Prevalence, service use and clinical correlates of hallucinations and delusions in an out-patient population from India.

BACKGROUND: Despite the persistent public health problem of positive psychotic symptoms, understanding of symptom specific prevalence rates, clinical correlates and service utilisation are sparse. AIMS: The current study aimed to establish prevalence, clinical and service utilisation correlates of hallucinations and delusions in people accessing outpatient clinics in Tamil Nadu, India. METHODS: Secondary patient data from outpatient clinics, over a 12-month period, in 2016, was used for analysis (N = 917). Based on the presence of positive psychotic symptoms (PPSx), the sample was divided into four groups for analysis- hallucinations-only (H), delusions-only (D), both hallucinations and delusions (HD) and neither PPSx (N-PPSx). RESULTS: Findings indicate that the most prevalent PPSx were hallucinations (10.7%) however, barriers to service utilisation and clinical correlates were associated predominantly with the D and the HD group; as was severe work impairment. Yet, this group was most likely to remain with psychiatric services. Lastly, diagnostic challenges were apparent within the sample. CONCLUSIONS: The study revealed that despite more barriers to service utilisation, persons with PPSx remain in contact with services. Yet prognosis remains only moderate at best, indicating other mediating and underlying factors impeding recovery may be interplaying and, therefore, a need for enhanced biopsychosocial approaches.

Clustered regularly interspaced short palindromic repeats-Cas system: diversity and regulation in Enterobacteriaceae.

Insights into the arms race between bacteria and invading mobile genetic elements have revealed the intricacies of the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system and the counter-defenses of bacteriophages. Incredible spacer diversity but significant spacer conservation among species/subspecies dictates the specificity of the CRISPR-Cas system. Researchers have exploited this feature to type/subtype the bacterial strains, devise targeted antimicrobials and regulate gene expression. This review focuses on the nuances of the CRISPR-Cas systems in Enterobacteriaceae that predominantly harbor type I-E and I-F CRISPR systems. We discuss the systems' regulation by the global regulators, H-NS, LeuO, LRP, cAMP receptor protein and other regulators in response to environmental stress. We further discuss the regulation of noncanonical functions like DNA repair pathways, biofilm formation, quorum sensing and virulence by the CRISPR-Cas system. The review comprehends multiple facets of the CRISPR-Cas system in Enterobacteriaceae including its diverse attributes, association with genetic features, regulation and gene regulatory mechanisms.

Improving Fracture Toughness of Tetrafunctional Epoxy with Functionalized 2D Molybdenum Disulfide Nanosheets.

In this work, improved fracture toughness of tetra-functional epoxy polymer was obtained using two-dimensional (2H polytype) molybdenum disulfide (MoS2) nano-platelets as a filler. Simultaneous in-situ exfoliation and functionalization of MoS2 were achieved in the presence of cetyltrimethylammonium bromide (CTAB) via sonication. The aim was to improve the dispersion of MoS2 nanoplatelets in epoxy and enhance the interfacial interaction between nanoplatelets and epoxy matrix. Epoxy nanocomposites with CTAB functionalized MoS2 (f-MoS2) nanoplatelets, ranging in content from 0.1 wt% up to 1 wt%, were fabricated. Modified MoS2 improved the fracture properties (81%) of tetrafunctional epoxy nanocomposites. The flexural strength and compressive strength improved by 64% and 47%, respectively, with 0.25 wt% loading of f-MoS2 nanoplatelets compared to neat epoxy. The addition of f-MoS2 nanoplatelets enhanced the thermomechanical properties of epoxy. This work demonstrated the potential of organically modified MoS2 nanoplatelets for improving the fracture and thermal behavior of tetrafunctional epoxy nanocomposites.

Factors associated with homelessness among women: a cross-sectional survey of outpatient mental health service users at The Banyan, India.

