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ABSTRACTSARS-CoV-2 has caused a global pandemic with significant humanity and economic loss since 2020. Currently, only limited options are available to treat SARS-CoV-2 infections for vulnerable populations. In this study, we report a universal fluorescence polarization (FP)-based high throughput screening (HTS) assay for SAM-dependent viral methyltransferases (MTases), using a fluorescent SAM-analogue, FL-NAH. We performed the assay against a reference MTase, NSP14, an essential enzyme for SARS-CoV-2 to methylate the N7 position of viral 5’-RNA guanine cap. The assay is universal and suitable for any SAM-dependent viral MTases such as the SARS-CoV-2 NSP16/NSP10 MTase complex and the NS5 MTase of Zika virus (ZIKV). Pilot screening demonstrated that the HTS assay was very robust and identified two candidate inhibitors, NSC 111552 and 288387. The two compounds inhibited the FL-NAH binding to the NSP14 MTase with low micromolar IC50. We used three functional MTase assays to unambiguously verified the inhibitory potency of these molecules for the NSP14 N7-MTase function. Binding studies indicated that these molecules are bound directly to the NSP14 MTase with similar low micromolar affinity. Moreover, we further demonstrated that these molecules significantly inhibited the SARS-CoV-2 replication in cell-based assays at concentrations not causing cytotoxicity. Furthermore, NSC111552 significantly synergized with known SARS-CoV-2 drugs including nirmatrelvir and remdesivir. Finally, docking suggested that these molecules bind specifically to the SAM-binding site on the NSP14 MTase. Overall, these molecules represent novel and promising candidates to further develop broad-spectrum inhibitors for the management of viral infections.

Introduction: Congenital diaphragmatic hernia (CDH) usually presents with respiratory distress at birth, which can be severe enough to cause cardiorespiratory failure. Late presentation of CDH is less common. CDH can be associated with malrotation, which is typically asymptomatic. Case presentation: We describe a case of a 7-year-old child who had non-specific gastrointestinal symptoms and no respiratory symptoms. The patient had been suffering from non-bilious vomiting for a week, had abdominal pain and was dehydrated and malnourished. Breath sounds were diminished and bowel sounds were present in the left hemithorax. A diagnosis of CDH was suggested on a chest x-ray and confirmed by a barium study. On exploration, a small-sized left CDH associated with malrotation and Ladd's bands were discovered. The diaphragmatic defect was closed primarily, and the malrotation corrected with a Ladd's procedure. The post-operative course was uneventful. Conclusion: Patients with non-specific gastrointestinal symptoms and a suspicious chest X-ray should undergo further imaging studies to rule out a CDH. Failure to do so can potentially lead to complications such as bowel obstruction and volvulus. Respiratory symptoms are uncommon in late-presenting CDH.

OBJECTIVE: To determine cut-off values for prostate specific antigen density (PSAD) in diagnosing prostate carcinoma in symptomatic patients. METHODS: This cross sectional, observational study conducted at Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan from June 2020 to May 2021. Symptomatic patients (309) having prostatic enlargement on ultrasound were selected through consecutive sampling. All the patients underwent prostate biopsy for histopathological diagnosis. Prostate specific antigen density was calculated and compared between different age groups and different diseases. ROC curve was constructed and area under the curve was calculated to find out cut-off values value for PSAD. Sensitivity, specificity and accuracy were calculated at the cut-off values. RESULTS: Among 309 patients of median age was 68 years (IQR 43 – 75). There was a significant difference of PSAD in different age groups (p

Objective: To determine lipid derangements in HIV-positive patients receiving anti-retroviral therapy (ART). Study Design: Comparative cross-sectional study. Place and Duration of study: Chemical Pathology Department, in cooperation with the Department of Virology at Armed Forces Institute of Pathology (AFIP), Rawalpindi Pakistan, from Mar 2019 to Mar 2020. Methodology: In this study, two groups were made. In Group-1, lipid profile estimation was done in HIV patients without treatment. In contrast, lipid profile estimation was done after one year of treatment with anti-retroviral drugs in Group-2. Results: One hundred and two HIV-positive subjects were included in our study. Of these patients, 88(86.27%) were males,and 14(13.73%) were females. Independent sample t-test revealed a statistically significant difference (p-value

