Catatonia in the peripartum: A cohort study using electronic health records.

BACKGROUND: Due to limited existing literature available on the presentation and treatment of catatonia in the peripartum, this retrospective descriptive cohort study aimed to examine demographic data, catatonic features, diagnoses pre- and post-catatonic episodes, treatment and the presence of obstetric complications. METHODS: Individuals with catatonia were identified in a previous study using anonymised electronic healthcare records from a large mental health trust in South-East London. The presence of features from the Bush-Francis Catatonia Screening Instrument was coded by the investigators and longitudinal data were extracted from structured fields and free text. RESULTS: 21 individuals were identified from the larger cohort, each of whom experienced one episode of catatonia in the postpartum period, and all had had an inpatient psychiatric admission. 13 patients (62 %) presented after their first pregnancy and 12 (57 %) experienced obstetric complications. 11 (53 %) attempted breastfeeding and 10 (48 %) received a diagnosis of a depressive disorder following the episode of catatonia. The majority presented with immobility or stupor, mutism, staring and withdrawal. All were treated with antipsychotics and 19 (90 %) received benzodiazepines. CONCLUSIONS: This study suggests that signs and symptoms of catatonia during the peripartum are similar to other catatonic presentations. However, the postpartum may be a period of high risk for catatonia and obstetric factors, such as birth complications, may be relevant.

Evaluation of a Pathway team for homeless mental health in-patients.

AIMS AND METHOD: The Pathway model is an enhanced care coordination model for homeless people in hospital. We aimed to evaluate the first attempt to apply it on psychiatric wards, which started in 2015 in South London. We developed a logic model which expressed how the Pathway approach might work. Two predictions from this model were tested, using propensity scores and regression to estimate the effect of the intervention among people who were eligible for it. RESULTS: The Pathway team theorised that their interventions would reduce length of stay, improve housing outcomes and optimise the use of primary care - and, more tentatively, reduce readmission and emergency presentations. We were able to estimate effects on length of stay (-20.3 days; 95% CI -32.5 to -8.1; P = 0.0012) and readmission (a non-significant reduction). CLINICAL IMPLICATIONS: The marked reduction in length of stay, explicable in terms of the logic model, constitutes preliminary support for the Pathway model in mental health services.

Azaindole Based Potentiator of Antibiotics against Gram-Negative Bacteria.

We discovered azaindole-based compounds with weak innate activity that exhibit substantial potentiation of antibacterial activities of different antibiotics, viz., rifampicin, erythromycin, solithromycin, and novobiocin in Gram-negative bacteria. In the presence of the azaindole derivatives, these antibiotics exhibited submicromolar minimum inhibitory concentrations (MICs) against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. The fold improvements in MIC of these antibiotics that were otherwise weak or inactive on their own against these bacteria were also observed against drug-resistant clinical isolates. Our studies indicate that this selective potentiation is probably through destabilization of the outer membrane's integrity, known to be regulated by the lipopolysaccharides (LPS). Thus, the azaindole based compounds described here open opportunities for those antibiotics that are otherwise ineffective due to LPS mediated entry barriers in Gram-negative bacteria.

Real-World Experience of Immunotherapy from India in Recurrent Squamous Cell Carcinoma of Head and Neck Cancer.

Background Recurrent metastatic head and neck squamous cell carcinoma (HNSCC) patients carry a poor prognosis and have limited therapeutic options. In the randomized phase-3 trial CheckMate 141, nivolumab showed benefit in overall survival (OS) with manageable toxicity. Nivolumab is available for clinical practice since 2017 in India. The aim of this study is to evaluate the efficacy and safety of nivolumab in real-world settings in India. Materials and Methods This is a retrospective, single-center study on the use of nivolumab with advanced or metastatic HNSCC in India. Eligible patients had histologically confirmed, recurrent squamous cell carcinoma of the head and neck (including metastatic disease) of the oral cavity, pharynx, or larynx that was not amenable to curative treatment, tumor progression, or recurrence after the administration of platinum-containing chemotherapy administered as adjuvant therapy or in the context of primary or recurrent disease. We assessed demographics, safety (the Common Terminology Criteria for Adverse Events Version 4.0), response evaluation (the Response Evaluation Criteria in Solid Tumors Version 1.1), progression-free survival (PFS), and OS. Results Among patients with platinum-refractory, recurrent HNSCC, and treatment with nivolumab resulted in median PFS of 2 months and median OS of 5 months, which is inferior to what was seen in CheckMate 141. Fifteen of 20 patients (75%) had progressive disease, 3 (15%) showed a partial response, and 2 (10%) had stable disease. Conclusion Nivolumab was well tolerated in our study with fewer toxic effects, and an inferior median survival was reached as compared with CheckMate 141 in platinum refractory, recurrent HNSCC patients treated with nivolumab because 90% of patients in our study received nivolumab as second-line therapy after progression. Our study encourages the use of nivolumab in this population.

