Blood-brain barrier disruption and edema formation due to prolonged starvation in wild-type mice.

INTRODUCTION: Different types of diseases have been treated by restricted caloric intake or fasting. Although during this long time, fasting protective measures, for example, supplements, are given to the patients to protect vital organs such as the liver and kidney, little attention is given to the brain. The current research aims to investigate hypoglycemia due to prolonged fasting disrupts blood-brain barrier (BBB) in mice. MATERIALS AND METHODS: Immunohistochemistry (IHC) and in situ hybridization (ISH) techniques were used to examine the expression of different genes. Evans blue extravasation and wet-dry technique were performed to evaluate the integrity of BBB and the formation of brain edema, respectively. RESULTS: We confirmed that hypoglycemia affected mice fasting brain by examining the increased expression of glucose transporter protein 1 and hyperphosphorylation of tau protein. We subsequently found downregulated expression of some genes, which are involved in maintaining BBB such as vascular endothelial growth factor (VEGF) in astrocytes and claudin-5 (a vital component of BBB) and VEGF receptor (VEGFR1) in endothelial cells by ISH. We also found that prolonged fasting caused the brain endothelial cells to express lipocalin-2, an inflammatory marker of brain endothelial cells. We performed Evans blue extravasation to show more dye was retained in the brain of fasted mice than in control mice as a result of BBB disruption. Finally, wet-dry method showed that the brain of prolonged fasted mice contained significantly higher amount of water confirming the formation of brain edema. Therefore, special attention should be given to the brain during treatment with prolonged fasting for various diseases. CONCLUSIONS: Our results demonstrated that hypoglycemia due to prolonged fasting disrupts BBB and produces brain edema in wild-type mice, highlighting the importance of brain health during treatment with prolonged fasting.

Exploring the gaps between training and expected job skills of public health graduates to identify: A way forward.

Objectives: To explore the non-alignment between what is taught in academic programmes for public health and what is actually needed or expected in the field. METHODS: The qualitative phenomenological study was conducted from October 2020 to April 2021 in Karachi after approval from the institutional ethics review board of Jinnah Sindh Medical University, Karachi. The sample comprised major stakeholders including representatives of public health institutions and organisations involved in the implementation of public health programmes. Data was collected through in-depth interviews and focus group discussions using a guide after content validation by an expert. Data was analysed using both inductive and deductive approaches. RESULTS: A total of 13 in-depth interviews and 5 focus group discussions were conducted. Regarding gaps in the process of curriculum development, 2 major concerns emerged; lack of comprehensive involvement of experts in different fields of public health in designing the curriculum, and the lack of incorporation of the feedback provided by students in revising the curriculum. Regarding the content of curriculum, three main themes emerged; theoretical nature of courses, lack of uniformity in all programmes, and poor local contextualisation. The casual approach of students and barriers faced by them in joining public health programmes also affected the quality of such programmes. CONCLUSIONS: Three broad areas of improvement were identified, which included improvement in curriculum, methods of learning, and improving students' approach.

Patient self-referral patterns in a developing country: characteristics, prevalence, and predictors.

