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Momina Khalid,1 Hiba Khalid,2 Sameer Bhimani,1 Simran Bhimani,2 Sheharyar Khan,3 Erum Choudry,4 Syed Uzair Mahmood5 1Department of Internal Medicine, Sindh Medical College, Jinnah Sindh Medical University, Karachi, Pakistan; 2Department of Internal Medicine, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan; 3Department of Medicine, Baqai Medical University, Karachi, Pakistan; 4Indus Hospital Research Center, The Indus Hospital and Health Network, Karachi, Pakistan; 5Department of Medicine, Health and Life Sciences, Queen’s University Belfast, Belfast, UKCorrespondence: Hiba KhalidDow Medical College, Dow University of Health Sciences, Baba-e-Urdu Road, Saddar, Karachi, 74200, PakistanTel +923094379571Email hibakhalid60@gmail.comPurpose: During the timeline of twenty years, several epidemics and pandemics have occurred. Yet, a consistent feature of these public health crises is the surge in the demand for healthcare services exceeds the availability.Materials and Methods: A cross-sectional web-based survey was conducted in the month of June and July 2020 in Karachi, Pakistan. The study participants included doctors and medical students residing in Karachi.Results: Out of 187 doctors, 74.3% were working during the COVID-19 pandemic, of which 58.3% were willing to work. Out of 200 medical students, 93.5% were not volunteering during the COVID-19 pandemic, of which 46% were willing to volunteer. Doctors strongly agreed that they would be willing to work during the COVID-19 pandemic if they were healthy and able to do so (57.2%), if they were provided personal protective equipment (PPE) (51.3%), and if they were guaranteed coverage of treatment cost if they get infected while working (57.8%). Medical students strongly agreed that they would be willing to volunteer during the COVID-19 pandemic if they were provided PPE (49.0%), and if their parents were supportive of their decision to volunteer (44.5%). Most doctors (54.5%) felt that they were extremely likely to get infected while working during the COVID-19 pandemic and 59.4% felt that in turn, they were extremely likely to infect their families as well. Most medical students (40.5%) felt that they were somewhat likely to get infected while volunteering during the COVID-19 pandemic and 55.5% felt that in turn, they were extremely likely to infect their family as well. In the event of infection with COVID-19, 51.3% doctors and 42.0% medical students felt that they would recover without hospitalization.Conclusion: Since future pandemics are likely, we encourage health-care policymakers to utilize the findings of this study to create a sustainable pandemic response.Keywords: coronavirus disease 2019, SARS-CoV-2, physicians, risk, infection

Agricultural workers are essential to the supply chain for our daily food, and yet, many face harmful work conditions, including garnished wages, and other labor violations. Workers on H-2A visas are particularly vulnerable due to the precarity of their immigration status being tied to their employer. Although worksite inspections are one mechanism to detect such violations, many labor violations affecting agricultural workers go undetected due to limited inspection resources. In this study, we identify multiple state and industry level factors that correlate with H-2A violations identified by the U.S. Department of Labor's Wage and Hour Division using a multilevel zero-inflated negative binomial model. We find that three state-level factors (average farm acreage size, the number of agricultural establishments with less than 20 employees, and higher poverty rates) are correlated with H-2A violations. These findings offer valuable insights into where H-2A violations are being detected at the state and industry levels., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Jafari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Coronavirus disease (COVID-19) is a global health emergency, with well over six hundred million infections and over six million deaths to date. Besides other ramifications, it is also associated with inflammation and an augmented risk of thromboembolic complications. Despite this, the risks and benefits of antithrombotic drugs in patients with mild to moderate COVID-19 have not been well-established and remain controversial., Objectives: To evaluate the safety and efficacy of antithrombotic drugs on mild to moderate symptomatic COVID-19 patients by performing an updated systematic review and meta-analysis., Methods: We queried electronic databases (PubMed, Cochrane Central, Scopus, and Embase) from their inception up to September 2022 for randomized controlled trials comparing antithrombotic drugs against placebo. The outcomes of interest were the need for hospital care, mortality, and thromboembolic events in the enrolled participants. Dichotomous outcomes were presented as risk ratio (RR) with 95 % confidence intervals (CIs) and were consolidated using random-effects model., Main Results: Five eligible studies (Rivaroxaban/Apixaban, two; enoxaparin, two; Sulodexide, one), consisting of 2,005 participants with mild to moderate COVID-19, were included. Pooled results show that antithrombotics, when compared to placebo, do not significantly reduce all-cause mortality (RR 0.51, 95 % CI 0.15-1.68; P = 0.27; I 2  = 0), thromboembolic events (RR 0.78, 95 % CI 0.17-3.51; P = 0.74; I 2  = 0), need for hospitalization (RR 0.73, 95 % CI 0.51-1.03; P = 0.08; I 2  = 0), nor significantly increase clinically relevant non-major bleeding events (RR 2.36, 95 % CI 0.56-9.89; P = 0.24; I 2  = 0). However, when Sulodexide was compared independently to other antithrombotics, it significantly reduced the need for hospitalization (RR 0.60, 95 % CI 0.37-0.95; P = 0.03)., Conclusions: Our pooled analysis was not able to establish statistically significant benefits or risks of using antithrombotic drugs in mild to moderate COVID-19 patients. To further improve our understanding of the efficacy, safety and risk profile of such a therapy, large sample randomized clinical trials are required on a wide scale., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: This meta-analysis compares His-Purkinje system pacing (HPSP), a novel cardiac resynchronization therapy (CRT) technique that targets the intrinsic conduction system of the heart, with conventional biventricular pacing (BiVP) in heart failure (HF) patients with left ventricular (LV) dysfunction and dyssynchrony., Methods: We searched multiple databases up to May 2023 and identified 18 studies (five randomized controlled trials and 13 observational studies) involving 1291 patients. The outcome measures were QRS duration, left ventricular ejection fraction (LVEF) improvement, left ventricular end-diastolic diameter (LVEDD) change, HF hospitalization, and New York Heart Association (NYHA) functional class improvement. We used a random-effects model to calculate odds ratios (OR), and mean differences (MD) with 95% confidence intervals (CI). We also assessed the methodological quality of the studies., Results: The mean LVEF was 30.7% and the mean follow-up duration was 8.1 months. Among LBBP, HBP, and BiVP, HBP provided the shortest QRS duration [MD: -18.84 ms, 95% CI: -28.74 to -8.94; p = 0.0002], while LBBP showed the greatest improvement in LVEF [MD: 5.74, 95% CI: 2.74 to 7.46; p < 0.0001], LVEDD [MD: -5.55 mm, 95% CI: -7.51 to -3.59; p < 0.00001], and NYHA functional class [MD: -0.58, 95% CI: -0.80 to --0.35; p < 0.00001]. However, there was no significant difference in HF hospitalization between HPSP and BiVP., Conclusion: LBBP as modality of HPSP demonstrated superior outcomes in achieving electrical ventricular synchrony and systolic function, as well as alleviating HF symptoms, compared to other pacing techniques., (© 2023 Wiley Periodicals LLC.)