The real-world experience with nivolumab in previously treated patients with advanced non-small cell lung cancer from a cancer center in India.

BACKGROUND: PDL-1 inhibitors have emerged as the new standard of care for second line treatment of NSCLC. METHODS: Eligible patients included, histologically proven NSCLC, ECOG (Eastern Cooperative Oncology Group) performance status of 0, 1 or 2, age 18 years and above, availability of pre-treatment tumor specimen, adequate end organ function, at least one prior platinum-based therapy. Patients who received a minimum of 6 doses of nivolumab were eligible. RESULTS: Eleven previously treated patients with chemotherapy, started on nivolumab from April of 2016 to December of 2018, were retrospectively studied and analysed. The median age of patients was 58 years. Eight (72.73%) of the eleven patients were male. Seven (63.64%) of the patients were current or former smokers. Majority of patients had non-squamous histology; seven (63.64%) adenocarcinoma and four (36.36%) squamous cell carcinoma. 5 (45.46%) of the patients received one prior therapy, three (27.27%) received two prior therapies, and three (27.27%) received three prior therapies. Four (36.36%) of the patients had brain metastasis. Two (18.18%) of the patients were more than 70 years of age. Median number of cycles of nivolumab administered were 10 (range, 6 to 21). At the time of analysis, the median PFS was 8 months (95% CI, 1.52-14.47) and median OS was 15 months (95% CI, 6.9-23.09). Treatment was well tolerated and generally side effects were grade 1 and grade 2, except two patients who develop grade 3/4 pneumonitis. CONCLUSIONS: This is a real-world study of eleven previously treated patients with chemotherapy, started on Nivolumab from April of 2016 to December of 2018. Although, our sample size was small, our data supports the use of nivolumab as a new treatment option for patients of stage 4 NSCLC.

Hyperprogression after immunotherapy.

INTRODUCTION: Checkpoint inhibitors demonstrate very good anticancer effects, and some patients are long-time responders. As our experience to use these drugs increases, we see more and more patients having different kind of side effects which are usually not seen with chemotherapy. We have observed a subset of patients who appear to be "hyper-progressors," with a greatly accelerated rate of tumor growth and clinical deterioration compared to pretherapy, which was also recently reported by Institut Gustave Roussy. MATERIALS AND METHODS: Medical records from all patients (N = 50) prospectively treated in our hospital by anti-PD-1/PD-L1 were analyzed. The tumor growth rate (TGR) prior ("REFERENCE;" REF) and upon ("EXPERIMENTAL"; EXP) anti-PD-1/PD-L1 therapy was compared to identify patients with accelerated tumor growth. Associations between TGR and overall survival (OS) were computed. RESULTS: Hyperprogressive disease (HPD) was defined as a RECIST progression at the first evaluation and as a ≥2-fold increase of the TGR between the REF and the EXP periods. Of 50 evaluable patients, four patients (8%) were considered as having HPD. At progression, patients with HPD had a higher rate of new lesions. HPD was associated with a worse outcome (OS). CONCLUSION: Hyperprogression was seen in 4 of 50 (8%) of patients, three of which had urothelial cancer and one malignant melanoma, treated with anti-PD-1 or anti-PD-L1 monotherapy. Patients, on immunotherapy, qualifying for hyperprogression had shorted OS. It is important to have a better understanding of hyperprogression on immunotherapy which shall be addressed in the ongoing immunotherapy studies.

Revisiting adjuvant ovarian suppression in premenopausal breast cancer patients.

Adjuvant ovarian suppression, on addition to chemotherapy, reduces the risk of breast cancer in pre-menopausal women after surgery and adjuvant hormonal therapy. Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) showed greater benefit with exemestane in high risk females in comparison to Tamoxifen. Ovarian Function Suppression (OFS) and exemestane became the standard of care, with 30% patients experiencing grade 3 and more side effects. Much higher benefit was seen in high risk group. But there are concerns about incomplete OFS (estrogen escape) with exemestane plus OFS. Updated analysis of TEXT AND SOFT showed better survival benefit with OFS plus Tamoxifen as compared to OFS plus exemestane. Overall survival is a better end point. Should preference be given to Tamoxifen over exemestane? Further research is required to get the final answer.