BACKGROUND: Efficient healthcare delivery and access to specialized care rely heavily on a well-established healthcare sector referral system. However, the referral system faces significant challenges in developing nations like Bangladesh. This study aimed to assess self-referral prevalence among patients attending tertiary care hospitals in Bangladesh and identify the associated factors. METHODS: This cross-sectional study was conducted at two tertiary care hospital, involving 822 patients visiting their outpatient or inpatient departments. A semi-structured questionnaire was used for data collection. The patients' mode of referral (self-referral or institutional referral) was considered the outcome variable. RESULTS: Approximately 58% of the participants were unaware of the referral system. Of all, 59% (485 out of 822) of patients visiting tertiary care hospitals were self-referred, while 41% were referred by other healthcare facilities. The primary reasons for self-referral were inadequate treatment (28%), inadequate facilities (23%), critical cases (14%), and lack of expert physicians (8%). In contrast, institutional referrals were mainly attributed to inadequate facilities to treat the patient (53%), inadequate treatment (47%), difficult-to-treat cases (44%), and lack of expert physicians (31%) at the time of referral. The private facilities received a higher proportion of self-referred patients compared to government hospitals (68% vs. 56%, p < 0.001). Among patients attending the study sites through institutional referral, approximately 10% were referred from community clinics, 6% from union sub-centers, 25% from upazila health complexes, 22% from district hospitals, 22% from other tertiary care hospitals, and 42% from private clinics. Patients visiting the outpatient department (adjusted odds ratio [aOR] 3.3, 95% confidence interval [CI] 2.28-4.82, p < 0.001), residing in urban areas (aOR 1.29, 95% CI 1.04-1.64, p = 0.007), belonging to middle- and high-income families (aOR 1.34, 95% CI 1.03-1.62, p = 0.014, and aOR 1.98, 95% CI 1.54-2.46, p = 0.005, respectively), and living within 20 km of healthcare facilities (aOR 3.15, 95% CI 2.24-4.44, p-value < 0.001) exhibited a higher tendency for self-referral to tertiary care facilities. CONCLUSIONS: A considerable number of patients in Bangladesh, particularly those from affluent urban areas and proximity to healthcare facilities, tend to self-refer to tertiary care centers. Inadequacy of facilities in primary care centers significantly influences patients to opt for self-referral.

Assessment of clinical validity of KPG index for 3D classification of impacted maxillary canines by cone beam computed tomography in patients.

OBJECTIVES: The primary objective of this study was to assess the validity of the KPG index in predicting the difficulty of treatment involving impacted maxillary canines. The secondary objective was to assess the reliability and reproducibility of the index. MATERIALS AND METHODS: A retrospective study was conducted on 96 maxillary impacted canines (MIC) in 60 patients aged 13-35 years. Cone-beam computed tomography (CBCT) scans were used to predict the treatment difficulty of MIC using the KPG index. Patient case files were assessed for the actual difficulty encountered in treating MIC. Cohen's kappa correlation coefficient was used for intra-observer reliability and Kendell's W test was used for inter-observer reliability. Spearman's correlation coefficient test was used to assess the correlation between predicted and actual treatment. RESULTS: Easy and moderately difficult cases exhibited a moderate correlation between actual and predicted treatment outcomes, whereas difficult cases displayed a weak correlation. The perfect correlation was observed exclusively in extremely difficult cases. The intra-observer reliability for assessing CBCT scans using the KPG guide was found to be 0.88, and the inter-rater reliability was 0.94. CONCLUSION: The KPG index displayed 87%, 71%, 50% and 100% validity in easy, moderately difficult, difficult, and extremely difficult cases, respectively. This index showed good reliability and reproducibility. However, it is imperative to consider a multitude of other factors, including the patient's age, presence of associated root resorption in adjacent teeth, and duration of treatment, to make an informed decision between surgical exposure and extraction.

Effects of interval training on haemodynamic variables after coronary artery bypass graft: A meta-analysis.

Objective: To assess the combined impact of interval training programme on haemodynamic variables, specifically blood pressure and heart rate, in patients having undergone coronary artery bypass graft surgery. METHODS: The meta-analysis was conducted from October to December 2022, and comprised search on PubMed, MEDLINE, Web of Science, PeDro, EMBASE, Science Direct, Cochrane Central Register of Controlled Clinical Trials, Google Scholar and Scopus electronic databases by two researchers independently for literature published between 2009 and 2020 related to the effects of interval training on coronary artery bypass graft patients. Meta-analysis was then performed to analyse the effects of an interval training on systolic blood pressure, diastolic blood pressure, and heart rate. The meta-analysis was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. RESULTS: Of the 122 studies initially located, 7 were related to the effects of different forms of interval trainings and their impact on systolic and diastolic blood pressure of the patients, and 5 studies analysing the effects of interval trainings on heart rate. Interval training showed mild improvement in decreasing SBP compared to control groups. Standardized mean difference suggested an effect size of -0.226 in random effect model (I2=52.01; p=0.064). Similarly, a small effect size of 0.136 (I2=39.19%, p=0.14) was observed for diastolic blood pressure. Also, there was a small effect size of 0.155 (I2= 28.08, p=0.23) observed for heart rate. Conclusion: Interval training programmes, including high-intensity interval training, low-volume interval training, and aerobic interval training, had a small effect on systolic blood pressure, whereas continuous training protocols had a similarly small effect size on diastolic blood pressure and heart rate.

