CHARIOT: a phase I study of berzosertib with chemoradiotherapy in oesophageal and other solid cancers using time to event continual reassessment method.

BACKGROUND: Berzosertib (M6620) is a highly potent (IC50 = 19 nM) and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. This trial assessed the safety, preliminary efficacy, and tolerance of berzosertib in oesophageal cancer (A1 cohort) with RT and advanced solid tumours (A2 cohort) with cisplatin and capecitabine. METHODS: Single-arm, open-label dose-escalation (Time-to-Event Continual Reassessment Method) trial with 16 patients in A1 and 18 in A2. A1 tested six dose levels of berzosertib with RT (35 Gy over 15 fractions in 3 weeks). RESULTS: No dose-limiting toxicities (DLTs) in A1. Eight grade 3 treatment-related AEs occurred in five patients, with rash being the most common. The highest dose (240 mg/m2) was determined as the recommended phase II dose (RP2D) for A1. Seven DLTs in two patients in A2. The RP2D of berzosertib was 140 mg/m2 once weekly. The most common grade ≥3 treatment-related AEs were neutropenia and thrombocytopenia. No treatment-related deaths were reported. CONCLUSIONS: Berzosertib combined with RT is feasible and well tolerated in oesophageal cancer patients at high palliative doses. Berzosertib with cisplatin and capecitabine was well tolerated in advanced cancer. Further investigation is warranted in a phase 2 setting. CLINICAL TRIALS IDENTIFIER: EU Clinical Trials Register (EudraCT) - 2015-003965-27 ClinicalTrials.gov - NCT03641547.

Synthesis and evaluation of coastal and marine biodiversity spatial information in the United Arab Emirates for ecosystem-based management.

The United Arab Emirates (UAE) host valuable coastal and marine biodiversity that is subjected to multiple pressures under extreme conditions. To mitigate impacts on marine ecosystems, the UAE protects almost 12% of its Exclusive Economic Zone. This study mapped and validated the distribution of key coastal and marine habitats, species and critical areas for their life cycle in the Gulf area of the UAE. We identified gaps in the current protection of these ecological features and assessed the quality of the data used. The overall dataset showed good data quality, but deficiencies in information for the coastline of the north-western emirates. The existing protected areas are inadequate to safeguard key ecological features such as mangroves and coastal lagoons. This study offers a solid basis to understand the spatial distribution and protection of marine biodiversity in the UAE. This information should be considered for implementing effective conservation planning and ecosystem-based management.

Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization.

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.

Mirogabalin besylate in the treatment of neuropathic pain.

Neuropathic pain (NeP) is a global cause of suffering and debilitation leading to significant morbidity and reduced quality of life. New treatments are needed to address the growing prevalence of NeP and its impact on sleep, mood and functionality. Mirogabalin besylate (mirogabalin, Tarlige) is a gabapentinoid therapy developed by Daiichi Sankyo which is approved in Japan for the treatment of postherpetic neuralgia and painful diabetic peripheral neuropathy. Mirogabalin has a potent pain-modulating effect with a unique high affinity and prolonged dissociation rate for the a2delta-1 subunit of voltage-gated calcium (Ca2+) channels (VGCCs) on the dorsal root ganglion resulting in more sustained analgesia compared with traditional gabapentinoids. Additionally, mirogabalin has a superior adverse events (AEs) profile due to a rapid dissociation from the a2delta-2 subunit of VGCCs potentially implicated in central nervous system-specific AEs. The most common AEs for mirogabalin are dizziness (approximately 8-16%), somnolence (approximately 6-24%) and headache (approximately 6-14%), with a lower incidence of constipation, nausea, diarrhea, vomiting, edema, fatigue and weight gain. Postmarketing studies are required to evaluate its analgesic durability and efficacy when combined with other antineuropathic agents such as tricyclics, duloxetine and tramadol/tapentadol.

Discovery of Novel, Potent, Brain-Permeable, and Orally Efficacious Positive Allosteric Modulator of α7 Nicotinic Acetylcholine Receptor [4-(5-(4-Chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide]: Structure-Activity Relationship and Preclinical Characterization.

