Immune checkpoint therapy-current perspectives and future directions.

Immune checkpoint therapy (ICT) has dramatically altered clinical outcomes for cancer patients and conferred durable clinical benefits, including cure in a subset of patients. Varying response rates across tumor types and the need for predictive biomarkers to optimize patient selection to maximize efficacy and minimize toxicities prompted efforts to unravel immune and non-immune factors regulating the responses to ICT. This review highlights the biology of anti-tumor immunity underlying response and resistance to ICT, discusses efforts to address the current challenges with ICT, and outlines strategies to guide the development of subsequent clinical trials and combinatorial efforts with ICT.

Histone lactylation drives CD8+ T cell metabolism and function.

The activation and functional differentiation of CD8+ T cells are linked to metabolic pathways that result in the production of lactate. Lactylation is a lactate-derived histone post-translational modification; however, the relevance of histone lactylation in the context of CD8+ T cell activation and function is not known. Here, we show the enrichment of H3K18 lactylation (H3K18la) and H3K9 lactylation (H3K9la) in human and mouse CD8+ T cells, which act as transcription initiators of key genes regulating CD8+ T cell function. Further, we note distinct patterns of H3K18la and H3K9la in CD8+ T cell subsets linked to their specific metabolic profiles. Additionally, we find that modulation of H3K18la and H3K9la by targeting metabolic and epigenetic pathways influence CD8+ T cell effector function, including antitumor immunity, in preclinical models. Overall, our study uncovers the potential roles of H3K18la and H3K9la in CD8+ T cells.

Health systems research in burn care: an evidence gap map.

BACKGROUND: Burn injury is associated with significant mortality and disability. Resilient and responsive health systems are needed for optimal response and care for people who sustain burn injuries. However, the extent of health systems research (HSR) in burn care is unknown. This review aimed to systematically map the global HSR related to burn care. METHODS: An evidence gap map (EGM) was developed based on the World Health Organization health systems framework. All major medical, health and injury databases were searched. A standard method was used to develop the EGM. RESULTS: A total of 6586 articles were screened, and the full text of 206 articles was reviewed, of which 106 met the inclusion criteria. Most included studies were cross-sectional (61%) and were conducted in hospitals (71%) with patients (48%) or healthcare providers (29%) as participants. Most studies were conducted in high-income countries, while only 13% were conducted in low-and middle-income countries, accounting for 60% of burns mortality burden globally. The most common health systems areas of focus were service delivery (53%), health workforce (33%) and technology (19%). Studies on health policy, governance and leadership were absent, and there were only 14 qualitative studies. CONCLUSIONS: Major evidence gaps exist for an integrated health systems response to burns care. There is an inequity between the burden of burn injuries and HSR. Strengthening research capacity will facilitate evidence-informed health systems and policy reforms to sustainably improve access to affordable, equitable and optimal burn care and outcomes.

Diseases and Disparities: The Impact of COVID-19 Disruptions on Sexual and Reproductive Health Services Among the HIV Community in India.

People with HIV navigate numerous challenges to access healthcare in India. The lockdown in response to the COVID-19 pandemic presents further challenges in accessing sexual and reproductive health (SRH) services. This research explored the impact of the pandemic on SRH services, and the depth of disruptions faced by people living with HIV (PLHIV) in accessing treatment. Using purposive sampling with maximum variation technique, we recruited and conducted 150 telephonic in-depth interviews with PLHIV and HIV care providers (HCPs) from five states in India (Karnataka, Tamil Nadu, Maharashtra, Andhra Pradesh, and Telangana). The interviews were recorded, transcribed, coded, and analyzed using interpretative phenomenological analysis. Five main themes were identified: the effect of COVID-19 on (1) access to care, (2) quality of care, (3) social determinants of health, (4) system and community resilience, and (5) support required to address population-specific vulnerabilities. Despite the availability of free government treatment services during the pandemic, profound disruptions in the SRH services, particularly antiretroviral therapy and HIV care, were reported by PLHIV and HCPs. This qualitative study revealed how existing inequities in HIV treatment and care are exacerbated by the pandemic. These findings highlight that the pandemic response should be community-centered to prevent extreme disruptions in healthcare which will have a disastrous effect on the lives of PLHIV.

