Longitudinal study of insomnia, suicidal ideation, and psychopathology in schizophrenia.

OBJECTIVE: Insomnia is a common comorbidity in schizophrenia. Increasing cross-sectional evidence suggests an association between insomnia and suicidal ideation (SI) and symptom severity in schizophrenia. We investigated longitudinal associations over 3 months between insomnia, suicidal ideation, and symptom severity in a group of patients with chronic schizophrenia. METHOD: We performed a secondary analysis of data from n = 305 participants from the Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy (PROACTIVE) schizophrenia trial using regression models. RESULTS: The prevalence of moderate-to-severe insomnia was 17.7 % at baseline and 13.6 % at 3 months, respectively. The prevalence of SI was 22 % at baseline and 22.5 % at 3 months. After controlling for potential confounders, improved SI from baseline to 3 months was associated with both baseline moderate-to-severe insomnia (OR = 3.81, 95 % CI 1.11-13.12, p = 0.034) and improvement in insomnia (OR = 3.50, 95 % CI 1.23-9.92, p = 0.013). Worsening SI from baseline to 3 months was associated with worsening insomnia (OR = 3.50, 95 % CI 1.23-9.92, p = 0.013), but not baseline insomnia. Improvement in BPRS total score from baseline to 3 months was associated with improvement in insomnia (ß = 0.17, p = 0.029), but not baseline insomnia. CONCLUSION: Insomnia is common in patients with chronic schizophrenia and insomnia showed significant associations with SI and psychopathology. Clinicians should consider insomnia when assessing suicide risk in patients with schizophrenia.

Multivalent human antibody-centyrin fusion protein to prevent and treat Staphylococcus aureus infections.

Treating and preventing infections by antimicrobial-resistant bacterial pathogens is a worldwide problem. Pathogens such as Staphylococcus aureus produce an array of virulence determinants, making it difficult to identify single targets for the development of vaccines or monoclonal therapies. We described a human-derived anti-S. aureus monoclonal antibody (mAb)-centyrin fusion protein ("mAbtyrin") that simultaneously targets multiple bacterial adhesins, resists proteolysis by bacterial protease GluV8, avoids Fc engagement by S. aureus IgG-binding proteins SpA and Sbi, and neutralizes pore-forming leukocidins via fusion with anti-toxin centyrins, while maintaining Fc- and complement-mediated functions. Compared with the parental mAb, mAbtyrin protected human phagocytes and boosted phagocyte-mediated killing. The mAbtyrin also reduced pathology, reduced bacterial burden, and protected from different types of infections in preclinical animal models. Finally, mAbtyrin synergized with vancomycin, enhancing pathogen clearance in an animal model of bacteremia. Altogether, these data establish the potential of multivalent mAbs for treating and preventing S. aureus diseases.

Longitudinal study of inflammation and relapse in schizophrenia.

INTRODUCTION: The clinical course of schizophrenia is often characterized by recurrent relapses. Blood inflammatory markers are altered in acute psychosis, and may be state markers for illness relapse in schizophrenia. Few studies have investigated longitudinal, intra-individual changes in inflammatory markers as a predictor of relapse. In the present study, we explored this association in a relapse prevention trial in patients with schizophrenia. METHODS: We analyzed blood inflammatory markers in 200 subjects, with a mean 11 samples per subject, during the 30 month Preventing Relapse in schizophrenia: Oral Antipsychotics Compared to Injectable: eValuating Efficacy (PROACTIVE) trial. Associations between longitudinal changes in inflammatory markers and relapse were analyzed using a within-subjects design. RESULTS: 70 (35 %) of subjects relapsed during the study period. There were no significant differences in mean inflammatory marker levels based on relapse status (yes/no). Baseline levels of inflammatory markers did not predict incident relapse. Among subjects who relapsed, there was a significant decrease in mean blood IL-6 (n = 38, p = 0.019) and IFN-γ (n = 44, p = 0.012) levels from the visit before the relapse to the visit after relapse. CONCLUSION: Although there was some evidence for inflammation as a potential state marker for acute psychosis, we did not find significant evidence for its utility as a relapse-predictive marker.