The discovery of a series of thiophenephenylsulfonamides as positive allosteric modulators (PAM) of α7 nicotinic acetylcholine receptor (α7 nAChR) is described. Optimization of this series led to identification of compound 28, a novel PAM of α7 nicotinic acetylcholine receptor (α7 nAChR). Compound 28 showed good in vitro potency, with pharmacokinetic profile across species with excellent brain penetration and residence time. Compound 28 robustly reversed the cognitive deficits in episodic/working memory in both time-delay and scopolamine-induced amnesia paradigms in the novel object and social recognition tasks, at very low dose levels. Additionally, compound 28 has shown excellent safety profile in phase 1 clinical trials and is being evaluated for efficacy and safety as monotherapy in patients with mild to moderate Alzheimer's disease.

Diabetic peripheral neuropathy in people with type 2 diabetes: too little too late.

Diabetic peripheral neuropathy in people with type 2 diabetes is poorly managed because of its insidious onset, delayed diagnosis and more complex aetiology resulting from the contribution of not only hyperglycaemia, but also ageing, hyperlipidaemia, hypertension and obesity. Because there is no US Food and Drug Adminstration-approved disease-modifying therapy for diabetic peripheral neuropathy, the key to ameliorating it in type 2 diabetes has to be through earlier diagnosis and timely multi-factorial risk factor reduction. The management of painful diabetic peripheral neuropathy also requires a detailed appraisal of the choice of therapy, taking into account efficacy, patient wishes, comorbidities, side effect profile and potential for abuse.

Retrospective cohort study of 925 OAGB procedures. The UK MGB/OAGB collaborative group.

BACKGROUND: Mini-One Anastomosis Gastric Bypass is a new operation that provides comparable outcomes to the common bariatric procedures. Revisional surgery is still needed after a number of MGB-OAGB procedures. The aim of this study is to report the causes and management of these revisions. METHODS: From 2010 to 2018, 925 MGB-OAGB operations were performed at 7 bariatric units across the United Kingdom and included in this retrospective cohort study. The data was retrospectively collected and analysed. The primary end point was the identification of the causes and management of revisions. Follow up ranged from 6 months to 3 years. RESULTS: Twenty-two patients [2.3%] required revisional surgery after MGB-OAGB. Five patients [0.5%] developed severe diarrhoea managed by shortening the bilio-pancreatic limb to 150 cm. Four patients [0.4%] developed afferent loop syndrome and bile reflux was reported in another 3 [0.3%] cases; all were managed by either conversion to Roux en Y Gastric Bypass or a Braun anastomosis. Postoperative bleeding was controlled laparoscopically in 3 patients [0.3%]. Liver decompensation that was reported in 2 patients [0.2%] was treated by shortening the BPL in one patient and a reversal to normal anatomy in another. The liver failure resolved in both patients. Other indications for revision included two gastro-jejunal stenosis [0.2%], one perforated ulcer [0.1%], one patient [0.1%] with excessive weight loss and one case [0.1%] of protein malnutrition. None of the 22 patients undergoing revisional surgery after MGB-OAGB died. Lost to follow up rate was 0.2%. CONCLUSION: Complications requiring revisional surgery after MGB-OAGB are uncommon [2.3%] and the majority can be managed by bilio-pancreatic limb shortening, the addition of a Braun side-to-side anastomosis or conversion to RYGB. Bilio-pancreatic limb length of 200 cm or more resulted in serious complications of liver failure, protein malnutrition, excessive weight loss and diarrhoea.

Oxadiazolyl thiazolidinedione as a non-adipogenic PPAR-γ partial agonist and its effect on glucose homeostasis in type 2 diabetes.