Molecular Interaction between Distal C-Terminal Domain of the CB1 Cannabinoid Receptor and Cannabinoid Receptor Interacting Proteins (CRIP1a/CRIP1b).

We have investigated the structure of the distal C-terminal domain of the of the CB1 cannabinoid receptor (CB1R) to study its interactions with CRIP1a and CRIP1b using computational techniques. The amino acid sequence from the distal C-terminal domain of CB1R (G417-L472) was found to be unique, as it does not share sequence similarity with other protein structures, so the structure was predicted using ab initio modeling. The computed model of the distal C-terminal region of CB1R has a helical region between positions 441 and 455. The CRIP1a and CRIP1b were modeled using Rho-GDI 2 as a template. The three-dimensional model of the distal C-terminal domain of the CB1R was docked with both CRIP1a as well as CRIP1b to study the crucial interactions between CB1R and CRIP1a/b. The last nine residues of CB1R (S464TDTSAEAL4722) are known to be a CRIP1a/b binding site. The majority of the key interactions were identified in this region, but notable interactions were also observed beyond theses nine residues. The multiple interactions between Thr418 (CB1R) and Asn61 (CRIP1a) as well as Asp430 (CB1R) and Lys76 (CRIP1a) indicate their importance in the CB1R-CRIP1a interaction. In the case of CRIP1b, multiple hydrogen bond interactions between Asn437 (CB1R) and Glu77 (CRIP1b) were observed. These interactions can be critical for CB1R's interaction with CRIP1a/b, and targeting them for further experimental studies can advance information about CRIP1a/b functionality.

Examining representation of women in leadership of professional medical associations in India.

Women constitute 70% of the global health workforce but are significantly underrepresented in leadership positions. In India, professional medical associations (PMAs) play a crucial role in shaping policy agenda in the health sector, but very little is known about gender diversity in their leadership. Therefore, we analysed the gender representation of current and past leaderships of Indian PMAs. Data of the current and past national leadership and leadership committees of 46 leading PMAs representing general, specialities, and super-specialities were extracted from their official websites. Gender composition of leadership was analysed using a sequential approach. For Indian Medical Association (IMA), the largest Indian PMA, an analysis of its 32 sub-chapters was also undertaken. The findings revealed that only 9 (19.5%) out of 46 associations are currently led by a woman. Leadership committees of half the associations have less than 20% women, while there were no women in the central committee of nine PMAs. Among past presidents, information was publicly available for 31 associations and all of them have had less than 20% of women presidents till date. Among the 64 individuals currently serving as presidents and secretaries of 32 sub-chapters of IMA, only three (4.6%) are women. Even in associations closely related to women's health, such as obstetrics and gynecology, pediatrics, and neonatology, unequal representation persists, highlighting male dominance. These results demonstrate significant gender disparities in PMA leadership in India, necessitating urgent efforts to promote gender equality. Gender-transformative leadership is crucial to develop gender-sensitive health care policies and practices which can serve as a catalyst for broader societal change.

Histone Lactylation Drives CD8 T Cell Metabolism and Function.

The activation and functional differentiation of CD8 T cells are linked to metabolic pathways that result in the production of lactate. Lactylation is a lactate-derived histone post-translational modification (hPTM); however, the relevance of histone lactylation in the context of CD8 T cell activation and function is not known. Here, we show the enrichment of H3K18-lactylation (H3K18la) and H3K9-lactylation (H3K9la) in human and murine CD8 T cells which act as transcription initiators of key genes regulating CD8 T cell phenotype and function. Further, we note distinct impacts of H3K18la and H3K9la on CD8 T cell subsets linked to their specific metabolic profiles. Importantly, we demonstrate that modulation of H3K18la and H3K9la by targeting metabolic and epigenetic pathways regulates CD8 T cell effector function including anti-tumor immunity in preclinical models. Overall, our study uncovers the unique contributions of H3K18la and H3K9la in modulating CD8 T cell phenotype and function intricately associated with metabolic state.

Delusional parasitosis: A case series.