Understanding ethics of reporting health related events in media: A qualitative phenomenological study in Karachi and Peshawar.

Objective: The specific objectives of this study were to identify the ethical issues in reporting of health-related events in media and suggest ways to improve it. Method: This was a qualitative phenomenological study conducted by APPNA Institute of Public Health, Jinnah Sindh Medical University in collaboration with Institute of Public Health, Khyber Medical University from January to April 2022. A total of 38 focus group discussions and in-depth interviews were conducted either face to face at place of convenience of interviewees or online. The participants were health reporters, healthcare workers (HCWs), and representatives of law enforcement agencies in two cities i.e., Karachi and Peshawar. Data were analyzed by using the deductive and inductive approaches, by four independent experts including the Principal Investigator (PI) and three research fellows. Results: Ethical issues related to health reporting in the field included interference of the reporters in rescue efforts during an emergency and interference in emergency medical care of the victims. In reporting, careless disregard for patient confidentiality and privacy; using unreliable sources of information; using wrong terminology; sensationalizing the news and jumping to conclusions in cases of malpractice were reported as main problems. Negative influences on health reporting included poor training of the reporters on health reporting ethics, organizational pressures, and lack of cooperation by relevant health authorities. Conclusion: The quality of health reporting can be improved by building the capacity of health reporters in understanding the ethical issues and their social responsibilities toward health.

A mixed methods systematic review of mental health self-care strategies for Arabic-speaking refugees and migrants.

BACKGROUND: Self-care strategies can improve mental health and wellbeing, however, the evidence on preferred strategies among Arabic-speaking refugees and migrants is unclear. This mixed methods systematic review aimed to identify and synthesise the global research on mental health self-care strategies used by these populations. METHODS: English and Arabic language studies reporting on positive mental health self-care strategies to address symptoms of posttraumatic stress disorder, generalised anxiety and depression in the target populations were identified by systematically searching eight electronic databases and grey literature. Studies were deemed eligible if they were published from 2000 onwards and included Arabic-speaking migrants, refugees or asylum seekers aged 12 years and above. A narrative synthesis of study characteristics and relevant key findings was undertaken. The review protocol was registered on PROSPERO (registration number CRD42021265456). RESULTS: Fifty-nine records reporting 57 studies were identified, the majority appearing after 2019. There were 37 intervention studies that incorporated a self-care component and 20 observational studies that reported on self-generated self-care practices. Across both study types, four broad groups of mental health self-care were identified-social, psychological, religious/spiritual, and other (e.g., expressive arts and exercise). Psychological strategies were the most reported self-care practice overall and featured in all intervention studies. Religious/spiritual and social strategies were more common in the observational studies. Intervention studies in diverse settings reported statistical improvements on a range of outcome measures. Observational studies reported a range of individual and community benefits. Linguistic, cultural and religious considerations, inherent in the observational studies, were variably addressed in the individual and group interventions. CONCLUSION: Overall, study participants experienced self-care as helpful although some encountered challenges in practicing their preferred strategies. Further research on mental health self-care strategies among Arabic-speaking refugees and migrants is needed in Western resettlement countries to guide mental health service delivery and primary healthcare initiatives for new arrivals and in transit countries.

Pseudo Primary Aldosteronism as Initial Presentation of Ectopic ACTH Syndrome in Metastatic Small Cell Lung Cancer.

