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ImportanceClinical trials have not established the optimal type, sequence, and duration of interventions for people at ultrahigh risk of psychosis.ObjectiveTo determine the effectiveness of a sequential and adaptive intervention strategy for individuals at ultrahigh risk of psychosis.Design, setting, and participantsThe Staged Treatment in Early Psychosis (STEP) sequential multiple assignment randomized trial took place within the clinical program at Orygen, Melbourne, Australia. Individuals aged 12 to 25 years who were seeking treatment and met criteria for ultrahigh risk of psychosis according to the Comprehensive Assessment of At-Risk Mental States were recruited between April 2016 and January 2019. Of 1343 individuals considered, 342 were recruited.InterventionsStep 1: 6 weeks of support and problem solving (SPS); step 2: 20 weeks of cognitive-behavioral case management (CBCM) vs SPS; and step 3: 26 weeks of CBCM with fluoxetine vs CBCM with placebo with an embedded fast-fail option of ω-3 fatty acids or low-dose antipsychotic medication. Individuals who did not remit progressed through these steps; those who remitted received SPS or monitoring for up to 12 months.Main outcomes and measuresGlobal Functioning: Social and Role scales (primary outcome), Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, Montgomery-Åsberg Depression Rating Scale, quality of life, transition to psychosis, and remission and relapse rates.ResultsThe sample comprised 342 participants (198 female; mean [SD] age, 17.7 [3.1] years). Remission rates, reflecting sustained symptomatic and functional improvement, were 8.5%, 10.3%, and 11.4% at steps 1, 2, and 3, respectively. A total of 27.2% met remission criteria at any step. Relapse rates among those who remitted did not significantly differ between SPS and monitoring (step 1: 65.1% vs 58.3%; step 2: 37.7% vs 47.5%). There was no significant difference in functioning, symptoms, and transition rates between SPS and CBCM and between CBCM with fluoxetine and CBCM with placebo. Twelve-month transition rates to psychosis were 13.5% (entire sample), 3.3% (those who ever remitted), and 17.4% (those with no remission).Conclusions and relevanceIn this sequential multiple assignment randomized trial, transition rates to psychosis were moderate, and remission rates were lower than expected, partly reflecting the ambitious criteria set and challenges with real-world treatment fidelity and adherence. While all groups showed mild to moderate functional and symptomatic improvement, this was typically short of remission. While further adaptive trials that address these challenges are needed, findings confirm substantial and sustained morbidity and reveal relatively poor responsiveness to existing treatments.Trial registrationClinicalTrials.gov Identifier: NCT02751632.

BackgroundWhether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown.MethodsIn a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated.ResultsAt a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group.ConclusionsAmong patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

Fragment-based drug discovery (FBDD) has emerged as a powerful strategy to confront the challenges faced by conventional drug development approaches, particularly in the context of central nervous system (CNS) disorders. FBDD involves the screening of libraries that comprise thousands of small molecular fragments, each no greater than 300 Da in size. Unlike the generally larger molecules from high-throughput screening that limit customisation, fragments offer a more strategic starting point. These fragments are inherently compact, providing a strong foundation with good binding affinity for the development of drug candidates. The minimal elaboration required to transition the hit into a drug-like molecule is not only accelerated, but also it allows for precise modifications to enhance both their activity and pharmacokinetic properties. This shift towards a fragment-centric approach has seen commercial success and holds considerable promise in the continued streamlining of the drug discovery and development process. In this review, we highlight how FBDD can be integrated into the CNS drug discovery process to enhance the exploration of a target. Furthermore, we provide recent examples where FBDD has been an integral component in CNS drug discovery programs, enabling the improvement of pharmacokinetic properties that have previously proven challenging. The FBDD optimisation process provides a systematic approach to explore this vast chemical space, facilitating the discovery and design of compounds piece by piece that are capable of modulating crucial CNS targets.