BACKGROUND: Homelessness has multifaceted and damaging effects on women with mental illness. This makes it imperative to identify and address the factors leading to homelessness among women with mental illness in order to inform policy on providing relevant services for this vulnerable population. METHOD: A cross-sectional survey was conducted among 346 women in active contact with one of four outpatient clinics at The Banyan, a non-profit organization in the Indian state of Tamil Nadu. A semi-structured instrument and modified version of the List of Threatening Experiences Questionnaire was used for data collection. Multivariate logistic regression analysis was used to examine predictive variables for homelessness among women with mental illness. RESULT: 32.65% of participants reported a history of homelessness. Less than 5 years of schooling (OR = 2.914, 95% CI = 1.027-8.269, P < 0.05) and disrupted relationships (OR = 1.807, 95% CI = 1.23-2.655, P < 0.01) were associated with a greater likelihood of women with mental illness to experience homelessness. CONCLUSION: In the study cohort, this was explained mainly by factors rooted in gender-based disadvantage. Further practice and research are needed to develop interventions that address issues with a sociological basis to mental illness and prevent these predictive factors.

Mobile application as a complementary tool for differential diagnosis in Neuro-ophthalmology: A multicenter cross-sectional study.

Purpose: Drawing differential diagnoses to a Neuro-ophthalmology clinical scenario is a difficult task for a neurology trainee. The authors conducted a study to determine if a mobile application specialized in suggesting differential diagnoses from clinical scenarios can complement clinical reasoning of a neurologist in training. Methods: A cross-sectional multicenter study was conducted to compare the accuracy of neurology residents versus a mobile medical app (Neurology Dx) in drawing a comprehensive list of differential diagnoses from Neuro-ophthalmology clinical vignettes. The differentials generated by residents and the App were compared with the Gold standard differential diagnoses adjudicated by experts. The prespecified primary outcome was the proportion of correctly identified high likely gold standard differential diagnosis by residents and App. Results: Neurology residents (n = 100) attempted 1500 Neuro-ophthalmology clinical vignettes. Frequency of correctly identified high likely differential diagnosis by residents was 19.42% versus 53.71% by the App (P < 0.0001). The first listed differential diagnosis by the residents matched with that of the first differential diagnosis adjudicated by experts (gold standard differential diagnosis) with a frequency of 26.5% versus 28.3% by the App, whereas the combined output of residents and App scored a frequency of 41.2% in identifying the first gold standard differential correctly. The residents correctly identified the first three and first five gold standard differential diagnosis with a frequency of 17.83% and 19.2%, respectively, as against 22.26% and 30.39% (P < 0.0001) by the App. Conclusion: A ruled based app in Neuro-ophthalmology has the potential to complement a neurology resident in drawing a comprehensive list of differential diagnoses.

Neurosurgery and Neurology Practices during the Novel COVID-19 Pandemic: A Consensus Statement from India.

BACKGROUND: The COVID-19 infection outbreak has aroused increasing attention and affected thousands of people nationwide. The long incubation period, high infectious rate, varied manifestation, and absence of effective treatment make it difficult to manage the disease transmission. OBJECTIVE: The intended goals are to encourage efficient management of neurological and neurosurgical patients, resource utilization, and protecting the healthcare provider during the COVID-19 epidemic. Herein, we present a consensus statement from various centers in India. METHODOLOGY: In addition to the literature review, recommendations were included from neurologists and neurosurgeons from various centers in India. RESULTS: Every patient presenting for treatment should be treated as a potential asymptomatic infected case. Patients should be categorized based upon the priority as acute (require immediate treatment/surgery within 24 h), sub-acute (requiring treatment within a maximum of 7-10 days), or chronic (requiring treatment within a month). Non-essential elective surgeries and outpatient clinics should be avoided after informing the patient(s). There is a high risk of aerosol dispersion during intubation and certain neurosurgical procedures particularly those involving drills and endoscopes. These procedures should be performed wearing full personal protective equipment. The workflow of the operating rooms should also be modified significantly. Minor modifications in personal and professional lifestyles and routine training to use the PPE will ensure efficient management of resources. CONCLUSION: These recommendations could be used to mitigate the risks and reduce exposure to other patients, public, and healthcare staff.