Ectopic adrenocorticotropic hormone (ACTH)-secreting syndrome (EAS) is a rare but often aggressive paraneoplastic syndrome. Patients with EAS typically present with high ACTH levels and rapid clinical progression in the setting of acute cortisol elevation, which can delay diagnosis due to a lack of typical Cushingoid features. High levels of ACTH have also been shown to stimulate the adrenal zona glomerulosa to oversecrete aldosterone. We present the case of a 58-year-old male individual presenting with new-onset hypertension and severe metabolic alkalosis with spontaneous hypokalemia, in the setting of elevated aldosterone and low renin levels, suggestive of primary aldosteronism. Subsequent biochemical testing, imaging, and pathology, however, revealed suppression of aldosterone with evidence of hypercortisolism in the setting of metastatic small cell lung cancer. This was, therefore, suggestive of pseudo primary aldosteronism in the setting of a paraneoplastic ectopic ACTH-producing syndrome. This case highlights that hypercortisolism, in the setting of EAS, can initially present with a clinical picture suggestive of hyperaldosteronism. The use of a dexamethasone suppression test can allow the clinician to differentiate between idiopathic bilateral adrenal hyperplasia and ectopic ACTH syndrome.

Splenic Infarction in Acute Cytomegalovirus and Epstein-Barr Virus Concomitant Infection.

In immunocompetent individuals, cytomegalovirus (CMV) infection can range from asymptomatic to infectious mononucleosis syndrome and can cause hemolysis. However, in immunocompromised individuals, the presentation may be complicated with various life-threatening complications. CMV-associated thrombosis is commonly reported in patients who are immunocompromised, especially in transplant recipients and in HIV-positive patients. We present a case of a previously healthy 29-year-old male patient who suffered a splenic infarction. He presented with high temperature, general malaise, and left-sided abdominal pain. He was diagnosed with CMV and Epstein-Barr virus concomitant infection. Serological studies confirmed an acute CMV infection superimposed on a chronic EBV infection.

Improving Kyphotic Postures and Neck Pain in Young Adults: A Meta-Analysis of Exercise-Based Interventions.

The study aimed to review the findings concerning the effects of exercises on Cobb angle and pain in patients suffering from cervical pain caused by thoracic kyphosis. Two investigators separately conducted a systematic review of the electronic literature from 2018 till 2022. PubMed, MEDLINE, Web of Science, Science Direct, Cochrane Central Register of Controlled Clinical Trials, Google Scholar, and Scopus were among the electronic databases that were accessed. This meta-analysis included 5 studies, published between 2019 and 2022. A sample size of 261 patients; included in 5 studies were estimated on Cobb angle and pain. The between-groups pooled random SMD for Cobb angle and pain showed a larger effect size of -2.146 and -1.126, respectively. The findings suggested that physical therapy exercise may result in larger changes among the Cobb angle and neck pain of kyphotic patients. Key Words: Exercise, Physical therapy, Cobb angle, Pain, Thoracic kyphotic angle, Conservative management.

A scoping review on integrated health campaigns for immunization in low- and middle-income countries.

Health campaign integration is a key implementation strategy outlined by the World Health Organization to achieve universal health coverage. This scoping review synthesizes the evidence on Integrated Health Campaigns (IHC) in the field of immunization in low- and middle-income countries (LMICs) regarding the most common strategies, facilitators and barriers. Four reviewers followed a systematic approach to identify, screen and analyse relevant articles. The team used three search engines (PubMed, Scopus and Google Scholar) to identify peer-reviewed journal articles as well as select institutional websites for grey literature publications. Full-text articles using any study design and across any time frame were included. Data were extracted following a predefined matrix, analysed deductively and presented in a narrative synthesis. Thirty articles (20 academic and 10 grey) were included in the final review. All studies included identified IHCs as effective when planning or implementation is integrated. The common strategies were: using resources efficiently in remote locations; using national immunization days to maximize impact; targeting specific age groups by selecting intervention sites that are frequented by that age group; building community ownership over the integrated program; and integrating programs that already share common elements. The key facilitators were: closing the gap between services and communities; planning, coordination and resource management both before and during integration; cost-effectiveness; and utilization of pre-existing infrastructure. The common barriers included seemingly optimized initial cost to appear feasible only in the short term and additional responsibilities on the field staff. This review finds IHCs a common practice in immunization and identifies gaps in evidence on evaluation; indicating the need for additional research. Strong evidence accounts IHCs to increase coverage, improve community acceptance of health services and strengthen the community models of health service delivery.

