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To describe the neurodevelopmental outcomes following extracorporeal membrane oxygenation (ECMO) in early infancy.Thirty-seven patients who had survived following ECMO support from 2008 to 2018 had their neurodevelopmental outcomes assessed and analysed using the Bayley Scales of Infant and Toddler Development. Developmental outcome was defined as impairment in any of the developmental domains of motor function, cognition and language with mild impairment being 1-2 standard deviations below the test mean, moderate being 2-3 standard deviations below and severe being greater than 3 standard deviations below.Of these 37 patients, the median age at admission to Paediatric Intensive Care Unit was 0.4 months (interquartile range 2.8 months) with all of the study patients having an underlying diagnosis of congenital cardiac disease and 37/40 (92.5%) ECMO runs occurring in the immediate post-operative period. Of the 29 patients who had had follow-up at 12 months of age or older, 3 (10.3%) had severe impairment, 4 (13.8%) had moderate impairment, 12 (41.3%) had mild impairment and 10 (34.5%) had no impairment. Gross motor function was most significantly impacted in 18/29 (62.1%) patients, of which 7/18 (38.9%) had severe impairment. This was followed by impairment of receptive language in 8/29 (27.6%) patients and expressive language in 6/29 (20.1%) patients.One in four infants undergoing ECMO treatment in early infancy has moderate to severe neurodevelopmental impairment. Gross motor and language are the most affected developmental domains.

BACKGROUND: The impact of gender on outcomes in patients suffering from coronavirus disease 2019 (COVID-19) is frequently debated. However, the synchronous influence of additional risk factors is seldom mentioned. With increasing emphasis on identifying patients who are at risk of complications from COVID-19, we decided to conduct a retrospective review to assess the influence of age and body mass index (BMI) on gender-based differences in outcomes. MATERIALS AND METHODS: A retrospective review of 1288 patients was conducted at a tertiary care hospital. Binary logistic regression was used to assess differences in risk factors and outcomes between genders. The associations between predictors and outcomes were described using odds ratios in tables, forest plots, and regression curves plotted using Sigma Plot. RESULTS: Majority of patients were women (53.6% vs. 46.4%). Median BMI in men was higher than women (p = 0.003). Key predictors for all-cause morbidity/mortality in men were diabetes, chronic kidney disease, and regular use of angiotensin-converting enzyme inhibitors. In women, age >65 and regular use of inhaled steroid were additional risk factors. Men had a higher risk of acute respiratory distress syndrome (2.83 [1.70–4.70]), acute renal failure (1.96 [1.20–3.20]), and had a longer length of stay (0.11 [1.52]). Obesity has a stronger bearing on outcomes in women, and age has a more pronounced effect on outcomes in men. CONCLUSION: Extremes of BMI and older age are associated with worse outcomes in both men and women. Obesity has a stronger bearing on outcomes of COVID-19 infection in women, while the effect of older age on outcomes is more pronounced in men.

Neglected tropical disease (NTD) is a set of 20 deadliest endemic diseases which shows its presence in most of the developing countries worldwide. Nearly 1 billion of the population are affected by it and suffered from poverty yearly. These diseases offer their own unique challenges and limitations towards effective prevention and treatment methods. Neglected tropical diseases are severe infections they may not kill the patient but debilitate the patient by causing severe skin deformities, disfigurement and horrible risks for several infections. Existing therapies for neglected diseases suffer from the loopholes like high degree of toxicity, side effects, low bioavailability, improper targeting and problematic application for affected populations. Progress in the field of nanotechnology in last decades suggested the intervention of nanocarriers to take over and drive the research and development to the next level by incorporating established drugs into the nanocarriers rather than discovering the newer drugs which is an expensive affair. These nanocarriers are believed to be a sure shot technique to fight infections at root level by virtue of its nanosize and ability to reach at cellular level. This article highlights the recent advances, rationale, targets and the challenges that are being faced to fight against NTDs and how the novel therapy tactics are able to contribute to its importance in prevention and treatment of NTDs.

Drug delivery systems (DDS) that can temporally control the rate and extent of release of therapeutically active molecules find applications in many clinical settings, ranging from infection control to cancer therapy. With an aim to design a locally implantable, controlled-release DDS, we demonstrated the feasibility of using cellulose nanocrystal (CNC)-reinforced poly (l-lactic acid) (PLA) composite beads. The performance of the platform was evaluated using doxorubicin (DOX) as a model drug for applications in triple-negative breast cancer. A facile, nonsolvent-induced phase separation (NIPS) method was adopted to form composite beads. We observed that CNC loading within these beads played a critical role in the mechanical stability, porosity, water uptake, diffusion, release, and pharmacological activity of the drug from the delivery system. When loaded with DOX, composite beads significantly controlled the release of the drug in a pH-dependent pattern. For example, PLA/CNC beads containing 37.5 wt % of CNCs showed a biphasic release of DOX, where 41 and 82% of the loaded drug were released at pH 7.4 and pH 5.5, respectively, over 7 days. Drug release followed Korsmeyer's kinetics, indicating that the release mechanism was mostly diffusion and swelling-controlled. We showed that DOX released from drug-loaded PLA/CNC composite beads locally suppressed the growth and proliferation of triple-negative breast cancer cells, MBA-MB-231, via the apoptotic pathway. The efficacy of the DDS was evaluated in human tissue explants. We envision that such systems will find applications for designing biobased platforms with programmed stability and drug delivery functions.

RING-B box-coiled coil (RBCC) domain of promyelocytic leukemia (PML) comprises a zinc finger motif that is targeted by arsenic trioxide (ATO) to treat acute promyelocytic leukemia (APL) pathogenesis. Preliminary evidence suggests that the PML-RBCC has different functional characteristics, but no structural details have been reported despite its importance in differential expression and cell-cycle regulation. Therefore, the recombinant h-PML-RBCC protein was purified to its homogeneity, and characterized for oligomeric behaviour which indicated that RBCC domain exists as a tetramer in solution. Furthermore, nano-DSF and circular-dichroism demonstrated that the tetrameric form preserves its native conformation along with thermal stability (Tm = 83.2 °C). In-silico-based PML-RBCC structure was used to perform the molecular dynamics simulation for 300 ns in the presence of zinc atoms, which demonstrated the differential dynamic of PML-RBCC tetrameric chains. MMPBSA analysis also indicated the role of hydrophobic interactions that favours stable tetrameric structure of PML-RBCC. ATO-induced secondary and tertiary structure changes were observed in PML-RBCC using circular dichroism and fluorescence spectroscopy. Dynamic light scattering and transmission electron microscopy revealed ATO-induced higher-order oligomerization and aggregation of PML-RBCC. The unique oligomeric nature of the h-PML-RBCC protein and its interactions with ATO will help to understand the mechanism of APL pathogenesis and drug resistance.

A study was undertaken to determine the contents of trace metals in 60 topsoils and 80 brinjal fruits samples from a famous brinjal-producing area of Bangladesh using atomic absorption spectrophotometer. The study also looked at soil pollution levels, dietary intake of nutritionally important trace elements, and human health risks from toxic metals induced by dermal soil exposure and consumption of brinjal. The content of Pb, Ni, Cd, Cu, Fe, Mn, and Zn in brinjal fruits harvested from farmer′s fields ranged from 0.204–0.729, 0.031–0.212, -1, respectively, while the amount of Cr was negligible. The calculated enrichment factors showed that 70, 50, and 25% of soil sampling sites had values in the 2.00–5.00 range for Pb, Zn, and Cd, respectively, while 30% of sites had values > 5.00 for Cd, indicating moderate to significant enrichment of these metals in the soil. The study also revealed that brinjal consumption provides a tiny amount of nutritionally important trace elements required for an adult human. Regarding the computed incremental lifetime cancer risks (ILCR), the study revealed that the values for Pb and Ni in all samples and Cd in 40% of samples were several hundred times higher for males and females than the USEPA threshold level due to oral ingestion of brinjal fruits. In contrast, dermal exposures to soil trace elements were within an acceptable range. The PCA results revealed that the contents of Cd, Pb, Ni, and Cu in soils showed strong positive correlations with those elements present in brinjal. The current study suggests future traceability research, focusing on pinpointing potential entry routes for toxic elements into the vegetable food chain.