Delusional parasitosis (DP) is an infrequent psychotic illness, where the patient has a false but firm belief that his body is infested with parasites. It can be primary or secondary. Usually, these patients consult nonpsychiatric specialties from where they are referred to psychiatry. The presentation of DP varies among patients, although it typically manifests as a crawling and pinpricking sensation. Hallucinations are commonly seen. Antipsychotics show good remission of symptoms. A series of seven cases of DP have been described, and the condition is briefly discussed.

Myeloid-specific KDM6B inhibition sensitizes glioblastoma to PD1 blockade.

Glioblastoma (GBM) tumors are enriched in immune-suppressive myeloid cells and are refractory to immune checkpoint therapy (ICT). Targeting epigenetic pathways to reprogram the functional phenotype of immune-suppressive myeloid cells to overcome resistance to ICT remains unexplored. Single-cell and spatial transcriptomic analyses of human GBM tumors demonstrated high expression of an epigenetic enzyme-histone 3 lysine 27 demethylase (KDM6B)-in intratumoral immune-suppressive myeloid cell subsets. Importantly, myeloid cell-specific Kdm6b deletion enhanced proinflammatory pathways and improved survival in GBM tumor-bearing mice. Mechanistic studies showed that the absence of Kdm6b enhances antigen presentation, interferon response and phagocytosis in myeloid cells by inhibition of mediators of immune suppression including Mafb, Socs3 and Sirpa. Further, pharmacological inhibition of KDM6B mirrored the functional phenotype of Kdm6b-deleted myeloid cells and enhanced anti-PD1 efficacy. This study thus identified KDM6B as an epigenetic regulator of the functional phenotype of myeloid cell subsets and a potential therapeutic target for enhanced response to ICT.

The Utility of Abdominal Ultrasound Following Negative Computed Tomography in Diagnosing Acute Pancreatitis.

Aim Acute pancreatitis is a diagnosis established by fulfillment of at least two out of three clinical features, including epigastric pain, elevated lipase, and/or radiographic evidence of acute pancreatitis. Computed tomography of the abdomen and pelvis (CTAP) is the gold standard imaging modality for evaluating acute pancreatitis. Although abdominal ultrasound (AUS) is increasingly utilized given the widespread availability and high sensitivity and specificity for detecting gallstone-related complications, including gallstone pancreatitis, the leading cause of acute pancreatitis in the US. However, recent literature has concluded that performing AUS following a negative CTAP rarely led to changes in management and imparted an increased length of service (LOS) in the ED. Our study investigated whether a similar relationship was observed when managing acute pancreatitis in the inpatient setting. We aimed to quantify how performing AUS influenced inpatient LOS for patients admitted for acute pancreatitis without radiographic evidence of acute pancreatitis on CTAP. We also aimed to quantify how AUS influenced the likelihood of subsequent intervention via endoscopic retrograde cholangiopancreatography (ERCP) or cholecystectomy, including the relative impact of certain demographic or clinical features. Methods A retrospective analysis was performed using a cohort of 6069 patient encounters extracted via the HCA Healthcare enterprise data warehouse (EDW) database. Inclusion criteria were all adult patients with an index admission for acute pancreatitis between January 1 and December 31, 2019, who underwent CTAP during admission. Patients younger than 18 years, with prior cholecystectomy, or without documentation of demographic or clinical data of interest were excluded. The primary outcome was to quantify how performing AUS within 48 hours impacted LOS for patients admitted for acute pancreatitis following negative CTAP. Secondary outcomes examined whether AUS changed management (i.e., per likelihood of subsequent ERCP or cholecystectomy). This included determining the influence of various demographic or clinical characteristics on the likelihood of intervention via ERCP or cholecystectomy. Linear regression was used to determine the effect of performing AUS on the duration of LOS. Logistic regression was used for covariate analysis based on demographic (BMI, sex, race, age) and clinical data (comorbid conditions, abnormal labs, and vital signs). Results Patients with acute pancreatitis who underwent AUS within 48 hours had a reduced LOS of 1.099 days. Patients who underwent AUS were 1.126 times more likely to undergo subsequent ERCP than those who received CTAP alone. Patients who received AUS following CTAP were also 2.711 times more likely to undergo subsequent cholecystectomy. Increasing age and BMI were correlated with an increased likelihood of ERCP and cholecystectomy. Males were less likely to undergo cholecystectomy (OR = 0.753) and ERCP (OR = 0.815) compared to females. Conclusion Performing AUS within 48 hours following negative CTAP in this cohort of patients admitted for acute pancreatitis was associated with a decreased LOS. Furthermore, patients who underwent AUS were more likely to undergo ERCP and even more likely to undergo cholecystectomy. The likelihood of ERCP and cholecystectomy increased proportionally to both age and BMI. Females were more likely than males to undergo subsequent ERCP or cholecystectomy.

