A randomised double-blind placebo-controlled trial of minocycline and/or Omega-3 fatty acids added to treatment as usual for At Risk Mental States (NAYAB): study protocol

Background The At Risk Mental State (ARMS) describes individuals at high risk of developing schizophrenia or psychosis. The use of antipsychotics in this population is not supported because most individuals with ARMS are unlikely to develop psychosis. Anti-inflammatory treatments and polyunsaturated fatty acids (PUFAs) may have some beneficial effects in the treatment of ARMS. There have been no controlled clinical trials that have investigated the use of minocycline for ARMS and no trials involving PUFAs in combination with other proposed treatments. There is a need to find effective, tolerable and inexpensive interventions for ARMS that are available both in high, low and middle-income countries. Methods A six-month intervention study of minocycline and/or Omega-3 fatty acids added to treatment as usual (TAU) in patients with ARMS will be conducted in Pakistan using a randomised, placebo-controlled, double-blind factorial design. 320 consenting patients with capacity will be recruited from community, general practitioner clinics and psychiatric units. Allowing for a 25% dropout rate, we will recruit 59 completing participants to each study arm, and 236 will complete in total. We will determine whether the addition of minocycline and/or Omega-3 fatty acids to TAU attenuates rate of transition from ARMS to first-episode psychosis and improves symptoms and/or level of functioning in ARMS. We will also investigate whether any candidate risk factors such as negative symptoms, influence treatment response in the ARMS group. The primary efficacy end-point is conversion to psychotic disorder at 12 months post study entry. Analysis will be by intention-to-treat, using analysis-of variance, chi-squared tests and adjusted odds ratios to assess between-group differences. Cox regression analyses will be used to analyse potential between-group differences in time-to-onset of psychosis. Discussion The outcomes of this trial will provide evidence of the potential benefits of minocycline and PUFAs in the treatment of ARMS. Both minocycline and PUFAs are inexpensive are readily available in low/middle-income countries such as Pakistan, and if evidenced, may prove to be safe and effective for treating ARMS

Who is absent and why? Factors affecting doctor absenteeism in Bangladesh.

Absenteeism by doctors in public healthcare facilities in rural Bangladesh is a form of chronic rule-breaking and is recognised as a critical problem by the government. We explored the factors underlying this phenomenon from doctors' perspectives. We conducted a facility-based cross-sectional survey in four government hospitals in Dhaka, Bangladesh. Junior doctors with experience in rural postings were interviewed to collect data on socio-demographic characteristics, work and living experience at the rural facilities, and associations with professional and social networks. Multiple logistic regression was used to determine the factors associated with rural retention. Of 308 respondents, 74% reported having served each term of their rural postings without interruptions. The main reasons for absenteeism reported by those who interrupted rural postings were formal training opportunities (65%), family commitments (41%), and a miscellaneous group of others (17%). Almost half of the respondents reported unmanageable workloads. Most (96%) faced challenges in their last rural posting, such as physically unsafe environments (70%), verbally abusive behaviour by patients/caregivers (67%) and absenteeism by colleagues that impacted them (48%). Respondents who did not serve their entire rural posting were less likely to report an unmanageable workload than respondents who did (AOR 0.39, 95% CI 0.22-0.70). Respondents with connections to influential people in the local community had a 2.4 times higher chance of serving in rural facilities without interruption than others (AOR 2.40, 95% CI 1.26-4.57). Our findings demonstrate that absenteeism is not universal and depends upon doctors' socio-political networks. Policy interventions rarely target unsupportive or threatening behaviour by caregivers and community members, a pivotal disincentive to doctors' willingness to work in underserved rural areas. Policy responses must promote opportunities for doctors with weak networks who are willing to attend work with appropriate support

A randomised double-blind placebo-controlled trial of minocycline and/or omega-3 fatty acids added to treatment as usual for at risk Mental States: The NAYAB study.

BackgroundInflammatory mechanisms are thought to contribute to the onset of psychosis in persons with an at-risk mental state (ARMS). We investigated whether the anti-inflammatory properties of minocycline and omega-3 polyunsaturated fatty acids (omega-3), alone or synergistically, would prevent transition to psychosis in ARMS in a randomised, double-blind, placebo-controlled trial in Pakistan.Methods10,173 help-seeking individuals aged 16-35 years were screened using the Prodromal Questionaire-16. Individuals scoring 6 and over were interviewed using the Comprehensive Assessment of At-Risk Mental States (CAARMS) to confirm ARMS. Participants (n = 326) were randomised to minocycline, omega-3, combined minocycline and omega-3 or to double placebo for 6 months. The primary outcome was transition to psychosis at 12 months.FindingsForty-five (13.8 %) participants transitioned to psychosis. The risk of transition was greater in those randomised to omega-3 alone or in combination with minocycline (17.3.%), compared to 10.4 % in those not exposed to omega-3; a risk-ratio (RR) of 1.67, 95 % CI [0.95, 2.92] p = 0.07. The RR for transitions on minocycline vs. no minocycline was 0.86, 95 % CI [0.50, 1.49] p > 0.10. In participants who did not become psychotic, CAARMS and depression symptom scores were reduced at six and twelve months (mean CAARMS difference = 1.43; 95 % CI [0.33, 1.76] p InterpretationIn keeping with other studies, omega-3 appears to have beneficial effects on ARMS and mood symptom severity but it increased transition to psychosis, which may reflect metabolic or developmental consequences of chronic poor nutrition in the population. Transition to psychosis was too rare to reveal a preventative effect of minocycline but minocycline did not improve symptom severity. ARMS symptom severity and transition to psychosis appear to have distinct pathogeneses which are differentially modulated by omega-3 supplementation.FundingThe study was funded by the Stanley Research Medical Institute