Harnessing the Immunomodulatory Effects of Radiation in Urinary Bladder Cancer.

The use of local radiation to elicit distant tumor response was proposed long back. The abscopal effect is regression of non-irradiated metastatic lesions at the distant site and there is an enormous therapeutic effect of immunomodulation. Radiation causes cancer cells to release antigens which mount an immune response, but this response is short lasting because cancer cells evade recognition by different mechanisms. Programmed Death Ligand-1 (PDL-1) pathway has been extensively studied. Combining immunotherapy and radiotherapy may result in long-term remissions especially for stage 4 cancer. Here we present a case of high grade urothelial carcinoma that progressed after four cycles of chemotherapy and after giving palliative radiation to urinary bladder he was started on nivolumab. First scan done after radiation and six cycles of nivolumab showed complete response. The patient continues to be in remission for the last 17 months from the start of radiation and immunotherapy that was started sequentially. Overall survival till date is 25 months.

Structure-activity relationship of uridine-based nucleoside phosphoramidate prodrugs for inhibition of dengue virus RNA-dependent RNA polymerase.

To identify a potent and selective nucleoside inhibitor of dengue virus RNA-dependent RNA polymerase, a series of 2'- and/or 4'-ribose sugar modified uridine nucleoside phosphoramidate prodrugs and their corresponding triphosphates were synthesized and evaluated. Replacement of 2'-OH with 2'-F led to be a poor substrate for both dengue virus and human mitochondrial RNA polymerases. Instead of 2'-fluorination, the introduction of fluorine at the ribose 4'-position was found not to affect the inhibition of the dengue virus polymerase with a reduction in uptake by mitochondrial RNA polymerase. 2'-C-ethynyl-4'-F-uridine phosphoramidate prodrug displayed potent anti-dengue virus activity in the primary human peripheral blood mononuclear cell-based assay with no significant cytotoxicity in human hepatocellular liver carcinoma cell lines and no mitochondrial toxicity in the cell-based assay using human prostate cancer cell lines.

Improving handover between triage and locality wards in a large mental health trust.

BACKGROUND: South London and Maudsley NHS Foundation Trust is the largest mental health trust in the UK, serving four boroughs in South East London. In 2014, the 'triage ward' system was introduced in three boroughs. Similar to an acute medical admission unit, the triage ward would rapidly assess and treat all new admissions. The patients would either be discharged or admitted to a 'locality ward' for further treatment. PROBLEM: The unforeseen consequences of the 'triage ward' system were duplications and omissions of medical tasks on receiving wards, which affected efficiency and quality of care. This was due to a lack of formal medical handover. We aimed to improve efficiency and patient safety by formalising the junior doctor handover between triage and locality wards, ensuring every patient transferred had a documented handover in their electronic notes. METHOD: We consulted our colleagues with a survey, ascertaining their views on the current system, the need for a more formalised system and what form that system should take. Using their feedback, we devised a handover template, to be completed for all patients transferred to locality wards. We then rolled the project out to the other two boroughs using the same methodology. RESULTS: A follow-up survey showed improvement in our baseline results and that the majority of transferred patients were formally handed over. Serious incident data showed a decrease in incident rates pre-intervention and post-intervention. The intervention was sustained a year later. The transfer of the intervention to other sites was problematic. DISCUSSION: The project showed the lack of handover was a concern shared by colleagues, and they considered our template a useful way of addressing this. The results suggested that the intervention was sustainable despite frequent rotations of staff. The difficulties in transferring an intervention to new sites are discussed.

Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design.

The discovery and optimization of non-nucleoside dengue viral RNA-dependent-RNA polymerase (RdRp) inhibitors are described. An X-ray-based fragment screen of Novartis' fragment collection resulted in the identification of a biphenyl acetic acid fragment 3, which bound in the palm subdomain of RdRp. Subsequent optimization of the fragment hit 3, relying on structure-based design, resulted in a >1000-fold improvement in potency in vitro and acquired antidengue activity against all four serotypes with low micromolar EC50 in cell-based assays. The lead candidate 27 interacts with a novel binding pocket in the palm subdomain of the RdRp and exerts a promising activity against all clinically relevant dengue serotypes.

Design, synthesis, and biological evaluation of indole-2-carboxamides: a promising class of antituberculosis agents.

