Advancing preclinical models of psychiatric disorders with human brain organoid cultures.

Psychiatric disorders are often distinguished from neurological disorders in that the former do not have characteristic lesions or findings from cerebrospinal fluid, electroencephalograms (EEGs), or brain imaging, and furthermore do not have commonly recognized convergent mechanisms. Psychiatric disorders commonly involve clinical diagnosis of phenotypic behavioral disturbances of mood and psychosis, often with a poorly understood contribution of environmental factors. As such, psychiatric disease has been challenging to model preclinically for mechanistic understanding and pharmaceutical development. This review compares commonly used animal paradigms of preclinical testing with evolving techniques of induced pluripotent cell culture with a focus on emerging three-dimensional models. Advances in complexity of 3D cultures, recapitulating electrical activity in utero, and disease modeling of psychosis, mood, and environmentally induced disorders are reviewed. Insights from these rapidly expanding technologies are discussed as they pertain to the utility of human organoid and other models in finding novel research directions, validating pharmaceutical action, and recapitulating human disease.

Visioning synthetic futures for yeast research within the context of current global techno-political trends.

Yeast research is entering into a new period of scholarship, with new scientific tools, new questions to ask and new issues to consider. The politics of emerging and critical technology can no longer be separated from the pursuit of basic science in fields, such as synthetic biology and engineering biology. Given the intensifying race for technological leadership, yeast research is likely to attract significant investment from government, and that it offers huge opportunities to the curious minded from a basic research standpoint. This article provides an overview of new directions in yeast research with a focus on Saccharomyces cerevisiae, and places these trends in their geopolitical context. At the highest level, yeast research is situated within the ongoing convergence of the life sciences with the information sciences. This convergent effect is most strongly pronounced in areas of AI-enabled tools for the life sciences, and the creation of synthetic genomes, minimal genomes, pan-genomes, neochromosomes and metagenomes using computer-assisted design tools and methodologies. Synthetic yeast futures encompass basic and applied science questions that will be of intense interest to government and nongovernment funding sources. It is essential for the yeast research community to map and understand the context of their research to ensure their collaborations turn global challenges into research opportunities.

Outbreak of SARS-CoV-2 B.1.617.2 (Delta) Variant Infections Among Incarcerated Persons in a Federal Prison - Texas, July-August 2021.

Incarcerated populations have experienced disproportionately higher rates of COVID-19-related illness and death compared with the general U.S. population, due in part to congregate living environments that can facilitate rapid transmission of SARS-CoV-2, the virus that causes COVID-19, and the high prevalence of underlying medical conditions associated with severe COVID-19 (1,2). The SARS-CoV-2 B.1.617.2 (Delta) variant has caused outbreaks among vaccinated and unvaccinated persons in congregate settings and large public gatherings (3,4). During July 2021, a COVID-19 outbreak involving the Delta variant was identified in a federal prison in Texas, infecting 172 of 233 (74%) incarcerated persons in two housing units. The Federal Bureau of Prisons (BOP) partnered with CDC to investigate. CDC analyzed data on infection status, symptom onset date, hospitalizations, and deaths among incarcerated persons. The attack rate was higher among unvaccinated versus fully vaccinated persons (39 of 42, 93% versus 129 of 185, 70%; p = 0.002).† Four persons were hospitalized, three of whom were unvaccinated, and one person died, who was unvaccinated. Among a subset of 70 persons consenting to an embedded serial swabbing protocol, the median interval between symptom onset and last positive reverse transcription-polymerase chain reaction (RT-PCR) test result in fully vaccinated versus unvaccinated persons was similar (9 versus 11 days, p = 0.37). One or more specimens were culture-positive from five of 12 (42%) unvaccinated and 14 of 37 (38%) fully vaccinated persons for whom viral culture was attempted. In settings where physical distancing is challenging, including correctional and detention facilities, vaccination and implementation of multicomponent prevention strategies (e.g., testing, medical isolation, quarantine, and masking) are critical to limiting SARS-CoV-2 transmission (5).

Drawing on the Past to Shape the Future of Synthetic Yeast Research.

Some years inspire more hindsight reflection and future-gazing than others. This is even more so in 2020 with its evocation of perfect vision and the landmark ring to it. However, no futurist can reliably predict what the world will look like the next time that a year's first two digits will match the second two digits-a numerical pattern that only occurs once in a century. As we leap into a new decade, amid uncertainties triggered by unforeseen global events-such as the outbreak of a worldwide pandemic, the accompanying economic hardship, and intensifying geopolitical tensions-it is important to note the blistering pace of 21st century technological developments indicate that while hindsight might be 20/20, foresight is 50/50. The history of science shows us that imaginative ideas, research excellence, and collaborative innovation can, for example, significantly contribute to the economic, cultural, social, and environmental recovery of a post-COVID-19 world. This article reflects on a history of yeast research to indicate the potential that arises from advances in science, and how this can contribute to the ongoing recovery and development of human society. Future breakthroughs in synthetic genomics are likely to unlock new avenues of impactful discoveries and solutions to some of the world's greatest challenges.