Selective Blood Cell Hitchhiking in Whole Blood with Ionic Liquid-Coated PLGA Nanoparticles to Redirect Biodistribution After Intravenous Injection.

Less than 5% of intravenously-injected nanoparticles (NPs) reach destined sites in the body due to opsonization and immune-based clearance in vascular circulation. By hitchhiking in situ onto specific blood components post-injection, NPs can selectively target tissue sites for unprecedentedly high drug delivery rates. Choline carboxylate ionic liquids (ILs) are biocompatible liquid salts <100X composed of bulky asymmetric cations and anions. This class of ILs has been previously shown to significantly extend circulation time and redirect biodistribution in BALB/c mice post-IV injection via hitchhiking on red blood cell (RBC) membranes. Herein, we synthesized & screened 60 choline carboxylic acid-based ILs to coat PLGA NPs and present the impact of structurally engineering the coordinated anion identity to selectively interface and hitchhike lymphocytes, monocytes, granulocytes, platelets, and RBCs in whole mouse blood for in situ targeted drug delivery. Furthermore, we find this nanoparticle platform to be biocompatible (non-cytotoxic), translate to human whole blood by resisting serum uptake and maintaining modest hitchhiking, and also significantly extend circulation retention over 24 hours in BALB/c healthy adult mice after IV injection. Because of their altered circulation profiles, we additionally observe dramatically different organ accumulation profiles compared to bare PLGA NPs. This study establishes an initial breakthrough platform for a modular and transformative targeting technology to hitchhike onto blood components with high efficacy and safety in the bloodstream post-IV administration.

Sporadic Hemiplegic Migraine.

An uncommon presentation of a migraine headache is hemiplegic migraine, which can clinically imitate other conditions including transient ischemic attacks and stroke with unilateral muscle weakness or hemiplegia. We present a 46-year-old female patient who was admitted with symptoms of a unilateral occipital headache, dysphagia and left-sided motor weakness. Diffusion magnetic resonance imaging (MRI) and brain tomography results were normal. A diagnosis of sporadic hemiplegic migraine was made after extensive workup and managed conservatively with solumedrol. The patient was discharged on prednisone and tetrahydrozoline ophthalmic solution with a drastic improvement in symptoms. On a follow-up visit, there was a complete resolution of symptoms.

Validation of HF-Bioelectrical Impedance Analysis versus Body Mass Index in Classifying Overweight and Obese Pakistani Adults.

Purpose: To determine the validity of hand-to-foot bioelectrical impedance analysis (HF-BIA) versus body mass index (BMI) to assess overweight and obesity status in adults against a reference method, dual-energy x-ray absorptiometry (DXA). Patients and Methods: It is a validation study conducted on 206 Pakistani adults ≥20 years recruited through convenience sampling technique at PNS Shifa Hospital and Jinnah Post Medical Centre, Karachi, Pakistan. Results: HF-BIA showed better sensitivity of 90.1% and 100% specificity with no false positive, but 9% false negative as compared to BMI which indicated 80.3% sensitivity and 100% specificity with a false-negative rate of 19.6%.HF-BIA also showed better sensitivity 80.9-97.1% with 100% specificity and PPV across all age groups. The correlation coefficient between BMI and DXA bf% (r=0.67) was moderate and less than the correlation coefficient between HF-BIA and DXA bf % (r=0.87). Kappa agreement showed weak to a fair agreement between BMI and DXA bf % (0.1 overall; 0.22 men; 0.14 women) compared to HF-BIA, which had a better agreement between BIA bf% and DXA bf% (0.43 overall; 0.46 men; 0.34 women). HF-BIA bf % demonstrated a better discriminatory power than BMI (AUC of ≥0.91) and was better predictor of body fat than BMI. Conclusion: HF-BIA is a more accurate method than BMI and may be used consistently throughout the country in primary care and research to identify the fat-based overweight and obese in the Pakistani population.

Limiting spread of VIM-positive Pseudomonas aeruginosa from colonized sink drains in a tertiary care hospital: A before-and-after study.