Objective: To determine the diagnostic accuracy of the Lactate Dehydrogenase, C-Reactive Protein and Ferritin in suspected patients of COVID-19. Study Design: Cross-sectional validation study. Place and Duration of Study: Pathology department of Combined Military Hospital Lahore in the month of May 2020. Methodology: We included 101 adult (>18 years) symptomatic suspected COVID-19 patients of both genders. Children, pregnant women and asymptomatic patients were excluded from study. Age, gender and results of Reverse Transcriptase Polymerase Chain Reaction, Lactate Dehydrogenase, C-Reactive Protein, ferritin were recorded. Results: Lactate Dehydrodenase had highest sensitivity (75%) with positive predictive value of 71.6% and diagnostic accuracy of 65.3% among three biochemical parameters studied. Receiver Operator Characteristic curve was studied. Area under curve of Lactate Dehydrogenase (AUC=0.65) and Ferritin (AUC=0.59) reflected their ability to prognosticate the presence of COVID19 disease. However, C-Reactive Protein (AUC=0.42) appeared to be a poor predictor of the disease. Conclusion: Raised serum Lactate Dehydrogenase (>490 U/L) and Ferritin (>152 ng/L) levels can be used to predict the Reverse Transcriptase Polymerase Chain Reaction positivity for COVID-19 in the population of suspected patients of COVID19. However, C-Reactive Protein is a poor predictor of COVID-19.

Body hydration is considered one of the most important physiological parameters to measure and one of the most challenging. Current methods to assess hydration are invasive and require costly clinical settings. The bio-impedance analysis offers a noninvasive and inexpensive tool to assess hydration, and it can be designed to be used in wearable health devices. The use of wearable electronics in healthcare applications has received increased attention over the last decade. New, emerging medical devices feature continuous patient monitoring and data collection to provide suitable treatment and preventive actions. In this paper, a model of human skin is developed and simulated to be used as a guide to designing a dehydration monitoring system based on a bio-impedance analysis technique. The study investigates the effect of applying different frequencies on the dielectric parameters of the skin and the resulting measured impedance. Two different interdigitated electrode designs are presented, and a comparison of the measurements is presented. The rectangular IDE is printed and tested on subjects to validate the bio-impedance method and study the interpretation of its results. The proposed design offers a classification criterion that can be used to assess dehydration without the need for a complex mathematical model. Further clinical testing and data are needed to refine and finalize the criteria.

BACKGROUND:Visceral leishmaniasis (VL) is a parasitic disease, transmitted by the sand fly species Phlebotomus argentipes in the Indian sub-continent. Effective vector control is highly desirable to reduce vector density and human and vector contact in the endemic communities with the aim to curtail disease transmission. We evaluated the effect of long lasting insecticide treated bed nets (LLIN) and bed nets impregnated with slow-release insecticide tablet K-O TAB 1-2-3 (jointly insecticide-treated nets or ITN) on VL incidence in a highly endemic sub-district (upazila) in Bangladesh. METHODS:Several distributions of LLIN or K-O TAB 1-2-3 for self-impregnation of bed nets at home took place in Fulbaria upazila, Mymensigh district from 2004 to 2008 under three research projects, respectively funded by CDC, Atlanta, USA (2004) and WHO-TDR, Geneva, Switzerland (2006 & 2008). We included all households (n = 8142) in the 20 villages that had benefited in the past from one of these interventions (1295 donated LLIN and 11,918 local bed nets impregnated with K-O TAB 1-2-3) in the "exposed cohort". We recruited a "non-exposed cohort" in villages with contemporaneously similar incidence rates who had not received such vector control interventions (7729 HHs from nine villages). In both cohorts, we visited all families house to house and ascertained any VL cases for the 3 year period before and after the intervention. We evaluated the incidence rate (IR) of VL in both cohorts as primary endpoint, applying the difference-in-differences method. RESULTS:The study identified 1011 VL cases (IR 140.47/10,000 per year [py]) before the intervention, of which 534 and 477 cases in the intervention and control areas respectively. The IR was 144.13/10,000 py (534/37050) and 136.59/10,000 py (477/34923) in the intervention and control areas respectively, with no significant difference (p = 0.3901) before the intervention. After the intervention, a total of 555 cases (IR 77.11/10,000 py) were identified of which 178 (IR 48.04/10,000 py) in the intervention and 377 (107.95/10,000 py) in the control area. The intervention area had a significant lower IR than the control area during follow up, rate difference = -59.91, p