ABSTRACT Tetracyclines serve as broad-spectrum antibiotics to treat bacterial infections. The discovery of new tetracycline resistance genes has led to new questions about the underlying mechanisms of resistance, gene transfer, and their relevance to human health. We tracked changes in the abundance of a 55-kbp conjugative transposon (CTn214) carrying tetQ, a tetracycline resistance gene, within a Bacteroides fragilis metagenome-assembled genome derived from shotgun sequencing of microbial DNA extracted from the ileal pouch of a patient with ulcerative colitis. The mapping of metagenomic reads to CTn214 revealed the multi-copy nature of a 17,044-nt region containing tetQ in samples collected during inflammation and uninflamed visits. B. fragilis cultivars isolated from the same patient during periods of inflammation harbored CTn214 integrated into the chromosome or both a circular, multi-copy, extrachromosomal region of the CTn214 containing tetQ and the corresponding integrated form. The tetracycline-dependent mechanism for the transmission of CTn214 is nearly identical to a common conjugative transposon found in the genome of B. fragilis (CTnDOT), but the autonomously amplified nature of a circular 17,044-nt region of CTn214 that codes for tetQ and the integration of the same sequence in the linear chromosome within the same cell is a novel observation. Genome and transcriptome sequencing of B. fragilis cultivars grown under different concentrations of tetracycline and ciprofloxacin indicates that tetQ in strains containing the circular form remains actively expressed regardless of treatment, while the expression of tetQ in strains containing the linear form increases only in the presence of tetracycline.IMPORTANCEThe exchange of antibiotic production and resistance genes between microorganisms can lead to the emergence of new pathogens. In this study, short-read mapping of metagenomic samples taken over time from the illeal pouch of a patient with ulcerative colitis to a Bacteroides fragilis metagenome-assembled genome revealed two distinct genomic arrangements of a novel conjugative transposon, CTn214, that encodes tetracycline resistance. The autonomous amplification of a plasmid-like circular form from CTn214 that includes tetQ potentially provides consistent ribosome protection against tetracycline. This mode of antibiotic resistance offers a novel mechanism for understanding the emergence of pathobionts like B. fragilis and their persistence for extended periods of time in patients with inflammatory bowel disease.

Louisiana has high coastal wetland loss rates due to natural processes such as subsidence and anthropogenic activities such as construction of river levees and dams, pervasive alteration of surface hydrology by local industries such as oil and gas, and navigation. With the exception of the Atchafalaya River discharge area, most of Louisiana's marsh coastline is retreating and coastal marshes are degrading. In the inactive degrading delta regions, there exists a previously uncharacterized landform referred to colloquially as coastal ‘land bridge’ marshes. Land bridge marshes are saline or brackish marshes fronting large estuarine bays or lakes with sufficient fetch and wave energy to supply high levels of resuspended sediments to the marsh surface. They are generally linear features that are oriented parallel to the coast and the shoreline front retreats landward due to erosion from wave energy. These marshes persist over time vertically due to input of resuspended sediments but are experiencing rapid edge erosion due to wave attack. Comparison of data from Louisiana's Coastal Reference Monitoring System (CRMS) sites show that land bridge marshes have a greater frequency of higher soil surface elevation and higher soil bulk density than non-land bridge marshes. Because land bridges are vertically stable relative to other coastal wetlands, identification of measures to sustain these landscape features is important. Simulations using MarshMorpho2D, a process-based reduced-complexity morphology model, suggest that protection barriers installed on the seaward side of land bridge marshes will attenuate wave energy and, thus, edge erosion. Shoreline protection that can reduce wave energy but still allow sediment input to marshes include living shorelines, rock barriers, and/or breakwaters. Periodic thin layer nourishment of the marsh surface may be necessary to help sustain vertical growth. Further, marsh creation projects directly landward of land bridge marshes may benefit from their protection from waves and as a source of sediment. Consideration of land bridge marshes as distinct marsh types in the State Master Plan and integrated modeling could help to identify measures to sustain these landscape features.

