, and 0.7%, respectively. Predictors of IA were male gender, age in years, age of first internet use in years, urban origin, accessing internet at college, mobile internet use, using internet to make online friendship, sleep disturbance, depression, anxiety, and stress. Qualitative study identified five major themes related to situations initiating internet use for nonacademic purpose, content of internet use, triggers for internet overuse/addiction (IA), perceived impact of IA, and measures to overcome IA. Conclusions: Internet addiction was found to be highly prevalent in college students across various streams. Qualitative results provide deeper insights into IA among college students. It is imperative to screen for IA among the students and devise suitable preventive interventions, which can be easily implemented at community level.

The study of the immune system its components biological processes physiological functioning types disorders and much more are all covered by the field of biology known as immunology. By defending our bodys cells tissues and organs from invasive infections through a variety of lines of defence the immunenbsp system serves as the bodys defence system. In general the immune system fights off disease-causing microbes and other foreign antigens by recognising and eliminating them. Our immune system can become weakened or stop working under certain circumstances which can cause various infectious diseases like the flu and fever as well as deadly conditions like cancer and AIDS. In order to understand the immune system its various components functions and other significance of immunology this article focuses on a detailed examination of immunology.

The crystal phase of pseudocapacitive materials significantly influences charge storage kinetics and capacitance; yet, the underlying mechanisms remain poorly understood. This study focuses on tungsten oxide (WO 3 ), a material exhibiting multiple crystal phases with potential for energy storage. Despite extensive research on WO 3 , the impact of different crystal structures on charge storage properties remains largely unexplored. Here, the successful synthesis and electrochemical characterization of tetragonal WO 3 are reported. This investigation demonstrates that tetragonal WO 3 exhibits superior energy storage capabilities compared to other WO 3 polymorphs. According to in situ Raman spectroscopy and ultraviolet photoelectron spectroscopy combined with in-depth electrochemical analyses, this enhancement is attributed to a unique charge storage mechanism and an expanded potential window facilitated by an engineered electrode work function. This study highlights the critical role of the crystal phase in optimizing the performance of pseudocapacitive materials and provides valuable insights for the development of next-generation energy storage devices., (© 2024 Wiley‐VCH GmbH.)

Sleep is essential for maintaining optimal health. Both sleep duration and quality have been linked to various physiological functions and physical and mental health outcomes. Nutrition has been shown to impact sleep parameters, from the nutrient composition of foods, such as tryptophan levels, to the physiological response to foods, such as the glucose response. However, the relationship between glycemic control and sleep, and its impact on next-day benefits, particularly on cognitive performance, remains complex and is not fully understood. This narrative review aims to explore the relationship between glycemia and sleep, and how it may affect cognitive performance the following day. The review includes data from observational and interventional studies, discussing mechanisms of action that may explain the modulating effect of glycemia on sleep and cognition. The evidence suggests that lower postprandial glucose and low variation of nocturnal glucose are associated with better sleep quality and shorter sleep onset latency. Good sleep quality, in turn, is positively associated with cognitive processes such as sustained attention and memory consolidation measured the next day after sleep. Future research opportunities lie in investigating the effects of modulating the glycemic and insulinemic responses through evening meals on sleep quality and next-day cognitive performance. Well-designed clinical trials involving healthy individuals are necessary to establish the effects of these interventions. Controlling glycemic and insulinemic profiles through the evening meal may have significant implications for improving sleep quality and cognitive performance, with potential impact on individual mental health, productivity, and overall well-being., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)

Strategies to bring clinical trials closer to patients gained momentum during the COVID-19 pandemic, enabling more participants to receive treatment and/or testing in their local communities. Incorporation of decentralized trial elements presents both opportunities and challenges, spanning regulatory, technical, and operational aspects. This ASCO research statement includes timely consensus-driven recommendations and a call for engagement of all research stakeholders. ASCO held multistakeholder meetings with leaders in oncology research and concluded that research-related regulatory and administrative requirements and burdens present critical barriers to decentralizing trials. One example is sponsor and contract research organization (CRO) use of US Food and Drug Administration (FDA)'s Statement of Investigator (Form 1572), which was found to exceed FDA's stated intent and used in conservative ways disproportionate to potential risks to participants and scientific integrity. As a result, research sites experience an avalanche of downstream administrative and regulatory activities that consume considerable resources. This statement recommends four key solutions to address such barriers and recalibrate regulatory and administrative expectations for decentralizing trials: (1) FDA should engage the research community in a public-private partnership to modernize standards and enable local access to trials; (2) sponsors and CROs should develop standards and protocols that accommodate flexible approaches, enable local participation, provide clarity around roles and requirements, and promote consistency; (3) research centers, networks, and sites should update policies and procedures to implement decentralized trial elements; and (4) research community should develop a streamlined, uniform mechanism to simplify regulatory data collection and documentation and use it consistently across trials. We can and must prioritize a concerted commitment to simplify and streamline regulatory requirements and practices to broaden access to and participation in cancer clinical trials.