Background Kikuchi-Fujimoto disease (KFD) or necrotizing histiocytic lymphadenitis, was described separately by both Kikuchi and Fujimoto in Japan in the early 1970’s. Despite its rarity in the pediatric population, it is an important differential in persistent lymphadenopathy. Familial cases of KFD in the literature are rare. Here we describe the first reported case of KFD in non-identical twin sisters. Case presentation Twin 1 presented with a 3-week history of worsening right-sided cervical lymphadenopathy, daily fevers, significant lethargy, weight loss and arthralgia of her knees and ankles at the age of 12 years in 2015. She had had an unremarkable medical history. A biopsy of her lymph nodes showed histiocytic necrosis consistent with KFD. Twin 2 presented with a three-week history of lethargy, fatigue, weight loss and left-sided posterior cervical chain lymphadenopathy at 16 years of age in 2018. She had a history of frequently relapsing nephrotic syndrome and celiac disease. A biopsy of her lymph nodes was undertaken and showed histiocytic necrosis consistent with KFD. Conclusions KFD is a rare but self-limiting pathological process of necrotizing histiocytic lymphadenitis. Although further research is needed, there is an increasing amount of evidence which suggests a multifactorial pathological basis of disease. The two cases we document here are the first reported cases of familial KFD in dizygotic HLA-identical twins which reinforces the likely HLA-linkage in the etiology of KFD.

In response to DNA damage, a synthetic lethal relationship exists between the cell cycle checkpoint kinase MK2 and the tumor suppressor p53. Here, we describe the concept of augmented synthetic lethality (ASL): depletion of a third gene product enhances a pre-existing synthetic lethal combination. We show that loss of the DNA repair protein XPA markedly augments the synthetic lethality between MK2 and p53, enhancing anti-tumor responses alone and in combination with cisplatin chemotherapy. Delivery of siRNA-peptide nanoplexes co-targeting MK2 and XPA to pre-existing p53-deficient tumors in a highly aggressive, immunocompetent mouse model of lung adenocarcinoma improves long-term survival and cisplatin response beyond those of the synthetic lethal p53 mutant/MK2 combination alone. These findings establish a mechanism for co-targeting DNA damage-induced cell cycle checkpoints in combination with repair of cisplatin-DNA lesions in vivo using RNAi nanocarriers, and motivate further exploration of ASL as a generalized strategy to improve cancer treatment., Cell cycle checkpoint kinase, MK2, is in synthetic relationship with p53 in the DNA damage response to chemotherapeutic agents. Here, the authors report XPA as a third gene in which simultaneous targeting of MK2 and XPA further enhances sensitivity to cisplatin in p53-deficient tumours.

Background The prevalence of urinary symptoms and infections among female garment factory workers in Bangladesh - a large developing country - is largely unknown. Garment sector is this country's main economic growth engine. Objectives This paper focuses on garment industry workers and compares the findings with another group of low socioeconomic status working women. Methods Urinary tract symptoms (UTS) were determined by self-reported survey including International Consultation on Incontinence Modular Questionnaire-Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) and urinary tract infection (UTI) was determined among a subset population by urine dipstick tests. Results Data were collected from 310 garment workers and 297 comparison workers. About one third of garment workers (31.94%) and comparison workers (29.97%) could take up to 3 toilet breaks in a day. Garment workers reported to be more sexually active and menstruation was more common among them compared to comparison workers. They reported a significantly higher prevalence of malodorous urine and vaginal discharge. Garment workers were found to have a significantly higher ICIQ-FLUTS score of voiding than comparison workers (0.44 vs. 0.27; p-value = 0.0167).Among the study respondents, 148 garment workers and 134 other workers provided urine samples and 21 (7.45%) were found to have UTI. After considering all the risk factors in multivariate model, garment work had a significant impact on the probability of having UTI with Odds Ratio of 5.46 (p-value = 0.0374; 95% CI = 1.10, 26.97) compared to other workers. Conclusions This study highlights the prevalence and burden of urinary symptoms and infections among female worker populations in Bangladesh.

Oral drug administration is the oldest and widely used method for drug administration. The objectives behind developing an oral drug delivery for the treatment of cancer are to achieve low cost treatment by utilizing novel techniques to target cancer through gut-associated lymphoid tissue (GALT) and to enhance patient comfort and compliance through a hospital-free treatment leading to "Chemotherapy at Home." Unfortunately, due to the physiological environment of the GIT and physicochemical properties of drug candidate, the efficacy of oral drug delivery methods is limited in the treatment of cancer. Due to their low hydrophilicity, high P-gp efflux and restricted intestinal permeability most of the anti-cancer drugs fail to achieve oral bioavailability. The review focuses on the efforts, challenges, opportunities and studies conducted by scientists worldwide on the oral administration of anticancer medications via nanocarriers such as liposomes, SLNs and dendrimers, because of their potential to overcome the epithelial barrier associated with GALT, as well as the applications of different polymers in targeting the cancer. The oral delivery can set newer horizons in cancer therapy to make it more patient friendly.

Background Knee osteoarthritis was reported as the second most prevalent condition in the national musculoskeletal survey. The purpose of this extended study was to identify risk factors for knee osteoarthritis in Bangladeshi adults. Methods This cross-sectional study was conducted in rural and urban areas of Bangladesh using stratified multistage cluster sample of 2000 adults aged 18 years or older recruited at their households. The Modified Community Oriented Program for Control of Rheumatic Disorders (COPCORD) questionnaire was used to collect data. The diagnosis of knee osteoarthritis was made using the decision tree clinical categorization criteria of the American College of Rheumatology. Univariate and multivariate logistic regression analyses were done to identify the risk factors for knee osteoarthritis. Results A total of 1843 individuals (892 men and 951 women) participated, and 134 had knee osteoarthritis yielding a prevalence of 7.3% (95% confidence interval (CI) 4.9 to 9.6%). The mean (standard deviation) age of the knee osteoarthritis patients was 51.7 (11.2) years. Multivariate logistic regression analysis found a significant association with increasing age (≥38 years OR 8.9, 95% CI 4.8–16.5; ≥58 years OR 13.9, 95% CI 6.9–28.0), low educational level (OR 1.7, 95% CI 1.0–2.7) and overweight (OR 1.9, 95% CI 1.2–2.9) with knee osteoarthritis. Knee osteoarthritis patients had a high likelihood of having work loss preceding 12 months (age and sex-adjusted OR 2.3; 95% CI 1.4–3.8; P Conclusions Knee osteoarthritis is a commonly prevalent musculoskeletal problem among Bangladeshi adults having link to work loss. Increasing age, low education and overweight are significant risk factors of knee osteoarthritis.

Prior to coronavirus disease 2019 (COVID-19), tuberculosis (TB) was the worst killer among infectious diseases. The union of these two obnoxious respiratory diseases can be devastating, with severe public health implications. The COVID-19 pandemic has affected all TB-elimination programmes due to the severe burden on healthcare systems and the diversion of funds and attention towards controlling the pandemic. The emerging data show that the COVID-19 pandemic caused a marked decrease in case notifications and bacille Calmette–Guérin immunisations, ultimately promoting disease transmission and increasing the susceptible population. The similarity between the clinical characteristics of TB and COVID-19 adds to the public health complications, with evidence of immune dysregulation in both cases leading to severe consequences. Clinical evidence suggests that severe acute respiratory syndrome coronavirus 2 infection predisposes patients to TB infection or may lead to reactivation of latent disease. Similarly, underlying TB disease can worsen COVID-19. Treatment options are limited in COVID-19; therefore, using immunosuppressive and immunomodulatory regimens that can modulate the concomitant bacterial infection and interaction with anti-TB drugs requires caution. Thus, considering the synergistic impact of these two respiratory diseases, it is crucial to manage both diseases to combat the syndemic of TB and COVID-19.