Pancreatic cancer is one of the leading causes for cancer-related deaths in the United States. Majority of patients present with unresectable or metastatic disease. For those that present with localized disease, a multidisciplinary approach is necessary to maximize survival and optimize outcomes. The quality and safety of surgery for pancreatic cancer have improved in recent years with increasing adoption of minimally invasive techniques and surgical adjuncts. Systemic chemotherapy has also evolved to impact survival. It is now increasingly being utilized in the neoadjuvant setting, often with concomitant radiation. Increased utilization of genomic testing in metastatic pancreatic cancer has led to better understanding of their biology, thereby allowing clinicians to consider potential targeted therapies. Similarly, targeted agents such as PARP inhibitors and immune checkpoint- inhibitors have emerged with promising results. In summary, pancreatic cancer remains a disease with poor long-term survival. However, recent developments have led to improved outcomes and have changed practice in the past decade. This review summarizes current practices in pancreatic cancer treatment and the milestones that brought us to where we are today, along with emerging therapies.

Introduction: Neurological harm from neonatal hyperbilirubinemia includes loss of hearing and encephalopathy. The current research used the “Brainstem Evoked Response Audiometry (BERA)” test to screen for as well as assess hearing loss in newborns who had recovered from hyperbilirubinemia. Materials and Procedures: A cross-sectional comparative investigation was conducted at a tertiary care center. Fifty neonates were included out of which 25 were healthy and 25 received treatment for the increased bilirubin. Prior to BERA testing, the subjects' ears were examined for any obstruction. Following a conventional lab procedure described, the BERA recordings were carried out after the neonate fell asleep on its own. The data collected were compared for the significance using the ANOVA, keeping P < 0.05 as significant. Results: In comparison to the controls, a large proportion of neonates in cases had BERA wave latencies that were delayed (I-R = 80, L = 84; III- R = 76, L = 84; V- R = 84, L = 88 percentages latencies). The percentage of subjects in whom the latencies was noted for the healthy neonates was lesser than the case group (I-R = 8, L = 24; III- R = 8, L = 8; V- R = 4, L = 12 percentages latencies). Comparable numbers of infants in each group had inter-peak latencies that were lengthy. Subjects in the case group showed that the threshold hearing as per the WHO grade was mild (R = 32, L = 36) and moderate (R = 32, L = 28). Conclusion: Elevated serum bilirubin may cause damage to hearing capability. After hyperbilirubinemia has been completely treated, BERA can detect even the slightest degree of hearing damage. BERA is therefore a useful technique for the quick recognition of hearing impairment in newborns. Early treatment helps in the prognosis so that the neurosensory systems can fully mature, and the patient can lead a quality life.

Musa paradisiaca, Tectona grandis and Thalia geniculata leaves used in the past as wrapping materials of Olèlè (steamed dough of cowpea enriched to the shrimps and other condiments), are being abandoned in favor of metal cans. This situation contributes to the lost of identity of this traditional food product. Two traditional processing methods which differ in the dehulling techniques are practiced to obtain Olèlè also called Magni magni or Moin moin. The objective of this study was to determine the effect of processing methods and wrapping materials on sensory characteristics of Olèlè and their consumer acceptability. For this purpose, sensory difference and overall acceptability tests and a sensory profile analysis were conducted. Thus, Olèlè differently wrapped was produced the day of the sensory evaluation and appreciated by sensory panelists. Panelists clearly distinguished Olèlè according to the processing method. Sixteen representative descriptors were identified to profile Olèlè. The leaves used for wrapping Olèlè had a significant effect on its sensory characteristics noted by the consumer panel with clearly distinct sensory profiles (p ≤ 0.05). The overall acceptability test revealed that the Olèlè wrapped in Musa paradisiaca leaves is the most appreciated, followed respectively by those wrapped with Tectona grandis leaves, Thalia geniculata leaves and one packaged in recycled tin cans.