Using back focal plane interferometry to probe the influence of Zernike aberrations in optical tweezers.

We experimentally investigate the influence of geometric aberrations in optical tweezers using back focal plane interferometry. We found that the introduction of coma aberrations causes significant modification to the Brownian motion of the trapped particle, producing an apparent cross-coupling between the in-plane aberrated axis and the weaker propagation axis. This coupling is evidenced by the emergence of a second dominant low frequency Lorentzian feature in the position power spectral density. The effect on Brownian motion was confirmed using a secondary unaberrated probe beam, ruling out the possibility of systematic optical effects related to the detection system.

Individual Placement and Support in Spinal Cord Injury: A Longitudinal Observational Study of Employment Outcomes.

OBJECTIVE: To determine the effects of a 24-month program of Individual Placement and Support (IPS) supported employment (SE) on employment outcomes for veterans with spinal cord injury (SCI). DESIGN: Longitudinal, observational multisite study of a single-arm, nonrandomized cohort. SETTING: SCI centers in the Veterans Health Administration (n=7). PARTICIPANTS: Veterans with SCI (N=213) enrolled during an episode of either inpatient hospital care (24.4%) or outpatient care (75.6%). More than half the sample (59.2%) had a history of traumatic brain injury (TBI). INTERVENTION: IPS SE for 24 months. MAIN OUTCOME MEASURE: Competitive employment. RESULTS: Over the 24-month period, 92 of 213 IPS participants obtained competitive jobs for an overall employment rate of 43.2%. For the subsample of participants without TBI enrolled as outpatients (n=69), 36 obtained competitive jobs for an overall employment rate of 52.2%. Overall, employed participants averaged 38.2±29.7 weeks of employment, with an average time to first employment of 348.3±220.0 days. Nearly 25% of first jobs occurred within 4 to 6 months of beginning the program. Similar employment characteristics were observed in the subsample without TBI history enrolled as outpatients. CONCLUSIONS: Almost half of the veterans with SCI participating in the 24-month IPS program as part of their ongoing SCI care achieved competitive employment, consistent with their expressed preferences at the start of the study. Among a subsample of veterans without TBI history enrolled as outpatients, employment rates were >50%. Time to first employment was highly variable, but quite long in many instances. These findings support offering continued IPS services as part of ongoing SCI care to achieve positive employment outcomes.

Efficacy of Low-Dose Buspirone for Restricted and Repetitive Behavior in Young Children with Autism Spectrum Disorder: A Randomized Trial.

OBJECTIVES: To determine safety and efficacy of the 5HT1A serotonin partial agonist buspirone on core autism and associated features in children with autism spectrum disorder (ASD). STUDY DESIGN: Children 2-6 years of age with ASD (N = 166) were randomized to receive placebo or 2.5 or 5.0 mg of buspirone twice daily. The primary objective was to evaluate the effects of 24 weeks of buspirone on the Autism Diagnostic Observation Schedule (ADOS) Composite Total Score. Secondary objectives included evaluating the effects of buspirone on social competence, repetitive behaviors, language, sensory dysfunction, and anxiety and to assess side effects. Positron emission tomography measures of tryptophan metabolism and blood serotonin concentrations were assessed as predictors of buspirone efficacy. RESULTS: There was no difference in the ADOS Composite Total Score between baseline and 24 weeks among the 3 treatment groups (P = .400); however, the ADOS Restricted and Repetitive Behavior score showed a time-by-treatment effect (P = .006); the 2.5-mg buspirone group showed significant improvement (P = .003), whereas placebo and 5.0-mg buspirone groups showed no change. Children in the 2.5-mg buspirone group were more likely to improve if they had fewer foci of increased brain tryptophan metabolism on positron emission tomography (P = .018) or if they showed normal levels of blood serotonin (P = .044). Adverse events did not differ significantly among treatment groups. CONCLUSIONS: Treatment with 2.5 mg of buspirone in young children with ASD might be a useful adjunct therapy to target restrictive and repetitive behaviors in conjunction with behavioral interventions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00873509.

Revival of saprotrophic and mycorrhizal basidiomycete cultures after 30 years in cold storage in sterile water.