Breast cancer type 2 susceptibility (BRCA2) protein plays an essential role in the repair mechanism of DNA double-strand breaks and interstrand cross-links by Homologous recombination. Germline mutations identified in the BRCA2 gene confer an increased risk of hereditary breast and ovarian cancer. Missense mutations are identified all over the gene, including the DNA binding region of BRCA2 that interacts with FANCD2. However, the majority of these missense mutations are classified as 'Variants of Uncertain Significance' due to a lack of structural, functional and clinical correlations. Therefore, multi-disciplinary in-silico, in-vitro and biophysical approaches have been explored to characterize an unclassified missense mutation, BRCA2 Arg2502Cys, identified from a case-control study. Circular-dichroism and Fluorescence spectroscopy show that the Arg2502Cys mutation in hBRCA2 (residues 2350-2545) decreases the α-helical/β-sheet propensity of the wild-type protein and perturb the tertiary structure conformation. Molecular dynamics simulations revealed alteration in the intramolecular H-bonds, overall compactness and stability of the hydrophobic core were observed in the mutant protein. Principle component analysis indicated that Arg2502Cys mutant exhibited comparatively large conformational transitions and periodic fluctuation. Therefore, to our conclusion, BRCA2 Arg2502Cys mutant perturbed the structural integrity and conformational dynamics of BRCA2.

A quantitative assessment was attempted to determine concentrations of total arsenic (As) in farmer's field soils and fruits of brinjal collected from two famous brinjals producing Upazila's, namely Melandaha and Islampur of Jamalpur district, Bangladesh. The study also evaluated cancer and non-cancer health risks for both males and females caused by dermal exposure of soils and dietary intake of brinjal grown in farmers' fields and sold at different markets of four country districts. The study findings revealed that 75% of soil sampling locations had enrichment factor (EFc) values 1.5, indicating the anthropogenic sources of As, and 50% of the sites possessed EFc values within the range of 2.0-5.0 indicated moderate enrichment of As. The mean concentrations of As in brinjal grown in farmers' fields and retailers of different markets of four districts were 0.18 and 0.39 µg g

We explored the potential of cellulose nanofiber (CNF) for designing prolonged-release, thin-film drug delivery systems (TF-DDS). These delivery systems can be used as locally deployable drug-releasing scaffolds for achieving spatial and temporal control over therapeutic concentration in target tissues. Using doxorubicin (DOX) as a model anticancer drug, CNF-based TF-DDS were prepared using different film-formation processes, such as solvent casting and lyophilization. Formulations were prepared with or without the incorporation of additional macromolecular additives, such as gelatin, to include further biomechanical functionality. We studied the films for their mechanical properties, thermal stability, wettability, porosity and in vitro drug release properties. Our experimental results showed that CNF-based films, when prepared via solvent casting method, showed optimized performance in terms of DOX loading, and prolonged-release than those prepared via lyophilization-based fabrication processes. Scanning electron microscopy (SEM) analysis of the CNF-based films showed uniform distribution of fiber entanglement, which provided the scaffolds with sufficient porosity and tortuosity contributing to the sustained release of the drug from the delivery system. We also observed that surface layering of gelatin on CNF films via dip-coating significantly increased the mechanical strength and reduced the wettability of the films, and as such, affected drug release kinetics. The performance of the TF-DDS was evaluated in-vitro against two pancreatic cancer cell lines, i.e. MIA PaCa-2 and PANC-1. We observed that, along with the enhancement of mean dissolution time (MDT) of DOX, CNF-based TF-DDS were able to suppress the proliferation of pancreatic cancer cells in a time-dependent fashion, indicating that the drug liberated from the films were therapeutically active against cancer cells. Additionally, TF-DDS were also tested ex-vivo on patient-derived xenograft (PDX) model of pancreatic ductal adenocarcinoma (PDAC). We observed that DOX released from the TF-DDS was able to reduce Ki-67 positive, pancreatic cancer cells in these models.

Purpose: On April 24, 2013 a building called "Rana Plaza" that housed several garment factories collapsed in Bangladesh. Around 1134 people died and more than 2500 sustained serious injuries. This study evaluates the change in income and occupation of the Rana Plaza survivors as well as their level of community participation and quality of life two years after the incident. It also aimed to gain insight into these survivors' success or failure in economic reintegration. Methods: A cross-sectional survey collected data from the injured garment workers using convenience sampling method. The Short Form 36 Items Questionnaire measured their quality of life, and the Participation Scale measured their community participation restriction level. Poor economic reintegration was defined when a survivor was not working or had an income less than 3000 Taka [US$36]/month. Results: Data were collected from 338 Rana Plaza survivors all of who were previously garment workers. Their income decreased substantially after the disaster. The majority were now engaged in earning livelihood from retail shop management and animal husbandry. A total of 124 survivors (36.6%) were found to be poorly economically reintegrated; females were found to be at greater odds (twice) of poor economic reintegration than males. Those with severe participation restriction scores had four times greater odds and who reported moderate restriction had two times greater odds of poor economic reintegration compared to those with no restriction. Conclusions: Survivors of Rana Plaza factory disaster were facing many health and economic challenges two years after the event. Implications for rehabilitation Rehabilitation service providers should document and describe the health status correctly to understand the burden and monitor the effectiveness of their intervention. Government needs to develop and strengthen rehabilitation capacity as more workers will be injured as the country rapidly industrializes. Factory owners should create light duty work opportunities and provide other workplace modification for injured workers to re-enter the workforce.

Hereditary spastic paraplegias (HSPs) are a diverse group of genetic conditions with variable severity and onset age. From a neurogenetic clinic, we identified 14 patients with very late-onset HSP, with symptoms starting after the age of 35. In this cohort, sequencing of known genetic causes was performed using clinically available HSP sequencing panels. We identified 4 patients with mutations in SPG7 and 3 patients with SPAST mutations, representing 50% of the cohort and indicating a very high diagnostic yield. In the SPG7 group, we identified novel variants in two patients. We have also identified two novel mutations in the SPAST group. We present sequencing data from cDNA and RT-qPCR to support the pathogenicity of these variants, and provide observations regarding the poor genotype-phenotype correlation in these conditions that should be the subject of future study.

Epigallocatechin‐3‐gallate (EGCG) has been considered an anticancer agent despite conflicting and discrepant bioavailability views. EGCG impairs the viability and self‐renewal capacity of triple‐negative breast cancer (TNBC) cells and makes them sensitive to estrogen via activating ER‐α. Surprisingly, the mechanism of EGCG’s action on TNBC cells remains unclear. CCN5/WISP‐2 is a gatekeeper gene that regulates viability, ER‐α, and stemness in TNBC and other types of cancers. This study aimed to investigate whether EGCG (free or encapsulated in nanoparticles) interacts with the CCN5 protein by emphasizing its bioavailability and enhancing its anticancer effect. We demonstrate that EGCG activates CCN5 to inhibit in vitro cell viability through apoptosis, the sphere‐forming ability via reversing TNBC cells’ stemness, and suppressing tumor growth in vivo. Moreover, we found EGCG‐loaded nanoparticles to be functionally more active and superior in their tumor‐suppressing ability than free‐EGCG. Together, these studies identify EGCG (free or encapsulated) as a novel activator of CCN5 in TNBC cells and hold promise as a future therapeutic option for TNBC with upregulated CCN5 expression., CCN5 acts as a tumor suppressor/anti‐invasive protein in TNBC. Free or encapsulated EGCG treatment promotes CCN5 expression in TNBC cells to suppress the growth and progression of TNBC.

A 25-year-old longsighted woman presented with a history of spectacle and contact lens induced exacerbation of Tourette syndrome symptoms. Preoperatively, she had very poor unaided vision (6/60), achieving good (6/9) vision in both eyes with spectacle correction. The patient underwent bilateral simultaneous implantation of phakic implantable collamer lens (ICL) implants (STAAR, USA) which sit in front of the natural lens. Postoperatively, her uncorrected visual acuity was markedly improved as were her manifestations of Tourette syndrome. She achieved her full potential of unaided vision (6/9). This is the first documented case of Tourette syndrome triggered by glasses and contact lenses in which bilateral phakic toric lens implants were effective in improving vision and controlling motor symptoms. Phakic toric ICL implantation is a reversible technique for the correction of visually significant ametropia in selected patients and has improved this patient’s quality of life.