To run a successful cattle business, you will have to select a cattle market where the cattle trader will purchase the cattle to be delivered whenever the customers need them, however, there are so many problems in the distribution of cattle to various markets. Hence, the objective of this paper was to evaluate the transportation problem models on cattle business in Niger state, Nigeria at a minimum cost using Russell’s Approximation Method by selecting seven cattle markets (Bangi, Beji, Ibeto, Kawon-Kontagora, Kuta, Mariga and Tungar-Malam) in Niger state for distribution to some selected locations in Akure, Ibadan, Ilorin, Ijebu-Ode, Lagos and Oshogbo in the South Western part of Nigeria at a minimum cost. The Russell’s Approximation method is used to find the Initial Basic Feasible Solution (N36, 703, 723.98). The optimality method is tested via Stepping Stone Method and found it to be not optimal. Furthermore, the optimal solution is found using MS Excel solver. The minimum cost of transportation is found to be N36, 159,785.13.

Abstract Preliminary evidence indicates beneficial effects of omega-3 polyunsaturated fatty acids (PUFAs) in early psychosis. The present study investigates the molecular mechanism of omega-3 PUFA-associated therapeutic effects in clinical high-risk (CHR) participants. Plasma samples of 126 CHR psychosis participants at baseline and 6-months follow-up were included. Plasma protein levels were quantified using mass spectrometry and erythrocyte omega-3 PUFA levels were quantified using gas chromatography. We examined the relationship between change in polyunsaturated PUFAs (between baseline and 6-month follow-up) and follow-up plasma proteins. Using mediation analysis, we investigated whether plasma proteins mediated the relationship between change in omega-3 PUFAs and clinical outcomes. A 6-months change in omega-3 PUFAs was associated with 24 plasma proteins at follow-up. Pathway analysis revealed the complement and coagulation pathway as the main biological pathway to be associated with change in omega-3 PUFAs. Moreover, complement and coagulation pathway proteins significantly mediated the relationship between change in omega-3 PUFAs and clinical outcome at follow-up. The inflammatory protein complement C5 and protein S100A9 negatively mediated the relationship between change in omega-3 PUFAs and positive symptom severity, while C5 positively mediated the relationship between change in omega-3 and functional outcome. The relationship between change in omega-3 PUFAs and cognition was positively mediated through coagulation factor V and complement protein C1QB. Our findings provide evidence for a longitudinal association of omega-3 PUFAs with complement and coagulation protein changes in the blood. Further, the results suggest that an increase in omega-3 PUFAs decreases symptom severity and improves cognition in the CHR state through modulating effects of complement and coagulation proteins.

