Integrated Assessment of GFAP and UCH-L1 for their utility in severity assessment and outcome prediction in Traumatic Brain Injury.

OBJECTIVES: This study aimed to explore the potential of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) as biomarkers for diagnosis and prognosis in mild and severe TBI cases, including TBI-related deaths. METHODS: This prospective cohort study includes 40 cases each of mild, severe, fatal TBI cases, and 40 healthy controls. Serum samples were collected from live patients at 8 and 20 h post injury for UCH-L1 and GFAP respectively, and from deceased patients within 6 h of death. RESULTS: Elevated levels of both GFAP and UCH-L1 were observed in patients with severe and fatal TBI cases. These biomarkers exhibited promising potential for predicting various Glasgow Outcome Scale Extended (GOSE) categories. Combining GFAP and UCH-L1 yielded higher predictive accuracy both for diagnosis and prognosis in TBI cases. The study additionally established specific cut-off levels for GFAP and UCH-L1 stratified according to the severity and prognosis. CONCLUSION: GFAP and UCH-L1 individually demonstrated moderate to good discrimination capacity in predicting TBI severity and functional outcomes. However, combining these biomarkers is recommended for improved diagnostic and prognostic utility. This precision tool can enhance patient care, enabling tailored treatment plans, ultimately reducing morbidity and mortality rates in TBI cases.

Evolution of transgender rights in India: Better late than never.

The progress of transgender rights in India has seen significant strides with milestones such as the National Legal Services Authority (NALSA) judgment and the enactment of the Transgender Persons (Protection of Rights) Act in 2019. The NALSA judgment recognized the right of transgender individuals to self-identify their gender. This decision led to the formal recognition of a 'third gender', advancing legislative and social reforms. Prior to this, transgender individuals faced substantial hurdles, including limited access to education, employment, and healthcare due to a lack of legal recognition. Within a few years, The Transgender Persons (Protection of Rights) Act established a framework that safeguards the rights of transgender individuals and prohibits discrimination based on gender. This legislation requires the government to take measures like promoting education, providing vocational training opportunities, ensuring accessible healthcare services, and offering social security support. It also addresses the healthcare needs of transgender individuals thereby contributing to their overall well being. The Support for Marginalised Individuals for Livelihood and Enterprise (SMILE) program and Garima Greh are initiatives that provide spaces and empower a marginalized transgender individuals and promoting their inclusion, justice and empowerment. This article explores the progress pertaining to transgender rights and welfare, while highlighting efforts undertaken by the Indian government.

Duplex kidney: An incidental autopsy finding of clinical and medico-legal significance.

Duplex kidney, a rare congenital anomaly characterised by dual urinary drainage from the kidney, is typically discovered incidentally, often during radiological imaging or autopsy procedures. We report a case of a 21-year-old male who died from injuries sustained in a road traffic accident. The autopsy examination showed an incidental finding of duplex kidney on the left side. We discuss the clinical and potential medico-legal significance of duplex kidney which also has implications in renal transplantation. Notably, the presence of duplex kidney can potentially serve as an identifier in forensic investigations, given its rare incidence.

Engaging Cancer Care Physicians in Off-Label Drug Clinical Trials: Human-Centered Design Approach.