Purpose: Targeted Agent and Profiling Utilization Registry is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and targetable genomic alterations. Two cohorts of patients with cyclin-dependent kinase inhibitor 2A ( CDKN2A )-mutated tumors treated with palbociclib are reported: one with head and neck cancer (HNC) with both squamous and nonsquamous cell histologies, and one with histology-pooled (HP) cancers., Methods: Eligible patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as objective response (OR) or stable disease (SD) of at least 16+ weeks duration. For the HNC cohort, Simon's two-stage design with a null DC rate of 15% versus 35% (power = 0.85; α = .10) was used. For the HP cohort, the null hypothesis of a DC rate of 15% was rejected if the lower limit of a one-sided 90% CI was >15%. Secondary end points included OR, safety, progression-free survival, overall survival, duration of response, and duration of SD., Results: Seventy patients with HNC (N = 28) or HP cancers (N = 42) were treated with palbociclib. For the HNC cohort, DC and OR rates were 40% (one-sided 90% CI, 27 to 100) and 4% (95% CI, <1 to 18), respectively. The null hypothesis was rejected ( P = .002). For the HP cohort, DC and OR rates were 13% (one-sided 90% CI, 6 to 100) and 5% (95% CI, <1 to 17), respectively. The null hypothesis was not rejected. Thirty-one of 70 patients experienced treatment-related grade 3 to 4 adverse events (AEs) or serious AEs, the most common including neutropenia, thrombocytopenia, and leukopenia., Conclusion: Palbociclib met prespecified criteria to declare a signal of activity in patients with HNC with CDKN2A alterations, but not in the HP cohort.

Purpose: Targeted Agent and Profiling Utilization Registry is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with biliary tract cancer (BTC) with ERBB2/3 amplification, overexpression, or mutation treated with pertuzumab plus trastuzumab are reported., Methods: Eligible patients had advanced BTC, measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, tumors with ERBB2/3 alterations, and a lack of standard treatment options. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease of at least 16+ weeks duration (SD16+) according to RECIST v1.1. Secondary end points included OR, progression-free survival, overall survival, duration of response, duration of stable disease, and safety., Results: Twenty-nine patients were enrolled from February 2017 to January 2022, and all had advanced BTC with an ERBB2/3 alteration. One patient was not evaluable for efficacy. One complete response, eight partial responses, and two SD16+ were observed for DC and OR rates of 40% (90% CI, 27 to 100) and 32% (95% CI, 16 to 52), respectively. The null hypothesis of 15% DC rate was rejected ( P = .0015). Four patients had at least one grade 3 adverse event (AE) or serious AE at least possibly related to treatment: anemia, diarrhea, infusion-related reaction, and fatigue., Conclusion: Pertuzumab plus trastuzumab met prespecified criteria to declare a signal of activity in patients with BTC and ERBB2/3 amplification, overexpression, or mutation.

Purpose: Targeted Agent and Profiling Utilization Registry (TAPUR) is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with soft tissue sarcoma with cyclin-dependent kinase 4 ( CDK4 ) amplification treated with palbociclib are reported., Methods: Eligible patients had measurable disease, Eastern Cooperative Oncology Group performance status 0 to 2, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as objective response (OR) or stable disease (SD) of at least 16+ weeks duration (SD16+) according to RECIST v1.1. The DC rate was estimated with a 90% CI. Secondary end points included OR, progression-free survival (PFS), overall survival (OS), duration of response, duration of SD, and safety., Results: Forty-two patients with CDK4 amplification were enrolled. One patient was not evaluable for efficacy. One patient with partial response and 18 with SD16+ were observed for DC and OR rates of 46% (90% CI, 36 to 100) and 2% (95% CI, <1 to 13), respectively. Median PFS was 16 weeks (95% CI, 9 to 28) and median OS was 69 weeks (95% CI, 31 to 111) for evaluable patients. Twenty patients had at least one grade 3 to 4 adverse event (AE) at least possibly related to palbociclib, including alanine aminotransferase increase, anemia, fatigue, hypophosphatemia, leukopenia, neutropenia, and thrombocytopenia. No serious AEs were reported., Conclusion: Palbociclib met prespecified criteria to declare a signal of antitumor activity in patients with sarcoma and CDK4 amplification.