This randomized clinical trial assesses the efficacy of cognitive remediation plus transcranial direct current stimulation targeting the prefrontal cortex in slowing cognitive decline, acutely improving cognition, and reducing progression to dementia in older adults with remitted major depressive disorder, mild cognitive impairment, or both. Key Points: Question: Does cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) slow cognitive decline in older adults with remitted major depressive disorder (rMDD) or mild cognitive impairment (MCI)? Findings: In this randomized clinical trial including 375 participants with rMDD or MCI, those randomized to receive active CR plus active tDCS experienced a slower cognitive decline over a median follow-up of 4 years than those randomized to receive sham-plus-sham treatments. The effects were more prominent in the rMDD (with or without MCI) than in the MCI without rMDD group. Meaning: The treatment of CR plus tDCS is effective in slowing cognitive decline in older adults with rMDD. Importance: Older adults with major depressive disorder (MDD) or mild cognitive impairment (MCI) are at high risk for cognitive decline. Objective: To assess the efficacy of cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) targeting the prefrontal cortex in slowing cognitive decline, acutely improving cognition, and reducing progression to MCI or dementia in older adults with remitted MDD (rMDD), MCI, or both. Design, Setting, and Participants: This randomized clinical trial was conducted at 5 academic hospitals in Toronto, Ontario, Canada. Participants were older adults who had rMDD (with or without MCI, age ≥65 y) or MCI without rMDD (age ≥60 y). Assessments were made at baseline, month 2, and yearly from baseline for 3 to 7 years. Interventions: CR plus tDCS (hereafter, active) or sham plus sham 5 days a week for 8 weeks followed by twice-a-year 5-day boosters and daily at-home CR or sham CR. Main Outcomes and Measures: The primary outcome was change in global composite cognitive score. Secondary outcomes included changes in 6 cognitive domains, moderating effect of the diagnosis, moderating effect of APOE ε4 status, change in composite score at month 2, and progression to MCI or dementia over time. Results: Of 486 older adults who provided consent, 375 (with rMDD, MCI, or both) received at least 1 intervention session (mean [SD] age, 72.2 [6.4] years; 232 women [62%] and 143 men [38%]). Over a median follow-up of 48.3 months (range, 2.1-85.9), CR and tDCS slowed cognitive decline in older adults with rMDD or MCI (adjusted z score difference [active − sham] at month 60, 0.21; 95% CI, 0.07 to 0.35; likelihood ratio test [LRT] P =.006). In the preplanned primary analysis, CR and tDCS did not improve cognition acutely (adjusted z score difference [active − sham] at month 2, 0.06, 95% CI, −0.006 to 0.12). Similarly, the effect of CR and tDCS on delaying progression from normal cognition to MCI or MCI to dementia was weak and not significant (hazard ratio, 0.66; 95% CI, 0.40 to 1.08; P =.10). Preplanned analyses showed treatment effects for executive function (LRT P =.04) and verbal memory (LRT P =.02) and interactions with diagnosis (P =.01) and APOE ε4 (P <.001) demonstrating a larger effect among those with rMDD and in noncarriers of APOE ε4. Conclusions and Relevance: The study showed that CR and tDCS, both targeting the prefrontal cortex, is efficacious in slowing cognitive decline in older adults at risk of cognitive decline, particularly those with rMDD (with or without MCI) and in those at low genetic risk for Alzheimer disease. Trial Registration: ClinicalTrials.gov Identifier: NCT02386670 [ABSTRACT FROM AUTHOR]

Abstract X-linked dystonia-parkinsonism (XDP) is a progressive adult-onset neurodegenerative disorder caused by insertion of a SINE-VNTR-Alu (SVA) retrotransposon in the TAF1 gene. The SVA retrotransposon contains a CCCTCT hexameric repeat tract of variable length, whose length is inversely correlated with age at onset. This places XDP in a broader class of repeat expansion diseases, characterized by the instability of their causative repeat mutations. Here, we observe similar inverse correlations between CCCTCT repeat length with age at onset and age at death and no obvious correlation with disease duration. To gain insight into repeat instability in XDP we performed comprehensive quantitative analyses of somatic instability of the XDP CCCTCT repeat in blood and in seventeen brain regions from affected males. Our findings reveal repeat length-dependent and expansion-based instability of the XDP CCCTCT repeat, with greater levels of expansion in brain than in blood. The brain exhibits regional-specific patterns of instability that are broadly similar across individuals, with cerebellum exhibiting low instability and cortical regions exhibiting relatively high instability. The spectrum of somatic instability in the brain includes a high proportion of moderate repeat length changes of up to 5 repeats, as well as expansions of ~ 20- > 100 repeats and contractions of ~ 20–40 repeats at lower frequencies. Comparison with HTT CAG repeat instability in postmortem Huntington’s disease brains reveals similar brain region-specific profiles, indicating common trans-acting factors that contribute to the instability of both repeats. Analyses in XDP brains of expansion of a different SVA-associated CCCTCT located in the LIPG gene, and not known to be disease-associated, reveals repeat length-dependent expansion at overall lower levels relative to the XDP CCCTCT repeat, suggesting that expansion propensity may be modified by local chromatin structure. Together, the data support a role for repeat length-dependent somatic expansion in the process(es) driving the onset of XDP and prompt further investigation into repeat dynamics and the relationship to disease.