BACKGROUND:Visceral leishmaniasis (VL) in the Indian subcontinent is a fatal disease if left untreated. Between 1994 to 2013, the Ministry of Health of Bangladesh reported 1,09,266 cases of VL and 329 VL related deaths in 37 endemic districts. Indoor residual spraying (IRS) using dichlorodiphenyltrichloroethane (DDT) was used by the national programme in the 1960s to control malaria. Despite findings of research trials demonstrating that the synthetic pyrethroid deltamethrin 5 WP was very effective at reducing vector densities, no national VL vector control operations took place in Bangladesh between 1999 to early 2012. In 2012, IRS using deltamethrin 5 WP was re-introduced by the national programme, which consisted of pre-monsoon spraying in eight highly endemic sub-districts (upazilas). The present study aims to evaluate the effectiveness of IRS on VL vectors, as well as the process and performance of the spraying activities by national programme staff. METHODS:Five highly endemic upazilas of Mymensingh district were purposively selected (Fulbaria, Trishal, Mukthagacha, Gaforgaon and Bhaluka) to conduct the present study using the WHO/TDR monitoring and evaluation tool kit. IRS operations, conducted by 136 squads/teams, and 544 spraymen, were observed using check lists and questionnaires included in the WHO/TDR monitoring and evaluation tool kit. A household (HH) acceptability survey of IRS was conducted in all study areas using a structured questionnaire in 600 HHs. To measure the efficacy of IRS, pre-IRS (two weeks prior) and post-IRS (at one and five months after), vector density was measured using CDC light traps for two consecutive nights. Bioassays, using the WHO cone-method, were carried out in 80 HHs (40 sprayed and 40 unsprayed) to measure the effectiveness of the insecticide on sprayed surfaces. RESULTS:Of the 544 spraymen interviewed pre-IRS, 60%, 3% and 37% had received training for one, two and three days respectively. During spraying activities, 64% of the spraying squads had a supervisor in 4 upazilas but only one upazila (Mukthagacha) achieved 100% supervision of squads. Overall, 72.8% of the spraying squads in the study upazilas had informed HHs members to prepare their houses prior to spraying. The required personal protective equipment was not provided by the national programme during our observations and the spraying techniques used by all sprayers were sub-standard compared to the standard procedure mentioned in the M&E toolkit. In the HH interviews, 94.8% of the 600 respondents said that all their living rooms and cattle sheds had been sprayed. Regarding the effectiveness measurements (i.e. reduction of vector densities), a total of 4132 sand flies were trapped in three intervals, of which 3310 (80.1%) were P. argentipes; 46.5% (1540) males and 53.5% (1770) females. At one month post-IRS, P. argentipes densities were reduced by 22.5% but the 5 months post-IRS reduction was only 6.4% for both male and female. The bioassay tests showed a mean corrected mortality of P. argentipes sand flies at one month post-IRS of 87.3% which dropped to 74.5% at 4 months post-IRS in three upazilas, which is below the WHO threshold level (80%). CONCLUSION:The national programme should conduct monitoring and evaluation activities to ensure high quality of IRS operations as a pre-condition for achieving a fast and sustained reduction in vector densities. This will continue to be important during the maintenance phase of VL elimination on the Indian subcontinent. Further research is needed to determine other suitable vector control option(s) when the case numbers are very low.