Pain management constitutes a pivotal aspect of palliative care. Certain instances of distressing pain are significantly relieved through interventional pain methodologies, demanding the expertise of pain specialists. Our perspective revolves around the integration of these 2 facets, envisaging a symbiotic relationship that could enhance patient outcomes. A prospective assessment was carried out within a collaborative clinic, uniting the realms of pain management and palliative medicine. Anonymized patient information was scrutinized to grasp the advantages of this amalgamation and identify strategies to address any inherent deficiencies. Furthermore, an illustrative case study was delineated, spotlighting the collaborative dynamics at a systemic level. During the period spanning from November 2020 to June 2021, a total of 43 patients received consultations at this collaborative clinic. Each patient was exposed to a comprehensive pain management regimen, with the most frequently conducted procedure being an intercostal nerve block, which was administered in 9.30% of cases. For the provision of effective pain relief within the palliative care context, the confluence of joint consultations from cancer pain specialists emerges as a requisite measure. This approach carries the promise of optimizing pain control and augmenting the quality of palliative care.

For individuals living in rural areas, access to cancer care can be difficult. Barriers to access cross international boundaries and have a negative impact on treatment outcomes. Current models to increase rural access in the United States are reviewed, as is a system-wide approach to this problem in Australia. Ongoing efforts to increase access to clinical trials for patients in rural areas are also discussed.

Purpose: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with various solid tumors with germline or somatic BRCA1/2 mutations treated with talazoparib are reported., Methods: Eligible patients had advanced solid tumors, measurable disease (RECIST), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Patients with germline BRCA -mutated human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer were not eligible for this study. Primary end point was disease control (DC) determined by investigator assessment of objective response (OR) or stable disease (SD) of at least 16 weeks duration (SD16+). The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power = 0.82; α = .10). Secondary end points were OR, progression-free survival, overall survival, duration of response, duration of SD, and safety., Results: Twenty-eight patients (20 cancer types) with BRCA1/2 mutations were enrolled from December 2019 to September 2021 and collapsed into a single histology pooled cohort for analysis. All patients were evaluable for efficacy. One complete response, nine partial response, and six SD16+ were observed for DC and OR rates of 57% (one-sided 90% CI, 43 to 100) and 36% (95% CI, 19 to 56), respectively. The null hypothesis of a 15% DC rate was rejected ( P < .001). Patients with OR had the following tumor types: breast (2), nonmelanoma skin, mesothelioma, stomach, uterus, non-small cell lung cancer, ovary, hepatocellular carcinoma, and pancreas. Thirteen patients had at least one grade 3-5 adverse event (AE) or serious AE at least possibly related to talazoparib. All were consistent with the drug label except bilirubin increase and hyponatremia (both grade 3 AEs)., Conclusion: Talazoparib demonstrated antitumor activity in patients with advanced solid tumors and BRCA1/2 mutations, including cancer types for which poly ADP-ribose polymerase inhibitors are not yet US Food and Drug Administration-approved.

Purpose: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results from cohorts of patients with metastatic breast cancer (BC) with FGFR1 and FGFR2 alterations treated with sunitinib are reported., Methods: Eligible patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease of at least 16 weeks duration (SD16+) according to RECIST v1.1. Secondary end points included OR, progression-free survival, overall survival, duration of response, duration of stable disease, and safety., Results: Forty patients with BC with FGFR1 (N = 30; amplification only n = 26, mutation only n = 1, both n = 3) or FGFR2 (N = 10; amplification only n = 2, mutation only n = 6, both n = 2) alterations were enrolled. Three patients in the FGFR1 cohort were not evaluable for efficacy; all patients in the FGFR2 cohort were evaluable. For the FGFR1 cohort, two patients with partial response and four with SD16+ were observed for DC and OR rates of 27% (90% CI, 13 to 100) and 7% (95% CI, 1 to 24), respectively. The null hypothesis of 15% DC rate was not rejected ( P = .169). No patients achieved DC in the FGFR2 cohort ( P = 1.00). Thirteen of the 40 total patients across both cohorts had at least one grade 3-4 adverse event or serious adverse event at least possibly related to sunitinib., Conclusion: Sunitinib did not meet prespecified criteria to declare a signal of antitumor activity in patients with BC with either FGFR1 or FGFR2 alterations. Other treatments and clinical trials should be considered for these patient populations.

