Recovery and serious mental illness: a review of current clinical and research paradigms and future directions

Introduction: Recovery from serious mental illness has historically not been considered a likely or even possible outcome. However, a range of evidence suggests the courses of SMI are heterogeneous with recovery being the most likely outcome. One barrier to studying recovery in SMI is that recovery has been operationalized in divergent and seemingly incompatible ways, as an objective outcome, versus a subjective process. Areas Covered: This paper offers a review of recovery as a subjective process and recovery as an objective outcome; contrasts methodologies utilized by each approach to assess recovery; reports rates and correlates of recovery; and explores the relationship between objective and subjective forms of recovery. Expert Commentary: There are two commonalities of approaching recovery as a subjective process and an objective outcome: (i) the need to make meaning out of one’s experiences to engage in either type of recovery and (ii) there exist many threats to engaging in meaning making that may impact the likelihood of moving toward recovery. We offer four clinical implications that stem from these two commonalities within a divided approach to the concept of recovery from SMI

Population genetic analysis of Chadian Guinea worms reveals that human and non-human hosts share common parasite populations

Following almost 10 years of no reported cases, Guinea worm disease (GWD or dracunculiasis) reemerged in Chad in 2010 with peculiar epidemiological patterns and unprecedented prevalence of infection among non-human hosts, particularly domestic dogs. Since 2014, animal infections with Guinea worms have also been observed in the other three countries with endemic transmission (Ethiopia, Mali, and South Sudan), causing concern and generating interest in the parasites’ true taxonomic identity and population genetics. We present the first extensive population genetic data for Guinea worm, investigating mitochondrial and microsatellite variation in adult female worms from both human and non-human hosts in the four endemic countries to elucidate the origins of Chad’s current outbreak and possible host-specific differences between parasites. Genetic diversity of Chadian Guinea worms was considerably higher than that of the other three countries, even after controlling for sample size through rarefaction, and demographic analyses are consistent with a large, stable parasite population. Genealogical analyses eliminate the other three countries as possible sources of parasite reintroduction into Chad, and sequence divergence and distribution of genetic variation provide no evidence that parasites in human and non-human hosts are separate species or maintain isolated transmission cycles. Both among and within countries, geographic origin appears to have more influence on parasite population structure than host species. Guinea worm infection in non-human hosts has been occasionally reported throughout the history of the disease, particularly when elimination programs appear to be reaching their end goals. However, no previous reports have evaluated molecular support of the parasite species identity. Our data confirm that Guinea worms collected from non-human hosts in the remaining endemic countries of Africa are Dracunculus medinensis and that the same population of worms infects both humans and dogs in Chad. Our genetic data and the epidemiological evidence suggest that transmission in the Chadian context is currently being maintained by canine hosts

Clinical outcome 10 years after attempted percutaneous transluminal coronary angioplasty in 856 patients.

Abstract OBJECTIVES: This study reports the 10-year outcome of 856 consecutive patients who underwent attempted coronary angioplasty at the Thoraxcenter during the years 1980 to 1985. BACKGROUND: Coronary balloon angioplasty was first performed in 1977, and this procedure was introduced into clinical practice at the Thoraxcenter in 1980. Although advances have been made, extending our knowledge of the long-term outcome in terms of survival and major cardiac events remains of interest and a valuable guide in the treatment of patients with coronary artery disease. METHODS: Details of survival, cardiac events, symptoms and medication were retrospectively obtained from the Dutch civil registry, medical records or by letter or telephone or from the patient's physician and entered into a dedicated data base. Patient survival curves were constructed, and factors influencing survival and cardiac events were identified. RESULTS: The procedural clinical success rate was 82%. Follow-up information was obtained in 837 patients (97.8%). Six hundred forty-one patients (77%) were alive, of whom 334 (53%) were symptom free, and 254 (40%) were taking no antianginal medication. The overall 5- and 10-year survival rates were 90% (95% confidence interval [CI] 87.6% to 92.4%) and 78% (95% CI 75.0% to 81.0%), respectively, and the respective freedom from significant cardiac events (death, myocardial infarction, coronary artery bypass surgery and repeat angioplasty) was 57% (95% CI 53.4% to 60.6%) and 36% (95% CI 32.4% to 39.6%). Factors that were found to adversely influence 10-year survival were age > or = 60 years (> or = 60 years [67%], 50 to 59 years [82%], or = 50% [80%]) and a history of previous myocardial infarction (previous myocardial infarction [72%], no previous infarction [83%]). These factors were also found to be independent predictors of death during the follow-up period by a multivariate stepwise logistic regression analysis. Other factors tested, with no influence on survival, were gender, procedural success and stability of angina at the time of intervention. CONCLUSIONS: The long-term prognosis of patients after coronary angioplasty is good, particularly in those <60 years old with single-vessel disease and normal left ventricular function. The majority of patients are likely to experience a further cardiac event in the 10 years after their first angioplasty procedure