BACKGROUND:A number of studies on visceral leishmaniasis (VL) vector control have been conducted during the past decade, sometimes came to very different conclusion. The present study on a large sample investigated different options which are partially unexplored including: (1) indoor residual spraying (IRS) with alpha cypermethrin 5WP; (2) long lasting insecticide impregnated bed-net (LLIN); (3) impregnation of local bed-nets with slow release insecticide K-O TAB 1-2-3 (KOTAB); (4) insecticide spraying in potential breeding sites outside of house using chlorpyrifos 20EC (OUT) and different combinations of the above. METHODS:The study was a cluster randomized controlled trial where 3089 houses from 11 villages were divided into 10 sections, each section with 6 clusters and each cluster having approximately 50 houses. Based on vector density (males plus females) during baseline survey, the 60 clusters were categorized into 3 groups: (1) high, (2) medium and (3) low. Each group had 20 clusters. From these three groups, 6 clusters (about 300 households) were randomly selected for each type of intervention and control arms. Vector density was measured before and 2, 4, 5, 7, 11, 14, 15, 18 and 22 months after intervention using CDC light traps. The impact of interventions was measured by using the difference-in-differences regression model. RESULTS:A total of 17,434 sand flies were collected at baseline and during the surveys conducted over 9 months following the baseline measurements. At baseline, the average P. argentipes density per household was 10.6 (SD = 11.5) in the control arm and 7.3 (SD = 8.46) to 11.5 (SD = 20.2) in intervention arms. The intervention results presented as the range of percent reductions of sand flies (males plus females) and rate ratios in 9 measurements over 22 months. Among single type interventions, the effect of IRS with 2 rounds of spraying (applied by the research team) ranged from 13% to 75% reduction of P. argentipes density compared to the control arm (rate-ratio [RR] ranged from 0.25 to 0.87). LLINs caused a vector reduction of 9% to 78% (RR, 0.22 to 0.91). KOTAB reduced vectors by 4% to 73% (RR, 0.27 to 0.96). The combination of LLIN and OUT led to a vector reduction of 26% to 86% (RR, 0.14 to 0.74). The reduction for the combination of IRS and OUT was 8% to 88% (RR, 0.12 to 0.92). IRS and LLIN combined resulted in a vector reduction of 13% to 85% (RR, 0.15 to 0.77). The IRS and KOTAB combination reduced vector densities by 16% to 86% (RR, 0.14 to 0.84). Some intermediate measurements for KOTAB alone and for IRS plus LLIN; and IRS plus KOTAB were not statistically significant. The bioassays on sprayed surfaces or netting materials showed favourable results (>80% mortality) for 22 months (IRS tested for 12 months). In the KOTAB, a gradual decline was observed after 6 months. CONCLUSIONS:LLIN and OUT was the best combination to reduce VL vector densities for 22 months or longer. Operationally, this is much easier to apply than IRS. A cost analysis of the preferred tools will follow. The relationship between vector density (males plus females) and leishmaniasis incidence should be investigated, and this will require estimates of the Entomological Inoculation Rate.