Advanced materials and chemo-specific designs at the nano/micrometer-scale have ensured revolutionary progress in next-generation clinically relevant technologies. For example, isolating a rare population of cells, like circulating tumor cells (CTCs) from the blood amongst billions of other blood cells, is one of the most complex scientific challenges in cancer diagnostics. The chemical tunability for achieving this degree of exceptional specificity for extra-cellular biomarker interactions demands the utility of advanced entities and multistep reactions both in solution and in the insoluble state. Thus, this review delineates the chemo-specific substrates, chemical methods, and structure–activity relationships (SARs) of chemical platforms used for isolation and enumeration of CTCs in advancing the relevance of liquid biopsy in cancer diagnostics and disease management. We highlight the synthesis of cell-specific, tumor biomarker-based, chemo-specific substrates utilizing functionalized linkers through chemistry-based conjugation strategies. The capacity of these nano/micro substrates to enhance the cell interaction specificity and efficiency with the targeted tumor cells is detailed. Furthermore, this review accounts for the importance of CTC capture and other downstream processes involving genotypic and phenotypic CTC analysis in real-time for the detection of the early onset of metastases progression and chemotherapy treatment response, and for monitoring progression free-survival (PFS), disease-free survival (DFS), and eventually overall survival (OS) in cancer patients.

Pancreatic ductal adenocarcinoma (PDAC), a metabolic disorder, remains one of the leading cancer mortality sources worldwide. An initial response to treatments, such as gemcitabine (GEM), is often followed by emergent resistance reflecting an urgent need for alternate therapies. The PDAC resistance to GEM could be due to ERK1/2 activity. However, successful ERKi therapy is hindered due to low ligand efficiency, poor drug delivery, and toxicity. In this study, to overcome these limitations, we have designed pH-responsive nanoparticles (pHNPs) with a size range of 100-150 nm for the simultaneous delivery of ERKi (SCH 772984) and GEM with tolerable doses. These pHNPs are polyethylene glycol (PEG)-containing amphiphilic polycarbonate block copolymers with tertiary amine side chains. They are systemically stable and capable of improving in vitro and in vivo drug delivery at the cellular environment's acidic pH. The functional analysis indicates that the nanomolar doses of ERKi or GEM significantly decreased the 50% growth inhibition (IC50) of PDAC cells when encapsulated in pHNPs compared to free drugs. The combination of ERKi with GEM displayed a synergistic inhibitory effect. Unexpectedly, we uncover that the minimum effective dose of ERKi significantly promotes GEM activities on PDAC cells. Furthermore, we found that pHNP-encapsulated combination therapy of ERKi with GEM was superior to unencapsulated combination drug therapy. Our findings, thus, reveal a simple, yet efficient, drug delivery approach to overcome the limitations of ERKi for clinical applications and present a new model of sensitization of GEM by ERKi with no or minimal toxicity.

Innate immune signaling and xenophagy are crucial innate defense strategies exploited by the host to counteract intracellular pathogens with ubiquitination as a critical regulator of these processes. These pathogens, including Mycobacterium tuberculosis (M. tb), co-opt the host ubiquitin machinery by utilizing secreted or cell surface effectors to dampen innate host defenses. Inversely, the host utilizes ubiquitin ligase-mediated ubiquitination of intracellular pathogens and recruits autophagy receptors to induce xenophagy. In the current article, we discuss the co-option of the ubiquitin pathway by the M. tb virulence effectors.Abbreviations: ANAPC2: anaphase promoting complex subunit 2; IL: interleukin; Lys: lysine (K); MAPK: mitogen-activated protein kinase; MAP3K7/TAK1; mitogen-activated protein kinase kinase kinase 7; M. tb: Mycobacterium tuberculosis; NFKB/NF-κB: nuclear factor kappa B subunit; PtpA: protein tyrosine phosphatase; SQSTM1/p62: sequestosome 1; V-ATPase: vacuolar-type H+-ATPase; UBA: a eukaryotic-like ubiquitin-associated domain.

The molecular architecture of pH-responsive amphiphilic block copolymers, their self-assembly behavior to form nanoparticles (NPs), and doxorubicin (DOX)-loading technique govern the extent of DOX-induced cardiotoxicity. We observed that the choice of pH-sensitive tertiary amines, surface charge, and DOX-loading techniques within the self-assembled NPs strongly influence the release and stimulation of DOX-induced cardiotoxicity in primary cardiomyocytes. However, covalent conjugation of DOX to a pH-sensitive nanocarrier through a "conditionally unstable amide" linkage (PCPY-cDOX; PC = polycarbonate and PY = 2-pyrrolidine-1-yl-ethyl-amine) significantly reduced the cardiotoxicity of DOX in cardiomyocytes as compared to noncovalently encapsulated DOX NPs (PCPY-eDOX). When these formulations were tested for drug release in serum-containing media, the PCPY-cDOX systems showed prolonged control over drug release (for ∼72 h) at acidic pH compared to DOX-encapsulated nanocarriers, as expected. We found that DOX-encapsulated nanoformulations triggered cardiotoxicity in primary cardiomyocytes more acutely, while conjugated systems such as PCPY-cDOX prevented cardiotoxicity by disabling the nuclear entry of the drug. Using 2D and 3D (spheroid) cultures of an ER + breast cancer cell line (MCF-7) and a triple-negative breast cancer cell line (MDA-MB-231), we unravel that, similar to encapsulated systems (PCPY-eDOX-type) as reported earlier, the PCPY-cDOX system suppresses cellular proliferation in both cell lines and enhances trafficking through 3D spheroids of MDA-MB-231 cells. Collectively, our studies indicate that PCPY-cDOX is less cardiotoxic as compared to noncovalently encapsulated variants without compromising the chemotherapeutic properties of the drug. Thus, our studies suggest that the appropriate selection of the nanocarrier for DOX delivery may prove fruitful in shifting the balance between low cardiotoxicity and triggering the chemotherapeutic potency of DOX.

SETTING: A large specialised chest hospital in Pakistan.OBJECTIVE: To study outcomes of comprehensive Xpert® MTB/RIF and universal rifampicin testing.DESIGN: A hospital-based, 3-year retrospective record review of registered TB patients.RESULTS: During the study, 11 744 TB patients were registered when the number of annual notifications remained stagnant. Xpert use increased dramatically in adults with pulmonary TB (PTB) from less than 1% tested with Xpert alone in 2016, to 81.6% by 2018. Significant increases were seen in bacteriologically confirmed PTB in adults from 64% to 77.3% (P < 0.001). No remarkable changes were seen in testing and confirmation of PTB in children or extrapulmonary TB. Significantly lower (P < 0.001) rifampicin resistance (RR) was observed among those with smear-negative compared to those with smear-positive results among new (1.0% vs. 5.1%) and previously treated PTB cases (2.0% vs. 14.4%). Most importantly, a significant decline in RR was observed among previously treated individuals, from 15.4% (95%CI 12.2–19.0) to 8.6% (95%CI 6.6–11.0) during the study. A decrease in RR was also documented in newly diagnosed PTB patients, but this was not statistically significant.CONCLUSION: Universal rifampicin testing is feasible in adult PTB patients; a decline in RR was seen among previously treated individuals with PTB.

Prediction of the three-dimensional (3D) structure of a protein from its sequence is important for studying its biological function. With the advancement in deep learning contact distance prediction and residue-residue coevolutionary analysis, significant progress has been made in both template-based and template-free protein structure prediction in the last several years. Here, we provide a practical guide for our latest MULTICOM protein structure prediction system built on top of the latest advances, which was rigorously tested in the 2018 CASP13 experiment. Its specific functionalities include: (1) prediction of 1D structural features (secondary structure, solvent accessibility, disordered regions) and 2D interresidue contacts; (2) domain boundary prediction; (3) template-based (or homology) 3D structure modeling; (4) contact distance-driven ab initio 3D structure modeling; and (5) large-scale protein quality assessment enhanced by deep learning and predicted contacts. The MULTICOM web server ( http://sysbio.rnet.missouri.edu/multicom_cluster/ ) presents all the 1D, 2D, and 3D prediction results and quality assessment to users via user-friendly web interfaces and e-mails. The source code of the MULTICOM package is also available at https://github.com/multicom-toolbox/multicom .