Background: Glaucoma is a leading cause of irreversible blindness globally and for decades, Molteno and Ahmed glaucoma implants, operating on different mechanisms, have been used to treat complicated glaucoma with varying success., Objective: To assess the safety and efficacy of the Molteno glaucoma implant (MGI) versus the Ahmed glaucoma valve (AGV) in patients with complicated glaucoma., Methods: We comprehensively searched PubMed, Google Scholar, Cochrane Library and Science Direct) from inception till July 2023 and studies comparing patients with MGI and those with AGV in patients with complicated glaucoma. The primary outcome was intra-ocular pressure reduction at different time intervals. Secondary outcomes included surgical success rate, hypertensive phase, anti-glaucoma medication (AGM) and total complications., Results: In this meta-analysis, four studies were included with a patient population of 257 with refractory, neovascular or advanced uncontrolled glaucoma. Postoperative intra-ocular pressure reduction did not show significant difference between the two groups (MD: -1.34, 95% CI [-2.78, 0.09]). From the secondary outcomes, surgical success rate (RR: 0.88, 95% CI [0.51,1.53]), hypertensive phase (RR: 0.74, 95% CI [0.39,1.40]) were insignificant. Postoperative anti-glaucoma medication (MD: -0.07, 95% CI [-0.79, -0.65] and total complications (RR:1.36, 95% CI [1.07, 1.72]) were significant., Conclusion: No significant difference was observed between the patients with MGI and AGV for the primary outcome. From the secondary outcome, AGV was associated with reduced anti-glaucoma medication use and significantly lowered the number of complications., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display&#95;record.php?RecordID=475539, identifier CRD42023475539., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Raja, Bhimani, Alim Ur Rahman, Salman, Saeed Shaikh, Raja, Zafar Sayeed, Feroze and Ahmed.)

Purpose: Patients undergoing medical procedures often experience pain and anxiety. These periprocedural outcomes can be overcome by providing a distraction using virtual reality (VR), decreasing their perception. VR has proved effective in reducing pediatric pain and anxiety; however, limited studies have confirmed its effectiveness in adults. We performed a systematic review and meta-analysis on the effectiveness of VR, as opposed to standard care, in reducing periprocedural pain and anxiety in adults., Methods: A systematic search of randomized controlled trials was conducted using the databases of MEDLINE, Cochrane CENTRAL, and Scopus. Trials involving patients (> 18 years) undergoing elective medical procedures conducted with or without local anesthesia and participating in VR therapy were included. Primary outcomes were pre-procedural anxiety, post-procedural anxiety, and intra-procedural pain. Pre-procedural pain, post-procedural pain, and intra-procedural anxiety were secondary outcomes., Results: Data from 10 studies shortlisted for inclusion revealed no significant association between the use of VR and lower pre-procedural anxiety compared to standard care (p > 0.05) (SMD = -0.02, 95% CI = -0.18 - 0.14, P = 0.81) but demonstrated that the use of VR was significantly associated with a reduction in post-procedural anxiety (SMD = -0.73, 95% CI = -1.08 - -0.39, P < 0.0001), intra-procedural pain (SMD = -0.61, 95% CI = -1.18 - -0.04, P = 0.04), and post-procedural pain (SMD = -0.25, 95% CI = -0.44 - -0.05, P = 0.01)., Conclusion: The use of VR caused a significant reduction in post-procedural anxiety, intra-procedural pain, and post-procedural pain in adults undergoing medical procedures, although the findings were insignificant concerning pre-procedural anxiety., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The current dogma is that chemoattractants G protein-coupled receptors activate β phospholipase C while receptor tyrosine kinases activate γ phospholipase C. Here, we show that chemoattractant/G protein-coupled receptor-mediated membrane recruitment of γ2 phospholipase C constitutes G protein-coupled receptor-mediated phospholipase C signaling and is essential for neutrophil polarization and migration during chemotaxis. In response to a chemoattractant stimulation, cells lacking γ2 phospholipase C (plcg2kd) displayed altered dynamics of diacylglycerol production and calcium response, increased Ras/PI3K/Akt activation, elevated GSK3 phosphorylation and cofilin activation, impaired dynamics of actin polymerization, and, consequently, defects in cell polarization and migration during chemotaxis. The study reveals a molecular mechanism of membrane targeting of γ2 phospholipase C and the signaling pathways by which γ2 phospholipase C plays an essential role in neutrophil chemotaxis., Competing Interests: Conflict of interest statement. The authors declare that they have no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pakistan is currently going through the worst-ever recorded flood crisis. The 2022 floods have created unprecedented destruction, especially in the coastal regions of the country. Almost one-third of Pakistan has drowned, merely as a consequence of climate change which is impacting many countries around the globe, with the South Asian countries at the greatest risk due to their proximity to the equator. The National Disaster Management Authority (NDMA) has reported millions of people to be affected by the catastrophic floods. The country is also going through a major economic crisis due to livestock and agriculture being destroyed, which has led to severe food shortages resulting in the flood victims being vulnerable to malnutrition as well. Health care has also been severely affected, with a serious outbreak of waterborne diseases including diarrhea, dengue fever, malaria. Thousands of pregnant women are unable to access maternity services and menstrual hygiene products are also unavailable in flood-stricken areas. The Government of Pakistan should address this urgent matter as a priority and necessary steps should be taken to try and contain this catastrophe., (© 2022 The Authors.)