Background: An estimated 6.7 million persons are living with dementia in the United States, a number expected to double by 2060. Persons experiencing moderate to severe dementia are 4 to 5 times more likely to fall than those without dementia, due to agitation and unsteady gait. Socially assistive robots fail to address the changing emotional states associated with agitation, and it is unclear how emotional states change, how they impact agitation and gait over time, and how social robots can best respond by showing empathy., Objective: This study aims to design and validate a foundational model of emotional intelligence for empathetic patient-robot interaction that mitigates agitation among those at the highest risk: persons experiencing moderate to severe dementia., Methods: A design science approach will be adopted to (1) collect and store granular, personal, and chronological data using Personicle (an open-source software platform developed to automatically collect data from phones and other devices), incorporating real-time visual, audio, and physiological sensing technologies in a simulation laboratory and at board and care facilities; (2) develop statistical models to understand and forecast the emotional state, agitation level, and gait pattern of persons experiencing moderate to severe dementia in real time using machine learning and artificial intelligence and Personicle; (3) design and test an empathy-focused conversation model, focused on storytelling; and (4) test and evaluate this model for a care companion robot (CCR) in the community., Results: The study was funded in October 2023. For aim 1, architecture development for Personicle data collection began with a search for existing open-source data in January 2024. A community advisory board was formed and met in December 2023 to provide feedback on the use of CCRs and provide personal stories. Full institutional review board approval was received in March 2024 to place cameras and CCRs at the sites. In March 2024, atomic marker development was begun. For aim 2, after a review of open-source data on patients with dementia, the development of an emotional classifier was begun. Data labeling was started in April 2024 and completed in June 2024 with ongoing validation. Moreover, the team established a baseline multimodal model trained and validated on healthy-person data sets, using transformer architecture in a semisupervised manner, and later retrained on the labeled data set of patients experiencing moderate to severe dementia. In April 2024, empathy alignment of large language models was initiated using prompt engineering and reinforcement learning., Conclusions: This innovative caregiving approach is designed to recognize the signs of agitation and, upon recognition, intervene with empathetic verbal communication. This proposal has the potential to have a significant impact on an emerging field of computational dementia science by reducing unnecessary agitation and falls of persons experiencing moderate to severe dementia, while reducing caregiver burden., International Registered Report Identifier (irrid): PRR1-10.2196/55761., (©Adeline Nyamathi, Nikil Dutt, Jung-Ah Lee, Amir M Rahmani, Mahkameh Rasouli, Donna Krogh, Erik Krogh, David Sultzer, Humayun Rashid, Hamza Liaqat, Riyam Jawad, Farhan Azhar, Ali Ahmad, Bilal Qamar, Taha Yasin Bhatti, Chet Khay, Jocelyn Ludlow, Lisa Gibbs, Julie Rousseau, Mahyar Abbasian, Yutong Song, Cheonkam Jeong, Sabine Brunswicker. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 04.10.2024.)

Political skill has been established as an antidote to workplace stress and strain. However, despite the scholarly attention it has attracted, we still know very little about mediating mechanisms that explain this relationship and the role of political skill dimensions in mitigating workplace stressors. Thus, in this study, we investigate the impact of perceived control as a mediating mechanism between the political skill dimensions (i.e., social astuteness, interpersonal influence, networking ability, apparent sincerity) and interpersonal conflict (i.e., stress arising due to social interactions). Structural equation modeling was applied to analyze the data collected from 370 employees in a textile organization. The study found that perceived control mediated the relationship of social astuteness, interpersonal influence, and networking ability with interpersonal conflict. It, however, did not mediate the link between apparent sincerity and interpersonal conflict. Limitations, implications, and directions for future research are also discussed., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Incorporating the conservation of resources theory as a comprehensive framework, this study investigates a cohesive conceptual model analyzing the impact of workplace ostracism on employees' innovative work behavior (IWB). The investigation further delves into the mediating influence of perceived control and the moderating roles of paradox mindset and support for innovation. Data collection employed a survey approach involving three-time lags through questionnaires administered to 513 employees within Pakistan's public sector organizations. The hypothesized relationships were evaluated using conditional process modeling. Our research sheds light on how perceived control mitigates the negative impact of ostracism. The paradox mindset is identified as a key moderator influencing cognitive resources and navigating ostracism. Support for innovation enhances the link between perceived control and innovative work behavior. In addition, limitations, future research directions, and implications of our findings for fostering creative workplaces are also discussed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ahmad 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.)

Glucagon-like peptide-1 (GLP-1) receptor agonists are used in diabetes management and can have a potential application in cancer therapy. While their involvement in cancer treatment is still being studied, recent research suggests they may have benefits in cancer therapy. A comprehensive literature search was conducted using search engines like Google Scholar, Scopus, and PubMed to explore the effects of GLP-1 receptor agonists in tumor suppression and regression. Mostly in-vitro studies on GLP-1 receptor agonists have shown promising effects in inhibiting cancer cell growth, inducing apoptosis, and modulating angiogenesis and have been reported to be beneficial in colon, prostate, gall bladder, ovarian, and endometrial carcinomas. However, concerns have been raised about potential tumorigeneses, as liraglutide has been reported to be associated with increased incidence of breast, thyroid, and pancreatic carcinomas. Whereas combination therapy of exendin-4 with gemcitabine may be beneficial in pancreatic cancer. GLP-1 receptor agonists may have significant potential in oncology, due to their various mechanisms of action and favorable safety profiles. Limited clinical application, lack of awareness, and the need for further research are current barriers. Future studies should focus on optimal dosage, patient selection, and interdisciplinary collaboration to integrate GLP-1 receptor agonists into routine oncological practice for improved outcomes, warranting large randomized clinical trials in this field.