Herein we report a hierarchically organized, water-dispersible ‘nanocage’ composed of cellulose nanocrystals (CNCs), which are magnetically powered by iron oxide (Fe3O4) nanoparticles (NPs) to capture circulating tumor cells (CTCs) in blood for head and neck cancer (HNC) patients. Capturing CTCs from peripheral blood is extremely challenging due to their low abundance and its account is clinically validated in progression-free survival of patients with HNC. Engaging multiple hydroxyl groups along the molecular backbone of CNC, we co-ordinated Fe3O4 NPs onto CNC scaffold, which was further modified by conjugation with a protein - transferrin (Tf) for targeted capture of CTCs. Owing to the presence of Fe3O4 nanoparticles, these nanocages were magnetic in nature, and CTCs could be captured under the influence of a magnetic field. Tf-CNC-based nanocages were evaluated using HNC patients’ blood sample and compared for the CTC capturing efficiency with clinically relevant Oncoviu platform. Conclusively, we observed that CNC-derived nanocages efficiently isolated CTCs from patient’s blood at 85% of cell capture efficiency to that of the standard platform. Capture efficiency was found to vary with the concentration of Tf and Fe3O4 nanoparticles immobilized onto the CNC scaffold. We envision that, Tf-CNC platform has immense connotation in ‘liquid biopsy’ for isolation and enumeration of CTCs for early detection of metastasis in cancer.

In pancreatic ductal adenocarcinoma (PDAC), early onset of hypoxia triggers remodeling of the extracellular matrix, epithelial-to-mesenchymal transition, increased cell survival, the formation of cancer stem cells, and drug resistance. Hypoxia in PDAC is also associated with the development of collagen-rich, fibrous extracellular stroma (desmoplasia), resulting in severely impaired drug penetration. To overcome these daunting challenges, we created polymer nanoparticles (polymersomes) that target and penetrate pancreatic tumors, reach the hypoxic niches, undergo rapid structural destabilization, and release the encapsulated drugs. In vitro studies indicated a high cellular uptake of the polymersomes and increased cytotoxicity of the drugs under hypoxia compared to unencapsulated drugs. The polymersomes decreased tumor growth by nearly 250% and significantly increased necrosis within the tumors by 60% in mice compared to untreated controls. We anticipate that these polymer nanoparticles possess a considerable translational potential for delivering drugs to solid hypoxic tumors.

BackgroundPakistan is among top five high burden countries for tuberculosis and drug resistant TB. Among rifampicin sensitive new pulmonary TB (PTB), prevalence of isoniazid resistance is 8.3% (95%CI: 7.0-10.7) and resistance to fluoroquinolone is higher (11·1%, 95%CI: 7·8-14·3) than isoniazid resistance.MethodFive year retrospective data (2015-2019) of drug susceptibility testing (DST) for Mycobacterium tuberculosis isolates, performed using recommended phenotypic (pDST) and/or genotypic (gDST) methods was analyzed stratified by rifampicin results for isoniazid resistance profiles and associated levofloxacin and pyrazinamide resistance.FindingsDST data was analyzed from 11045 TB patients. Isolates were tested using pDST (87%), gDST (92%) and both methods (79.5%). For both rifampicin and isoniazid, a significant difference (P < .001) was noted between resistance detected by pDST and gDST. Among isolates, tested by both methods (8787), 49% were resistant to rifampicin and 51.7% to isoniazid with discordance in resistant results of 15.8% for each, with 13.2% (570) of rifampicin resistance reported sensitive by pDST and 14.2% (660) of isoniazid resistance missed by gDST. Estimated isoniazid resistance among rifampicin sensitive new PTB, extrapulmonary TB and previously treated PTB was 9.8% (95%CI: 8.7-11.1), 6.8% (95%CI: 5.4-8.5) and 14.6% (95%CI: 11.8-17.9) respectively. Significant differences were reported between the genotypic profile of isoniazid resistance associated with rifampicin-resistant and sensitive isolates including detectable mutations (87% vs 71.6%), frequency of inhA (7.6% and 30.2%) and katG mutations (76.1% vs 41.2%) respectively. Among rifampicin resistant and sensitive isolates, a significantly higher level of resistance to levofloxacin and pyrazinamide was seen associated with isoniazid resistance.ConclusionThere are risks and many challenges in implementing WHO recommended treatment for isoniazid resistant tuberculosis. The laboratory based surveillance can complement random surveys in country specific planning for TB diagnostics and appropriate treatment regimens.

Background Pakistan is fifth among high burden countries for tuberculosis. A steady increase is seen in extrapulmonary tuberculosis (EPTB), which now accounts for 20% of all notified TB cases. There is very limited information on the epidemiology of EPTB. This study was performed with the aim to describe the demographic characteristics, clinical manifestations and treatment outcomes of EPTB patients in Pakistan. Method We performed descriptive analysis on routinely collected data for cohorts of TB patients registered nationwide in 2016 at health facilities selected using stratified convenient sampling. Findings Altogether 54092 TB including 15790 (29.2%) EPTB cases were registered in 2016 at 50 study sites. The median age was 24 years for EPTB and 30 years for PTB patients. The crude prevalence of EPTB in females was 30.5% (95%CI; 29.9–31.0) compared to 27.9% (95%CI; 27.3–28.4) in males. The likelihood of having EPTB (OR), was 1.1 times greater for females, 2.0 times for children, and 3.3 times for residents of provinces in the North-West. The most common forms of EPTB were pleural (29.6%), lymphatic (22.7%) and abdominal TB (21.0%). Pleural TB was the most common clinical manifestation in adults (34.2%) and abdominal TB in children (38.4%). An increase in the prevalence of pleural and osteoarticular and decline in lymphatic and abdominal TB was observed with advancing age. Diversity in demography and clinical manifestations were noted between provinces. The treatment success rate for all type EPTB was significantly high compared to bacteriology confirmed PTB with the exception of EPTB affecting CNS with a high mortality rate. Conclusions The study provides an insight into demography, clinical manifestations and treatment outcomes of EPTB. Further studies are needed to explain significant diversities observed between provinces, specific risk factors and challenges concerning EPTB management.

Standard cell proliferation assays use bulk media drug concentration to ascertain the potency of chemotherapeutic drugs; however, the relevant quantity is clearly the amount of drug actually taken up by the cell. To address this discrepancy, we have developed a flow cytometric clonogenic assay to correlate the amount of drug in a single cell with the cell’s ability to proliferate using a cell tracing dye and doxorubicin, a naturally fluorescent chemotherapeutic drug. By varying doxorubicin concentration in the media, length of treatment time, and treatment with verapamil, an efflux pump inhibitor, we introduced 10[superscript 5]–10[superscript 10] doxorubicin molecules per cell; then used a dye-dilution assay to simultaneously assess the number of cell divisions. We find that a cell’s ability to proliferate is a surprisingly conserved function of the number of intracellular doxorubicin molecules, resulting in single-cell IC[subscript 50] values of 4–12 million intracellular doxorubicin molecules. The developed assay is a straightforward method for understanding a drug’s single-cell potency and can be used for any fluorescent or fluorescently labeled drug, including nanoparticles or antibody–drug conjugates., Hertz Foundation (Fellowship), National Science Foundation (U.S.). Graduate Research Fellowship Program, Pfizer Inc., National Cancer Institute (U.S.) (David H. Koch Institute for Integrative Cancer Research at MIT. Support (Core) Grant P30-CA14051)

A ligand decorated, synthetic polypeptide block copolymer platform with environment-responsive capabilities was designed. We evaluated the potential of this system to function as a polymersome for targeted-delivery of a systemic chemotherapy to tumors. Our system employed click chemistry to provide a pH-responsive polypeptide block that drives nanoparticle assembly, and a ligand (folic acid) conjugated PEG block that targets folate-receptor over-expressing cancer cells. These nanocarriers were found to encapsulate a high loading of conventional chemotherapeutics (e.g. doxorubicin at physiological pH) and release the active therapeutic at lysosomal pH upon cellular uptake. The presence of folic acid on the nanoparticle surface facilitated their active accumulation in folate-receptor-overexpressing cancer cells (KB), compared to untargeted carriers. Folate-targeted nanoparticles loaded with doxorubicin also showed enhanced tumor accumulation in folate-receptor positive KB xenografts, resulting in the suppression of tumor growth in an in vivo hind flank xenograft mouse model.

BRCA1 associated ring domain protein 1(BARD1) is a tumor suppressor protein having a wide role in cellular processes like cell-cycle checkpoint, DNA damage repair and maintenance of genomic integrity. Germ-line mutation Gln 564 His discovered in linker region of BARD1 leads to loss of binding to Cleavage stimulating factor (CstF50), which in turn instigates the premature mRNA transcript formation and apoptosis. We have studied the dynamics of ARD domain present in the BARD1 wild-type and mutant protein in association with CstF50 using biophysical, biochemical and molecular dynamics simulations. It has been observed that the ARD domain is relatively more flexible than the BRCT domain of BARD1. Further relative orientations of both the ARD and BRCT domains varies due to the highly flexible nature of the connecting linker region present between the domains. It has been observed that mutant ARD domain is more dynamic in nature compared to wild-type protein. Molecular docking studies between BARD1 Gln 564 His mutant and CstF50 shows the loss of interactions. Furthermore, domain motion of ARD present in BARD1 was stabilized when complexed with CstF50.