Responsive mental health systems to address the poverty, homelessness and mental illness nexus: The Banyan experience from India.

BACKGROUND: Mental health has gained prominence as a global public health priority. However, a substantial treatment gap persists in many low- and middle-income countries. Within this scenario, the nexus between homelessness, poverty and mental illness represents a particularly complex issue. This article presents the experience of The Banyan, a 25 years old non-profit organisation providing mental health care to people living in poverty in Tamil Nadu, India. CASE PRESENTATION: The case study describes the evolution of The Banyan using a timeline narrative. By applying an action learning framework, the organisation's evolution through four lifecycles, strategy and the key elements underlying mental health system responses are identified and presented. 'User centred' and 'service integration' emerge as the main dimensions of The Banyan's responsive health system. Relating to these two attributes, a typology of services is derived, indicating the responsiveness of mental health systems in addressing complex problems. The role of the organisational culture and the expressed values during the transition is considered. CONCLUSIONS: The case study serves as an example of how responsive mental health systems may be constructed with both a user centred and a service integration focus.

Synovial sarcoma of the heart: A case report and literature review.

Primary cardiac tumors are of rare presentation. We present a case of synovial sarcoma of the right atrium treated in our institution. An initial diagnosis of right atrial myxoma was made based on clinico-radiological features. Intra-operatively, an irregular mass was found. Histopathologically, it was reported as monophasic synovial sarcoma. Immunohistochemistry was positive for S-100, B-cell lymphoma-2, MIC-2 and calretinin. Patient received adjuvant chemotherapy and is currently free of disease for 2 years and on regular follow-up.

What do service users want? A content analysis of what users may write in psychiatric advance directives in India.

Although psychiatric advance directives give service users control over their care, very few studies exist on the content of PADs. This paper aims to contribute to this evidence base by presenting the content of psychiatric advance directives in India. Participants were 75 clients seeking outpatient care at a mental health services organisation in Tamil Nadu, India, who agreed to draft a PAD. Most clients were comfortable with appointing a representative (usually a family member) to make decisions on their behalf during a period of decisional incapacity or relapse, were willing to accept admission to the hospital/clinic and take medication if required, wanted to have a trusted person to discuss their mental health problems. No client used the opportunity to outright refuse treatment. This study highlights an important first step in improving the quality of mental health care by documenting user preferences for care in India. More in-depth research is needed to elicit rich descriptions of experiences of care and user-centred understanding of rights.

Primary ovarian mucinous carcinoma with signet ring cells - report of a rare case.

Presence of signet ring cells in ovarian neoplasms are commonly encountered in Krukenberg tumours of ovary. Unusual presence in primary ovarian mucinous tumours may create a diagnostic difficulty. To the best of our knowledge only very few such cases have been reported in the literature indicating their rarity. We report a case of primary ovarian mucinous carcinoma with signet ring cells. The purpose of this presentation is to sensitize the pathologists to consider primary mucinous carcinoma as a differential diagnosis in tumours with signet ring cells.

Unpacking the psychiatric advance directive in low-resource settings: an exploratory qualitative study in Tamil Nadu, India.

BACKGROUND: Psychiatric advance directives, a tool to document preferences for care in advance of decisional incapacity, have been shown to benefit persons with mental illness in a number of countries through improving medication adherence, reducing symptoms from escalating in a crisis, accelerating recovery, and enhancing service user autonomy. While concepts such as autonomy are important in a number of high-income country settings, it remains unclear whether tools like psychiatric advance directives are suitable in a different context. The recent introduction of the psychiatric advance directive into draft legislation in India prompts the question as to how feasible psychiatric advance directives are in the Indian context. The aim of this study is to explore the feasibility and utility of PADs in India, with a focus on the need for individual control over decision making and barriers to implementation, by exploring views of its central stakeholders, service users and carers. METHODS: Qualitative semi-structured interviews (n = 51) with clients (n = 39) and carers (n = 12) seeking mental health treatment at outpatient clinics in urban and rural settings provided by a non-profit organisation in Tamil Nadu, India. RESULTS: Clients engaged in a number of forms of decision-making (passive, active, and collaborative) depending on the situation and decision at hand, and had high levels of self-efficacy. Most clients and carers were unfamiliar with PADs, and while some clients felt it is important to have a say in treatment wishes, carers expressed concerns about service user capacity to make decisions. After completing PADs, clients reported an increase in self-efficacy and an increased desire to make decisions. CONCLUSIONS: The introduction of psychiatric advance directives in India appears to be associated with positive outcomes for some service users, however, there is a need to better understand how this tool can be adapted to better suit the care context in India and hold meaning and value for service users to complete.