The familiar glitazone anti-diabetics are thiazolidinedione derivatives, known to elicit action through full agonistic activity on PPAR-γ receptors. Full agonists are known for the side effect of weight gain, while partial agonists are weak to non-adipogenic compounds possessing anti-diabetic property. This work identified a new synthetic oxadiazolyl thiazolidinedione (OXTZD) as a ligand for PPAR-γ receptor with partial agonist activity and less transactivation potential compared to rosiglitazone through in-vitro PPAR-γ competitive binding assay and PPAR-γ transactivation-based luciferase reporter assay, respectively. OXTZD did not induce significant lipid accumulation when compared to differentiation control which contained insulin in PPAR-γ-dependent adipogenesis assay. In-vivo studies have proved that OXTZD effectively reduced blood glucose level in type 2 diabetic rats and also improved glucose tolerance and insulin sensitivity. After 15 days of oral treatment with OXTZD, rats did not gain weight, suggesting that OXTZD was effective in suppressing the weight gain. Molecular docking of OXTZD to PPAR-γ, predicted hydrogen bonds with SER342, ARG288, and CYS285 residues in arm III of the ligand binding domain which are unique to the partial agonists. Results of in-vitro, in-vivo, and docking studies were in good correlation to the fact that OXTZD is a PPAR-γ partial agonist having glucose-lowering property and lacks the side effect of weight gain. In conclusion, OXTZD could be developed as a therapeutic agent for diabetes and/or serve as a lead compound for further drug design studies targeting PPAR-γ for effective management of type 2 diabetes without inducing weight gain.

Subpectoral biceps tenodesis using a novel anterior cortical button technique.

BACKGROUND: Various surgical treatments are described in the literature for biceps pathology. METHOD: The techniques currently described for subpectoral tenodesis involve the use of suture anchors, interference screws, bicortical suture buttons or unicortical suture buttons. RESULTS: A review of 31 patients with a subpectoral biceps tenodesis using the anterior cortical button technique is presented. CONCLUSIONS: We describe a novel technique, which provides an opportunity to obtain a robust cortical and intramedullary tenodesis, performed under direct vision without the risk of drilling the far cortex and therefore avoiding any potential for neurological injury. There is no cortical implant, which may lead to a diaphyseal stress riser and subsequent fracture risk.

What is causing high polio vaccine dropout among Pakistani children?

OBJECTIVES: Although the antipolio drive is undertaken across Pakistan, there are still children who have not received any oral polio vaccine or are unable to complete recommended doses of polio vaccine. This study aims at empirically analyzing the associated factors with the no oral polio vaccination (OPV) and OPV dropout groups of children in Pakistan. STUDY DESIGN: This is a cross-sectional study. METHODS: Data were obtained from the three waves of Pakistan Demographic and Health Survey of children aged between 12 and 23 months (1990-1991: n = 1214; 2006-2007: n = 1522; 2012-2013: n = 2074). Children who received no OPV and those who drop out of polio vaccination (OPV1-OPV3) were considered as outcome variables. The bivariate relationship of outcome variable with each socio-economic, demographic, and spatial variable is estimated with a P-value of <0.01. For both no OPV and OPV dropout children, we used logistic regression analysis separately. RESULTS: The percentage of children aged 12-23 months who dropped out of OPV1-OPV3 vaccination was about 76% in the year 1990-1991; 21% in 2006-2007, and 17.5% in 2012-2013 at the national level. Among all indicators, provinces, rural versus urban residence, the mother's age at marriage, the child's birth place (home versus hospital), parental education, and household wealth status are significant predictors of no OPV and/or OPV dropout in Pakistan. Among provinces, Balochistan, Khyber Pakhtunkhwa (KPK), and Sindh are the lagging provinces. CONCLUSION: Improving the socio-economic status of women helps decrease the chance of polio dropout and thus improves service delivery and program implementation.

Should all acromioclavicular joint injections be performed under image guidance?