X-linked Dystonia-Parkinsonism (XDP) is an inherited, X-linked, adult-onset movement disorder characterized by degeneration in the neostriatum. No therapeutics alter disease progression. The mechanisms underlying regional differences in degeneration and adult onset are unknown. Developing therapeutics requires a deeper understanding of how XDP-relevant features vary in health and disease. XDP is possibly due, in part, to a partial loss of TAF1 function. A disease-specific SINE-VNTR-Alu (SVA) retrotransposon insertion occurs within intron 32 of TAF1 , a subunit of TFIID involved in transcription initiation. While all XDP males are usually clinically affected, females are heterozygous carriers generally not manifesting the full syndrome. As a resource for disease modeling, we characterized eight iPSC lines from three XDP female carrier individuals for X chromosome inactivation status and identified clonal lines that express either the wild-type X or XDP haplotype. Furthermore, we characterized XDP-relevant transcript expression in neurotypical humans, and found that SVA-F expression decreases after 30 years of age in the brain and that TAF1 is decreased in most female samples. Uniquely in the caudate nucleus, TAF1 expression is not sexually dimorphic and decreased after adolescence. These findings indicate that regional-, age- and sex-specific mechanisms regulate TAF1 , highlighting the importance of disease-relevant models and postmortem tissue. We propose that the decreased TAF1 expression in the adult caudate may synergize with the XDP-specific partial loss of TAF1 function in patients, thereby passing a minimum threshold of TAF1 function, and triggering degeneration in the neostriatum. Significance Statement XDP is an inherited, X-linked, adult-onset movement disorder characterized by degeneration in the neostriatum. No therapeutics alter disease progression. Developing therapeutics requires a deeper understanding of how XDP-relevant features vary in health and disease. XDP is possibly due to a partial loss of TAF1 function. While all XDP males are usually affected, females are heterozygous carriers generally not manifesting the full syndrome. As a resource for disease modeling, we characterized eight stem cell lines from XDP female carrier individuals. Furthermore, we found that, uniquely in the caudate nucleus, TAF1 expression decreases after adolescence in healthy humans. We hypothesize that the decrease of TAF1 after adolescence in human caudate, in general, may underlie the vulnerability of the adult neostriatum in XDP., Competing Interests: Authors report no conflict of interest, (Copyright © 2022 D’Ignazio et al.)

Background Chronic liver disease (CLD) is one of the most significant causes of morbidity and mortality among the pediatric age group. The identification of the etiology of the disease is of utmost importance for the effective management of the disease. Objective To determine the various causes of CLD in pediatric patients attending a large public sector pediatric hospital. Patients and methods A prospective cross-sectional study was conducted at the National Institute of Child Health, Karachi, Pakistan from August 1, 2021, to February 28, 2022. All patients below 16 years of age of either gender with more than three months of symptoms duration on admission were enrolled. The diagnosis was labeled after the standard reference ranges for the pediatric age group. Results Of 136 patients, the mean age was 4.42 ± 3.92 years. More than half of the patients were males (76, 55.9%). Hepatitis B (31, 22.8%), idiopathic (23, 16.9%), glycogen storage disorder (GSD) (21, 15.4%), and Wilson disease (14, 10.3%) were the most common cause of CLD. A significant association of hepatitis was observed with age (p-value < 0.001), residence (p-value = 0.048), symptomatic (p-value < 0.001), total bilirubin level (p-value = 0.003), direct bilirubin level (p-value = 0.002), and albumin level (p-value = 0.003). Whereas a significant association of GSD was observed with age (p-value = 0.001), residence (p-value < 0.001), and serum glutamic pyruvic transaminase (SGPT) level (p-value = 0.033). Conclusion In our cohort, hepatitis B, idiopathic, GSD, and Wilson disease were the most common causes of CLD in pediatric patients. Moreover, age, residence, symptomatic, total bilirubin level, direct bilirubin level, SGPT, and albumin level were the important predictor variables., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Sardar et al.)