This study reports level of community integration and life satisfaction among individuals who sustained traumatic spinal cord injuries, received institutional rehabilitation care services, and went back to live in the community in Bangladesh. It examines the impact of type of injury, demographic characteristics, socio-economic profile, and secondary health conditions on community integration and life satisfaction and explores the association between these two measures.Individuals with spinal cord injury were telephone interviewed by the Centre for the Rehabilitation of the Paralysed, Bangladesh from February to June of 2014. Data were collected from the subjects on type of injury, demographic and socio-economic profile, and secondary health conditions. The outcome measures were determined by using two validated tools - Community Integration Questionnaire and Life Satisfaction 9 Questionnaire.Total community integration and life satisfaction scores were 15.09 and 3.69, respectively. A significant positive relationship between community integration and life satisfaction was revealed. Type of injury, gender, and age were found to be significant predictors of both community integration and life satisfaction scores. Higher education was significantly related to community integration and life satisfaction scores.Participants scored low in total community integration and life satisfaction, suggesting there is a great need to develop interventions by governmental and non-governmental organizations to better integrate individuals with spinal cord injury in the community. Implications for Rehabilitation Government and non-government organizations should offer disability friendly public transportation facilities for individuals with spinal cord injury so that they can return to education, resume employment, and involve in social activities. Entrepreneurs and businesses should develop assistive devices featuring low technology, considering the rural structure and housing conditions in Bangladesh. Innovations being made in assistive technology should be supported by subsidies and grants. They should also plan to offer injury appropriate employment opportunities for individuals who suffer major injuries like spinal cord injury in Bangladesh. Housing facilities with accessible bathrooms, kitchens and stairs should be designed and offered for this population to improve their ability to self-care and decrease the dependence on caregivers for household tasks such as - cooking meals and taking care of children.

The purpose of the study was to determine the disease profile of patients attending the low vision clinic of a tertiary eye care hospital at National Institute of OphthalmologyHospital (NIOH), Dhaka, Bangladesh July 2016 to June 2017. Low vision and blindness are major causes of morbidity and an economic burden on the individual, family and the country. Low vision service has emerged as a major challenge faced by the developing countries .so prompt diagnosis; early treatment and early use of low vision devices can improve the quality of life. It was a prospective observational study conducted in low vision clinic at a tertiary care hospital in Bangladesh for one year. A total 419 patient, aged 6-60 years among them 267(63.7%) were male and 152(36.3%) were female. The leading causes of low vision in patient attending the low vision clinic were Retinitis pigmentosa (31.3%) macular dystrophy/stargards diseasesmaculopathy (20.3%) and myopia with macular degeneration (14.8%). The percentage of visual impaired (6/18-6/60) were 38.3%, severely visual impaired (6/60-3/60) were 24.4%(3/60) 37.3%. Almost all the patient was prescribed spectacles and Telescope for distant vision, Hand held magnifier and video magnifier were prescribed for near vision. Vision improved with low vision devices (6/18 or better) in 49.5%, (6/18-6/60) in 47.3%, (6/60-3/60) in 2.8%, (3/60) in 0.3% patient. Vision with low vision devices were significantly changes (p=0.001). The present study shows that hereditary ocular anomalies (Retinitis pigmentosa, macular dystrophy, myopic degeneration) and amblyopia were more common causes of low vision in this part of world.

Microscopy-based tuberculosis (TB) diagnosis i.e. Ziehl-Neelsen screening still remains the primary diagnostic method in resource poor and high TB burden countries, however this method has poor sensitivity (~60%). Bringing three million TB patients who are left undiagnosed under the treatment has been a major focus as part of END-TB strategy across the world. We have developed a portable set-up called ‘SeeTB’ that converts a bright-field microscope into fluorescence microscope (FM) with minimal interventions. SeeTB, a total internal reflection-based fluorescence excitation system allows visualization of auramine-O stained bacilli efficiently with high signal-to-noise ratio. Along with the device, we have developed a sputum-processing reagent called ‘CLR’ that homogenizes and digests the viscous polymer matrix of sputum. We have compared the performance of SeeTB system in 237 clinical sputum samples along with FM, GeneXpert and liquid culture. In comparison with culture as gold standard, FM has sensitivity of 63.77% and SeeTB has improved sensitivity to 76.06%. In comparison with GeneXpert, FM has sensitivity of 73.91% while SeeTB has improved sensitivity to 85.51%. However, there is no significant change in the specificity between FM and SeeTB system. In short, SeeTB system offers the most realistic option for improved TB case identification in resource-limited settings.

Members of the human Zyxin family are LIM domain-containing proteins that perform critical cellular functions and are indispensable for cellular integrity. Despite their importance, not much is known about their structure, functions, interactions and dynamics. To provide insights into these, we used a set of in-silico tools and databases and analyzed their amino acid sequence, phylogeny, post-translational modifications, structure-dynamics, molecular interactions, and functions. Our analysis revealed that zyxin members are ohnologs. Presence of a conserved nuclear export signal composed of LxxLxL/LxxxLxL consensus sequence, as well as a possible nuclear localization signal, suggesting that Zyxin family members may have nuclear and cytoplasmic roles. The molecular modeling and structural analysis indicated that Zyxin family LIM domains share similarities with transcriptional regulators and have positively charged electrostatic patches, which may indicate that they have previously unanticipated nucleic acid binding properties. Intrinsic dynamics analysis of Lim domains suggest that only Lim1 has similar internal dynamics properties, unlike Lim2/3. Furthermore, we analyzed protein expression and mutational frequency in various malignancies, as well as mapped protein-protein interaction networks they are involved in. Overall, our comprehensive bioinformatic analysis suggests that these proteins may play important roles in mediating protein-protein and protein-nucleic acid interactions.

We report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential isolates from 30 drug-resistant-tuberculosis patients on bedaquiline-containing regimens were retrospectively tested for bedaquiline resistance by MIC testing and by the detection of mutations in relevant genes. We documented cases failing therapy that developed specific mutations in Rv0678 and had increased MICs associated with cross-resistance to clofazimine during treatment., We report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential isolates from 30 drug-resistant-tuberculosis patients on bedaquiline-containing regimens were retrospectively tested for bedaquiline resistance by MIC testing and by the detection of mutations in relevant genes. We documented cases failing therapy that developed specific mutations in Rv0678 and had increased MICs associated with cross-resistance to clofazimine during treatment. This study underlines the relevance of surveillance programs following the introduction of new drugs.

In 24 April 2013, Rana Plaza - a high-rise building in Bangladesh where garments were being made for the Western markets collapsed. In this study, we report on the surviving workers' physical strength, self-efficacy, and disability level one year after the disaster.This cross-sectional study took place at the Centre for the Rehabilitation of the Paralysed (CRP) which provided care for more than 600 victims. For this study, upper extremity strength among the survivors was assessed by dynamometer hand grip (HG) and lower extremity strength by five time sit to stand test (FTSST). The WHODAS tool measured level of disability and General Self-Efficacy questionnaire measured self-efficacy. Post-traumatic stress disorder (PTSD) prevalence was determined by the PCL-scale.The study recruited 181 injured workers. The mean disability score among them was 49.8 (SD 17.5) and mean self-efficacy score was 24.9 (SD 6.9). In multivariate models, after adjusting for age, gender, education, injury profile, employment, marital status and job category, self-efficacy was found to be higher among those who scored above median HG test score [β= -2.32 (95% CI: -4.63, -0.01)] and FTSST performance score [β= -2.69 (95% CI: -4.93, -0.46)]. The disability level was found to be significantly associated with PTSD score [β = 0.84 (95% CI: 0.62, 1.06)] and self-efficacy score [β= -0.45 (95% CI: -0.78, -0.13)].There is an immense need to develop and deliver effective post-injury recovery, rehabilitation and return-to-work programs for injured workers in resource poor countries. Implications for Rehabilitation The study findings suggest that one year after the factory disaster in Bangladesh, the injured workers are suffering from a high degree of disability, low physical performance and reporting low self-efficacy. The national and international stakeholders including Western buyers, aid agencies, NGOs, worker advocacy groups, consumer associations and the government of Bangladesh can be updated on the progress made so far. There is an immense need to develop and deliver effective post-injury recovery, rehabilitation and return-to-work programs for injured workers in resource poor countries. International organizations like ILO, WHO, World Bank can help developing countries in building these capacities.