BACKGROUND: Using a human-centered design (HCD) approach can provide clinical trial design teams with a better understanding of the needs, preferences, and attitudes of clinical trial stakeholders. It can also be used to understand the challenges and barriers physician stakeholders face in initiating and completing clinical trials, especially for using off-label drugs (OLDs) to treat unmet clinical needs in cancer treatment. However, the HCD approach is not commonly taught in the context of clinical trial design, and few step-by-step guides similar to this study are available to demonstrate its application. OBJECTIVE: This study aims to demonstrate the feasibility and process of applying an HCD approach to creating clinical trial support resources for physician stakeholders to overcome barriers to pursuing clinical trials for OLDs to treat cancer. METHODS: An HCD approach was used to develop OLD clinical trial support concepts. In total, 45 cancer care physicians were contacted, of which 15 participated in semistructured interviews to identify barriers to prescribing OLDs or participating in cancer OLD clinical trials. Design research is qualitative-it seeks to answer "why" and "how" questions; thus, a sample size of 15 was sufficient to provide insight saturation to address the design problem. The team used affinity mapping and thematic analysis of qualitative data gathered from the interviews to inform subsequent web-based co-design sessions, which included creative matrix exercises and voting to refine and prioritize the ideas used in the final 3 recommended concepts. RESULTS: The findings demonstrate the potential of HCD methods to uncover important insights into the barriers physicians face in participating in OLD clinical trials or prescribing OLDs, such as recruitment challenges, low willingness to prescribe without clinical data, and stigma. Notably, only palliative care participants self-identified as "frequent prescribers" of OLDs, despite high national OLD prescription rates among patients with cancer. Participants found the HCD approach engaging, with 60% (9/15) completing this study; scheduling conflicts caused most of the dropouts. Over 150 ideas were generated in 3 co-design sessions, with the groups voting on 15 priority ideas that the design team then refined into 3 final recommendations, especially focused on increasing the participation of physicians in OLD clinical trials. CONCLUSIONS: Using participatory HCD methods, we delivered 3 concepts for clinical trial support resources to help physician stakeholders overcome barriers to pursuing clinical trials for OLDs to treat cancer. Overall, integrating the HCD approach can aid in identifying important stakeholders, such as prescribing physicians; facilitating their engagement; and incorporating their perspectives and needs into the solution design process. This paper highlights the process, methods, and potential of HCD to improve cancer clinical trial design. Future work is needed to train clinical trial designers in the HCD approach and encourage adoption in the field.

Ant bite artifacts in a case of hanging.

Artifacts produced by postmortem animal scavenging are commonly encountered at autopsy. Knowledge of the pattern of artifacts produced by postmortem animal scavenging is essential for the correct interpretation of the autopsy finding. In household deaths, such artifacts are usually caused by domestic animals and by small insects such as flies, ants, beetles, etc. Ants are one of the early scavengers which feed on the dead bodies. The artifacts produced by the postmortem ant activity are usually superficial and non-bleeding type. Rarely, in the congested body regions and areas of marked hypostasis, postmortem bleeding artifacts due to ant bites are possible. In the reported case of hanging, such postmortem bleeding artifacts were present over both the legs, predominantly over the left leg. Typical ant bite lesions in the form of superficial excoriations were also present over the peri-ligature area, over and around both nipples and over the lower part of the abdomen. Morphologically, postmortem bleeding artifacts produced by ant bites exhibit four patterns: droplet pattern, stripe pattern, pool pattern, and mixed pattern. In this case, a mixed pattern (droplet pattern and stripe pattern) of postmortem bleeding artifacts was observed. The presence of postmortem bleeding artifacts over the lower limbs was attributed to the pooling of the blood due to suspension of the body, followed by passive escape of blood due to ant bites. The possibility of such artifacts produced by ant bites should be considered when the origin of the lesion is unclear.

An unusual case of high-voltage electrocution of a truck driver due to inadvertent contact of the truck with an overhead wire.

Electrocution deaths are mostly accidental. However, reconstruction of events in unusual electrocution death is challenging. This article reports an accidental death due to electrocution in a highly unusual circumstance, in which a truck driver reversing his vehicle was electrocuted when his truck inadvertently touched an overhead high-voltage wire. The electric injury marks were present over the sole of the right foot. The scene investigation revealed that the high-voltage wire was loose and was below the level of the prescribed height. The truck was passing over an elevated area made up of dirt and stone. The interior of the cabin of the truck revealed a few non-insulated metallic areas over the floor of the truck, between the accelerator and the brake, which were attributed as the sources of entry of electricity into the body. The electric injury marks were different than those usually seen in high-voltage electrocution as there was an intermediate object (truck) involved, and the contact period between the truck and the electric wire was minimal. This fatality was attributed to the non-proper insulation of the interior of the truck, the negligent driving of the truck driver over the elevated surface, and the loose high-voltage wire without proper maintenance.