BACKGROUND: In healthcare environments, sinks are being increasingly recognized as reservoirs for multidrug-resistant Gram-negative bacteria. In our hospital, carbapenemase-producing, Verona Integron-encoded Metallo-beta-lactamase (VIM)-positive Pseudomonas aeruginosa (VIM-PA) was detected at low endemicity in patients, and environmental culturing revealed that sink drains were primary reservoirs. Therefore, an intervention was initiated in several wards to install sink drain plugs as physical barriers against splashing to prevent transmission of VIM-PA from drain reservoirs to the surrounding sink environment. AIM: To assess the efficacy of the intervention on limiting spread of VIM-PA. METHODS: Swabs were taken from inner sink environments (i.e. drains), and outer sink environments (i.e. wash basins, faucet aerators, and countertops) twice before and three times after the intervention. Siphon water and drain wells were also sampled before and at the moment of the intervention, respectively. All samples were screened for VIM-PA, and isolates were typed with multiple-locus variable-number tandem repeat analysis (MLVA). RESULTS: There was a significant reduction in VIM-PA positivity in both inner (P-value <0.001) and outer (P-value 0.001) sink environments after the intervention. However, VIM-PA recolonization was observed in the inner sink environments of patient rooms, and also in rooms exclusive to healthcare personnel, over time. Surfaces in the outer sink environment were rarely positive for VIM-PA after the intervention. MLVA revealed three genetic clusters, with one found in all wards and room types during the study period. CONCLUSIONS: Drain plugs are a simple and effective infection prevention and control measure to contain spread of VIM-PA from drain reservoirs.

Evaluation of conditional cash transfers and mHealth audio messaging in reduction of risk factors for childhood malnutrition in internally displaced persons camps in Somalia: A 2 × 2 factorial cluster-randomised controlled trial.

BACKGROUND: Cash transfer programmes are increasingly used in humanitarian contexts to help address people's needs across multiple sectors. However, their impact on the key objectives of reducing malnutrition and excess mortality remains unclear. mHealth interventions show great promise in many areas of public health, but evidence for their impact on reducing the risk factors for malnutrition is uncertain. We therefore implemented a trial to determine the impacts of 2 interventions in a protracted humanitarian context, a cash transfer conditionality and mHealth audio messages. METHODS AND FINDINGS: A 2 × 2 factorial cluster-randomised trial was implemented in camps for internally displaced people (IDP) near Mogadishu, Somalia, starting in January 2019. The main study outcomes were assessed at midline and endline and included coverage of measles vaccination and the pentavalent immunisation series, timely vaccination, caregiver's health knowledge, and child diet diversity. Twenty-three clusters (camps) were randomised to receive or not receive conditional cash transfers (CCTs) and an mHealth intervention, and 1,430 households were followed up over 9 months. All camps received cash transfers made at emergency humanitarian level (US$70/household/month) for 3 months followed by a further 6 months at a safety net level (US$35). To be eligible to receive cash, households in camps receiving CCT were required to take their children <5 years age to attend a single health screening at a local clinic and were issued with a home-based child health record card. Participants in camps receiving the mHealth intervention were asked (but not required) to listen to a series of audio messages about health and nutrition that were broadcast to their mobile phone twice a week for 9 months. Participants and investigators were not blinded. Adherence to both interventions was monitored monthly and found to be high (>85%). We conducted intention-to-treat analysis. During the humanitarian intervention phase, the CCT improved coverage of measles vaccination (MCV1) from 39.2% to 77.5% (aOR 11.7, 95% CI [5.2, 26.1]; p < 0.001) and completion of the pentavalent series from 44.2% to 77.5% (aOR 8.9, 95% CI [2.6, 29.8]; p = < 0.001). By the end of the safety net phase, coverage remained elevated from baseline at 82.2% and 86.8%, respectively (aOR 28.2, 95% CI [13.9, 57.0]; p < 0.001 and aOR 33.8, 95% CI [11.0, 103.4]; p < 0.001). However, adherence to timely vaccination did not improve. There was no change in the incidence of mortality, acute malnutrition, diarrhoea, or measles infection over the 9 months of follow-up. Although there was no evidence that mHealth increased Mother's knowledge score (aOR 1.32, 95% CI [0.25, 7.11]; p = 0.746) household dietary diversity increased from a mean of 7.0 to 9.4 (aOR 3.75, 95% CI [2.04, 6.88]; p < 0.001). However, this was not reflected by a significant increase in child diet diversity score, which changed from 3.19 to 3.63 (aOR 2.1, 95% CI [1.0, 4.6]; p = 0.05). The intervention did not improve measles vaccination, pentavalent series completion, or timely vaccination, and there was no change in the incidence of acute malnutrition, diarrhoea, measles infection, exclusive breastfeeding, or child mortality. No significant interactions between the interventions were found. Study limitations included the limited time available to develop and test the mHealth audio messages and the necessity to conduct multiple statistical tests due to the complexity of the study design. CONCLUSIONS: A carefully designed conditionality can help achieve important public health benefits in humanitarian cash transfer programmes by substantially increasing the uptake of child vaccination services and, potentially, other life-saving interventions. While mHealth audio messages increased household diet diversity, they failed to achieve any reductions in child morbidity, malnutrition, or mortality. TRIAL REGISTRATION: ISRCTN ISRCTN24757827. Registered November 5, 2018.