The Future of Endowed Chairs in Academic Medicine.

As the landscape of philanthropy changes following the COVID-19 pandemic, this commentary considers the future of endowed chairs in academic medicine in the light of articles by Thorndyke and colleagues and by Chin-Hong and colleagues in this issue. The authors evaluate the traditional allocation of endowed chairs, which can attract and retain talented faculty and can support focused research far into the future, while other gifts may support more timely concerns, but over a shorter term. The authors weigh the benefits and challenges of allocation of endowed chairs, such as the need to improve representation, diversity, equity, and inclusion, and opportunities to support early-career investigators or research teams. New endowed positions can be challenging to establish, as there may be competition with learner scholarship programs and programmatic support. Leadership turnover of university presidents and deans can slow philanthropic growth and make recruitment and fundraising for new positions even more challenging. The authors discuss the balance of institutional priorities and ways to use endowed chairs for scholarship in evolving areas of medicine and science. They further suggest working with donors to develop more adaptable gift agreements, which will allow institutions to transform endowed positions to meet changing needs while preserving the intentions of the donor. To maintain endowed chairs as a worthwhile and relevant outlet for philanthropy, one which donors will enthusiastically support, it is essential to align them with the changing needs of the institution and the broader environment of academic medicine.

International Medical Graduates in the United States Psychiatry Workforce.

OBJECTIVE: This study describes the supply, distribution, and characteristics of international medical graduate (IMG) psychiatrists who provide services in the USA. METHODS: Cross-sectional study design, using descriptive statistics based on combined data from the American Medical Association (2020 Physician Masterfile) and the Educational Commission for Foreign Medical Graduates. RESULTS: International medical graduates continue to make significant contributions to the US physician workforce. As a group, they represent 29% of active psychiatrists in the USA, compared to 23% in all other medical specialties. Many IMG psychiatrists were US citizens who obtained their medical degrees outside the USA or Canada, often in the Caribbean. In some states (i.e., Florida, New Jersey), over 40% of active psychiatrists are IMGs. Over 30% of IMG psychiatrists graduated from medical schools in India and Pakistan. CONCLUSIONS: This study provides an overview of the psychiatric workforce in the USA, quantifying the specific contribution of IMGs. Several factors, including immigration policies, continued expansion of US medical schools, and the number of available residency positions, could impact the flow of IMGs to the US. Longitudinal studies are needed to better understand the implications for workforce composition and distribution, and their potential impact on the care of psychiatric patients.

25-Hydroxyvitamin D and metabolic-related laboratory values in women with schizophrenia and hyperprolactinemia.

Schizophrenia is a severe mental disorder with various medical comorbidities and early mortality. Hyperprolactinemia is common in women and its impact on sexual function, galactorrhea and amenorrhea is well known. This paper evaluates the risk of 25-hydroxy vitamin D deficiency and other metabolic related laboratory abnormalities in women with schizophrenia having hyperprolactinemia (N = 43). The mean prolactin level in these women was 88.5 ± 56.0 ng/mL. We found that 100% of women were overweight of which 74% (32/43) of the women were obese, 56% (23/41) had abnormal total cholesterol levels and 30% (13/43) had high fasting blood glucose. Vitamin D levels were considered deficient or inadequate in 37% of women. We did not see significant correlations of prolactin with laboratory measures, however all female patients had elevated and high prolactin levels, leading to low variability in a small sample, which may have precluded seeing any direct relationships. Recognizing prolactin related side effects and understanding the role of other health measures seen in women with antipsychotic induced hyperprolactinemia in our female patients are critical steps toward better personalization of their care and recovery.

Rare coding variants in ten genes confer substantial risk for schizophrenia.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P < 2.14 × 10-6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.

Staphylococcus aureus in Non-Cystic Fibrosis Bronchiectasis: Prevalence and Genomic Basis of High Inoculum ß-Lactam Resistance.