Fostering Resilient Health Systems in India: Providing Care for PLHIV Under the Shadow of COVID-19.

Introduction: The novel coronavirus or COVID-19 has resulted in major human casualties, and extreme socio-economic crises causing catastrophic disturbances to health systems and communities alike. This study qualitatively explores the challenges experienced by healthcare providers while providing services to people living with HIV (PLHIV) during the pandemic outbreak and subsequent lockdown in India. The paper also explores strategies developed and adopted to provide continued care for PLHIV. Methods: Using an empirical phenomenological approach, qualitative in-depth telephonic interviews were conducted with 19 HIV care providers from five states in India. The recorded interviews were transcribed and analyzed using inductive thematic analysis with the help of Dedoose software. Results: From the analysis of participants' narratives, three main themes emerged: (1) Challenges of working during a pandemic; (2) Remodeling care delivery to ensure continuity of services; (3) Resilience. Discussion: Our findings highlight the challenges that providers faced, despite which, adaptive efforts were made to continue providing quality care for PLHIV through ingenious and innovative strategies. To foster resilient health systems, health workers are the primary stakeholders. We recommend formal social protection, comprehensive primary healthcare support, and sufficient capacity building for health workers for their self-care and pandemic preparedness.

Voriconazole Induced Cutaneous Squamous Cell Carcinoma in an Immunocompetent Patient.

Voriconazole therapy can be associated with hair loss, vision changes, and skin phototoxicity, but rarely is it associated with the development of skin cancer. We present a case of an immunocompetent 42-year-old Caucasian male with a past medical history significant for chronic pulmonary aspergillosis (CPA) and prior cutaneous squamous cell carcinoma (cSCC) of the left hand who arrived at our clinic for evaluation of an enlarging, non-tender left preauricular mass over the past six months. He had diffuse actinic changes and appeared older relative to his age. He had a fair complexion but was compliant with sun protection measures and minimized unnecessary ultraviolet (UV) light exposure. His left-sided facial mass was excised, and the final pathology was consistent with cSCC. His only home medication was oral voriconazole 200 mg once daily for six years for pulmonary aspergillosis. He was negative for human immunodeficiency virus (HIV) and had no history of prior transplant operations. This case highlights the importance of recognizing voriconazole as an independent risk factor in the development of cSCC, especially in patients on chronic therapy for aspergillosis.

Gastric Antral Diverticula: A Rare Diverticula with a Unique Presentation.

Gastric diverticula are the least common gastrointestinal diverticula. Patients can be diagnosed incidentally on EGD or present with variable symptoms such as abdominal fullness, anorexia, and perforation. Gastric diverticula can be acquired from malignancy, peptic ulcer disease, or prior surgery or be congenital. Treatment varies based on symptomatology ranging from conservative medical management with proton pump inhibitors to surgical treatment with open or laparoscopic resection. We present a case of a 73-year-old female with acquired gastric diverticulum presenting as a gastric outlet obstruction who was successfully treated with conservative medical therapy.

Intestinal Dysbiosis Disguised as a Rectal Fistula Treated With Autologous Fecal Microbiota Transplantation.