Spontaneous retroperitoneal and intracranial hemorrhage following streptokinase therapy in acute myocardial infarction: An autopsy case report.

Bleeding complications following thrombolytic treatment for acute myocardial infarction (AMI) are not infrequent, among which intracranial hemorrhage is commonly reported. In contrast, retroperitoneal hematoma following the administration of thrombolytics is rarely reported in the literature. We are reporting a case of a middle-aged man, who presented with left-sided chest pain and was diagnosed with acute coronary syndrome with anterior wall ST elevation AMI. The patient was administered with thrombolytic drugs, including streptokinase and heparin. Percutaneous coronary intervention in the form of Coronary angioplasty with stent insertion was done to the left anterior descending artery, given coronary artery disease. The blood investigations showed elevated activated partial thromboplastin time and prothrombin time. The patient developed vomiting, altered sensorium, and left-sided weakness, and a non-contrast computerized tomography brain was done, which showed acute hemorrhage involving the right frontal lobe with intraventricular extension, so the ventricular drain was placed. The patient developed cardiac arrest and died on the third day. On autopsy examination, the brain showed subarachnoid hemorrhage, intraparenchymal hemorrhage over the right frontal lobe, and clotted blood in all the ventricles. A retroperitoneal hematoma of around 1500 cc was seen over the left side of the peritoneal cavity. This case highlights that although intracranial hemorrhage is a known complication after administrating thrombolytic therapy, clinicians should also be aware of the possibility of retroperitoneal hemorrhage. This case emphasizes the value of an autopsy in determining the cause of death in such situations.

ChatGPT in medical research: challenging time ahead.

Since its launch, ChatGPT, an artificial intelligence-powered language model tool, has generated significant attention in research writing. The use of ChatGPT in medical research can be a double-edged sword. ChatGPT can expedite the research writing process by assisting with hypothesis formulation, literature review, data analysis and manuscript writing. On the other hand, using ChatGPT raises concerns regarding the originality and authenticity of content, the precision and potential bias of the tool's output, and the potential legal issues associated with privacy, confidentiality and plagiarism. The article also calls for adherence to stringent citation guidelines and the development of regulations promoting the responsible application of AI. Despite the revolutionary capabilities of ChatGPT, the article highlights its inability to replicate human thought and the difficulties in maintaining the integrity and reliability of ChatGPT-enabled research, particularly in complex fields such as medicine and law. AI tools can be used as supplementary aids rather than primary sources of analysis in medical research writing.

Taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape.

A major cause of cancer recurrence following chemotherapy is cancer dormancy escape. Taxane-based chemotherapy is standard of care in breast cancer treatment aimed at killing proliferating cancer cells. Here, we demonstrate that docetaxel injures stromal cells, which release protumor cytokines, IL-6 and granulocyte colony stimulating factor (G-CSF), that in turn invoke dormant cancer outgrowth both in vitro and in vivo. Single-cell transcriptomics shows a reprogramming of awakened cancer cells including several survival cues such as stemness, chemoresistance in a tumor stromal organoid (TSO) model, as well as an altered tumor microenvironment (TME) with augmented protumor immune signaling in a syngeneic mouse breast cancer model. IL-6 plays a role in cancer cell proliferation, whereas G-CSF mediates tumor immunosuppression. Pathways and differential expression analyses confirmed MEK as the key regulatory molecule in cancer cell outgrowth and survival. Antibody targeting of protumor cytokines (IL-6, G-CSF) or inhibition of cytokine signaling via MEK/ERK pathway using selumetinib prior to docetaxel treatment prevented cancer dormancy outgrowth suggesting a novel therapeutic strategy to prevent cancer recurrence.

Further explorations into the role of mast cells in deaths associated with fatal asphyxia: an immunohistochemical study utilizing CD 117 marker.