Indole-2-carboxamides have been identified as a promising class of antituberculosis agents from phenotypic screening against mycobacteria. One of the hits, indole-2-carboxamide analog (1), had low micromolar potency against Mycobacterium tuberculosis (Mtb), high mouse liver microsomal clearance, and low aqueous solubility. Structure-activity relationship studies revealed that attaching alkyl groups to the cyclohexyl ring significantly improved Mtb activity but reduced solubility. Furthermore, chloro, fluoro, or cyano substitutions on the 4- and 6-positions of the indole ring as well as methyl substitution on the cyclohexyl ring significantly improved metabolic stability. 39 and 41, the lead candidates, displayed improved in vitro activity compared to most of the current standard TB drugs. The low aqueous solubility could not be mitigated because of the positive correlation of lipophilicity with Mtb potency. However, both compounds displayed favorable oral pharmacokinetic properties in rodents and demonstrated in vivo efficacy. Thus, indole-2-carboxamides represent a promising new class of antituberculosis agents.

Harnessing clinical psychiatric data with an electronic assessment tool (OPCRIT+): the utility of symptom dimensions.

Progress in personalised psychiatry is dependent on researchers having access to systematic and accurately acquired symptom data across clinical diagnoses. We have developed a structured psychiatric assessment tool, OPCRIT+, that is being introduced into the electronic medical records system of the South London and Maudsley NHS Foundation Trust which can help to achieve this. In this report we examine the utility of the symptom data being collected with the tool. Cross-sectional mental state data from a mixed-diagnostic cohort of 876 inpatients was subjected to a principal components analysis (PCA). Six components, explaining 46% of the variance in recorded symptoms, were extracted. The components represented dimensions of mania, depression, positive symptoms, anxiety, negative symptoms and disorganization. As indicated by component scores, different clinical diagnoses demonstrated distinct symptom profiles characterized by wide-ranging levels of severity. When comparing the predictive value of symptoms against diagnosis for a variety of clinical outcome measures (e.g. 'Overactive, aggressive behaviour'), symptoms proved superior in five instances (R(2) range: 0.06-0.28) whereas diagnosis was best just once (R(2):0.25). This report demonstrates that symptom data being routinely gathered in an NHS trust, when documented on the appropriate tool, have considerable potential for onward use in a variety of clinical and research applications via representation as dimensions of psychopathology.

A translation inhibitor that suppresses dengue virus in vitro and in vivo.

We describe a novel translation inhibitor that has anti-dengue virus (DENV) activity in vitro and in vivo. The inhibitor was identified through a high-throughput screening using a DENV infection assay. The compound contains a benzomorphan core structure. Mode-of-action analysis indicated that the compound inhibits protein translation in a viral RNA sequence-independent manner. Analysis of the stereochemistry demonstrated that only one enantiomer of the racemic compound inhibits viral RNA translation. Medicinal chemistry was performed to eliminate a metabolically labile glucuronidation site of the compound to improve its in vivo stability. Pharmacokinetic analysis showed that upon a single subcutaneous dosing of 25 mg/kg of body weight in mice, plasma levels of the compound reached a C(max) (maximum plasma drug concentration) above the protein-binding-adjusted 90% effective concentration (EC(90)) value of 0.96 µM. In agreement with the in vivo pharmacokinetic results, treatment of DENV-infected mice with 25 mg/kg of compound once per day reduced peak viremia by about 40-fold. However, mice treated with 75 mg/kg of compound per day exhibited adverse effects. Collectively, our results demonstrate that the benzomorphan compounds inhibit DENV through suppression of RNA translation. The therapeutic window of the current compounds needs to be improved for further development.

Inhibition of dengue virus RNA synthesis by an adenosine nucleoside.

We recently reported that (2R,3R,4R,5R)-2-(4-amino-pyrrolo[2,3-d]pyrimidin-7-yl)-3-ethynyl-5-hydroxy-methyl-tetrahydro-furan-3,4-diol is a potent inhibitor of dengue virus (DENV), with 50% effective concentration (EC(50)) and cytotoxic concentration (CC(50)) values of 0.7 microM and >100 microM, respectively. Here we describe the synthesis, structure-activity relationship, and antiviral characterization of the inhibitor. In an AG129 mouse model, a single-dose treatment of DENV-infected mice with the compound suppressed peak viremia and completely prevented death. Mode-of-action analysis using a DENV replicon indicated that the compound blocks viral RNA synthesis. Recombinant adenosine kinase could convert the compound to a monophosphate form. Suppression of host adenosine kinase, using a specific inhibitor (iodotubercidin) or small interfering RNA (siRNA), abolished or reduced the compound's antiviral activity in cell culture. Studies of rats showed that (14)C-labeled compound was converted to mono-, di-, and triphosphate metabolites in vivo. Collectively, the results suggest that this adenosine inhibitor is phosphorylated to an active (triphosphate) form which functions as a chain terminator for viral RNA synthesis.