Interval delivery of 5HT2A agonists using multilayered polymer films.

There is an urgent unmet medical need to develop therapeutic options for the ~50% of depression patients suffering from treatment-resistant depression, which is difficult to treat with existing psycho- and pharmaco-therapeutic options. Classical psychedelics, such as the 5HT2A agonists, have re-emerged as a treatment paradigm for depression. Recent clinical trials highlight the potential effectiveness of 5HT2A agonists to improve mood and psychotherapeutic growth in treatment-resistant depression patients, even in those who have failed a median of four previous medications in their lifetime. Moreover, microdosing could be a promising way to achieve long-term alleviation of depression symptoms without a hallucinogenic experience. However, there are a gamut of practical barriers that stymie further investigation of microdosing 5HT2A agonists, including: low compliance with the complicated dosing regimen, high risk of diversion of controlled substances, and difficulty and cost administering the long-term treatment regimens in controlled settings. Here, we developed a drug delivery system composed of multilayered cellulose acetate phthalate (CAP)/Pluronic F-127 (P) films for the encapsulation and interval delivery of 5HT2A agonists from a fully biodegradable and biocompatible implant. CAPP film composition, thickness, and layering strategies were optimized, and we demonstrated three distinct pulses from the multilayered CAPP films in vitro. Additionally, the pharmacokinetics and biodistribution of the 5HT2A agonist 2,5-Dimethoxy-4-iodoamphetamine (DOI) were quantified following the subcutaneous implantation of DOI-loaded single and multilayered CAPP films. Our results demonstrate, for the first time, the interval delivery of psychedelics from an implantable drug delivery system and open the door to future studies into the therapeutic potential of psychedelic delivery.

Reimagining diaspora diplomacy during the COVID-19 crisis in India.

Diasporas are organized groups motivated by common cultural, ideological, political and religious values and common concerns for their countries of origin. Diaspora diplomacy has gained prominence worldwide, particularly in India, spurred by harrowing images of deaths and devastation due to the COVID-19 pandemic. A new generation of diaspora professionals modeled as social entrepreneurs uses collaborative and non-profit models to establish relationships with their counterparts to facilitate medical services and research. Teleradiology and telepsychiatry facilitate communication between diaspora members and their counterparts. We propose a common telehealth platform to standardize advice given by the Indian diaspora in the Global North as protocols change rapidly in acute pandemics. Consideration should be given to the well-known digital divide in India and other low- and middle-income countries. We advocate for diaspora members to train themselves in the art of global health diplomacy, to promote transparency and accountability in the collection of funds and a mandatory provision of outcome measurement by independent monitors rather than through social media. In the long run, Indian-Americans should play an active role in strengthening the domain of public health, which has historically been neglected in India, by focusing on the country's long-term infrastructure needs. The lessons learned from various diaspora efforts should be independently evaluated and recorded as best practice for future pandemics and humanitarian crises.

Frequency Of CD34 Expression In Acute Lymphoblastic Leukaemia And Its Correlation With Clinicopathological Characteristics: A Single Centre Experience From Pakistan.