Effect of integrated yogic practices on positive and negative emotions in healthy adults.

BACKGROUND: Studies on affective wellbeing have shown the beneficial role of positive emotions on cognitive processing and the harmful role of negative emotions on coping, stress and health status. Studies have shown that yoga practices reduce anxiety and depression and improve wellbeing. OBJECTIVE: The aims of the study were to, (i) examine the safety and feasibility of conducting a weeklong free yoga camp, and (ii) assess its impact on the negative and positive affect in normal healthy volunteers. MATERIALS AND METHODS: In this open-arm study450 participants were taught integrated yoga module. It included asanas, pranayama, relaxation, notional correction and devotional sessions. Assessment was carried out on the first and last day of the camp, using a modified version of Positive Affect Negative Affect Scale (PANAS). It has ten questions each to measure positive (PA) and negative affect (NA). Nine questions have been added which are referred as other positive affect (OPA) and other negative affect (ONA) domains. RESULTS: Three hundred and twelve sets of pre-post data were analyzed. There was an increase in PA of PANAS by 13% (P<0.001, Wilcoxon's signed rank test) and OPA by 17% (P<0.001). The NA reduced by 47% (P<0.001) and ONA by 48% (P<0.001). CONCLUSION: It is feasible and safe to conduct a weeklong yoga camp in an urban setting, and integrated yoga practices can reduce the negative affect and increase the positive affect within one week.

Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics.

Fragment Based Drug Discovery (FBDD) continues to advance as an efficient and alternative screening paradigm for the identification and optimization of novel chemical matter. To enable FBDD across a wide range of pharmaceutical targets, a fragment screening library is required to be chemically diverse and synthetically expandable to enable critical decision making for chemical follow-up and assessing new target druggability. In this manuscript, the Pfizer fragment library design strategy which utilized multiple and orthogonal metrics to incorporate structure, pharmacophore and pharmacological space diversity is described. Appropriate measures of molecular complexity were also employed to maximize the probability of detection of fragment hits using a variety of biophysical and biochemical screening methods. In addition, structural integrity, purity, solubility, fragment and analog availability as well as cost were important considerations in the selection process. Preliminary analysis of primary screening results for 13 targets using NMR Saturation Transfer Difference (STD) indicates the identification of uM-mM hits and the uniqueness of hits at weak binding affinities for these targets.

Discovery of antibacterial biotin carboxylase inhibitors by virtual screening and fragment-based approaches.

As part of our effort to inhibit bacterial fatty acid biosynthesis through the recently validated target biotin carboxylase, we employed a unique combination of two emergent lead discovery strategies. We used both de novo fragment-based drug discovery and virtual screening, which employs 3D shape and electrostatic property similarity searching. We screened a collection of unbiased low-molecular-weight molecules and identified a structurally diverse collection of weak-binding but ligand-efficient fragments as potential building blocks for biotin carboxylase ATP-competitive inhibitors. Through iterative cycles of structure-based drug design relying on successive fragment costructures, we improved the potency of the initial hits by up to 3000-fold while maintaining their ligand-efficiency and desirable physicochemical properties. In one example, hit-expansion efforts resulted in a series of amino-oxazoles with antibacterial activity. These results successfully demonstrate that virtual screening approaches can substantially augment fragment-based screening approaches to identify novel antibacterial agents.