The third Sustainable Development Goal (SDG), to ensure healthy lives and promote well-being for all at all ages, has particular relevance and implementation challenges amongst people living with rare diseases such as cystic fibrosis (CF). Although the treatment and projected outcome of CF has significantly improved with the advent of CF transmembrane conductance regulator protein modulator (CFTRm) therapy, there remains significant global inequality with regards to access to these life-saving and life-altering drugs. Elexacaftor, tezacaftor, and ivacaftor (ETI) triple combination therapy, first licensed in the United States in 2019, has rapidly become the standard of care for children aged 6 years and older in most high-income countries for individuals with CFTR variants responsive to ETI. Negotiated agreements for access to ETI are currently in place in North America,Europe, Israel ,Australia and New Zealand. However, less priority has been given to negotiate agreements for access to CFTRm in low-middle income countries(LMIC) with significant CF populations such as Central and South America, India, the Middle East, and Southern Africa. These countries and individuals living with CF are therefore effectively being left behind, in direct conflict with the stated principle of the 2030 SDGs. In this review, we highlight the current global inequity in access to CFTRm drugs and its impact on widening disparities between high-income countries and LMIC in CF outcomes and survival. We further discuss the reasons for this inequity and explore the ethical- and human rights-based principles and dilemmas that clinicians, families, governments, and healthcare funders must consider when prioritizing fair and affordable access to expensive CFTRm drugs. Lastly, we propose possible solutions to overcoming the barriers to accessing affordable CFTRm drugs in LMIC and illustrate with examples how access to drug therapies for other conditions have been successfully negotiated in LMIC through innovative partnerships between governments and pharmaceutical industries.

Background and aimsCultured cell suspensions have been the preferred model to study the apoplast as well as to monitor metabolic and cell cycle-related changes. Previous work showed that methyl jasmonate (MeJA) inhibits leaf growth in a CORONATINE INSENSITIVE 1 (COI1)-dependent manner, with COI1 being the jasmonate (JA) receptor. Here, the effect of COI1 overexpression on the growth of stably transformed arabidopsis cell cultures is described.MethodsTime-course experiments were carried out to analyse gene expression, and protein and metabolite levels.Key resultsBoth MeJA treatment and the overexpression of COI1 modify growth, by altering cell proliferation and expansion. DNA content as well as transcript patterns of cell cycle and cell wall remodelling markers were altered. COI1 overexpression also increases the protein levels of OLIGOGALACTURONIDE OXIDASE 1, BETA-GLUCOSIDASE/ENDOGLUCANASES and POLYGALACTURONASE INHIBITING PROTEIN2, reinforcing the role of COI1 in mediating defence responses and highlighting a link between cell wall loosening and growth regulation. Moreover, changes in the levels of the primary metabolites alanine, serine and succinic acid of MeJA-treated Arabidopsis cell cultures were observed. In addition, COI1 overexpression positively affects the availability of metabolites such as β-alanine, threonic acid, putrescine, glucose and myo-inositol, thereby providing a connection between JA-inhibited growth and stress responses.ConclusionsThis study contributes to the understanding of the regulation of growth and the production of metabolic resources by JAs and COI1. This will have important implications in dissecting the complex relationships between hormonal and cell wall signalling in plants. The work also provides tools to uncover novel mechanisms co-ordinating cell division and post-mitotic cell expansion in the absence of organ developmental control.

AimPrevious research indicates that preventive intervention is likely to benefit patients "at risk" of psychosis, in terms of functional improvement, symptom reduction and delay or prevention of onset of threshold psychotic disorder. The primary aim of the current study is to test outcomes of ultra high risk (UHR) patients, primarily functional outcome, in response to a sequential intervention strategy consisting of support and problem solving (SPS), cognitive-behavioural case management and antidepressant medication. A secondary aim is to test biological and psychological variables that moderate and mediate response to this sequential treatment strategy.MethodsThis is a sequential multiple assignment randomised trial (SMART) consisting of three steps: Step 1: SPS (1.5 months); Step 2: SPS vs Cognitive Behavioural Case Management (4.5 months); Step 3: Cognitive Behavioural Case Management + Antidepressant Medication vs Cognitive Behavioural Case Management + Placebo (6 months). The intervention is of 12 months duration in total and participants will be followed up at 18 months and 24 months post baseline.ConclusionThis paper reports on the rationale and protocol of the Staged Treatment in Early Psychosis (STEP) study. With a large sample of 500 UHR participants this study will investigate the most effective type and sequence of treatments for improving functioning and reducing the risk of developing psychotic disorder in this clinical population.