Background: This study was carried out to determine the frequency of CD34 positivity in acute lymphoblastic leukaemia (B-ALL) in our population and to report its association with the clinicopathological profile at the time of diagnosis. Methods: The cross-sectional study was conducted at National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan, from March 2020 till December 2020.Newly diagnosed patients were selected, from both genders and all age groups. Relevant history and findings of physical examination were recorded. Immunohistochemistry was done on trephine biopsy and molecular studies were carried on bone marrow aspirates or peripheral blood samples. Results: Out of 105 patients enrolled, 67 (63.8%) were males, with a male to female ratio (M: F) 1.8:1. Of the total patients, 62 (59.04%) were above 15 years of age. CD34 was expressed in 73 (69.5%) cases. Lymphadenopathy, splenomegaly, and hepatomegaly were separately noted in context to CD 34 expression in 22 (66.6%), 24 (64.8%), and 14 (58.3%) patients, respectively. CNS disease was seen in a total of 3(2.75%) subjects, in which 2 (66.6%) of the patients had CD34 expression. Total 81 patients in our study fall into the high-risk group out of which CD 34 expression was seen in 58(71.6%) subjects. Cytogenetic analysis, BCR-ABL p190, and MLL gene rearrangement were investigated in all participants. Cytogenetic analysis revealed an abnormality in 20 (19%) cases out of which 13 (17.8%) cases were from CD34 positive group. Conclusion: Our study reported CD34 expression in more than two-thirds of cases. High-risk disease was significantly associated with CD34 expression.

Dual-Responsive Glycopolymers for Intracellular Codelivery of Antigen and Lipophilic Adjuvants.

Traditional approaches to vaccines use whole organisms to trigger an immune response, but they do not typically generate robust cellular-mediated immunity and have various safety risks. Subunit vaccines composed of proteins and/or peptides represent an attractive and safe alternative to whole organism vaccines, but they are poorly immunogenic. Though there are biological reasons for the poor immunogenicity of proteins and peptides, one other key to their relative lack of immunogenicity could be attributed to the poor pharmacokinetic properties of exogenously delivered proteins and peptides. For instance, peptides often aggregate at the site of injection and are not stable in biological fluids, proteins and peptides are rapidly cleared from circulation, and both have poor cellular internalization and endosomal escape. Herein, we developed a delivery system to address the lack of protein immunogenicity by overcoming delivery barriers as well as codelivering immune-stimulating adjuvants. The glycopolymeric nanoparticles (glycoNPs) are composed of a dual-stimuli-responsive block glycopolymer, poly[2-(diisopropylamino)ethyl methacrylate]-b-poly[(pyridyl disulfide ethyl methacrylate)-co-(methacrylamidoglucopyranose)] (p[DPA-b-(PDSMA-co-MAG)]). This polymer facilitates protein conjugation and cytosolic release, the pH-responsive release of lipophilic adjuvants, and pH-dependent membrane disruption to ensure cytosolic delivery of antigens. We synthesized p[DPA-b-(PDSMA-co-MAG)] by reversible addition-fragmentation chain transfer (RAFT) polymerization, followed by the formation and physicochemical characterization of glycoNPs using the p[DPA-b-(PDSMA-co-MAG)] building blocks. These glycoNPs conjugated the model antigen ovalbumin (OVA) and released OVA in response to elevated glutathione levels. Moreover, the glycoNPs displayed pH-dependent drug release of the model hydrophobic drug Nile Red while also exhibiting pH-responsive endosomolytic behavior as indicated by a red blood cell hemolysis assay. GlycoNPs coloaded with OVA and the toll-like receptor 7/8 (TLR-7/8) agonist Resiquimod (R848) activated DC 2.4 dendritic cells (DCs) significantly more than free OVA and R848 and led to robust antigen presentation of the OVA epitope SIINFEKL on major histocompatibility complex I (MHC-I). In sum, the dual-stimuli-responsive glycopolymer introduced here overcomes major protein and peptide delivery barriers and could vastly improve the immunogenicity of protein-based vaccines.