Asphyxia-related deaths have always been a challenging task in the speciality of forensic pathology. Apart from helpful macroscopical signs (e.g., strangulation mark, cyanosis, petechial haemorrhage, and lung oedema), recent literature indicates that prolonged asphyxia is sufficient to induce an increase in mast cells (MC). Inflammatory cells migrate from the bone marrow to the lungs, aiding in the diagnosis of fatal asphyxial deaths. HIF1-α, a key regulator protein, is released from lung tissue capillaries during catastrophic hypoxia circumstances, as previously demonstrated in immunohistochemistry (IHC) research. The present study analyzed lung samples from 164 medico-legal autopsy cases, including 57 asphyxia/hypoxia deaths and 107 controls (non-asphyxial deaths). Peribronchial, perivascular and perialveolar MCs were detected using CD117 antibody, and the average of MCs in each of these locations was noted in each case. The results indicated a statistically significant increase in peribronchial and perialveolar mast cells (MC) in fatal asphyxial deaths, including those caused by hanging, drowning, or postural asphyxia. Peri-bronchial MC in lung sections of asphyxial deaths were in the range of 0.2-5.4 and in non-asphyxial samples were in the range of 0.0-2.2. Peri-alveolar MCs in lung sections of asphyxial deaths were in the range of 0.0-0.6 and in non-asphyxial samples were in the range of 0.0-0.2. Our data suggest that mast cells (MC) play an important role in fatal hypoxia-related mortality and CD 117 may be a reliable marker for detection of mast cells in asphyxial deaths. It could be very beneficial to forensic pathologists tasked with differentiating fatal asphyxia fatalities from other causes of death.

Delayed Death Due to Lightning: An Autopsy Case Report Highlighting Diagnostic and Medicolegal Issues.

The incidences of lightning strikes are not infrequent. The electric discharge of the lightning strike produces extreme heat and high amperage current, but fatality is reported in only about 10% to 30% of lightning cases. The spectrum of injuries due to lightning strikes can vary from no external injuries to typical external injuries. Merely the presence of superficial injuries due to lightning should not be considered sufficient to dismiss the case as non-serious. Rather clinicians should be wary of internal damage due to the effect of the lightning current as well as delayed complications of the lightning which can be fatal. Similarly, during an autopsy, the forensic pathologist should also investigate for the changes/damage in the internal organs due to the effect of lightning current. The present case reports the incidence of death due to delayed complications of a lightning strike which primary doctors initially overlooked. This case also discusses the histopathological changes in the internal organs due to lightning which can be helpful in the autopsy diagnosis of lightning, particularly in cases with no external or nonspecific injuries.

Non-canonical integrin signaling activates EGFR and RAS-MAPK-ERK signaling in small cell lung cancer.

Background: Small cell lung cancer (SCLC) is an extremely aggressive cancer type with a patient median survival of 6-12 months. Epidermal growth factor (EGF) signaling plays an important role in triggering SCLC. In addition, growth factor-dependent signals and alpha-, beta-integrin (ITGA, ITGB) heterodimer receptors functionally cooperate and integrate their signaling pathways. However, the precise role of integrins in EGF receptor (EGFR) activation in SCLC remains elusive. Methods: We analyzed human precision-cut lung slices (hPCLS), retrospectively collected human lung tissue samples and cell lines by classical methods of molecular biology and biochemistry. In addition, we performed RNA-sequencing-based transcriptomic analysis in human lung cancer cells and human lung tissue samples, as well as high-resolution mass spectrometric analysis of the protein cargo from extracellular vesicles (EVs) that were isolated from human lung cancer cells. Results: Our results demonstrate that non-canonical ITGB2 signaling activates EGFR and RAS/MAPK/ERK signaling in SCLC. Further, we identified a novel SCLC gene expression signature consisting of 93 transcripts that were induced by ITGB2, which may be used for stratification of SCLC patients and prognosis prediction of LC patients. We also found a cell-cell communication mechanism based on EVs containing ITGB2, which were secreted by SCLC cells and induced in control human lung tissue RAS/MAPK/ERK signaling and SCLC markers. Conclusions: We uncovered a mechanism of ITGB2-mediated EGFR activation in SCLC that explains EGFR-inhibitor resistance independently of EGFR mutations, suggesting the development of therapies targeting ITGB2 for patients with this extremely aggressive lung cancer type.