Purpose: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study is a pragmatic basket trial evaluating antitumor activity of approved targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from cohorts of patients with high tumor mutational burden (HTMB, defined as ≥9 mutations per megabase) with advanced colorectal cancer (CRC) and other advanced cancers treated with pembrolizumab are reported., Methods: Eligible patients were 18 years and older with measurable tumors and a lack of standard treatment options, an Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function. The primary end point was disease control (DC), defined as complete or partial response or stable disease (SD) of at least 16-weeks duration. For the CRC cohort, Simon's two-stage design with a null DC rate of 15% versus 35% (power = 0.85; α = .10) was used. Low accruing histology-specific cohorts were collapsed into one histology-pooled (HP) cohort. For the HP cohort, the null hypothesis of a DC rate of 15% was rejected if the lower limit of a one-sided 90% CI was >15%. Secondary end points included objective response (OR), safety, progression-free survival, overall survival, duration of response, and duration of SD., Results: Seventy-seven patients with HTMB with CRC (n = 28) or advanced cancers (n = 49) were treated with pembrolizumab. For the CRC cohort, the DC rate was 31% ( P = .04) and the OR rate was 11%. For the HP cohort, the DC rate was 45% (one-sided 90% CI, 35 to 100) and the OR rate was 26%. The null hypothesis of a 15% DC rate was rejected for both cohorts. Twelve of 77 patients experienced treatment-related grade 3 adverse events (AEs) or serious AEs, including two deaths., Conclusion: Pembrolizumab demonstrated antitumor activity in pretreated patients with advanced cancers and HTMB.

Alzheimer's disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta (Aβ) plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including Aβ, phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and mitochondrial dysfunction appears up to 15 years before the onset of clinical AD symptoms. As glucose utilization is compromised in the brain of patients with AD, ketone bodies (KBs) may serve as an alternative source of energy. KBs are generated from the β-oxidation of fatty acids, which are enhanced following consumption of ketogenic diets with high fat, moderate protein, and low carbohydrate. KBs have been shown to cross the blood brain barrier to improve brain energy metabolism. This review comprehensively summarizes the current literature on how increasing KBs support brain energy metabolism. In addition, for the first time, this review discusses the effects of ketogenic diet on the putative AD biomarkers such as Aβ, tau (mainly p-tau 181), GFAP, and NFL, and discusses the role of KBs on neuroinflammation, oxidative stress, and mitochondrial metabolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ramezani, Fernando, Eslick, Asih, Shadfar, Bandara, Hillebrandt, Meghwar, Shahriari, Chatterjee, Thota, Dias, Garg and Martins.)