INTRODUCTION: Steroid and local anaesthetic injection to the acromioclavicular joint (ACJ) is a very common diagnostic and therapeutic procedure, which is often performed in the outpatient department. However, it can be difficult to localize this joint because of its small size, presence of osteophytes and variable morphology in the population. We performed a study to determine whether the use of an image intensifier (X-ray guidance), in theatre, improves the accuracy of this injection. METHODS: This was a prospective study carried out between March 2014 and March 2015. The injections were performed by two senior orthopaedic surgeons. First, we clinically palpated the ACJ and marked the area over this point as A. Then, with the use of a needle and an image intensifier in a single plane, we identified the actual location of the ACJ and marked this point as B. We measured the distance between A and B in millimetres (mm) and determined the accuracy of the injections. Further analysis taking into account the ACJ capsular attachments was also performed. RESULTS: In total, 45 patients and 50 injections were included in the study; five patients had repeated injections at different times. We found that only 12 injections (24%) were palpated to be correct with no discrepancies between A and B (95% confidence interval: 14-37%). For the remaining 38 injections (76%), the use of an image intensifier had significantly improved the accuracy of ACJ location ( p < 0.05). Taking the capsular attachments of the ACJ into consideration reduced the number of inaccurate injections to 27 (54%). CONCLUSION: We recommend the use of an image intensifier (or ultrasound guidance) to accurately determine the location of the ACJ for steroid and local anaesthetic injections. This prevents an injection into the wrong place, which can lead to wrong diagnosis and/or suboptimal treatment.

Investigation of transferrin interaction with medicinally important noble metal ions using affinity capillary electrophoresis.

Transferrins (TFs) consist of a large group of glycoproteins, whose function is to transport iron across the cell membrane. Apart from iron, serum transferrin can also bind several other metal ions and hence can offer a potential route for the delivery of these metal ions into the cellular fluids. In the present study the interaction behavior of nine noble metal ions, Ag+, Au+, Au3+, Os3+, Pd2+, Pt4+, Rh3+, Ru3+ and Ir3+ with transferrin was investigated by affinity capillary electrophoresis (ACE) using the dynamic mobility shift mode. A proper rinsing procedure was applied to regenerate the capillary tube. The influence of these metal ions on transferrin was studied through comparison of the mobility ratios of free protein and protein-metal ion complex. The interaction results were expressed by the normalized difference of the mobility ratios (ΔR/Rf) and its confidence intervals. Most of the tested metal ions showed significant interaction with transferrin with small confidence intervals, except Ag+, Au+ and Rh3+ that exhibited very weak interactions. Maximum interaction was observed between transferrin and Ir3+, followed by Pd2+ that also showed strong affinity towards the test protein. The screening results were compared with Bovine Serum Albumin (BSA)- and Human Serum Albumin (HSA)-noble metal ions interactions. An excellent precision (% RSD of mobility ratios were less than 1%, except for transferrin-Pd2+ interaction ≈ 4%) was recorded for repeated runs of transferrin-metal ions interactions. This study contributes to the understanding of the affinity of transferrin to the tested metal ions and will provide preliminary information for the investigation of other protein-ligands interactions.

Application of real-time quantitative polymerase chain reaction assay to detect Legionella pneumophila in patients of community-acquired pneumonia in a tertiary care hospital.

Legionella pneumophila is one of the important pathogen responsible for community -acquired pneumonia attributing for 1-5% of cases. Since early and accurate therapy reduces mortality, rapid and reliable diagnostic methods are needed. A total of 134 samples of blood, urine and respiratory tract fluids were collected. Blood was tested for IgG, IgM and IgA antibodies using commercially available kits. A total of 8 (6%) samples were found to be positive for L. pneumophila by quantitative reverse transcription polymerase chain reaction (qRT-PCR), compared to conventional PCR where 6 (4.4%) samples were positive. Serology was positive in a total of 32 (23%) cases though only 3 (2.2%) of the PCR-positive cases were positive by serology as well. These results suggest that real-time PCR can detect Legionella infection early in the course of the disease before serological response develops.

Effect of some phytoconstituents on Fe2+/ascorbate induced lipid peroxidation.