Abstract Since the first discovery of reverse transcriptase in bacteria, and later in archaea, bacterial and archaeal retroelements have been defined by their common enzyme that coordinates diverse functions. Yet, evolutionary refinement has produced distinct retroelements across the tree of microbial life that are perhaps best described in terms of their programmed RNA—a compact sequence that preserves core information for a sophisticated mechanism. From this perspective, reverse transcriptase has been selected as the modular tool for carrying out nature’s instructions in various RNA templates. Beneficial retroelements—those that can provide a fitness advantage to their host—evolved to their extant forms in a wide array of microorganisms and their viruses, spanning nearly all habitats. Within each specialized retroelement class, several universal features seem to be shared across diverse taxa, while specific functional and mechanistic insights are based on only a few model retroelement systems from clinical isolates. Currently, little is known about the diversity of cellular functions and ecological significance of retroelements across different biomes. With increasing availability of isolate, metagenome-assembled, and single-amplified genomes, the taxonomic and functional breadth of prokaryotic retroelements is coming into clearer view. This review explores the recently characterized classes of beneficial, yet accessory retroelements of bacteria and archaea. We describe how these specialized mechanisms exploit a form of fixed mobility, whereby the retroelements do not appear to proliferate selfishly throughout the genome. Moreover, we discuss computational approaches for systematic identification of retroelements from vast sequence repositories and highlight recent discoveries in terms of their apparent distribution and ecological significance in nature. Lastly, we present a new perspective on the eco-evolutionary significance of these genetic elements in marine bacteria and demonstrate approaches that enable the characterization of their environmental diversity through metagenomics.

Aim and Objectives: 1. To study the clinical outcome, growth and glycaemic control, 2. To study the frequency and type of genetic mutations. Methods: This is a retrospective study with a review of data of medical records from 2008 till date. Results: Twelve patients (six males) with neonatal diabetes mellitus (NDM) were identified. Median (interquartile range – (IQR)) age at diagnosis was 72 (31–95) days with a history of consanguinity in 75%. The median birth weight (range) was 2345 (900–3300) g. Follow-up data were available for eight patients with a median age at (IQR) follow-up of 3.3 (3–5.3) years. At follow-up, the mean annual HbA1c was 8.2% at a mean insulin dose of 1.1 U/kg/d. One patient with Wolcott-Rallison syndrome (WRS) and 21α-hydroxylase deficiency had poor growth and intellectual difficulty. The rest demonstrated satisfactory growth with an increase of mean weight centile from 2nd to 13th, height centile from 6.5th to 20th and normal neuro-cognitive development. Eleven patients underwent genetic testing with a molecular diagnosis in 54% (6/11): EIF2AK3 (n = 2) and one each in INS, PDX1, IL2RA and FOXP3. None had variants in ABCC8 or KCNJ11. One with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome underwent haematopoietic stem cell transplant (HSCT) and later succumbed. Conclusion: Our study demonstrates good clinical outcomes among NDM patients without immune dysfunction. Molecular diagnosis was attained only in around half of the patients (54%) with a great genetic heterogeneity.

