Effect of abrocitinib on skin biomarkers in patients with moderate-to-severe atopic dermatitis.

BACKGROUND: This is the first report on the effects of abrocitinib, a Janus kinase 1-selective inhibitor, on the expression of skin biomarkers in patients with moderate-to-severe atopic dermatitis (AD). METHODS: JADE MOA (NCT03915496) was a double-blind Phase 2a trial. Adults were randomly assigned 1:1:1 to receive monotherapy with once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 weeks. The primary endpoint was change from baseline in markers of inflammation (matrix metalloproteinase [MMP]-12), epidermal hyperplasia (keratin-16 [KRT16]), T-helper 2 (Th2) immune response (C-C motif chemokine ligand [CCL]17, CCL18, and CCL26), and Th22 immune response (S100 calcium binding protein A8, A9, and A12 [S100A8, S100A9, and S100A12]) in skin through 12 weeks. RESULTS: A total of 46 patients received abrocitinib 200 mg (n = 14), abrocitinib 100 mg (n = 16), or placebo (n = 16). Abrocitinib improved AD clinical signs and reduced itch. Gene expression of MMP-12, KRT16, S100A8, S100A9, and S100A12 was significantly decreased from baseline with abrocitinib 200 mg (at Weeks 2, 4, and 12) and abrocitinib 100 mg (at Weeks 4 and 12) in a dose-dependent manner. Abrocitinib 200 mg resulted in significant decreases from baseline in CCL17 expression at Week 12 and CCL18 expression at Weeks 2, 4, and 12; no significant decreases were observed for CCL26. CONCLUSIONS: Alongside improvements in clinical signs and symptoms of AD, 12 weeks of abrocitinib treatment resulted in downregulation of genes associated with inflammation, epidermal hyperplasia, and Th2 and Th22 immune responses in the skin of patients with moderate-to-severe AD.

Multiparametric magnetic resonance imaging features of giant intracranial tuberculomas.

OBJECTIVES: To evaluate Magnetic Resonance Imaging (MRI) features of Giant Tuberculomas (GT) of the brain and deduce characteristic imaging phenotypes which may differentiate GT from higher grade glioma. METHODS: A retrospective analysis of MRI was done on Tuberculomas of size >2 cm. The diagnosis was established by histopathology or presumed from size reduction on follow-up MRI while on empirical anti-tubercular therapy (ATT). Multimodality characteristics of GT on T1/T2W, Fluid attenuation recovery (FLAIR), Diffusion-Weighted imaging (DWI), Susceptibility Weighted Imaging (SWI), Spectroscopy (MRS) and Perfusion weighted sequences were assessed. These imaging features were also evaluated in WHO Grade IV, IDH-wild type glioma (histopathologically and genetically proven) and a comparative analysis of the imaging features between GT and glioma was done. RESULTS: Thirty-two GT and 20 glioma were evaluated. Pronounced intralesional T2 hypointensity (n = 8;25%), T2 hyperintense crescent beneath the periphery (n = 25, 78.1%), T2W lamellated/whorled appearance (n = 17;53.125%), hyperintense rim on T1W MT (n = 25;78.1%), peripheral rim of diffusion restriction (n = 22; 68.75%), peripheral rim of blooming on SWI (n = 20, 62.5%), prominent lipid resonance on MR spectroscopy (n = 30; 93.75%), overshoot of the signal intensity-time curve above the base line (n = 9/10; 90%) on dynamic susceptibility contrast (DSC) perfusion, were remarkable imaging characteristics. Reduction of peripheral T1 hyperintensity, compaction of T2 hypointense core, expansion of sub-marginal T2 hyperintense rim and increased peripheral susceptibility (n = 20; 62.5%) during follow-up imaging, while on ATT, were standout features. GT could be differentiated from WHO grade IV (IDH-wild type) glioma on the basis of a significantly higher proportion of GTs showing a whorled/lamellated appearance, T1 hyperintense rim, T2 hypointense core, DWI-ADC mismatch, well-defined rim on SWI, prominent lipid peak on MRS and a submarginal T2 hyperintense rim. GT showed a higher normalized ADC ratio from the core as well as the rim. Significantly higher proportion of glioma showed a T1 hypointense and T2 hyperintense core and a nodular rim enhancement. A significantly higher r CBV, Choline to creatine, choline to NAA ratio and mean thickness of the peripheral enhancing rim were defining features among gliomas. CONCLUSION: Neuroimaging features of GT have been elucidated. Reduction of peripheral T1 hyperintensity, compaction of T2 hypointense core, expansion of sub-marginal T2 hyperintense rim, and increased peripheral susceptibility on follow-up may be considered imaging markers of response to anti-tubercular therapy. Multiparametric MRI features can differentiate GT from WHO grade IV (IDH-wild type) glioma.