Competing Interests: N/A.

While HDAC inhibitors have shown promise in hematologic cancers, their efficacy remains limited in solid cancers. In the present study, we evaluated the immunomodulatory properties of the HDAC6 inhibitor, Citarinostat (ACY241) on lung tumor immune compartment and its therapeutic potential in combination with Oxaliplatin. As a single agent, ACY241 treatment promoted increased infiltration, activation, proliferation, and effector function of T cells in the tumors of lung adenocarcinoma-bearing mice. Furthermore, tumor-associated macrophages exhibited downregulated expression of inhibitory ligands in favor of increased MHC and co-stimulatory molecules in addition to higher expression of CCL4 that favored increased T cell numbers in the tumors. RNA-sequencing of tumor-associated T cells and macrophages after ACY241 treatment revealed significant genomic changes that is consistent with improved T cell viability, reduced inhibitory molecular signature, and enhancement of macrophage capacity for improved T cell priming. Finally, coupling these ACY241-mediated effects with the chemotherapy drug Oxaliplatin led to significantly enhanced tumor-associated T cell effector functionality in lung cancer-bearing mice and in patient-derived tumors. Collectively, our studies highlight the molecular underpinnings of the expansive immunomodulatory activity of ACY241 and supports its suitability as a partner agent in combination with rationally selected chemotherapy agents for therapeutic intervention in NSCLC., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Rationale: Palatability and incentive value influence animal food choice. Dopamine D2/3 receptor signaling may mediate the effects of palatability and incentive value on choice. Dopamine signaling is disrupted in attention-deficit hyperactivity disorder (ADHD). Investigating behavioral choice processes under D2/3 receptor agonists will help elucidate behavioral and pharmacological correlates of ADHD., Objectives: To determine (1) how changes in incentive value affects choice of actions for outcomes that differ in palatability; (2) the effects of the D2/3 agonist quinpirole on choice based on palatability and incentive value; (3) how choice differs in spontaneously hypertensive rats (SHR; ADHD model) compared with control strains., Methods: Rats responded instrumentally for two food outcomes (chocolate and grain pellets) that differed in palatability. Following specific satiety of one outcome, rats underwent a choice test. Prior to the choice test, rats were given intra-peritoneal quinpirole (0.01-0.1 mg/kg) body weight. These manipulations were conducted in three strains of rats: SHR rats; the normotensive Wistar-Kyoto (WKY) controls; and Wistar outbred (WIS) controls., Results: All rat strains responded more vigorously for chocolate pellets compared with grain pellets. Quinpirole reduced the effects of palatability and dose-dependently increased the effects of incentive value on choice. SHR rats were the least influenced by incentive value, whereas WKY rats were the least influenced by palatability., Conclusions: These results show that D2/3 signaling modulates choice based on palatability and incentive value. Disruption of this process in SHR rats may mirror motivational impairments observed in ADHD., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Neutrophils sense and migrate through an enormous range of chemoattractant gradients through adaptation. Here, we reveal that in human neutrophils, calcium-promoted Ras inactivator (CAPRI) locally controls the GPCR-stimulated Ras adaptation. Human neutrophils lacking CAPRI ( capri kd ) exhibit chemoattractant-induced, nonadaptive Ras activation; significantly increased phosphorylation of AKT, GSK-3α/3β, and cofilin; and excessive actin polymerization. capri kd cells display defective chemotaxis in response to high-concentration gradients but exhibit improved chemotaxis in low- or subsensitive-concentration gradients of various chemoattractants, as a result of their enhanced sensitivity. Taken together, our data reveal that CAPRI controls GPCR activation-mediated Ras adaptation and lowers the sensitivity of human neutrophils so that they are able to chemotax through a higher-concentration range of chemoattractant gradients., Competing Interests: The authors declare no competing interest.