Computed Tomographic Evaluation of Cranial Suture Obliteration for Age Estimation in an Indian Population.

BACKGROUND: Age estimation is a critical aspect of human identification. Age is assessed using cranial suture obliteration, pelvic morphological changes, epiphyseal fusion of long bones, dental maturation, and other standard methods. METHODS: The present study investigated three-dimensional (3D) computed tomography (CT) scans of 263 individuals (183 males and 80 females) to assess the extent of ectocranial suture closure. The assessment of obliteration was done using a three-stage scoring method. Spearman's correlation coefficient (p < 0.05) was calculated to assess the relationship between cranial suture closure and chronological age. Simple and multiple linear regression models were developed using the cranial suture obliteration scores to estimate age. RESULTS: The standard errors of the estimate using multiple linear regression models developed for estimating age using obliteration scores of sagittal, coronal, and lambdoid sutures were 15.08 years in males, 13.27 years in females, and 14.74 years in the total study population. CONCLUSION: This study concludes that in the absence of additional skeletal age markers, this method can be used alone or in conjunction with other well-established methods of age assessment.

Fatal exsanguination following complete transection of femoral vessels due to angle grinder injury in an industrial accident.

Angle grinders are one of the most dangerous and frequently used tools in industrial settings. Angle grinder injuries range from superficial cuts to deep penetrating injuries with underlying fracture-dislocation and vascular trauma. The injuries caused by angle grinders mostly involve the head, face, or upper limbs, while the lower limb is an unusual site. The high-speed rotating disc of the angle grinders does not respect anatomical boundaries or structures; therefore, the injuries caused may be disfiguring, permanently incapacitating, or even fatal. We report a fatal case of an angle grinder injury to the lower limb. The victim sustained a sharp cut over the left thigh while woodworking in an industrial setup. The rotating disc of an angle grinder had transected the skin, subcutaneous fat and muscles, and both the femoral vessels of the left side, which led to fatal exsanguination within 10 min of the incident.

Knowledge, Attitude and Practices (KAP) of Medical Professionals on Euthanasia: A Study From a Tertiary Care Centre in India.

INTRODUCTION: Euthanasia or mercy killing has remained as a matter of extensive debate and ethical conflicts in the scientific literature. Discussions on this theme have got legal, religious, political and philosophical ramifications. AIM OF THE STUDY: The present study aimed to assess the knowledge, attitude and practices of medical professionals in a tertiary care hospital. METHODS: After taking prior approval from the institutional ethics committee a structured questionnaire was prepared and distributed among 200 consenting medical professionals in a tertiary care centre in the North-Western region of India. RESULTS: 50% of the respondents said that they were sure of the existing regulation on euthanasia in India. When gender differences were considered a significant difference (p=0.0147) was found between the two sexes regarding the alternate decision maker for deciding euthanasia. It was observed that there was a significant difference(p=0.0055) between those with the age more than 30 years and aged less than 30 years regarding the type of euthanasia that is justifiable. DISCUSSION: In the present study, the percentage of doctors favouring euthanasia is higher than compared in previous studies. The view of euthanasia is highly variable in different studies. Even though passive euthanasia has been legalised recently, there is an apprehension that it might be misused.