A narrative review of gaps in the provision of integrated care for noncommunicable diseases in India.

BACKGROUND: Low- and middle-income countries (LMICs) account for a higher burden of noncommunicable diseases (NCD) and home to a higher number of premature deaths (before age 70) from NCDs. NCDs have become an integral part of the global development agenda; hence, the scope of action on NCDs extends beyond just the health-related sustainable development goal (SDG 3). However, the organization and integration of NCD-related health services have faced several gaps in the LMIC regions such as India. Although the national NCD programme of India has been in operation for a decade, challenges remain in the integration of NCD services at primary care. In this paper, we have analysed existing gaps in the organization and integration of NCD services at primary care and suggested plausible solutions that exist. METHOD: The identification of gaps is based out of a review of peer-reviewed articles, reports on national and global guidelines/protocols. The gaps are organized and narrated at four levels such as community, facility, health system, health policy and research, as per the WHO Innovative Care for Chronic Conditions framework (WHO ICCC). RESULT: The review found that challenges in the identification of eligible beneficiaries, shortage and poor capacity of frontline health workers, poor functioning of community groups and poor community knowledge on NCD risk factors were key gaps at the community level. Challenges at facility level such as poor facility infrastructure, lack of provider knowledge on standards of NCD care and below par quality of care led to poor management of NCDs. At the health system level, we found, organization of care, programme management and monitoring systems were not geared up to address NCDs. Multi-sectoral collaboration and coordination were proposed at the policy level to tackle NCDs; however, gaps remained in implementation of such policies. Limited research on the effect of health promotion, prevention and, in particular, non-medical interventions on NCDs was found as a key gap at the research level. CONCLUSION: This paper reinforces the need for an integrated comprehensive model of NCD care especially at primary health care level to address the growing burden of these diseases. This overarching review is quite relevant and useful in organizing NCD care in Indian and similar LMIC settings.

Designing a comprehensive Non-Communicable Diseases (NCD) programme for hypertension and diabetes at primary health care level: evidence and experience from urban Karnataka, South India.

BACKGROUND: India accounts for more than two-third of mortality due to non-communicable diseases (NCDs) in south-east Asia. The burden is high in Karnataka, one of the largest states in southern India. There is a need for integration of disease prevention, health promotion, treatment and care within the national program at primary level. A public-private partnership initiative explored evidence gaps to inform a health system based, integrated NCD programme across care continuum with a focus on hypertension and diabetes. METHODS: The study was conducted during 2017-18 in urban parts of Mysore city, covering a population of 58,000. Mixed methods were used in the study; a population-based screening to estimate denominators for those with disease and at risk; cross-sectional surveys to understand distribution of risk factors, treatment adherence and out of pocket expenses; facility audits to assess readiness of public and private facilities; in-depth interviews and focus group discussions to understand practices, myths and perceptions in the community. Chi-square tests were used to test differences between the groups. Framework analysis approach was used for qualitative analysis. RESULTS: Twelve and 19% of the adult population had raised blood sugar and blood pressure, respectively, which increased with age, to 32 and 44% for over 50 years. 11% reported tobacco consumption; 5.5%, high alcohol consumption; 40%, inadequate physical activity and 81%, inappropriate diet consumption. These correlated strongly with elderly age and poor education. The public facilities lacked diagnostics and specialist services; care in the private sector was expensive. Qualitative data revealed fears and cultural myths that affected treatment adherence. The results informed intervention design across the NCD care continuum. CONCLUSIONS: The study provides tools and methodology to gather evidence in designing comprehensive NCD programmes in low and middle income settings. The study also provides important insights into public-private partnership driving effective NCD care at primary care level.

Metabolic syndrome and cardiovascular disease risk assessment among human immunodeficiency virus-infected individuals on antiretroviral therapy.