Chemotaxis, which is G protein-coupled receptor (GPCR)-mediated directional cell migration, plays pivotal roles in diverse human diseases, including recruitment of leukocytes to inflammation sites and metastasis of cancer. It is still not fully understood how eukaryotes sense and chemotax in response to chemoattractants with an enormous concentration range. A genetically traceable model organism, Dictyostelium discoideum , is the best-studied organism for GPCR-mediated chemotaxis. Recently, we have shown that C2GAP1 controls G protein coupled receptor-mediated Ras adaptation and chemotaxis. Here, we investigated the molecular mechanism and the biological function of C2GAP1 membrane targeting for chemotaxis. We show that calcium and phospholipids on the plasma membrane play critical roles in membrane targeting of C2GAP1. Cells lacking C2GAP1 ( c2gapA - ) displayed an improved chemotaxis in response to chemoattractant gradients at subsensitive or low concentrations (<100 nM), while exhibiting impaired chemotaxis in response to gradients at high concentrations (>1 μM). Taken together, our results demonstrate that the membrane targeting of C2GAP1 enables Dictyostelium to sense chemoattractant gradients at a higher concentration range. This mechanism is likely an evolutionarily conserved molecular mechanism of Ras regulation in the adaptation and chemotaxis of eukaryotes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Xu, Bhimani, Pots, Wen, Jeon, Kortholt and Jin.)

Objective: Congenitally corrected transposition of the great arteries (ccTGA) encompasses a diverse morphologic cohort, for which multiple treatment pathways exist. Understanding surgical outcomes among various pathways and their determinants are challenged by limited sample size and follow-up, and heterogeneity. We sought to investigate these questions with a large cohort of ccTGA patients presenting at different ages and representing the full therapeutic spectrum., Methods: Retrospective review of 240 patients diagnosed with ccTGA from Cleveland Clinic coupled with prospective cross-sectional follow-up. Forty-six patients whose definitive procedure was completed elsewhere were excluded. Time-related survival was described among treatment pathways using actuarial, time-varying covariate, and competing risks analyses. Temporal trends in longitudinal valve and ventricular function were assessed using nonlinear mixed-effects models., Results: Median follow-up was 10 years. Seventy-nine patients with ccTGA underwent anatomic repair, 45 physiologic repair, 24 Fontan palliation, and 6 primary transplant. Forty patients managed expectantly had excellent long-term survival when considered from time of presentation, but benefited from failures captured following transition to physiologic repair or transplant. Morphologic right ventricular dysfunction after physiologic repair increased from 68% to 85% after 5 years, whereas morphologic left ventricular function was stable in anatomic repair, especially with early surgery. Transplant-free survival at 15 years for anatomic and physiologic repair was 80% and 71%, respectively., Conclusions: Early anatomic repair may be preferable to physiologic repair for select ccTGA patients. Late attrition after physiologic repair represents failure of expectant management and progressive tricuspid valve and morphologic right ventricular dysfunction compared with anatomic repair, where morphologic left ventricular function is relatively preserved., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Macropinocytosis and phagocytosis are the processes by which eukaryotic cells use their plasma membrane to engulf liquid or a large particle and give rise to an internal compartment called the macropinosomes or phagosome, respectively. Dictyostelium discoideum provides a powerful system to understand the molecular mechanism of these two fundamental cellular processes that impact human health and disease. Recent developments in fluorescence microscopy allow direct visualization of intracellular signaling events with high temporal and spatial resolution. Here, we describe methods to visualize temporospatial activation or localization of key signaling components that are crucial for macropinocytosis and phagocytosis using confocal fluorescence microscopy.

Coronary artery disease in palliated hypoplastic left heart syndrome is uncommon. Myocardial infarction from a coronary thrombus, serving as a substrate for ventricular arrhythmia in Fontan physiology, is under-reported despite known hypercoagulopathic state. Traditional risk factors for coronary artery occlusion include intracardiac thrombi, hyperlipidemia, and hypertension. Baffle leaks and abnormal ventriculocoronary fistulae found in these patients are contributing factors. We sought to assess and describe coronary artery involvement in this complex patient population. Our research highlights both the need to assess distal coronary vasculature and to thoroughly evaluate hemodynamics and biventricular function with new-onset troponin leak or ventricular arrhythmias.

Marburg Virus (MARV), along with the Ebola virus, belongs to the family of Filovirus and is cause of a lethal and severely affecting hemorrhagic fever. The Marburgvirus genus includes two viruses: MARV and Ravn. MARV has been recognized as one of utmost importance by the World Health Organization (WHO). The case fatality rate of the virus ranges from 24.0 to 88.0% which demonstrates its lethal nature and the need for its widespread information. The first case of the Marburgvirus disease (MARD) was reported in 1967 when lab personnel working with African green monkeys got infected in Germany and Serbia simultaneously. Following the initial case, many more outbreaks occurred around the world such as Uganda, Angola, Congo, Kenya and even in the United States in 2008. It was soon found out that the MARV was a zoonotic virus and mainly contracted from animal-to-human contact and further transmitted via human-to-human contact. The Egyptian fruit bat (Rousettus aegyptiacus) is known to be one of the significant sources of the infection and tourists visiting caves inhabited by these bats or workers accessing mines, populated by the bats, are at an increased risk of contracting the illness. The incubation period ranges from 2-21 days and the clinical outcome can be broken down into three phases: initial generalized phase (day 1-4), early organ phase (day 5 to 13) and either a late organ/convalescence phase (day 13 onwards). Furthermore, the treatment of MARD is solely based on supportive care. Much has been investigated in over the past half-century of the initial infection but only a few treatment options show promising results. In addition, special precaution is advised whilst handling the patient or the biospecimens. Disease-modifying agents and inhibitors of viral replications show constructive outcomes. It is crucial to identify the host of the virus and educate the populations that are greatly at risk of the disease. While much is being investigated to devise a vaccine, it is important to educate Health Care Workers (HCWs) and close contacts facing the illness. Stopping the transmission remains the best measure that can be taken.