Background and Objectives: The prevalence of child sexual abuse (CSA) in India is 18–50% depending on the population studied. To devise strategies for prevention of CSA at the primary care level, we studied the prevalence of CSA amongst college students aged 17–25 years. Methods: A group of medical students and their friends were sent, an anonymous questionnaire validated by experts via WhatsApp. The questionnaire assessed demography, occurrence of prior CSA and details of the sexual abuse. Results: About 574 students participated in the study. The majority of respondents were female (380, 66.2%). About 467 (81.2%) of participants were from South India. Of the 380 women and 194 men who consented to participate in the study, 218 (57.3%) and 65 (33.5%), respectively, said that they had been sexually abused in the past (p < 0.00001). The event commonly occurred at 12–14 years (22.6%), but about 53% of victims were

Summary: Background: Continuous glucose monitoring (CGM) improves glycaemia for people affected by type 1 diabetes (T1D), but is not funded in Aotearoa/New Zealand. This study explores the impact of non-funded CGM on equity of access and associated glycaemic outcomes. Methods: Cross-sectional population-based study collected socio-demographic (age, gender, prioritised ethnicity, socioeconomic status) and clinical data from all regional diabetes centres in New Zealand with children

Aims. Diabetic ketoacidosis (DKA) is not well characterised in New Zealand. This study is aimed at characterising the change in epidemiology and severity of DKA from 2000 to 2019 at a tertiary hospital in the Waikato region of New Zealand. Methods. A retrospective clinical data review of all patients admitted to Waikato District Health Board hospitals with DKA was undertaken. Characteristics and severity of DKA were assessed by type of DKA admission (diagnosed at admission, nonrecurrent, and recurrent), ethnicity, social deprivation, intensive care unit (ICU) admission, and length of hospital stay, with linear regression reporting on changes over time. Results. There were 1254 admissions for DKA (564 individual patients), two-thirds being recurrent events. Nonrecurrent DKA patients were younger, whilst recurrent admissions for DKA were associated with T1D, female gender, greater socioeconomic deprivation, and rural living (all P values < 0.01). DKA admission increased 8-fold between 2000 and 2019, mostly due to an increased number of recurrent events, particularly in Māori and female patients (P

Sand and mud reaching the Mississippi River Delta (MRD) via distributary channels created the delta lobes that, in aggregate, make up the current Deltaic Plain (DP). Sediments transported to the west in the coastal boundary current, in turn, have built the “downstream” Chenier Plain (CP). We review options for restoring the CP coast between the beach dune system and the first series of Cheniers that fronts the Gulf of Mexico (GOM) for ∼200 km to the west of the DP, and contributes 30% to total area of the MRD. The CP was built by marine rather than fluvial processes that have resulted in episodic westward and onshore transport of fine-grained sediments delivered to the inner shelf by the Atchafalaya River distributary. Long-term restoration of the MRD is currently proceeding under the Louisiana Coastal Protection and Restoration Authority (CPRA). Projects to stabilize the CP coast are being proposed and built to test whether coastal defense structures like breakwaters and groins designed to retard erosion on sandy coasts can be adapted for use on muddy shores where cohesive sediments predominate. An estimated 30 to 50 Mt y−1 of resuspended mud is moved past the CP coast by the coastal boundary current in a feature described as the “Atchafalaya Mud Stream.” Mid- to late-Holocene MRD lobes on the west side of the DP similarly contributed mud to the same part of the inner shelf. Then, as now, a portion of this near-shore suspended sediment flux was diverted into shore-welded mudflats that were colonized by marsh vegetation that offset local shoreline retreat. The CP is a regressive coastal feature, formed since sea level rise and marine transgression slowed, and it has experienced a 19% wetland loss since the early 1930s. Coastal retreat, up to more than 10 m y−1, prevails along more than half of the CP shore. Most structures built on the CP coast are constructed of lightweight materials to reduce settlement and lower deployment costs. If the generally positive results to date are validated, then designs can be optimized to increase transmissivity of high-density “fluid mud” (>10 g l−1) during low-frequency swell, while reducing energy transmission in the higher frequency band occupied by locally generated seas that seem to be most destructive to newly created mudflats and marshes. We show that restoration in the CP can be enhanced by taking advantage of the land building capabilities of mud stored in the nearshore and delivered to the coast during storms. The goal is to use engineered structures to increase the rate at which mud is deposited and retained at the shore, thereby harnessing natural processes to reinforce the coast. The use of dredged sediments for wetland creation augments coastal shoreline enhancement.