Rationale: The pathobiology of Staphylococcus aureus in non-cystic fibrosis bronchiectasis (nCFB) is poorly defined. When present at high density or "inoculum," some methicillin-sensitive S. aureus (MSSA) can inefficiently degrade antistaphylococcal ß-lactam antibiotics via BlaZ penicillinases (termed the "inoculum effect" [IE]). Given the high burden of organisms in bronchiectatic airways, this is particularly relevant. Objectives: Drawing from a prospectively collected biobank, we sought to understand the prevalence, natural history, potential for transmission, and antibiotic resistance profiles among nCFB-derived MSSA isolates. Methods: All individuals attending a regional consultancy nCFB clinic with sputum collected between 1981 and 2017 were considered, and those with one or more S. aureus-positive cultures composed the cohort. Each individual's most recent biobank isolate was subjected to whole-genome sequencing (including the blaZ gene), antibacterial susceptibility testing, and comparative ß-lactam testing at standard (5 × 105 colony-forming unit [cfu]/ml) and high (5 × 107 cfu/ml) inocula to assess for the IE and pronounced IE. Results: Seventy-four (35.4%) of 209 individuals had one or more sputum samples with S. aureus (68 MSSA, 6 methicillin-resistant S. aureus). Those with S. aureus infection were more likely to be female. Among 60 of 74 MSSA isolates subjected to whole-genome sequencing, no evidence of transmission was identified, although specific multilocus sequence typing types were prevalent, including ST-1, ST-15, ST-30, and ST-45. Antibiotic resistance was uncommon, except for macrolides (∼20%). Among the 60 MSSA samples, the prevalence of IE and pronounced IE was observed to be drug specific: meropenem (0% and 0%, respectively), cefepime (3% and 5%, respectively), ceftazidime (8% and 0%, respectively), cloxacillin (12% and 0%, respectively), cefazolin (23% and 0%, respectively), and piperacillin-tazobactam (37% and 17%, respectively). The cefazolin IE was associated with blaZ type A (P < 0.01) and ST-30 (P < 0.01), whereas the piperacillin-tazobactam IE was associated with type C blaZ (P < 0.001) and ST-15 (P < 0.05). Conclusions:S. aureus infection was common, although no evidence of transmission was apparent in our nCFB cohort. Although routine susceptibility testing did not identify significant resistance, inoculum-related resistance was found to be relevant for commonly used nCFB antibiotics, including cefazolin and piperacillin-tazobactam. Given previous associations between IEs and negative patient outcomes, further work is warranted to understand how this phenotype impacts nCFB disease progression.

Spatial and temporal distances in a virtual global world: Lessons from the COVID-19 pandemic.

The experience of COVID-19 prompted us to rethink the imperatives of distance for the organization of value-creating activities globally. We advance a conceptualization of distance as representing separation in both space and time and posit that these distance dimensions represent different kinds of separation and require varied theoretical attention. We delineate the intrinsic qualities of spatial and temporal distances and theorize the impact of this extended conceptualization of distance on major tenets of international business theory and their predictions regarding the patterns of international business activity. We illustrate the ways by which varying configurations of spatial and temporal distances serve different value-creating activities and draw their implications for countries' global integration. We advance a call for more attention to time and temporal distance and their impact on the ways firms organize their value-creating activities in an increasingly virtual world.

L'expérience de COVID-19 nous a incités à repenser les impératifs de la distance pour l'organisation d'activités créatrices de valeur au niveau mondial. Nous conceptualisons la distance comme un construit représentant la séparation à la fois dans l'espace et dans le temps, et postulons que ces dimensions de la distance représentent différents types de séparation et nécessitent une attention théorique variée. Nous spécifions les qualités intrinsèques des distances temporelles et spatiales, et théorisons l'impact de cette conceptualisation étendue de la distance sur les principaux principes de la théorie des affaires internationales et leurs prédictions en matière de configurations d'activité en commerce international. Nous illustrons les façons dont diverses configurations de distances spatiales et temporelles servent différentes activités créatrices de valeur, et élaborons les implications pour l'intégration mondiale des pays. Nous appelons à accorder davantage d'attention au temps et à la distance temporelle, ainsi qu'à leur impact sur la manière dont les entreprises organisent leurs activités créatrices de valeur dans un monde de plus en plus virtuel.