Competing Interests: Conflict of Interests: The authors declare no conflict of interest to declare.

The human immunodeficiency virus (HIV) is currently a global threat with an estimated 38.6 million people affected with HIV worldwide. According to the Joint United Nations Program on HIV/AIDS (UNAIDS), since 2004 the total number of cases of HIV in Pakistan has risen from 2700 to 130,000. In light of the rising burden of HIV/AIDS across the country, it is essential that medical students possess appropriate knowledge regarding the subject. Therefore, we aimed to assess the knowledge, attitude and practice of medical students towards HIV patients in their pre-clinical and post-clinical years in Karachi, Pakistan. A cross-sectional study was conducted among 518 pre-clinical (year 1 and 2) and post-clinical (year 3, 4, and 5) medical students from two medical schools in Karachi during the months of October - December 2019. Similar numbers of participants were taken from each year. Data were analyzed using SPSS. Descriptive statistics were used to report frequencies and proportions for categorical responses. Chi-square and Kruskal-Wallis tests were used as the primary statistical tests. About 55% of participants were female, and most belonged to the Islamic faith. More than half of the participants learned about HIV from books (315/518), followed by medical personnel (287/518). A quarter (134/518) of the participants believed HIV could be transmitted by sharing saliva, more than half of whom consisted of pre-clinical year students. Over half the participants (60.4%) knew that there was a difference between HIV and AIDs, most of whom belonged to the 5th year group. When detecting HIV, only about 30% of participants knew about indirect fluorescent antibody. Regarding attitudes, one-third would not be friends with a person diagnosed with HIV/AIDS. As a medical officer, a large majority (76.6%; n=397/518) of the participants would be anxious or somewhat anxious. Two-thirds believed that treating an HIV patient can make them contract HIV, and a majority of participants (333/518) did not feel adequately prepared to deal with the psycho-social problems of an HIV/AIDS patient. Finally, regarding practice, only one-third of the participants were willing to treat an HIV/AIDS patient, most of whom belonged to the pre-clinical 2nd year group and fewer to the post-clinical 3rd year group. Knowledge amongst medical students regarding HIV/AIDS was generally high, although there are some knowledge inadequacies which require more emphasis in the medical school curriculum. However, contrasting with the level of knowledge, in terms of attitude the majority were anxious or somewhat anxious when treating an HIV patient, and only one-third were willing to treat a patient with HIV.

Ebola Virus Disease (EVD), also known as Ebola Hemorrhagic Fever (EHF), initially emerged over 40 years ago in the Democratic Republic of Congo. Endemic to Africa, outbreaks have been recorded in six African countries since its detection in 1976. Fruit bats are believed to be the natural hosts of Ebola viruses (EBoV), with humans and other mammals serving as accidental hosts. Transmission of EBoV has been reported in various ways, including human to human transmission through close contact with blood and bodily fluids. The virus has an incubation period ranging from two to twenty-one days, followed by a multitude of clinical manifestations such as the sudden onset of high fever, chills and myalgia depicting a flu-like syndrome. It is usually diagnosed based on several clinical symptoms such as the sudden onset of illness, high fevers for less than three weeks, and at least two hemorrhagic symptoms despite no predisposing factors. This generally provides enough evidence for clinicians to consider EHF and begin supportive treatment until the virus is confirmed through laboratory findings. Management of patients involves supportive care such as maintaining fluid along with electrolyte balance, blood pressure and oxygen saturation. This also includes treating complications arising from secondary infections. The main options include: prophylactic strategies, anti-viral therapy for EVD, immunotherapies, vaccines, and ZMapp. Finally, the key to managing EBoV epidemics is to stop the transmission of disease in the most severely affected population, as prevention has become of utmost importance to alleviate the significant physical and economic burden.

Objective: To establish a better understanding of physicians' knowledge and beliefs, and to compare distinctions in knowledge, attitude and perception of junior and senior doctors regarding rational use of antibiotics., Methods: The cross-sectional study was conducted at a tertiary care hospital in Karachi, from June 1 to July 31, 2016, and comprised senior and junior doctors. A 26-item questionnaire divided in three sections was used to test knowledge, attitude and perception of the subjects regarding rational use of antibiotics. Data was analysed using SPSS 23., Results: Of the 200 subjects, 132(66%) were senior doctors; 68(34%) were junior; 116(58%) were females; 84(42%) were males; and the highest number of respondents were from General Medicine 65(32.5%). While 182(91%) doctors realised that antibiotic resistance was a pressing issue, only 131(65.5%) felt confident about their prescriptions and 94(47%) admitted that they over-prescribed antibiotics. Among young physicians, 13(19.1%) believed that antibiotics did not cause side effects even when prescribed unnecesarily. Also, 47(69.1%) junior doctors felt that patients' demands influenced their prescriptions compared to 66(50%) senior doctors (p=0.01)., Conclusions: Although physicians were found to be knowledgeable about rational use of antibiotics, there were gaps in knowledge and perception.