Fecal microbiota transplantation (FMT) has been efficacious in the treatment of intestinal dysbiosis, derangement of the native intestinal microflora, and the indications for autologous FMT are growing. A 69-year-old Caucasian man with a past medical history of paraplegia secondary to motor vehicle accident and sigmoid-end colostomy presented to his gastroenterologist with the complaint of rectal discharge. A complicated medical course pre-dated his presentation and included multiple decubitus ulcers requiring debridement and several courses of broad-spectrum antibiotics. The rectal discharge was initially presumed to be from a fistula leading to one of his ulcers; however, workup with anoscopy, flexible sigmoidoscopy, and magnetic resonance imaging of the pelvis showed no visible perirectal abscess or connection to the sigmoid colon through a fistula. Intestinal dysbiosis was an alternative theory considered to be the cause of his copious rectal discharge due to his several courses of broad-spectrum antibiotics and prolonged inactivity of his gut. This prompted a trial treatment plan utilizing autologous FMT, with the patient administering enemas containing his own stool to the distal limb of his bowel. As a result of this treatment, the patient's chief complaint completely resolved within days of initiating treatment, although symptoms did eventually return. We would like to propose that further randomized studies should be done to investigate autologous FMT as a treatment for patients suffering from intestinal dysbiosis following sigmoid-end colostomy.

Rapid severe sepsis from Pseudomonas fluorescens/putida bacteremia due to skin and soft tissue infection - A case report.

INTRODUCTION: Pseudomonas fluorescens (P. fluorescens) and Pseudomonas putida (P. putida) are uncommon causes of skin and soft tissue infections (SSTIs). They are rarely associated with bacteremia and fatality. When presenting with sepsis/shock, patients are usually immunocompromised. Our case highlights the importance of early recognition, source control and antimicrobial choice. CASE PRESENTATION: We present a case of an immunocompetent 57 year old female who presented with rapidly progressive septic shock in the setting of P. fluorescens/putida bacteremia. The patient continued to deteriorate despite empiric antimicrobial coverage and aggressive source control. CLINICAL DISCUSSION: P. putida and P. fluorescens are gram negative bacillus bacteria that are ubiquitous in soil and water however have been reported as an opportunistic human pathogen capable of causing nosocomial infection especially in immunocompromised patients. Patients with bacteremia and shock should initially be covered with broad antimicrobial coverage for gram positive, gram negative as well as gas producing organisms and deescalate based on cultures and sensitivities. Along with antibiotics, aggressive source control is found to be the key to successful treatment in these patients. CONCLUSION: Our case highlights an immunocompetent patient with rapid progressive sepsis and associated multisystem organ failure. We emphasize the importance of early recognition in these patients and treatment with appropriate antimicrobial therapy followed by source control.

Newly acquired factor VIII deficiency in a male Ex-smoker - A case report.

INTRODUCTION: Acquired hemophilia A (AHA) also known as acquired factor VIII (FVIII) deficiency is an acquired inhibition of coagulation by antibodies that either inhibit the activity or increase the clearance of a clotting factor (FVIII). Mortality in patients presenting with AHA is related to bleeding and hemorrhage, therefore rapid diagnosis and effective treatment are needed. CASE PRESENTATION: We present a case of a 59-year-old male with acquired VIII deficiency presenting with diffuse ecchymosis and bleeding diathesis. The patient was treated successfully with steroids and rituximab. CLINICAL DISCUSSION: It is a rare autoimmune disorder caused by neutralization of Factor VIII by IgG antibodies. This can lead to severe, life threatening bleeding. Treatment involves replacement of FVIII and immunosuppression. CONCLUSION: A key point to successfully treating AHA is to remove inhibitors and stop bleeding. Mortality in patients presenting with AHA is related to the bleeding and hemorrhage, therefore rapid diagnosis and effective treatment are needed.

Impact of COVID-19 on obsessive-compulsive disorder: A case series.

A public health emergency of international concern, novel coronavirus disease (COVID-19), began in Wuhan, China, in December 2019. Since then, it has been caused a pandemic along with serious mental health problems. No other disorder is more vulnerable to the current situation than obsessive-compulsive disorder (OCD). Our case series focuses on the effects of COVID-19 on OCD along with its various manifestations. Most of our patients had exacerbated symptoms during the current situation, but there were also new onset OCD cases triggered by a variety of stressors.