Anticancer agents can impair ovarian function, resulting in premature menopause and associated long-term health effects. Ovarian toxicity is not usually adequately assessed in trials of anticancer agents, leaving an important information gap for patients facing therapy choices. This American Society of Clinical Oncology (ASCO) statement provides information about the incorporation of ovarian toxicity measures in trial design. ASCO recommends: (1) measurement of ovarian toxicity in relevant clinical trials of anticancer agents that enrol post-pubertal, pre-menopausal patients; (2) collection of ovarian function measures at baseline and at 12-24 months after anticancer agent cessation, as a minimum, and later in line with the trial schedule; and (3) assessment of both clinical measures and biomarkers of ovarian function. ASCO recognises that routine measurement of ovarian toxicity and function in cancer clinical trials will add additional complexity and burden to trial resources but asserts that this issue is of such importance to patients that it cannot continue to be overlooked., Competing Interests: Declaration of interests WC reports honoraria from AstraZeneca, Pfizer, Merck Serono, and Eisai. RAA reports grants or contracts (research funding) and consulting fees from Roche Diagnostics. ND reports employment by AstraZeneca; grants or contracts (research funding) from Amgen, Novartis, Genentech, Lilly, Pfizer, Daiichi Sankyo, and Immunomedics; and travel, accommodations, expenses, and stock options from AstraZeneca. DS reports grants or contracts (research funding) from Janssen; consulting fees (advisory role) from Janssen Oncology, AstraZeneca, Boston Scientific, Bayer, Blue Earth, Varian Medical Systems, Pfizer, and Myovant Sciences; and honoraria from Varian Medical Systems. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Osteoporosis and Alzheimer's disease (AD) mainly affect older individuals, and the possibility of an underlying link contributing to their shared epidemiological features has rarely been investigated. In the current study, we investigated the association between levels of plasma sclerostin (SOST), a protein primarily produced by bone, and brain amyloid-beta (Aβ) load, a pathological hallmark of AD. The study enrolled participants meeting a set of screening inclusion and exclusion criteria and were stratified into Aβ- (n = 65) and Aβ+ (n = 35) according to their brain Aβ load assessed using Aβ-PET (positron emission tomography) imaging. Plasma SOST levels, apolipoprotein E gene (APOE) genotype and several putative AD blood-biomarkers including Aβ40, Aβ42, Aβ42/Aβ40, neurofilament light (NFL), glial fibrillary acidic protein (GFAP), total tau (t-tau) and phosphorylated tau (p-tau181 and p-tau231) were detected and compared. It was found that plasma SOST levels were significantly higher in the Aβ+ group (71.49 ± 25.00 pmol/L) compared with the Aβ- group (56.51 ± 22.14 pmol/L) (P < 0.01). Moreover, Spearman's correlation analysis showed that plasma SOST concentrations were positively correlated with brain Aβ load (ρ = 0.321, P = 0.001). Importantly, plasma SOST combined with Aβ42/Aβ40 ratio significantly increased the area under the curve (AUC) when compared with using Aβ42/Aβ40 ratio alone (AUC = 0.768 vs 0.669, P = 0.027). In conclusion, plasma SOST levels are elevated in cognitively unimpaired older adults at high risk of AD and SOST could complement existing plasma biomarkers to assist in the detection of preclinical AD., (© 2023. The Author(s).)

Purpose: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket study evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancers with genomic alterations known to be drug targets. Results of a cohort of patients with solid tumors with ATM mutations treated with nivolumab plus ipilimumab are reported., Methods: Eligible patients had measurable disease (RECIST v.1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Primary end point was disease control (DC), defined as complete (CR) or partial (PR) response or stable disease (SD) of at least 16 weeks duration (SD16+). Low-accruing histology-specific cohorts with ATM mutations treated with nivolumab plus ipilimumab were collapsed into a single histology-pooled cohort for this analysis. The results were evaluated based on a one-sided exact binomial test with a null DC rate of 15% versus 35% (power = .84; α = .10). Secondary end points were objective response (OR), progression-free survival, overall survival, duration of response, duration of SD, and safety., Results: Twenty-nine patients with 10 tumor types with ATM mutations were enrolled from January 2018 to May 2020. One patient was not evaluable for efficacy. One CR, three PR, and three SD16+ were observed for DC and OR rates of 24% ( P = .13; one-sided 90% CI: 14 to 100) and 14% (95% CI: 4 to 32), respectively. The null hypothesis of 15% DC rate was not rejected. Eleven patients had one treatment-related grade 3 adverse event (AE) or serious AE. There were two treatment-related patient deaths including immune-related encephalitis and respiratory failure., Conclusion: Nivolumab plus ipilimumab did not meet prespecified criteria to declare a signal of activity in patients with solid tumors with ATM mutations.

Laparoscopic Heller's cardiomyotomy is the surgical procedure of choice in the management of oesophageal achalasia. It is critical to confirm the completeness of the myotomy and mucosal integrity at the conclusion of the procedure. This is conventionally achieved by intraoperative endoscopy and dynamic air leak test. Other modalities that can be used to confirm the myotomy and the integrity of the mucosa at the myotomy site are oesophageal manometry and a methylene blue dye study, respectively. Indocyanine green (ICG) has been in clinical use for more than six decades. The real-time integration of ICG fluorescence with laparoscopy is a relatively new breakthrough. Here, we present a novel method of using real-time near-infrared ICG fluorescence for confirming the completeness of the myotomy and mucosal integrity at the myotomy site post laparoscopic Heller's myotomy. This is the first report on the use of ICG in laparoscopic Heller's cardiomyotomy that we are aware of., Competing Interests: None