The striatum represents the main input structure of the basal ganglia, receiving massive excitatory input from the cortex and the thalamus. The development and maintenance of cortical input to the striatum is crucial for all striatal function including many forms of sensorimotor integration, learning, and action control. The molecular mechanisms regulating the development and maintenance of corticostriatal synaptic transmission are unclear. Here we show that the guidance cue, Semaphorin 3F and its receptor Neuropilin 2 (Nrp2), influence dendritic spine maintenance, corticostriatal short-term plasticity, and learning in adult male and female mice. We found that Nrp2 is enriched in adult layer V pyramidal neurons, corticostriatal terminals, and in developing and adult striatal spiny projection neurons (SPNs). Loss of Nrp2 increases SPN excitability and spine number, reduces short-term facilitation at corticostriatal synapses, and impairs goal-directed learning in an instrumental task. Acute deletion of Nrp2 selectively in adult layer V cortical neurons produces a similar increase in the number of dendritic spines and presynaptic modifications at the corticostriatal synapse in the Nrp2 -/- mouse, but does not affect the intrinsic excitability of SPNs. Furthermore, conditional loss of Nrp2 impairs sensorimotor learning on the accelerating rotarod without affecting goal-directed instrumental learning. Collectively, our results identify Nrp2 signaling as essential for the development and maintenance of the corticostriatal pathway and may shed novel insights on neurodevelopmental disorders linked to the corticostriatal pathway and Semaphorin signaling. SIGNIFICANCE STATEMENT The corticostriatal pathway controls sensorimotor, learning, and action control behaviors and its dysregulation is linked to neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here we demonstrate that Neuropilin 2 (Nrp2), a receptor for the axon guidance cue semaphorin 3F, has important and previously unappreciated functions in the development and adult maintenance of dendritic spines on striatal spiny projection neurons (SPNs), corticostriatal short-term plasticity, intrinsic physiological properties of SPNs, and learning in mice. Our findings, coupled with the association of Nrp2 with ASD in human populations, suggest that Nrp2 may play an important role in ASD pathophysiology. Overall, our work demonstrates Nrp2 to be a key regulator of corticostriatal development, maintenance, and function, and may lead to better understanding of neurodevelopmental disease mechanisms., (Copyright © 2019 the authors.)

Background The amount of literature shedding light upon eating disorders in developing countries, such as Pakistan, is scarce. This is partially because talking about such matters is considered taboo in the general population. Night Eating Syndrome's (NES) link with depression and obesity has been established; however, presently, no study has been conducted which solely focuses on NES's correlation with self-esteem. Therefore, to bridge this knowledge gap, we conducted this study to assess the prevalence of NES in Karachi and its association with self-esteem. Methods We conducted a cross-sectional study in August 2018 using convenience sampling in 395 individuals, out of which 197 belonged to the age group 18-24 and 198 to 25-30. The participants were interviewed for their gender, body mass index (BMI), and their level of education. The participants were asked to complete a structured, standardized questionnaire assessment, which comprised of questions from the Night Eating Questionnaire (NEQ) and Rosenberg Self-Esteem scale (RSE). The eating habits of the participants and the level of self-esteem were assessed using four- and five-point Likert scales. Kruskal-Wallis and chi-square tests were used as the primary statistical tests. Results Out of the 395 respondents, more than half of the respondents were females (n = 235/395, 59.5%). About one-fourth (n = 92/395, 23.3%) of the participants had a BMI of greater than 25.0 kg/m 2 . More than one-third of the underweight (n = 20/55, 36.4%) and overweight population (n = 33/92, 35.9%) had low self-esteem, while more than one-fourth (n = 25/92, 27.2%) of the overweight participants fulfilled the criteria of NES. The final outcomes showed that 14.4% of the participants had NES, and 4.6% of the participants had low self-esteem. Conclusion Our results pointed out to a significant relationship between NES and self-esteem. Furthermore, NES and self-esteem also had a significant association with age, gender, and BMI. Additionally, awareness regarding eating and mental disorders should be done in countries like Pakistan, where talking in regard to such matters is considered taboo. Given the various factors that further strengthen the positive relationship between NES and low self-esteem, these factors can be the targets on which the treatment can be focused., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2019, Batra et al.)