A retrospective study of patients with locally advanced cancer of the cervix treated with neoadjuvant chemotherapy followed by radical surgery.

New concept of downstaging locally advanced cancer of the cervix (LACC) with neoadjuvant chemotherapy (NACT), to make it resectable, is of great interest and needs to be explored. This is a retrospective study of 56 LACC patients. Efficacy of NACT was measured in terms of optimal pathological response (OR). Percentage of patients who needed adjuvant radiotherapy and disease-free interval at 2 years was evaluated. Clinically, 49 patients (87.5%) responded well to NACT with TIP regimen (paclitaxel, ifosfamide, and cisplatin) and underwent radical surgery. Adjuvant radiation was given for adverse factors in histopathology. Recurrences were noted; 46.4% of patients were in stage 2b, followed by 25% in stage IIIb; 92.8% of patients had squamous cell carcinoma. Optimal pathological response was seen in 15 patients (30.6%) with complete response in 8 patients (16.3%). Four patients (8.2%) had deposits in the parametrium, and 11 (22.4%) had positive nodes. On gross examination, 48.9% of patients had complete disappearance of cervical growth, and there was no microscopic evidence of cervical malignancy in 16.3%. In 20.4% of patients, cervical cancer was reduced to cervical intraepithelial neoplasia or microinvasion. Thirty-four patients (69.4%) needed full adjuvant radiotherapy. Overall, 14 patients (25.92%) had recurrence, with 11 (22.44%) being in NACT and radical surgery group. At 2 years, disease-free interval for 49 patients who underwent radical surgery was 69%. This study suggests that LACC patients who respond to NACT are surgically resectable with pathological cure in some cases, who are then spared from adjuvant radiation, which is given when recurrence occurs. However, with advancing stage, the percentage of OR decreases, and the need of adjuvant radiation increases.

A small-molecule dengue virus entry inhibitor.

The incidence of dengue fever epidemics has increased dramatically over the last few decades. However, no vaccine or antiviral therapies are available. Therefore, the need for safe and effective antiviral drugs has become imperative. The entry of dengue virus into a host cell is mediated by its major envelope (E) protein. The crystal structure of the E protein reveals a hydrophobic pocket that is presumably important for low-pH-mediated membrane fusion. High-throughput docking with this hydrophobic pocket was performed, and hits were evaluated in cell-based assays. Compound 6 was identified as one of the inhibitors and had an average 50% effective concentration of 119 nM against dengue virus serotype 2 in a human cell line. Mechanism-of-action studies demonstrated that compound 6 acts at an early stage during dengue virus infection. It arrests dengue virus in vesicles that colocalize with endocytosed dextran and inhibits NS3 expression. The inhibitors described in this report can serve as molecular probes for the study of the entry of flavivirus into host cells.

Molecular cloning and expression of two HSP70 genes in the prawn, Macrobrachium rosenbergii.

Two complementary deoxyribonucleic acid (cDNA) clones encoding 2 different 70-kDa heat shock proteins (HSPs) were isolated from the prawn Macrobrachium rosenbergii. The cDNA clones were 2448 and 2173 bp in length and contained 1950- and 1734-bp open reading frames (ORFs), respectively. The ORFs encoded 649- and 577-amino acid polypeptides, which were named Mar-HSC70 and Mar-HSP70, respectively, according to the sequence identities with other known HSC70s and HSP70s and based on their inducibility in response to heat shock stress (at 35 degrees C). Genomic DNA sequence analysis revealed no introns in either gene. The major structural differences between the 2 proteins were a 60-amino acid segment and a 14-amino acid segment present in the N-terminal and C-terminal, respectively, of Mar-HSC70 that were not found in Mar-HSP70. Northern blotting and semiquantitative reverse transcription-polymerase chain reaction analyses indicated that the Mar-HSP70 gene was expressed under heat shock (35 degrees C) stress in a non-tissue-specific manner. In contrast, Mar-HSC70 messenger ribonucleic acid was constitutively expressed in every tissue except muscle, and its expression in response to heat shock (at 35 degrees C) changed only in muscle.