Purpose: The Targeted Agent and Profiling Utilization Registry Study is a pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from a cohort of patients with lung cancer and ERBB2 mutation or amplification treated with pertuzumab plus trastuzumab (P + T) are reported., Methods: Eligible patients had advanced lung cancer of any histology, no standard treatment options, measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and tumors with ERBB2 mutation or amplification. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) per RECIST v. 1.1 or stable disease (SD) of at least 16 weeks duration (SD16+). Secondary end points included safety, duration of response, duration of SD, progression-free survival, and overall survival., Results: Twenty-eight patients with lung cancer (27 non-small-cell, 1 small-cell) and ERBB2 mutation (n = 15), ERBB2 amplification (n = 12), or both (n = 1) were enrolled from November 2016 to July 2020. All patients were evaluable for efficacy and toxicity. Three patients with partial response (two ERBB2 mutation; one both mutation and amplification) and seven patients with SD16+ (five ERBB2 mutation; two amplification) were observed for a DC rate of 37% (95% CI, 21 to 50; P = .005) and OR rate of 11% (95% CI, 2 to 28). Five patients had one or more grade 3 or 4 adverse or serious adverse events at least possibly related to P + T., Conclusion: Combination P + T showed evidence of antitumor activity in heavily pretreated patients with non-small-cell lung cancer and ERBB2 mutation or amplification, particularly those with ERBB2 exon 20 insertion mutations.

Introduction: Plasma amyloid beta (Aβ)1-42/Aβ1-40 ratio, phosphorylated-tau181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) are putative blood biomarkers for Alzheimer's disease (AD). However, head-to-head cross-sectional and longitudinal comparisons of the aforementioned biomarkers across the AD continuum are lacking., Methods: Plasma Aβ1-42, Aβ1-40, p-tau181, GFAP, and NfL were measured utilizing the Single Molecule Array (Simoa) platform and compared cross-sectionally across the AD continuum, wherein Aβ-PET (positron emission tomography)-negative cognitively unimpaired (CU Aβ-, n = 81) and mild cognitive impairment (MCI Aβ-, n = 26) participants were compared with Aβ-PET-positive participants across the AD continuum (CU Aβ+, n = 39; MCI Aβ+, n = 33; AD Aβ+, n = 46) from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) cohort. Longitudinal plasma biomarker changes were also assessed in MCI (n = 27) and AD (n = 29) participants compared with CU (n = 120) participants. In addition, associations between baseline plasma biomarker levels and prospective cognitive decline and Aβ-PET load were assessed over a 7 to 10-year duration., Results: Lower plasma Aβ1-42/Aβ1-40 ratio and elevated p-tau181 and GFAP were observed in CU Aβ+, MCI Aβ+, and AD Aβ+, whereas elevated plasma NfL was observed in MCI Aβ+ and AD Aβ+, compared with CU Aβ- and MCI Aβ-. Among the aforementioned plasma biomarkers, for models with and without AD risk factors (age, sex, and apolipoprotein E (APOE) ε4 carrier status), p-tau181 performed equivalent to or better than other biomarkers in predicting a brain Aβ-/+ status across the AD continuum. However, for models with and without the AD risk factors, a biomarker panel of Aβ1-42/Aβ1-40, p-tau181, and GFAP performed equivalent to or better than any of the biomarkers alone in predicting brain Aβ-/+ status across the AD continuum. Longitudinally, plasma Aβ1-42/Aβ1-40, p-tau181, and GFAP were altered in MCI compared with CU, and plasma GFAP and NfL were altered in AD compared with CU. In addition, lower plasma Aβ1-42/Aβ1-40 and higher p-tau181, GFAP, and NfL were associated with prospective cognitive decline and lower plasma Aβ1-42/Aβ1-40, and higher p-tau181 and GFAP were associated with increased Aβ-PET load prospectively., Discussion: These findings suggest that plasma biomarkers are altered cross-sectionally and longitudinally, along the AD continuum, and are prospectively associated with cognitive decline and brain Aβ-PET load. In addition, although p-tau181 performed equivalent to or better than other biomarkers in predicting an Aβ-/+ status across the AD continuum, a panel of biomarkers may have superior Aβ-/+ status predictive capability across the AD continuum., Highlights: Area under the curve (AUC) of p-tau181 ≥ AUC of Aβ42/40, GFAP, NfL in predicting PET Aβ-/+ status (Aβ-/+).  AUC of Aβ42/40+p-tau181+GFAP panel ≥ AUC of Aβ42/40/p-tau181/GFAP/NfL for Aβ-/+.  Longitudinally, Aβ42/40, p-tau181, and GFAP were altered in MCI versus CU.  Longitudinally, GFAP and NfL were altered in AD versus CU.  Aβ42/40, p-tau181, GFAP, and NfL are associated with prospective cognitive decline.  Aβ42/40, p-tau181, and GFAP are associated with increased PET Aβ load prospectively., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Aims: Biliary tract cancer (BTC) is a rare, lethal, heterogeneous group of cancers often diagnosed at an advanced stage. While gemcitabine plus cisplatin is the standard of care for first-line treatment of locally advanced or metastatic BTC, no globally accepted standard of care currently exists for second-line treatment of BTC following chemotherapy. However, the treatment landscape is evolving with approvals for therapies targeting actionable mutations. This study aimed to characterize treatment patterns and survival in patients with locally advanced or metastatic BTC., Methods: Patients with advanced or metastatic BTC in the Surveillance, Epidemiology, and End Results Medicare database between 2010 and 2015 (N = 2063) were included; patients with nonprimary BTC were excluded. Patient and clinical characteristics, line and type of therapy, and overall survival of patients were analyzed., Results: Only 45.5% (n = 938) of patients initiated systemic therapy within 90 days of diagnosis. The most common event following diagnosis was initiation of first-line therapy, and the most common event following first-line treatment was death. Median survival ranged from 5.0 months for patients receiving second-line fluoropyrimidine to 9.7 months for patients receiving second-line gemcitabine. Duration of therapy ranged from 0.7 months for patients receiving second-line fluoropyrimidine to 3.7 months for patients receiving first-line gemcitabine plus cisplatin therapy., Conclusion: Overall survival from diagnosis was poor and influenced by age, sex, stage, mobility limitations, comorbidity burden, poverty, and previous cancer. Treatment patterns varied for patients who progressed following first-line therapy, as there was no consensus second-line treatment for locally advanced or metastatic BTC without clinically targetable mutations., (© 2023 The Authors.)