The striatum mediates a broad range of cognitive and motor functions. Within the striatum, recently discovered tyrosine hydroxylase expressing interneurons (THINs) provide a source of intrastriatal synaptic connectivity that is critical for regulating striatal activity, yet the role of THIN's in behavior remains unknown. Given the important role of the striatum in reward-based behaviors, we investigated whether loss of striatal THINs would impact instrumental behavior in mice. We selectively ablated striatal THINs in TH-Cre mice using chemogenetic techniques, and then tested THIN-lesioned or control mice on three reward-based striatal-dependent instrumental tests: (a) progressive ratio test; (b) choice test following selective-satiety induced outcome devaluation; (c) outcome reinstatement test. Both striatal-THIN-lesioned and control mice acquired an instrumental response for flavored food pellets, and their behavior did not differ in the progressive ratio test, suggesting intact effort to obtain rewards. However, striatal THIN lesions markedly impaired choice performance following selective-satiety induced outcome devaluation. Unlike control mice, THIN-lesioned mice did not adjust their choice of actions following a change in outcome value. In the outcome reinstatement test THIN-lesioned and control mice showed response invigoration by outcome presentation, suggesting the incentive properties of outcomes were not disrupted by THIN lesions. Overall, we found that striatal THIN lesions selectively impaired goal-directed behavior, while preserving motoric and appetitive behaviors. These findings are the first to describe a function of striatal THINs in reward-based behavior, and further illustrate the important role for intrastriatal interneuronal connectivity in behavioral functions ascribed to the striatum more generally., (© 2019 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: Periprosthetic joint infection (PJI) remains a devastating complication following total joint arthroplasty. Current animal models of PJI do not effectively recreate the clinical condition and thus provide limited help in understanding why treatments fail. We developed a mouse model of the first-stage surgery of a 2-stage revision for PJI involving a 3-dimensionally printed Ti-6Al-4V implant and a mouse-sized cement spacer that elutes vancomycin., Methods: Vancomycin was mixed with polymethylmethacrylate (PMMA) cement and inserted into custom-made mouse-sized spacer molds. Twenty C57BL/6 mice received a proximal tibial implant and an intra-articular injection of 3 × 10 colony-forming units of Staphylococcus aureus Xen36. At 2 weeks, 9 mice underwent irrigation and debridement of the leg with revision of the implant to an articulating vancomycin-loaded PMMA spacer. Postoperatively, mice underwent radiography and serum inflammatory-marker measurements. Following euthanasia of the mice at 6 weeks, bone and soft tissues were homogenized to quantify bacteria within periprosthetic tissues. Implants and articulating spacers were either sonicated to quantify adherent bacteria or examined under scanning electron microscopy (SEM) to characterize the biofilm., Results: Vancomycin-loaded PMMA spacers eluted vancomycin for ≤144 hours and retained antimicrobial activity. Control mice had elevated levels of inflammatory markers, radiographic evidence of septic loosening of the implant, and osseous destruction. Mice treated with a vancomycin-loaded PMMA spacer had significantly lower levels of inflammatory markers (p < 0.01), preserved tibial bone, and no intra-articular purulence. Retrieved vancomycin-loaded spacers exhibited significantly lower bacterial counts compared with implants (p < 0.001). However, bacterial counts in periprosthetic tissue did not significantly differ between the groups. SEM identified S. aureus encased within biofilm on control implants, while vancomycin-loaded spacers contained no bacteria., Conclusions: This animal model is a clinically representative model of PJI treatment. The results suggest that the antimicrobial effects of PMMA spacers are tightly confined to the articular space and must be utilized in conjunction with thorough tissue debridement and systemic antibiotics., Clinical Relevance: These data provide what we believe to be the first insight into the effect of antibiotic-loaded cement spacers in a clinically relevant animal model and justify the adjunctive use of intravenous antibiotics when performing a 2-stage revision for PJI.

Background: Propionibacterium acnes ( P. acnes ) has become increasingly recognized as a cause of periprosthetic joint infection (PJI)., Questions/purposes: It is not currently known if the clinical presentation of P. acnes varies depending on the joint being infected., Methods: We retrospectively reviewed patients infected with P. acnes after total hip, knee, and shoulder arthroplasty from two institutions. Patients were classified as having a PJI based on the Musculoskeletal Infection Society criteria and were excluded if they had a polymicrobial culture. Patient demographics, preoperative laboratory values, and microbiology data were analyzed., Results: Eighteen knees, 12 hips, and 35 shoulders with a P. acnes PJI were identified. Median ESR was significantly higher in the knee (38.0 mm/h, IQR 18.0-58.0) and hip (33.5 mm/h, IQR 15.3-60.0) groups compared to the shoulder group (11.0 mm/h, IQR 4.5-30.5). C-reactive protein levels were higher in the knee (2.0 mg/dl, IQR 1.3-8.9) and hip (2.4 mg/dl, IQR 0.8-4.9) groups compared to the shoulder group (0.7 mg/dl, IQR 0.6-1.5). Median synovial fluid WBC was significantly higher in the knee group than shoulder group (19,950 cells/mm 3 , IQR 482-60,063 vs 750 cells/mm 3 , IQR 0-2825, respectively). Peripheral blood WBC levels were similar between groups, as was mean time of P. acnes growth in culture. Clindamycin resistance was present in all groups., Conclusion: The manner in which a patient with P. acnes PJI presents is joint specific. Inflammatory markers were significantly higher in the knee and hip groups compared to the hip and shoulder groups, and long hold anaerobic cultures up to 14 days are necessary to accurately identify this organism.