La experiencia de COVID-19 nos instó repensar los imperativos de la distancia para la organización de actividades de creación de valor a nivel mundial. Avanzamos una conceptualización de la distancia como representación de la separación tanto en el espacio como en el tiempo y planteamos que estas dimensiones de la distancia representan diferentes tipos de separación y requieren una atención teórica variada. Delineamos las cualidades intrínsecas de las distancias espaciales y temporales y teorizamos el impacto de esta conceptualización ampliada de la distancia en los principales postulados de la teoría de los negocios internacionales y sus predicciones en relación con los patrones de la actividad de negocios internacionales. Ilustramos el modo en que las distintas configuraciones de las distancias espaciales y temporales sirven para diferentes actividades de creación de valor y extraemos sus implicaciones para la integración global de los países. Hacemos un llamamiento para que se preste más atención a la distancia temporal y al tiempo y a su impacto en la forma en que las empresas organizan sus actividades de creación de valor en un mundo cada vez más virtual.

A experiência do COVID-19 nos levou a repensar os imperativos de distância para a organização de atividades de criação de valor globalmente. Avançamos uma conceituação de distância como representação de separação tanto em espaço quanto em tempo e postulamos que essas dimensões de distância representam diferentes tipos de separação e requerem atenção teórica distinta. Delineamos as qualidades intrínsecas das distâncias espaciais e temporais e teorizamos o impacto dessa conceituação estendida de distância nos principais pilares da teoria em negócios internacionais e suas previsões a respeito dos padrões de atividade em negócios internacionais. Ilustramos formas pelas quais distintas configurações de distâncias espaciais e temporais atendem a diferentes atividades de criação de valor e descrevemos suas implicações para a integração global de países. Propomos um apelo por maior atenção a tempo e distância temporal e seu impacto nas maneiras pelas quais empresas organizam suas atividades de criação de valor em um mundo cada vez mais virtual.

Prognostic value of polygenic risk scores for adults with psychosis.

Polygenic risk scores (PRS) summarize genetic liability to a disease at the individual level, and the aim is to use them as biomarkers of disease and poor outcomes in real-world clinical practice. To date, few studies have assessed the prognostic value of PRS relative to standards of care. Schizophrenia (SCZ), the archetypal psychotic illness, is an ideal test case for this because the predictive power of the SCZ PRS exceeds that of most other common diseases. Here, we analyzed clinical and genetic data from two multi-ethnic cohorts totaling 8,541 adults with SCZ and related psychotic disorders, to assess whether the SCZ PRS improves the prediction of poor outcomes relative to clinical features captured in a standard psychiatric interview. For all outcomes investigated, the SCZ PRS did not improve the performance of predictive models, an observation that was generally robust to divergent case ascertainment strategies and the ancestral background of the study participants.

A Meta-Analysis of Brain-Derived Neurotrophic Factor Effects on Brain Volume in Schizophrenia: Genotype and Serum Levels.

AIM: The Val66Met single-nucleotide polymorphism (SNP) on the BDNF gene has established pleiotropic effects on schizophrenia incidence and morphologic alterations in the illness. The effects of brain-derived neurotrophic factor (BDNF) on brain volume measurements are however mixed seeming to be less established for most brain regions. The current meta-analytic review examined (1) the association of the Val66Met SNP and brain volume alterations in schizophrenia by comparing Met allele carriers to Val/Val homozygotes and (2) the association of serum BDNF with brain volume measurements. METHOD: Studies included in the meta-analyses were identified through an electronic search of PubMed and PsycInfo (via EBSCO) for English language publications from January 2000 through December 2017. Included studies had conducted a genotyping procedure of Val66Met or obtained assays of serum BDNF and obtained brain volume data in patients with psychotic disorders. Nonhuman studies were excluded. RESULTS: Study 1 which included 52 comparisons of Met carriers and Val/Val homozygotes found evidence of lower right and left hippocampal volumes among Met allele carriers with schizophrenia. Frontal measurements, while also lower among Met carriers, did not achieve statistical significance. Study 2 which included 7 examinations of the correlation between serum BDNF and brain volume found significant associations between serum BDNF levels and right and left hippocampal volume with lower BDNF corresponding to lower volumes. DISCUSSION: The meta-analyses provided evidence of associations between brain volume alterations in schizophrenia and variations on the Val66Met SNP and serum BDNF. Given the limited number of studies, it remains unclear if BDNF effects are global or regionally specific.