Background: Astrocyte reactivity is an early event along the Alzheimer's disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18F-SMBT-1 PET in AD., Objective: The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers., Methods: Plasma GFAP and Aβ were measured using the Simoa® platform in participants who underwent brain 18F-SMBT-1 and Aβ-PET imaging, comprising 54 healthy control (13 Aβ-PET+ and 41 Aβ-PET-), 11 mild cognitively impaired (3 Aβ-PET+ and 8 Aβ-PET-) and 6 probable AD (5 Aβ-PET+ and 1 Aβ-PET-) individuals. Linear regressions were used to assess associations of interest., Results: Plasma GFAP was associated with 18F-SMBT-1 signal in brain regions prone to early Aβ deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE ɛ4 genotype, and soluble Aβ (plasma Aβ42/40 ratio), plasma GFAP was associated with 18F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE ɛ4 genotype and insoluble Aβ (Aβ-PET), plasma GFAP was associated with 18F-SMBT-1 signal in the SG., Conclusion: There is an association between plasma GFAP and regional 18F-SMBT-1 PET, and this association appears to be dependent on brain Aβ load.

Purpose: TAPUR is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. The results of a cohort of patients with colorectal cancer (CRC) with BRAF mutations treated with cobimetinib (C) plus vemurafenib (V) are reported., Methods: Eligible patients had advanced CRC, no standard treatment options, measurable disease (RECIST), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, tumors with BRAF V600E/D/K/R mutations, and no MAP2K1/2 , MEK1/2 , or NRAS mutations. C was taken 60 mg orally once daily for 21 days followed by seven days off, and V was taken 960 mg orally twice daily. Simon's two-stage design was used with a primary study end point of objective response or stable disease of at least 16 weeks duration. Secondary end points were progression-free survival, overall survival, and safety., Results: Thirty patients were enrolled from August 2016 to August 2018; all had CRC with a BRAF V600E mutation except one patient with a BRAF K601E mutation. Three patients were not evaluable for efficacy. Eight patients with partial responses and six patients with stable disease of at least 16 weeks duration were observed for disease control and objective response rates of 52% (95% CI, 35 to 65) and 30% (95% CI, 14 to 50), respectively. The null hypothesis of 15% disease control rate was rejected ( P < .0001). Thirteen patients had at least one grade 3 adverse event or serious adverse event at least possibly related to C + V: anemia, decreased lymphocytes, dyspnea, diarrhea, elevated liver enzymes, fatigue, hypercalcemia, hypophosphatemia, rash, photosensitivity, and upper gastrointestinal hemorrhage., Conclusion: The combination of C + V has antitumor activity in heavily pretreated patients with CRC with BRAF mutations.