Background: Periprosthetic joint infection (PJI) is a devastating complication following total joint arthroplasty. Current animal models of PJI are limited because of a lack of quantitative methods and failure to effectively recreate the periprosthetic space. We therefore developed a murine PJI model involving a 3-dimensionally printed Ti-6Al-4V implant capable of bearing weight and permitting quantitative analysis of periprosthetic bacterial load and evaluation of biofilm., Methods: Twenty-five 12-week-old C57BL/6 mice received a unilateral proximal tibial implant and intra-articular injection of either 3 × 10 colony forming units (CFUs) of Staphylococcus aureus Xen 36 or saline solution. Postoperatively, mice underwent gait analysis, knee radiographs, and serum inflammatory marker measurements. Following euthanasia at 2 or 6 weeks, bone and soft tissues were homogenized to quantify bacteria within periprosthetic tissues. Implants were either sonicated to quantify adherent bacteria or examined under scanning electron microscopy (SEM) to characterize biofilm., Results: All mice survived surgery and were not systemically septic. The control mice immediately tolerated weight-bearing and had normal inflammatory markers and radiographic signs of osseointegration. Infected mice had difficulty walking over time, exhibited radiographic findings of septic implant loosening, and had significantly elevated inflammatory markers. Periprosthetic tissues of the infected animals displayed a mean of 4.46 × 10 CFUs of S. aureus at 2 weeks and 2.53 × 10 CFUs at 6 weeks. Viable S. aureus was quantified on retrieved implant surfaces. SEM demonstrated S. aureus cocci in clusters encased within biofilm., Conclusions: This animal model is, to our knowledge, the most clinically representative PJI replication to date. It is the first that we know of to produce infection through the same method hypothesized to occur clinically, utilize a weight-bearing implant that can osseointegrate, and provide quantitative data on 8 aspects of PJI, including radiographic features, inflammatory markers, and bacterial loads., Clinical Relevance: This novel animal model is, to our knowledge, the first to provide a load-bearing translational representation of clinical PJI that effectively recreates the periprosthetic space.

A major limiting factor in the longevity of total hip replacement is the wear rate of the hip bearing. As manufacturing technology has improved during the past several decades, much attention has been focused on developing newer generations of polyethylene that have lower rates of wear while minimizing free radical formation and subsequent osteolysis. The turning point for the manufacture of polyethylene was moving from gamma irradiation in air to irradiation in a low oxygen environment, which reduced free radical formation while increasing the wear resistance. New polyethylene manufacturing methods, including multiple cycles of irradiation and annealing, have resulted in greater wear resistance. Wear analysis studies are essential to determine if these new liners actually show a benefit from prior generations of polyethylene and, more importantly, if they are safe to use. This study involved a single center retrospective review of 60 patients with a mean follow-up of 5.5 years who underwent primary total hip arthroplasty with a second-generation highly cross-linked polyethylene manufactured by 3 cycles of sequential irradiation and annealing. Linear and volumetric wear rates were determined from digitized radiographs using contemporary wear analysis software. The mean linear wear rate for the entire group was 0.025 millimeters per year (mm/y). This value represents a linear wear rate 2.7 times less than that of a first-generation highly cross-linked polyethylene and 4.2 times less than that of a conventional polyethylene. At an average of 5 years, compared with a first-generation highly cross-linked polyethylene, a second-generation highly cross-linked polyethylene appears to show significant improvement regarding wear. [Orthopedics. 2016; 39(6):e1178-e1182.]., (Copyright 2016, SLACK Incorporated.)

Background: Long-term fixation of uncemented joint implants requires early mechanical stability and implant osseointegration. To date, osseointegration has been unreliable and remains a major challenge in cementless total knee arthroplasty. We developed a murine model in which an intra-articular proximal tibial titanium implant with a roughened stem can be loaded through the knee joint. Using this model, we tested the hypothesis that intermittent injection of parathyroid hormone (iPTH) would increase proximal tibial cancellous osseointegration., Methods: Ten-week-old female C57BL/6 mice received a subcutaneous injection of PTH (40 μg/kg/day) or a vehicle (n = 45 per treatment group) five days per week for six weeks, at which time the baseline group was killed (n = 6 per treatment group) and an implant was inserted into the proximal part of the tibiae of the remaining mice. Injections were continued until the animals were killed at one week (n = 7 per treatment group), two weeks (n = 14 per treatment group), or four weeks (n = 17 per treatment group) after implantation. Outcomes included peri-implant bone morphology as analyzed with micro-computed tomography (microCT), osseointegration percentage and bone area fraction as shown with backscattered electron microscopy, cellular composition as demonstrated by immunohistochemical analysis, and pullout strength as measured with mechanical testing., Results: Preimplantation iPTH increased the epiphyseal bone volume fraction by 31.6%. When the data at post-implantation weeks 1, 2, and 4 were averaged for the iPTH-treated mice, the bone volume fraction was 74.5% higher in the peri-implant region and 168% higher distal to the implant compared with the bone volume fractions in the same regions in the vehicle-treated mice. Additionally, the trabecular number was 84.8% greater in the peri-implant region and 74.3% greater distal to the implant. Metaphyseal osseointegration and bone area fraction were 28.1% and 70.1% higher, respectively, in the iPTH-treated mice than in the vehicle-treated mice, and the maximum implant pullout strength was 30.9% greater. iPTH also increased osteoblast and osteoclast density by 65.2% and 47.0%, respectively, relative to the values in the vehicle group, when the data at post-implantation weeks 1 and 2 were averaged., Conclusions: iPTH increased osseointegration, cancellous mass, and the strength of the bone-implant interface., Clinical Relevance: Our murine model is an excellent platform on which to study biological enhancement of cancellous osseointegration., (Copyright © 2015 by The Journal of Bone and Joint Surgery, Incorporated.)