Exploration of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides as potent, orally active Factor Xa inhibitors with extended duration of action.

Aiming to improve upon previously disclosed Factor Xa inhibitors, a series of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides were explored with the intent of increasing the projected human half-life versus 5 (projected human t(1/2)=6 h). A stereospecific route to compounds containing a 4-aryl-4-hydroxypyrrolidine scaffold was developed, resulting in several compounds that demonstrated an increase in the half-life as well as an increase in the in vitro potency compared to 5. Reported herein is the discovery of 26, containing a (2R,4S)-4-hydroxy-4-(2,4-difluorophenyl)-pyrrolidine scaffold, which is a selective, orally bioavailable, efficacious Factor Xa inhibitor that appears suitable for a once-daily dosing (projected human t(1/2)=23 h).

Discovery and SAR of benzyl phenyl ethers as inhibitors of bacterial phenylalanyl-tRNA synthetase.

A series of benzyl phenyl ethers (BPEs) is described that displays potent inhibition of bacterial phenylalanyl-tRNA synthetase. The synthesis, SAR, and select ADMET data are provided.

A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore.

As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious gram-negative pathogens including Haemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity.

Structure of a small-molecule inhibitor complexed with GlmU from Haemophilus influenzae reveals an allosteric binding site.

N-Acetylglucosamine-1-phosphate uridyltransferase (GlmU) is an essential enzyme in aminosugars metabolism and an attractive target for antibiotic drug discovery. GlmU catalyzes the formation of uridine-diphospho-N-acetylglucosamine (UDP-GlcNAc), an important precursor in the peptidoglycan and lipopolisaccharide biosynthesis in both Gram-negative and Gram-positive bacteria. Here we disclose a 1.9 A resolution crystal structure of a synthetic small-molecule inhibitor of GlmU from Haemophilus influenzae (hiGlmU). The compound was identified through a high-throughput screening (HTS) configured to detect inhibitors that target the uridyltransferase active site of hiGlmU. The original HTS hit exhibited a modest micromolar potency (IC(50) approximately 18 microM in a racemic mixture) against hiGlmU and no activity against Staphylococcus aureus GlmU (saGlmU). The determined crystal structure indicated that the inhibitor occupies an allosteric site adjacent to the GlcNAc-1-P substrate-binding region. Analysis of the mechanistic model of the uridyltransferase reaction suggests that the binding of this allosteric inhibitor prevents structural rearrangements that are required for the enzymatic reaction, thus providing a basis for structure-guided design of a new class of mechanism-based inhibitors of GlmU.

Rational protein engineering in action: the first crystal structure of a phenylalanine tRNA synthetase from Staphylococcus haemolyticus.

In this article, we describe for the first time the high-resolution crystal structure of a phenylalanine tRNA synthetase from the pathogenic bacterium Staphylococcus haemolyticus. We demonstrate the subtle yet important structural differences between this enzyme and the previously described Thermus thermophilus ortholog. We also explain the structure-activity relationship of several recently reported inhibitors. The native enzyme crystals were of poor quality--they only diffracted X-rays to 3-5A resolution. Therefore, we have executed a rational surface mutagenesis strategy that has yielded crystals of this 2300-amino acid multidomain protein, diffracting to 2A or better. This methodology is discussed and contrasted with the more traditional domain truncation approach.

The discovery of (2R,4R)-N-(4-chlorophenyl)-N- (2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (PD 0348292), an orally efficacious factor Xa inhibitor.

Herein, we report the discovery of novel, proline-based factor Xa inhibitors containing a neutral P1 chlorophenyl pharmacophore. Through the additional incorporation of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one 22, as a P4 pharmacophore, we discovered compound 7 (PD 0348292). This compound is a selective, orally bioavailable, efficacious FXa inhibitor that is currently in phase II clinical trials for the treatment and prevention of thrombotic disorders.