Characterization of Viral RNA-Induced Protein Kinase R Dimerization and Activation

Protein kinase R (PKR) is a key component of the interferon-induced immune response to viral stress. It contains two N-terminal dsRNA binding domains (dsRBD) and a C-terminal serine/threonine kinase domain separated by a 90 residue unstructured linker of unknown function. PKR is activated by viral dsRNAs via dimerization and autophosphorylation of specific serine and threonine residues. We have developed an assay to measure dimerization of PKR while bound to various dsRNAs using Fӧrster resonance energy transfer. This is the first direct measurement of PKR dimerization upon dsRNAs binding. Our results show that inactive dimers of PKR exist in solution, and that a specific back-to-back dimer configuration is essential for activation. The role of the interdomain linker was determined by characterizing linker deleted constructs of PKR. We propose that the unstructured linker may exist to negatively regulate PKR activation by limiting it’s binding stoichiometry and curbing dsRNA-independent activation. The role of the second dsRNA binding domain was probed by mutating residues likely to contact dsRNA. Collectively, the studies presented here provide new insight on the elusive mechanism of dsRNA induced PKR activation

Recent Advances in PROTAC-Based Antiviral Strategies

Numerous mysteries of cell and molecular biology have been resolved through extensive research into intracellular processes, which has also resulted in the development of innovative technologies for the treatment of infectious and non-infectious diseases. Some of the deadliest diseases, accounting for a staggering number of deaths, have been caused by viruses. Conventional antiviral therapies have been unable to achieve a feat in combating viral infections. As a result, the healthcare system has come under tremendous pressure globally. Therefore, there is an urgent need to discover and develop newer therapeutic approaches against viruses. One such innovative approach that has recently garnered attention in the research world and can be exploited for developing antiviral therapeutic strategies is the PROteolysis TArgeting Chimeras (PROTAC) technology, in which heterobifunctional compounds are employed for the selective degradation of target proteins by the intracellular protein degradation machinery. This review covers the most recent advancements in PROTAC technology, its diversity and mode of action, and how it can be applied to open up new possibilities for creating cutting-edge antiviral treatments and vaccines

Recent Advances in PROTAC-Based Antiviral Strategies

Numerous mysteries of cell and molecular biology have been resolved through extensive research into intracellular processes, which has also resulted in the development of innovative technologies for the treatment of infectious and non-infectious diseases. Some of the deadliest diseases, accounting for a staggering number of deaths, have been caused by viruses. Conventional antiviral therapies have been unable to achieve a feat in combating viral infections. As a result, the healthcare system has come under tremendous pressure globally. Therefore, there is an urgent need to discover and develop newer therapeutic approaches against viruses. One such innovative approach that has recently garnered attention in the research world and can be exploited for developing antiviral therapeutic strategies is the PROteolysis TArgeting Chimeras (PROTAC) technology, in which heterobifunctional compounds are employed for the selective degradation of target proteins by the intracellular protein degradation machinery. This review covers the most recent advancements in PROTAC technology, its diversity and mode of action, and how it can be applied to open up new possibilities for creating cutting-edge antiviral treatments and vaccines

Routing through efficient channel assignment in cognitive radio networks

In Cognitive Radio Networks (CRNs) there is much dynamicity due to the activities of primary users which results in instability of routes. Therefore, an efficient routing protocol based on good channel assignment strategy is required in CRNs. A good channel selection strategy makes route stable by selecting channels having larger capacity and greater availability time. Therefore, the focus of this chapter is joint channel assignment and routing in CRNs, which provides a comprehensive survey on routing and channel assignment in CRNs. First, the importance of joint channel assignment and routing for successful communication in cognitive radio networks is discussed. Then classification and challenges related to channel assignment and routing are discussed in detail. In order to establish reliable routes in CRNs, some factors are discussed that further enhance the communication in CRNs. Finally, guidelines for the development of efficient routing protocols are discussed.</p

Mixture Designs in orthogonal blocks using F-squares

John (1984) used latin squares for the construction of orthogonal block designs for the Scheffé\u27s quadratic model in mixture experiments. Draper et al. (1993) discussed mixture designs for four components in orthogonal blocks, which were extended by Prescott et al. (1993) for five components. Lewis et al. (1994) generalized it for q components and gave general methods of constructing designs for q ≥3 mixture components in two or more orthogonal blocks. In this paper, we consider the case of equal volume fractions and construct orthogonal blocks of blends using F-squares. We present a general algorithm for obtaining mates of F-squares that are required for constructing orthogonal blocks. Moreover for four components, we obtain the D-, A- and E-optimal designs for the class of orthogonal block designs obtained using F-squares for Scheffé\u27s quadratic mixture model