The cardinal features of vestibular dysfunction are illusory self-motion (vertigo) and spatial disorientation. Testing 18 acute focal cortical lesion patients, Kaski et al. show that temporoparietal junction lesions impair vestibular-guided spatial orientation but not self-motion perception. Distinct cortical substrates thus mediate the vestibular percepts of spatial orientation and self-motion., When we walk in our environment, we readily determine our travelled distance and location using visual cues. In the dark, estimating travelled distance uses a combination of somatosensory and vestibular (i.e. inertial) cues. The observed inability of patients with complete peripheral vestibular failure to update their angular travelled distance during active or passive turns in the dark implies a privileged role for vestibular cues during human angular orientation. As vestibular signals only provide inertial cues of self-motion (e.g. velocity, °/s), the brain must convert motion information to distance information (a process called ‘path integration’) to maintain our spatial orientation during self-motion in the dark. It is unknown, however, what brain areas are involved in converting vestibular-motion signals to those that enable such vestibular-spatial orientation. Hence, using voxel-based lesion–symptom mapping techniques, we explored the effect of acute right hemisphere lesions in 18 patients on perceived angular position, velocity and motion duration during whole-body angular rotations in the dark. First, compared to healthy controls’ spatial orientation performance, we found that of the 18 acute stroke patients tested, only the four patients with damage to the temporoparietal junction showed impaired spatial orientation performance for leftward (contralesional) compared to rightward (ipsilesional) rotations. Second, only patients with temporoparietal junction damage showed a congruent underestimation in both their travelled distance (perceived as shorter) and motion duration (perceived as briefer) for leftward compared to rightward rotations. All 18 lesion patients tested showed normal self-motion perception. These data suggest that the cerebral cortical regions mediating vestibular-motion (‘am I moving?’) and vestibular-spatial perception (‘where am I?’) are distinct. Furthermore, the congruent contralesional deficit in time (motion duration) and position perception, seen only in temporoparietal junction patients, may reflect a common neural substrate in the temporoparietal junction that mediates the encoding of motion duration and travelled distance during vestibular-guided navigation. Alternatively, the deficits in timing and spatial orientation with temporoparietal junction lesions could be functionally linked, implying that the temporoparietal junction may act as a cortical temporal integrator, combining estimates of self-motion velocity over time to derive an estimate of travelled distance. This intriguing possibility predicts that timing abnormalities could lead to spatial disorientation.

A pH-responsive nanoparticle platform, based on PEG-b-poly (carbonate) block copolymers have been proposed that can respond to low pH as found in many cancer micro- and intracellular environment, including that in pancreatic cancer. The hydrophobic domain, i.e., the poly (carbonate) segment has been substituted with tertiary amine side chains, such as N, Nʹ-dibutylethylenediamine (pKa = 4.0, DB) and 2-pyrrolidin-1-yl-ethyl-amine (pka = 5.4, Py) to generate two different sets of block copolymers namely PEG-DB and PEG-PY systems. These side-chain appended amines promote disassembly of nanoparticles and activation of drug release in response to pH conditions mimicking extra- (pH 6.9–6.5) and intracellular compartments (5.5–4.5, from early endosome to lysosome) of cancer tissues respectively. A frontline chemotherapy used for pancreatic cancer, i.e., gemcitabine (GEM) and a Hedgehog inhibitor (GDC 0449) has been used as the model combination to evaluate the encapsulation and pH-dependent release efficiency of these block copolymers. We found that, depending on the tertiary amine side chains appended to the polycarbonate segment, these block copolymers self-assemble to form nanoparticles with the size range of 100–150 nm (with a critical association concentration value in the order of 10−6 M). We also demonstrated an approach where GEM and GDC 0449-encapsulated PEG-DB and PEG-PY nanoparticles, responsive to two different pH conditions, when mixed at a 1:1 vol ratio, yielded a pH-dependent co-release of the encapsulated contents. We envision that such release behaviour can be exploited to gain spatiotemporal control over drug accumulation in pathological compartments with different pH status. The mixture of pH-responsive nanoparticles was found to suppress pancreatic cancer cell proliferation when loaded with anticancer agents in vitro. Cell-proliferation assay showed that both variants of PEG-b-polycarbonate block copolymers were inherently non-toxic. We have also immobilized iRGD peptide on intracellularly activable PEG-DB systems to augment cellular uptake. These targeted nanoparticles were found to promote selective internalization of particles in pancreatic cancer cells and tumor tissue.

Hyperbranched polyglycerol (hPG) has been used as a multivalent scaffold to develop a series of nanocarriers capable of high-affinity encapsulation of copper (Cu). A rationally selected set of Cu-complexing motifs has been conjugated to hPG hydroxyl groups to render the constructs potentially usable as exogenous sources of Cu for addressing different pathological conditions associated with Cu-deficiency. We have utilized a newly discovered route to attach Cu-binding domains exclusively within a hPG core by selective differentiation between the primary and secondary hydroxyl groups of the polyol. These hPG-derivatives were found to form a stable complex with Cu ions depending on the type of immobilized ligands and corresponding degree of functionalization. In addition, these Cu-bearing nano-complexes demonstrated moderately cationic surface charge resulting in adjustable protein-binding characteristics and low cellular toxicity profile. We envision that these Cu-loaded hPG nanocarriers can be used as a stable platform to transport the metal ion across the systemic circulation to supply bioavailable quantity of Cu in disease-afflicted tissues.

In 2017, the American College of Cardiology (ACC) and American Heart Association (AHA) released updated guidelines on the definition of hypertension, and blood pressure thresholds for initiation of antihypertensive medication. Our objective was to assess the change in prevalence of hypertension, risk factors, and identify populations recommended for treatment among Bangladeshi adults, based on the 2017 ACC/AHA guidelines. Data for this analysis were collected from a population-based nationally representative sample of 1843 Bangladeshi adults, aged ≥18 years in 2015. Hypertension was defined based on two definitions: the JNC 7 guidelines (SBP ≥ 140 or DBP ≥ 90 mmHg), and the 2017 ACC/AHA guidelines (SBP ≥ 130 mmHg, or DBP ≥ 80 mmHg), or a self-reported diagnosis of hypertension. Based on the 2017 ACC/AHA guidelines, the prevalence of hypertension was 40.7% (95% CI: 38.5–43.0). The prevalence of JNC 7 definition of hypertension was 17.9% (95% CI: 16.2–19.7), indicating a 22.8% increase in prevalence. Based on both definitions, urban residents, older adults, adults with low physical activity, obese, abdominally obese, and diabetic adults were more likely to have hypertension. Based on current JNC 7 guidelines, only half of hypertensive adults were aware of having hypertension. Among those aware of their condition, 75% were taking medication based on self-report. Using the 2017 ACC/AHA guidelines, the prevalence of hypertension will more than double in Bangladesh. Newly diagnosed hypertensive adults will be considered high-risk for cardiovascular disease leading to a larger burden on Bangladesh’s health system. However, implementation of the ACC/AHA guidelines may improve prevention efforts where lifestyle changes are appropriate.