Achieving intracellular delivery of protein therapeutics within cells remains a significant challenge. Although custom formulations are available for some protein therapeutics, the development of non-toxic delivery systems that can incorporate a variety of active protein cargo and maintain their stability, is a topic of great relevance. This study utilized ionic polyphosphazenes (PZ) that can assemble into supramolecular complexes through non-covalent interactions with different types of protein cargo. We tested a PEGylated graft copolymer (PZ-PEG) and a pyrrolidone containing linear derivative (PZ-PYR) for their ability to intracellularly deliver FITC-avidin, a model protein. In endothelial cells, PZ-PYR/protein exhibited both faster internalization and higher uptake levels than PZ-PEG/protein, while in cancer cells both polymers achieved similar uptake levels over time, although the internalization rate was slower for PZ-PYR/protein. Uptake was mediated by endocytosis through multiple mechanisms, PZ-PEG/avidin colocalized more profusely with endo-lysosomes, and PZ-PYR/avidin achieved greater cytosolic delivery. Consequently, a PZ-PYR-delivered anti-F-actin antibody was able to bind to cytosolic actin filaments without needing cell permeabilization. Similarly, a cell-impermeable Bax-BH3 peptide known to induce apoptosis, decreased cell viability when complexed with PZ-PYR, demonstrating endo-lysosomal escape. These biodegradable PZs were non-toxic to cells and represent a promising platform for drug delivery of protein therapeutics.

We aimed to examine the association between soft drink consumption and asthma and lung function among Qatari adults. In the cross-sectional study, we used data from 986 Qatari participants aged 20 years and above attending the Qatar Biobank Study. Usual consumption of soft drink was assessed using a food frequency questionnaire. Lung function was measured by spirometry and asthma was based on self-report. The associations between soft drink consumption and asthma and lung function were assessed using multivariable logistic and linear regression, respectively. In total, 65 participants out of 986 (6.6%) reported having asthma. A clear dose-response relationship between soft drink consumption and asthma was found. High soft drink consumers (≥7 times/week) were 2.60 (95% CI 1.20⁻5.63) times more likely to have asthma as compared to non-consumers. The association was partly mediated by BMI and inflammation. Diet soft drink consumption was positively associated with asthma (OR 1.12 (95% CI 1.02⁻1.23)) but not with lung function. Regular soft drink consumption was inversely associated with FEV1, but not with FVC. In conclusion, soft drink consumption is positively associated with asthma in Qatari adults. The association is partly mediated by obesity and inflammation. Limiting soft drink consumption should be taken into consideration for asthma prevention.

A series of biodegradable drug delivery polymers with intrinsic multifunctionality have been designed and synthesized utilizing a polyphosphazene macromolecular engineering approach. Novel water-soluble polymers, which contain carboxylic acid and pyrrolidone moieties attached to an inorganic phosphorus-nitrogen backbone, were characterized by a suite of physicochemical methods to confirm their structure, composition, and molecular sizes. All synthesized polyphosphazenes displayed composition-dependent hydrolytic degradability in aqueous solutions at neutral pH. Their formulations were stable at lower temperatures, potentially indicating adequate shelf life, but were characterized by accelerated degradation kinetics at elevated temperatures, including 37 °C. It was found that synthesized polyphosphazenes are capable of environmentally triggered self-assembly to produce nanoparticles with narrow polydispersity in the size range of 150-700 nm. Protein loading capacity of copolymers has been validated via their ability to noncovalently bind avidin without altering biological functionality. Acid-induced membrane-disruptive activity of polyphosphazenes has been established with an onset corresponding to the endosomal pH range and being dependent on polymer composition. The synthesized polyphosphazenes facilitated cell-surface interactions followed by time-dependent, vesicular-mediated, and saturable internalization of a model protein cargo into cancer cells, demonstrating the potential for intracellular delivery.