Survivin, an inhibitor of apoptosis protein is a biomarker of significance in prognostication of many malignancies. In the current study we investigated the serum survivin levels in patients with oral submucosal fibrosis (OSMF) and squamous cell carcinoma (OSCC). Serum was isolated from, peripheral blood collected of clinically and histopathologically confirmed OSMF and OSCC patients. Circulating level of survivin was measured in patients and control subjects by ELISA and analyzed further using Kruskal-Wallis test and two-sample Wilcoxon rank-sum (Mann-Whitney) test. Serum Survivin levels were significantly reduced in the OSCC group as compared to the control group. No significant correlation was noted between the serum survivin level and various clinicopathological characteristics of OSCC and OSMF patients. Our study suggests that free, wild form of circulating survivin probably has no role in predicting the prognosis of oral cancer or the malignant transformation potential of oral submucosal fibrosis., Competing Interests: Conflict of interestNo potential conflicts of interest were disclosed., (© Association of Otolaryngologists of India 2020.)

Cholesterol levels have been repeatedly linked to Alzheimer's Disease (AD), suggesting that high levels could be detrimental, but this effect is likely attributed to Low-Density Lipoprotein (LDL) cholesterol. On the other hand, High-Density Lipoproteins (HDL) cholesterol levels have been associated with reduced brain amyloidosis and improved cognitive function. However, recent findings have suggested that HDL-functionality, which depends upon the HDL-cargo proteins associated with HDL, rather than HDL levels, appears to be the key factor, suggesting a quality over quantity status. In this report, we have assessed the HDL-cargo (Cholesterol, ApoA-I, ApoA-II, ApoC-I, ApoC-III, ApoD, ApoE, ApoH, ApoJ, CRP, and SAA) in stable healthy control (HC), healthy controls who will convert to MCI/AD (HC-Conv) and AD patients (AD). Compared to HC we observed an increased cholesterol/ApoA-I ratio in AD and HC-Conv, as well as an increased ApoD/ApoA-I ratio and a decreased ApoA-II/ApoA-I ratio in AD. Higher cholesterol/ApoA-I ratio was also associated with lower cortical grey matter volume and higher ventricular volume, while higher ApoA-II/ApoA-I and ApoJ/ApoA-I ratios were associated with greater cortical grey matter volume (and for ApoA-II also with greater hippocampal volume) and smaller ventricular volume. Additionally, in a clinical status-independent manner, the ApoE/ApoA-I ratio was significantly lower in APOE ε4 carriers and lowest in APOE ε4 homozygous. Together, these data indicate that in AD patients the composition of HDL is altered, which may affect HDL functionality, and such changes are associated with altered regional brain volumetric data., (© 2022 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Our objectives were to evaluate the role of procalcitonin in identifying bacterial co-infections in hospitalized COVID-19 patients and quantify antibiotic prescribing during the 2020 pandemic surge. Hospitalized COVID-19 patients with both a procalcitonin test and blood or respiratory culture sent on admission were included in this retrospective study. Confirmed co-infection was determined by an infectious diseases specialist. In total, 819 patients were included; 335 (41%) had an elevated procalcitonin (>0.5 ng/mL) and of these, 42 (13%) had an initial bacterial co-infection. Positive predictive value of elevated procalcitonin for co-infection was 13% while the negative predictive value was 94%. Ninety-six percent of patients with an elevated procalcitonin received antibiotics (median 6 days of therapy), compared to 82% with low procalcitonin (median 4 days of therapy) (adjusted OR:3.3, P < 0.001). We observed elevated initial procalcitonin in many COVID patients without concurrent bacterial co-infections which potentially contributed to antibiotic over-prescribing., (Copyright © 2022 Elsevier Inc. All rights reserved.)