GWAS significance thresholds for deep phenotyping studies can depend upon minor allele frequencies and sample size.

An important issue affecting genome-wide association studies with deep phenotyping (multiple correlated phenotypes) is determining the suitable family-wise significance threshold. Straightforward family-wise correction (Bonferroni) of p < 0.05 for 4.3 million genotypes and 335 phenotypes would give a threshold of p < 3.46E-11. This would be too conservative because it assumes all tests are independent. The effective number of tests, both phenotypic and genotypic, must be adjusted for the correlations between them. Spectral decomposition of the phenotype matrix and LD-based correction of the number of tested SNPs are currently used to determine an effective number of tests. In this paper, we compare these calculated estimates with permutation-determined family-wise significance thresholds. Permutations are performed by shuffling individual IDs of the genotype vector for this dataset, to preserve correlation of phenotypes. Our results demonstrate that the permutation threshold is influenced by minor allele frequency (MAF) of the SNPs, and by the number of individuals tested. For the more common SNPs (MAF > 0.1), the permutation family-wise threshold was in close agreement with spectral decomposition methods. However, for less common SNPs (0.05 < MAF ≤ 0.1), the permutation threshold calculated over all SNPs was off by orders of magnitude. This applies to the number of individuals studied (here 777) but not to very much larger numbers. Based on these findings, we propose that the threshold to find a particular level of family-wise significance may need to be established using separate permutations of the actual data for several MAF bins.

Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world's population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. METHODS: We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. RESULTS: Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10-30) and African American (P < .0005) participants in CSP #572. CONCLUSIONS: We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.

Treatment-Resistant Schizophrenia.

Although, gratifyingly, research on the treatment of schizophrenia has increasingly focused on first-episode and prodromal patient populations, it is still recognized that many patients with more chronic illnesses exhibit a suboptimal response to treatments. This suboptimal response with continuation of symptoms is represented in the term treatment-resistant schizophrenia (TRS). This article addresses contemporary definitions as well as updated guidelines for patients with TRS.

The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia.

(Reprinted with permission from The American Journal of Psychiatry 2020; 177:868-872).

Emerging From the COVID-19 Crisis With a Stronger Health Care Workforce.

The COVID-19 pandemic has highlighted the limitations of the current health care workforce. As health care workers across the globe have been overwhelmed by the crisis, oversight entities and training programs have sought to loosen regulations to support ongoing care. Notably, however, workforce challenges preceded the current crisis. Now may be the time to address these underlying workforce challenges and emerge from the COVID-19 pandemic with a stronger health care workforce.Building upon historical exemplars in the context of the current crisis, the authors of this Perspective provide a roadmap to rapidly and safely increase the workforce for COVID-19 and beyond. The authors recommend the following: (1) a comprehensive approach to guide health care workforce development, (2) streamlining transitions to the next level of practice, (3) reciprocity among state licensing boards or national licensure, (4) payment reform to support a strengthened health care workforce, and (5) efforts by employers to ensure the ongoing safety and competence of the bolstered workforce. These steps require urgent collaboration among stakeholders commensurate with the acuity of the pandemic. Implemented together, these actions could address not only the novel challenges presented by COVID-19 but also the underlying inadequacies of the health care workforce that must be remedied to create a healthier society.