Aligning evidence generation and use across health, development, and environment

© 2019 The Authors Although health, development, and environment challenges are interconnected, evidence remains fractured across sectors due to methodological and conceptual differences in research and practice. Aligned methods are needed to support Sustainable Development Goal advances and similar agendas. The Bridge Collaborative, an emergent research-practice collaboration, presents principles and recommendations that help harmonize methods for evidence generation and use. Recommendations were generated in the context of designing and evaluating evidence of impact for interventions related to five global challenges (stabilizing the global climate, making food production sustainable, decreasing air pollution and respiratory disease, improving sanitation and water security, and solving hunger and malnutrition) and serve as a starting point for further iteration and testing in a broader set of contexts and disciplines. We adopted six principles and emphasize three methodological recommendations: (1) creation of compatible results chains, (2) consideration of all relevant types of evidence, and (3) evaluation of strength of evidence using a unified rubric. We provide detailed suggestions for how these recommendations can be applied in practice, streamlining efforts to apply multi-objective approaches and/or synthesize evidence in multidisciplinary or transdisciplinary teams. These recommendations advance the necessary process of reconciling existing evidence standards in health, development, and environment, and initiate a common basis for integrated evidence generation and use in research, practice, and policy design

Derived maternal genotypes_Dmedinensis

Derived maternal genotypes_Dmedinensi

ChatGPT Versus Consultants:Blinded evaluation on answering otorhinolaryngology case–based questions

Background : Large language models (LLMs), such as ChatGPT (Open AI), are increasingly used in medicine and supplement standard search engines as information sources. This leads to more “consultations” of LLMs about personal medical symptoms. Objective : This study aims to evaluate ChatGPT’s performance in answering clinical case–based questions in otorhinolaryngology (ORL) in comparison to ORL consultants’ answers. Methods : We used 41 case-based questions from established ORL study books and past German state examinations for doctors. The questions were answered by both ORL consultants and ChatGPT 3. ORL consultants rated all responses, except their own, on medical adequacy, conciseness, coherence, and comprehensibility using a 6-point Likert scale. They also identified (in a blinded setting) if the answer was created by an ORL consultant or ChatGPT. Additionally, the character count was compared. Due to the rapidly evolving pace of technology, a comparison between responses generated by ChatGPT 3 and ChatGPT 4 was included to give an insight into the evolving potential of LLMs. Results : Ratings in all categories were significantly higher for ORL consultants (P<.001). Although inferior to the scores of the ORL consultants, ChatGPT’s scores were relatively higher in semantic categories (conciseness, coherence, and comprehensibility) compared to medical adequacy. ORL consultants identified ChatGPT as the source correctly in 98.4% (121/123) of cases. ChatGPT’s answers had a significantly higher character count compared to ORL consultants (P<.001). Comparison between responses generated by ChatGPT 3 and ChatGPT 4 showed a slight improvement in medical accuracy as well as a better coherence of the answers provided. Contrarily, neither the conciseness (P=.06) nor the comprehensibility (P=.08) improved significantly despite the significant increase in the mean amount of characters by 52.5% (n= (1470-964)/964; P<.001). Conclusions : While ChatGPT provided longer answers to medical problems, medical adequacy and conciseness were significantly lower compared to ORL consultants’ answers. LLMs have potential as augmentative tools for medical care, but their “consultation” for medical problems carries a high risk of misinformation as their high semantic quality may mask contextual deficits.Peer reviewe

A conserved maternal-specific repressive domain in Zelda revealed by Cas9-mediated mutagenesis in <i>Drosophila melanogaster</i>

<div><p>In nearly all metazoans, the earliest stages of development are controlled by maternally deposited mRNAs and proteins. The zygotic genome becomes transcriptionally active hours after fertilization. Transcriptional activation during this maternal-to-zygotic transition (MZT) is tightly coordinated with the degradation of maternally provided mRNAs. In <i>Drosophila melanogaster</i>, the transcription factor Zelda plays an essential role in widespread activation of the zygotic genome. While Zelda expression is required both maternally and zygotically, the mechanisms by which it functions to remodel the embryonic genome and prepare the embryo for development remain unclear. Using Cas9-mediated genome editing to generate targeted mutations in the endogenous <i>zelda</i> locus, we determined the functional relevance of protein domains conserved amongst Zelda orthologs. We showed that neither a conserved N-terminal zinc finger nor an acidic patch were required for activity. Similarly, a previously identified splice isoform of <i>zelda</i> is dispensable for viability. By contrast, we identified a highly conserved zinc-finger domain that is essential for the maternal, but not zygotic functions of Zelda. Animals homozygous for mutations in this domain survived to adulthood, but embryos inheriting these loss-of-function alleles from their mothers died late in embryogenesis. These mutations did not interfere with the capacity of Zelda to activate transcription in cell culture. Unexpectedly, these mutations generated a hyperactive form of the protein and enhanced Zelda-dependent gene expression. These data have defined a protein domain critical for controlling Zelda activity during the MZT, but dispensable for its roles later in development, for the first time separating the maternal and zygotic requirements for Zelda. This demonstrates that highly regulated levels of Zelda activity are required for establishing the developmental program during the MZT. We propose that tightly regulated gene expression is essential to navigate the MZT and that failure to precisely execute this developmental program leads to embryonic lethality.</p></div

ZLD-PB is the dominant isoform expressed both in the embryo and imaginal disc.