BACKGROUND: The association of cardiovascular risk with first-line antiretroviral therapy (ART) in Indians has been a matter of concern with the background of a high risk in South Asians. AIMS: This study aimed to compare metabolic syndrome and its components, dyslipidemia, insulin resistance, and cardiovascular risk among patients on first-line ART (Group 1) with age-matched, ART-naïve human immunodeficiency virus (HIV)-infected patients (Group 2) and normal controls (Group 3). METHODS: Patients attending a tertiary care center in Mysore were enrolled in the study after obtaining informed consent and controls were chosen from relatives of patients. RESULTS: The total number of patients enrolled in the study was 217 (males 111; females 106), and the mean age of these patients was 34.1 ± 7.4 years. The number of patients in Group 1 (HIV+, ART experienced) was 76; in Group 2 (HIV+, ART naïve) was 71, and in Group 3 (HIV-) was 70. There was no statistically significant difference in the prevalence of metabolic syndrome between the three groups. On comparing the components of metabolic syndrome, serum triglycerides (mg/dl) were significantly higher in the ART group (Group 1: 149.5 [interquartile range (IQR): 84-187], Group 2: 108 [IQR: 74-152], and Group 3: 141.5 [IQR: 89-192]; P = 0.014) and serum high-density lipoprotein cholesterol was higher in HIV-uninfected individuals (Group 1: 37.5 ± 11.83, Group 2: 31.5 ± 12.23, and Group 3: 40.1 ± 12.09; P = 0.0002). There was no association between metabolic syndrome, duration of HIV, and type of first-line ART. Total and low-density lipoprotein (LDL) cholesterol were significantly higher in the ART group. Homeostatic model assessment and Framingham scores did not reveal any significant difference across the three groups. CONCLUSION: HIV-infected individuals on ART had higher levels of triglycerides, LDL, and total cholesterol, but no increased cardiovascular risk compared to other groups.

A history of hookworm vaccine development.

The human hookworms Necator americanus and Ancylostoma duodenale remain among the most common infections of humans in areas of rural poverty in the developing regions of the world, with an estimated 1 billion people infected with one or more of these parasites. Herein, we review the nearly 100 years of research, development, animal testing, and fieldwork that have led to our current progress in recombinant hookworm vaccines. We begin with the identification of hookworm at the start of the 20th century in Southern US, then discuss the progress in developed countries to eliminate human hookworm infection, and then the industrial development and field use in the 1970s a canine hookworm vaccine(Ancylostoma caninum), and finally our progress to date in the development and clinical testing of an array of recombinant antigens to prevent human hookworm disease from N. americanus infection. Special attention is given to the challenges faced in the development of a vaccine against a blood-feeding nematode, including the epidemiology of infection (high prevalence of infection), pathogenesis (chronic infection that increases with the age of the host), and a robust immune response that fails to confer the protection in the host and a concomitant absence of correlates of protection by a successful vaccine could be developed and tested. Finally, we provide the optimal and acceptable profiles of a human hookworm vaccine, including the proposed indication, target population, and route of administration, as developed by the Human Hookworm Vaccine Initiative, the only group currently working on vaccines targeting this parasite.

A comparative evaluation of thoracic and lumbar epidural fentanyl for post thoracotomy pain.

Thirty patients undergoing closed mitral valvotomy were prospectively randomised to receive either thoracic or lumbar epidural catheter. General anaesthesia consisted of morphine sulphate 0.15 mg/kg (single dose given before skin incision), thiopentone sodium 4-6 mg/kg, vecuronium and halothane titrated to stable haemodynamics. In the immediate postoperative period, pain was assessed by VAS (visual analogue scale) and VRS (verbal ranking score) and an epidural fentanyl bolus of 1.5 microg/kg was given followed by an infusion of 0.4 microg/kg/hr. Pain was assessed after 30 min and if pain relief was still inadequate, another fentanyl bolus of 1 microg/kg was administered, followed by an increase in infusion rate to 0.6 microg/kg/hr. If two consecutive pain scores were satisfactory (VAS <4, VRS <1) maintenance dose of fentanyl was decreased by 0.2 microg/kg/hr. Thoracic group received significantly less total dose of fentanyl in 24 hrs period (446.7 +/- 101.70 microg) compared with the lumbar group (705.33 +/- 181.03 microg) (p<0.01). The mean infusion rate was also significantly less in the thoracic group as compared with the lumbar group (0.44 +/- 0.08 microg/kg/hr vs 0.61 +/- 11 microg/kg/hr, p<0.001). The side effects were comparable between both the groups and none of the patients had significant respiratory depression. The data suggest that thoracic epidural fentanyl infusion is superior to lumbar infusion for post thoracotomy pain relief because of smaller dose requirement.