The Association of Improved Overall Survival with NSAIDs in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) are commonly used in the management of patients with advanced non-small cell lung cancer (NSCLC), but response is suboptimal. Preclinical data suggest ICI efficacy may be enhanced with concomitant nonsteroidal anti-inflammatory (NSAID) medications. PATIENTS AND METHODS: In this retrospective study, the Veterans Health Administration Corporate Data Warehouse was queried for patients diagnosed with NSCLC and treated with ICI from 2010 to 2018. Concomitant NSAID use was defined as NSAID dispensation by a VA pharmacy within 90 days of the any ICI infusion. To mitigate immortal time bias, patients who started NSAIDs 60 or more days after ICI initiation were excluded from analysis. Survival was measured from start of ICI. RESULTS: We identified 3634 patients with NSCLC receiving ICI; 2336 (64.3%) were exposed to concomitant NSAIDs. On multivariable analysis, NSAIDs were associated with better overall survival (HR = 0.90; 95% CI, 0.83-0.98; P = .010). When stratifying by NSAID type, diclofenac was the only NSAID with significant association with overall survival (HR = 0.75; 95% CI, 0.68-0.83; P < .001). Propensity score matching of the original cohort yielded 1251 patients per cohort balanced in characteristics. NSAIDs remained associated with improved overall survival (HR = 0.85; 95% CI, 0.78-0.92; P < .001). CONCLUSION: This study of Veterans with NSCLC treated with ICI demonstrated that concomitant NSAIDs are associated with longer OS. This may indicate that NSAIDs can enhance ICI-induced antitumor immunity and should prospectively validated.

Impact of concomitant fibrates on immunotherapy outcomes for advanced non-small cell lung cancer.

BACKGROUND: Peroxisome proliferator-activated receptor agonists such as fibrates restore oxidative metabolism in cytotoxic T-lymphocytes, thereby enhancing response to immune checkpoint inhibitors (ICI) in preclinical models. However, there is no evidence in humans on the clinical impact of fibrates as an adjunct to ICI. METHODS: In this cohort study of Veterans with non-small cell lung cancer (NSCLC) receiving ICI, fibrate exposure was defined as a prescription filled within 90 days of an ICI infusion. Overall survival (OS), measured from the start of ICI, was compared between exposed and unexposed Veterans. Cox multivariable analysis (MVA) was used to identify factors associated with OS. A sensitivity analysis of Veterans with stage IV NSCLC who received docetaxel without ICI was similarly performed. RESULTS: The ICI cohort included 3593 Veterans, of whom 301 (8.5%) coincidentally received a fibrate. Veterans receiving fibrates were more likely to be older, white, male, and married, and to have greater comorbidity burden, but less likely to receive chemotherapy. Coincidental fibrates were associated with improved OS both on MVA (HR 0.86, 95%CI 0.75-0.99) and in a matched subset (HR 0.75, 95%CI 0.63-0.90). In contrast, among the cohort of 968 Veterans treated with chemotherapy, fibrates did not have a significant impact on OS by MVA (HR 0.99, 95%CI 0.79-1.25) or in a matched subset (HR 1.02, 95%CI CI 0.75-1.39). CONCLUSIONS: Concomitant fibrates are associated with improved OS among NSCLC patients receiving ICI but not among those receiving chemotherapy. This hypothesis-generating observation supports a potential role for fibrates as an adjunct to immunotherapy.

Readily available drugs and other interventions to potentially improve the efficacy of immune checkpoint blockade in cancer.

To improve the efficacy of immune checkpoint inhibitors (ICIs) for cancer treatment, various strategies, including combination therapies with repurposed drugs, are being explored. Several readily available interventions with potential to enhance programmed death 1 (PD-1) blockade have been identified. However, these interventions often remain overlooked due to the lack of financial incentives for their development, making them financial orphans. This review summarizes current knowledge regarding off-label drugs, supplements, and other readily available interventions that could improve the efficacy of PD-1 blockade. The summary of each intervention includes the proposed mechanism of action for combination with checkpoint inhibitors and data from animal and human studies. Additionally, we include summaries of common interventions to be avoided by patients on PD-1 blockade. Finally, we present approaches for conducting further studies in patients, with the aim of expediting the clinical development of these interventions. We strive to increase awareness of readily available combination therapies that may advance cancer immunotherapy and help patients today.