Current treatment options for debilitating bone diseases such as osteosarcoma, osteoporosis, and bone metastatic cancer are suboptimal and have low efficacy. New treatment options for these pathologies require targeted therapy that maximizes exposure to the diseased tissue and minimizes off-target side effects. This work investigates an approach for generating functional and targeted drug carriers specifically for treating primary osteosarcoma, a disease in which recurrence is common and the cure rate has remained around 20%. This approach utilizes the modularity of Layer-by-Layer (LbL) assembly to generate tissue-specific drug carriers for systemic administration. This is accomplished via surface modification of drug-loaded nanoparticles with an aqueous polyelectrolyte, poly(acrylic acid) (PAA), side-chain functionalized with alendronate, a potent clinically used bisphosphonate. Nanoparticles coated with PAA-alendronate are observed to bind and internalize rapidly in human osteosarcoma 143B cells. Encapsulation of doxorubicin, a front-line chemotherapeutic, in an LbL-targeted liposome demonstrates potent toxicity in vitro. Active targeting of 143B xenografts in NCR nude mice with the LbL-targeted doxorubicin liposomes promotes enhanced, prolonged tumor accumulation and significantly improved efficacy. This report represents a tunable approach towards the synthesis of drug carriers, in which LbL enables surface modification of nanoparticles for tissue-specific targeting and treatment., National Institutes of Health (U.S.) (P30 CA14051 (NCI)), National Institutes of Health (U.S.) (5 U54 CA151884–02 (CCNE)), National Institutes of Health (U.S.) (R01 AG029601 (NIA)), National Institutes of Health (U.S.) (R01 EB010246 (NIBIB)), David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute Swanson Biotechnology Center), National Science Foundation (U.S.) (Graduate Research Fellowship), National Health and Medical Research Council (Australia), Massachusetts Institute of Technology (David H. Koch (1962) Chair Professorship in Engineering)

Mixed retrospective-prospective cohort study. To determine 2-year survival following discharge from hospital after spinal cord injury in Bangladesh. Bangladesh. Medical records were used to identify all patients admitted in 2011 with a recent spinal cord injury to the Centre for Rehabilitation of the Paralysed, a large Bangladeshi hospital that specialises in care of people with spinal cord injury. Patients or their families were subsequently visited or contacted by telephone in 2014. Vital status and, where relevant, date and cause of death were determined by verbal autopsy. 350 of 371 people admitted with a recent spinal cord injury in 2011 were discharged alive from hospital. All but eleven were accounted for two years after discharge (97% follow-up). Two-year survival was 87% (95% CI 83% to 90%). Two-year survival of those who were wheelchair-dependent was 81% (95% CI 76% to 86%). The most common cause of death was sepsis due to pressure ulcers. In Bangladesh, approximately one in five people with spinal cord injury who are wheelchair-dependent die within two years of discharge from hospital. Most deaths are due to sepsis from potentially preventable pressure ulcers.

Neonates are predisposed to bacterial infection which are an important cause of early childhood morbidity and mortality globally. It has been proposed that procalcitonin has significant utility as a diagnostic marker for bacterial infection in febrile neonates when compared to C-reactive protein (CRP). The aim of this study is to conduct a literature search to find the best available evidence to answer the clinical question of the utility of procalcitonin when compared to CRP as a predictor of bacterial infection in febrile neonates.Medline/PubMed was searched using the terms 'procalcitonin', 'C-reactive protein', 'bacterial infection' and 'neonatal sepsis'. Three systematic reviews relevant to the clinical question were identified and the key article selected for critical appraisal was the systematic review by Yu et al. (2010).The appraised literature concludes that procalcitonin has moderate accuracy in diagnosing neonatal sepsis, but suggests it should be considered only within the context of other clinical parameters and other relevant investigations. The studies included in the systematic review were of variable quality, showed considerable heterogeneity in their methods and evidence of possible publication bias.Further research is required before definitive recommendations can be made about the utility of procalcitonin compared with CRP as a diagnostic marker for neonatal sepsis and bacterial infection in clinical practice.

BackgroundThe high prevalence and severity of methamphetamine (MA) abuse demands greater neurobiological understanding of its etiology.MethodsWe conducted immunoblotting and in vivo microdialysis procedures in MA high/low drinking mice, as well as in isogenic C57BL/6J mice that varied in their MA preference/taking, to examine the glutamate underpinnings of MA abuse vulnerability. Neuropharmacological and Homer2 knockdown approaches were also used in C57BL/6J mice to confirm the role for nucleus accumbens (NAC) glutamate/Homer2 expression in MA preference/aversion.ResultsWe identified a hyperglutamatergic state within the NAC as a biochemical trait corresponding with both genetic and idiopathic vulnerability for high MA preference and taking. We also confirmed that subchronic subtoxic MA experience elicits a hyperglutamatergic state within the NAC during protracted withdrawal, characterized by elevated metabotropic glutamate 1/5 receptor function and Homer2 receptor-scaffolding protein expression. A high MA-preferring phenotype was recapitulated by elevating endogenous glutamate within the NAC shell of mice and we reversed MA preference/taking by lowering endogenous glutamate and/or Homer2 expression within this subregion.ConclusionsOur data point to an idiopathic, genetic, or drug-induced hyperglutamatergic state within the NAC as a mediator of MA addiction vulnerability.

Background: Depression is a growing health issue in both developed and developing countries. General unawareness at the population level, lack of training among health care providers and scarcity of resources including treatment opportunities may conceal the real burden of depression in developing countries, and more epidemiological studies on its prevalence and risk factors are critically needed. Aim: This study reports the prevalence of depression and its associated risk factors among female garment factory workers in Bangladesh – a major supplier country of clothes for the Western market. This research should generate useful evidence for national and international stakeholders who have an interest in improving health, safety and well-being of outsourced factory workers. Methods: A survey was conducted on a sample of 600 lower socio-economic status working women including garment workers. This survey collected data on demographic and health profile of these workers. The primary outcome was depression as measured by Patient Health Questionnaire 9. It also obtained data on traumatic life events and post-traumatic stress disorder. Results: The prevalence of depression was 23.5%: 20.9% among garment workers and 26.4% among others. Part-time employment (odds ratio-OR): 2.36, 95% confidence interval (95% CI): 1.01–5.51), chronic pain (OR: 1.67, 95% CI: 1.01–2.78), two or more traumatic life events (OR: 6.43, 95% CI: 2.85–14.55) and dysuria (OR: 2.50, 95% CI: 1.02–6.15) were found to be significantly associated with depression among these workers in multivariate regression model. Depression prevalene lowered by 11% among these workers for every additional monthly earning of 1,000 taka (US$12). Conclusion: Depression is a multifaceted health issue with many personal, social, economic and health determinants and consequences. This study demonstrates that the prevalence of moderate-to-severe depression among working women in Bangladesh is quite high. Prevention and treatment of depression in developing countries and societies can reduce suffering, lower incidence of suicide, and prevent economic loss. Creating awareness on outsourced workers’ poor mental health may help in developing initiatives to protect and preserve their well-being.

S009-131, a coumarin-chalcone hybrid, had been shown to possess anti-proliferative and anti-tumour effect by triggering apoptosis. In this report, we investigated role of DNA damage signalling pathway in S009-131 induced cancer cell death. Here we show that S009-131 causes DNA damage by potential binding to the minor groove which led to the phosphorylation and activation of ATM and DNA-PK, but not ATR, at earlier time points in order to initiate repair process. S009-131 induced DNA damage response triggered activation of p53 through phosphorylation at its key residues. Pharmacological inhibition of PIKKs abrogated S009-131 induced phosphorylation of p53 at Ser 15. DNA damage induced phosphorylation resulted in reduced proteasomal degradation of p53 by disrupting p53-MDM2 interaction. Additionally, our docking studies revealed that S009-131 might also contribute to increased cellular p53 level by occupying p53 binding pocket of MDM2. Posttranslational modifications of p53 upon S009-131 treatment led to enhanced affinity of p53 towards responsive elements (p53-RE) in the promoter regions of target genes and increased transcriptional efficiency. Together, the results suggest that S009-131 cleaves DNA through minor groove binding and eventually activates PIKKs associated DNA damage response signalling to promote stabilization and enhanced transcriptional activity of p53 through posttranslational modifications at key residues.

Wnt signalling has been implicated in breast cancer, and in particular aberrant β-catenin-independent Wnt signalling has been associated with breast cancer metastasis and Tamoxifen resistance. Despite Wnt pathway involvement in many human cancers, attempts to target the pathway therapeutically have been disappointing. The recent discovery that the receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a novel Wnt receptor provides a potential new therapeutic and diagnostic target. To clarify the role of ROR2 in breast cancer, we investigated its expression via ROR2 immunohistochemistry in a clinical cohort of breast cancer patients, and via in vitro studies incorporating both overexpression and knock-down of ROR2. ROR2 was expressed in the majority of breast cancer patients (87 %), including those classed as triple negative. Breast cancer patients expressing ROR2 had a significantly shorter overall survival than those lacking ROR2 expression (P