Platinum complexes are the most widely used anticancer drugs; however, new generations of agents are needed. The organoiridium(III) complex [(η(5) -Cp(xbiph) )Ir(phpy)(Cl)] (1-Cl), which contains π-bonded biphenyltetramethylcyclopentadienyl (Cp(xbiph) ) and C^N-chelated phenylpyridine (phpy) ligands, undergoes rapid hydrolysis of the chlorido ligand. In contrast, the pyridine complex [(η(5) -Cp(xbiph) )Ir(phpy)(py)](+) (1-py) aquates slowly, and is more potent (in nanomolar amounts) than both 1-Cl and cisplatin towards a wide range of cancer cells. The pyridine ligand protects 1-py from rapid reaction with intracellular glutathione. The high potency of 1-py correlates with its ability to increase substantially the level of reactive oxygen species (ROS) in cancer cells. The unprecedented ability of these iridium complexes to generate H2 O2 by catalytic hydride transfer from the coenzyme NADH to oxygen is demonstrated. Such organoiridium complexes are promising as a new generation of anticancer drugs for effective oxidant therapy., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Platinum complexes related to cisplatin, cis-[PtCl2(NH3)2], are successful anticancer drugs; however, other transition metal complexes offer potential for combating cisplatin resistance, decreasing side effects, and widening the spectrum of activity. Organometallic half-sandwich iridium (Ir(III)) complexes [Ir(Cp(x))(XY)Cl](+/0) (Cp(x) = biphenyltetramethylcyclopentadienyl and XY = phenanthroline (1), bipyridine (2), or phenylpyridine (3)) all hydrolyze rapidly, forming monofunctional G adducts on DNA with additional intercalation of the phenyl substituents on the Cp(x) ring. In comparison, highly potent complex 4 (Cp(x) = phenyltetramethylcyclopentadienyl and XY = N,N-dimethylphenylazopyridine) does not hydrolyze. All show higher potency toward A2780 human ovarian cancer cells compared to cisplatin, with 1, 3, and 4 also demonstrating higher potency in the National Cancer Institute (NCI) NCI-60 cell-line screen. Use of the NCI COMPARE algorithm (which predicts mechanisms of action (MoAs) for emerging anticancer compounds by correlating NCI-60 patterns of sensitivity) shows that the MoA of these Ir(III) complexes has no correlation to cisplatin (or oxaliplatin), with 3 and 4 emerging as particularly novel compounds. Those findings by COMPARE were experimentally probed by transmission electron microscopy (TEM) of A2780 cells exposed to 1, showing mitochondrial swelling and activation of apoptosis after 24 h. Significant changes in mitochondrial membrane polarization were detected by flow cytometry, and the potency of the complexes was enhanced ca. 5× by co-administration with a low concentration (5 μM) of the γ-glutamyl cysteine synthetase inhibitor L-buthionine sulfoximine (L-BSO). These studies reveal potential polypharmacology of organometallic Ir(III) complexes, with MoA and cell selectivity governed by structural changes in the chelating ligands.

Artificial enzymes: half-sandwich arene ruthenium(II) and cyclopentadienyl iridium(III) complexes containing N,N-chelated ligands can use NADH as a source of hydride for the reduction of ketones. Moreover, cyclopentadienyl phenanthroline iridium(III) derivatives at micromolar concentrations are robust catalysts for the production of H(2) from NADH in water and can raise the NAD(+)/NADH ratio in cancer cells., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Hepatitis B and hepatitis C are global health care problems causing morbidity and mortality. Much of it could be prevented by better education of the masses regarding its spread. The study was conducted to assess the knowledge base of internet users of Pakistan to help in formulating education strategies., Methods: A survey questionnaire consisting of 20 close ended questions was designed and hosted on a website. The responses submitted at the website were auto-emailed to the author., Results: A total of 1024 complete responses were included. The survey shows increased level of awareness according to the educational status. The knowledge status of lowest education level was also adequate possibly due to access to internet to these respondents., Conclusion: Internet users in Pakistan have adequate core knowledge regarding hepatitis.