Transition metals like iron and copper, present inside the body system play a key role in the production of reactive oxygen radicals. These free radicals, causative agents of lipid peroxidation, not only damage proteins and DNA but also gradually changes the cellular membrane structure and ultimately leads to the loss of function and integrity. Uncontrolled lipid peroxidation results in various age related diseases, malignancy, infective diseases and injuries. Antioxidants and other phytochemical constituents present in the various plants are known to protect cells from such reactive oxygen species (ROS)-mediated damages. Here, we evaluated the effect of certain phytoconstituents present in the well-known medicinal plants on ROS scavenging using rat liver homogenate. The basal lipid peroxidation was found to be 0.1625±0.0095 ngMDA/min/mg protein, which got induced to 0.7938±0.0478 ngMDA/min/mg protein in the presence of Fe2+/ascorbate system. In this context, acteoside, berberine, catechin, 3´5-dihydroxyflavone7-o-ß-D-galacturonide-4-o-ß-D-glucopyranoside (a flavonoid glycoside from cumin), silibin and tetrahydrocurcumin decreased both basal and Fe2+/ascorbate induced lipid peroxidation as determined by thiobarbituric acid reaction. On the other hand, agnuside, andrographolide, picroside-I, negunoside, oleanolic acid, and glycerrihizin, showed enhancement in both basal and induced lipid peroxidation. Phytoconstituents which have decreased both basal and Fe2+/ascorbate induced lipid peroxidation may act as defensive against the deadly effects of ROS, causative agents of lipid peroxidation and other diseases either alone or in combination with diet/nutritional supplements.

Risk factors involved in spread of HCV in patients from sub urban Rawalpindi and their association with existing genotypes.

The current epidemiological study was designed to trace the involved risk factors in Hepatitis C Virus (HCV) spread and to identify any association between HCV genotypes and risk factors. Blood samples were taken from 400 participants and viral genotyping was performed in order to find any possible relationship between the risk factors and genotypes. Major genotypes included 3, 1, 4 and several untypeable ones with prevalence rates 65%, 22.5%, 2.75% and 9.75% respectively. Surgery and dental procedure were strongly related to the spread of genotype 3b, while genotype 1b was strongly related to blood transfusion and dental procedures as a single combination risk factor. On the other hand genotypes 1a, 3a, 4 and the untypeable genotypes, were equally affected by all reported risk factors. The probability of occurrence of genotype 3a with reference to dental procedures was 11%. Dental procedures, unsafe injection and surgical procedures are the main risk factors while the blood transfusion in combination with dental procedures has emerged as a potent risk factor in the transmission of HCV.

Reduced length of stay with minimally invasive repair of ruptured achilles tendon.

Minimally invasive techniques to repair ruptured achilles tendons have been developed to enhance recovery following tendon repair and decrease wound complications associated with open repair. We investigated outcomes of minimally invasive and open repair of acutely ruptured achilles tendons at our institution. We compared all cases of achilles tendon repair at our department, using open techniques and minimally invasive techniques with the Achillon device, over a two year period. Length of stay and operating time was recorded, as were any complication rates, including tendon re-rupture. Post-operatively functional outcome questionnaires were sent to all patients. In total 39 patients underwent open repair and 26 underwent minimally invasive repair. Length of stay was significantly shorter in the minimally invasive group, with 58% of minimally invasive cases performed as a day case, compared to 31.1% of open cases (p = 0.02). There was no difference in complication rates, including re-rupture, or functional outcome scores. Minimally invasive repair of ruptured achilles tendons results in reduced length of stay, compared to open repair. There is no evidence of weaker tendon repairs with minimally invasive techniques. Overall functional outcomes between both groups appear similar. Level of Evidence : III.

Platelet-Rich-Plasma Injections in Treating Lateral Epicondylosis: a Review of the Recent Evidence.

Lateral epicondylosis is common, with various treatment modalities. Platelet-rich-plasma injections from autologous blood have recently been used in centres worldwide for the treatment of tennis elbow. We review and present the recent published evidence on the effectiveness of PRP injections for lateral epicondylosis. Nine studies met our inclusion criteria including 6 RCT's for the purpose of analysis. PRP injections have an important and effective role in the treatment of this debilitating pathology, in cases where physiotherapy has been unsuccessful.