<p>(A) Schematic of predicted transcripts from the <i>zld</i> locus (<i>above</i>). Boxes indicate exons with coding sequence (light gray) and untranslated regions (dark gray). The length of the resulting mRNA is given in nucleotides (nt). Two gRNAs flanking the downstream exon of <i>zld-RD</i> used to generate an isoform specific deletion are shown. Schematics of the predicted protein products for each splice variant (<i>below</i>) with amino acid numbers in <i>D</i>. <i>melanogaster</i> ZLD shown above. Above are the approximate locations of the transcriptional-activation and DNA-binding domains as demonstrated in Hamm et al (2015) [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007120#pgen.1007120.ref020" target="_blank">20</a>]. (B) Confocal images of embryos homozygous for either an N-terminal mCherry-tagged ZLD or for ZLD-PD-mCherry at stages 5, 12–13, and 14–16. The first column shows the maximum projection images for mCherry-ZLD expressing embryos. All other images show a single confocal slice. ZLD-PD-mCherry (1) and (2) indicate embryos from two distinct editing events. (C) Confocal images of mCherry-ZLD isoforms demonstrating the endogenous ZLD and ZLD-PD specific expression in third instar larval wing discs. Outlines show the borders of the wing discs as determined by transmitted light images. All images shown are the maximum projection. (D) Immunoblot for ZLD on S2 extract from cells expressing either ZLD-PB or ZLD-PD or total lysate from third instar wing discs. (E) Sequence of <i>zld-RD</i> following Cas9-mutagenesis demonstrating removal of the splice acceptor and coding sequence. Small insertions (red sequence) and deletions (dashed lines) shown. Lower case letters indicate intron sequence. Capital letters indicate exonic sequence.</p

Conserved residues in the second zinc finger domain shared with JAZ-like zinc fingers are essential for wild-type ZLD activity.

<p>(A) Alignment of the second zinc finger of ZLD with the consensus amino acids in JAZ domains. Bold indicates amino acids shared between the consensus and ZLD with red indicating the zinc-chelating cysteines and histidines and blue indicating additional shared residues. Underlined residues are those that contact double-stranded RNA. (B) Alignment of amino acid sequence of second zinc finger in ZLD with other insect species. Green bars below the sequence indicate residues conserved in all arthropods that contain the ZnF2 domain, as identified by Ribeiro et al. [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007120#pgen.1007120.ref025" target="_blank">25</a>]. Red dots indicate conserved cysteine and histidine domains in the C₂H₂ zinc finger. Blue dots indicate the amino acids conserved in JAZ zinc fingers. Point mutations generated in the endogenous <i>zld</i> locus by Cas9-mediated genome engineering are shown above. (C) Wild-type DNA sequence coding for the targeted ZLD domains (<i>below</i>) with mutated nucleotides generated by homology directed repair (<i>above</i>) are shown. Blue arrowhead indicates Cas9 cleavage site. (D) Immunoblot with anti-ZLD antibodies demonstrates wild-type levels of protein expression from the allele harboring point mutations in the conserved JAZ-domain amino acids. Protein levels were assayed on total protein lysate from embryos 1–2 hours after egg laying (AEL) maternally inheriting both the mutated allele and a superfolder GFP-tagged allele that is fully functional, allowing internal normalization. (E) Viability and fertility of heterozygous and homozygous animals carrying point mutations in the JAZ domain amino acids. ^aPercent recovered was calculated in comparison to heterozygous FM7 female siblings. Percent based on Mendelian inheritance. ^bViablity was determined by crossing to a <i>w</i>^<i>1118</i> mate. (F) Fold activation of luciferase reporters driven by either a wild-type <i>scute</i> promoter (WT) or one with mutations in the ZLD-binding sites (MUT). Immunoblot with anti-ZLD antibodies demonstrates comparable levels of ZLD expression. n = 3, error bars indicated +/- standard deviation.</p

The second zinc finger in ZLD is required for maternal, but not zygotic function.

<p>(A) Viability and fertility of heterozygous and homozygous animals carrying point mutations in zinc finger 1 (ZnF1), the acidic domain (EDD), or zinc finger 2 (ZnF2). ^aPercent recovered was calculated in comparison to heterozygous FM7 female siblings. Percent based on Mendelian inheritance. ^bViability was determined by crossing to a <i>w</i>^<i>1118</i> mate. (B) Immunoblots with anti-ZLD antibodies demonstrate wild-type levels of protein expression from alleles harboring point mutations in conserved domains. Protein levels were assayed on total protein lysate from embryos 1–2 hours after egg laying (AEL) maternally inheriting both the mutated allele and a superfolder GFP-tagged allele that is fully functional, allowing internal normalization.</p