Management of psychotic and mood disorders in intellectual disability: A case series.

People with intellectual disability (ID) have a greater frequency of psychiatric illnesses, ranging from 10% to 80%, as compared to the general population. It has been proven that mood stabilizers are beneficial in the management of behavior issues in people with ID. Here, we report a series of five cases with mild and moderate ID with behavioral disturbances including mood and psychotic symptoms managed successfully with sodium valproate as the part of the treatment.

A Retrospective Review of Upper Gastrointestinal Bleed Outcomes During Hospital Admission While on Oral Anticoagulation.

Introduction Direct-acting oral anticoagulants (DOACs) are approved for stroke prevention in non-valvular atrial fibrillation and treatment of venous thromboembolism. Most recent guidelines recommend DOACs over warfarin for most diagnoses given their predictable pharmacodynamics, lack of required monitoring, and safety profile. Specific outcomes such as shock, acute renal failure, and blood transfusion requirement while on oral anticoagulation compared to no anticoagulation remain unknown in patients with upper gastrointestinal (GI) bleeds.  Methods This retrospective study used the HCA Healthcare Enterprise Data Warehouse (EDW) to analyze 13,440 patients aged >18 years that were admitted with an upper GI bleed from January 2017 to December 2019. The patients were categorized based on oral anticoagulant (i.e. rivaroxaban, apixaban, dabigatran and warfarin). The control group was patients admitted with an upper GI bleed not on oral anticoagulation. We evaluated the severity of upper GI bleeds while on oral anticoagulation based on the outcomes: mortality rate, length of stay, acute renal failure, shock, and need for packed red blood cell transfusions (pRBC). Comorbid conditions assessed were coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), heart failure (HF), atrial fibrillation (AF), venous thromboembolism (VTE), peripheral vascular disease (PVD), tobacco abuse, alcohol abuse, and chronic kidney disease (CKD). Home use of proton pump inhibitors (PPI), aspirin, and P2Y12 inhibitors were also evaluated.  Results Patients on a DOAC without home PPI have a mortality odds ratio of 3.066 with a confidence interval (CI) greater than 95% (1.48-6.26, p<0.05) compared to patients on a DOAC and home PPI. Patients on warfarin and no home PPI have a mortality odds ratio of 5.55 (95% CI (1.02-30.35), p<0.05) compared to those on warfarin with home PPI use. In the no anticoagulation group, those not on PPI have an odds ratio of 3.28 (95% CI (2.54-4.24), p<0.05) of death compared to home PPI use. There was no statistical difference in mortality between each DOAC and warfarin.  There was no difference in the presence of acute renal failure or shock when comparing each DOAC, warfarin, and no medication. For patients presenting with GI bleed, 0.8414 units of pRBC were transfused. Patients not on oral anticoagulation were found to have statistically significant decrease in pRBC transfusion if they did not report alcohol use, CKD, HF, AF, VTE, PVD. Patients on DOACs and alcohol use have an average pRBC transfusion count that is 0.922 units more than those without reported alcohol use (p=0.006). In the warfarin group, there was no statistical significance noted when comparing pRBC transfusions and also when comparing to baseline comorbidities. Conclusion The retrospective study leads us to conclude that overall, patients taking the DOACs or warfarin had no statistically significant increase in RBC transfusions, length of stay, shock, acute renal failure, or mortality rate compared to patients who were not on oral anticoagulation. Home PPI use was shown to lower odds of mortality in patients on anticoagulation who presented with upper GI bleeding. PPI use had no effect on the need for transfusion or length of stay in patients on anticoagulation. These results can help predict which patients are likely to have higher mortality based on the use of home PPIs.

Underrecognized Zieve's syndrome, A case report.

Zieve's syndrome (ZS) is a triad of hemolytic anemia, cholestatic jaundice and hyperlipidemia that presents in the setting of alcohol abuse and liver disease. ZS is not well known and remains underdiagnosed. We present a case of ZS in a 38-year-old female with a history of chronic alcohol abuse and pancreatitis to raise awareness of ZS. It is important for ZS to be recognized promptly to avoid unnecessary and possibly harmful interventions.