Vegetatively colonized agar cores of 54 basidiomycete fungal isolates were stored at 5 °C in tubes of sterile distilled water without manipulation for 30 years. The cultures represented 28 isolates of saprotrophic fungi and 26 isolates of mycorrhizal fungi. These cultures came from a group of 57 fungal isolates that were determined to be viable after 20 years of cold-water storage. Overall, 47 of the 54 isolates (87%) grew vigorously when revived after storage for 30 years. Of the 28 saprotrophic fungal isolates, 26 revived (93%); of the 26 mycorrhizal fungal isolates, 21 revived (81%). Eight of 13 isolates (62%) of Laccaria were viable after 30 years, which was considerably less viable than what was found after 20 years for this genus of mycorrhizal fungi. However, a greater percentage of isolates of Laccaria bicolor (83%) were viable than isolates of Laccaria laccata (43%), suggesting that 30 years is approaching the maximum limit for storage in cold sterile water for certain species. Considering the original 135 fungal isolates that were stored in sterile cold water from which this set was derived, overall survival after 30 years of storage was 42%; however, saprotrophic fungi demonstrated considerably greater viability (70%) than mycorrhizal fungi (21%).

Optimising plasma levels of clozapine during metabolic interactions: a review and case report with adjunct rifampicin treatment.

BACKGROUND: Clozapine is the only licensed medication for treatment-resistant schizophrenia. The metabolism of clozapine is affected by multiple pharmacokinetic interactions, so the co-administration of adjunct medications can have a significant clinical effect. The anti- tuberculosis medication rifampicin is a potent inducer of the cytochrome P450 system and therefore can cause a reduction in the plasma concentration of clozapine. There is limited clinical evidence regarding co-administration of these medications; in particular there is a lack of data regarding the effect on plasma clozapine levels, which is the key factor determining clinical efficacy. This is clinically relevant given evidence of an increased risk of tuberculosis in patients with schizophrenia. CASE PRESENTATION: We present a case of a 28 year old British man with a diagnosis of schizoaffective disorder who presented with persistent psychotic symptoms. He developed a systemic inflammatory condition, diagnosed as tuberculosis, and was commenced on a six month course of treatment that included rifampicin. This case presents comprehensive data to illustrate the effect on clozapine plasma levels of a complete course of tuberculosis therapy. CONCLUSION: This case report provides guidance to clinicians in managing drug interactions between clozapine and rifampicin to enable safe and effective treatment. The co-administration of these medications is likely to increase as the existing underuse of clozapine is recognised whilst the incidence of tuberculosis increases.

Pharmacology, physiology and performance: occupational drug use and HIV risk among female entertainment and sex workers in Cambodia.

BACKGROUND: In Cambodia, HIV prevalence among female entertainment and sex workers (FESW) is up to twenty times higher than in the general population. Use of amphetamine-type stimulants (ATS) has been associated with increased risk of HIV and other sexually transmitted infections in key populations, including FESW. While one in four Cambodian FESW report recent ATS use, little attention has been paid to how the occupational contexts of sex work shape patterns of use. Currently, no HIV prevention interventions target ATS use in this population. METHODS: We conducted in-depth interviews with FESW (n = 30) with the goal of exploring experiences and motivations for ATS use and informing the development of a conditional cash transfer (CCT) intervention designed to reduce ATS use and HIV risk. Interviews were conducted and transcribed in Khmer and translated into English. Interview narratives were read and re-read and emerging themes reviewed and refined to develop an initial coding scheme. Data were formally coded using both open and axial coding to clarify and consolidate initial themes. RESULTS: The most common driver of ATS use among FESW was increased functionality. ATS was seen as a performance enhancer, acting as an appetite suppressant and enabling women to meet the physiological demands of sex work, including long working hours, multiple clients and extended sexual transactions. While our results are consistent with studies linking ATS use to heightened sexual risk, via unprotected and/or prolonged sex, for women in the current study, the negative consequences of ATS use were outweighed by perceived functional benefits. CONCLUSIONS: FESW in Cambodia harness the pharmacological properties of ATS to meet the physiological demands of sex work in a context of limited economic opportunities. There is an urgent need to both provide Cambodian women with options for income generation that do not risk their health and to better regulate the conditions of sex work to provide safer working environments. Structural and economic interventions, including CCT programmes, combined with awareness and enforcement of sex workers' rights, are also necessary to facilitate harm reduction and occupational health and work safety within the Cambodian sex and entertainment industry.

Engineering biology and climate change mitigation: Policy considerations.

Engineering biology (EngBio) is a dynamic field that uses gene editing, synthesis, assembly, and engineering to design new or modified biological systems. EngBio applications could make a significant contribution to achieving net zero greenhouse gas emissions. Yet, policy support will be needed if EngBio is to fulfil its climate mitigation potential. What form should such policies take, and what EngBio applications should they target? This paper reviews EngBio's potential climate contributions to assist policymakers shape regulations and target resources and, in so doing, to facilitate democratic deliberation on desirable futures.

Alternative paths to value.

Hospitals must look beyond forming an ACO for ways to thrive in this new environment.

Electrophysiological examination of embodiment in vision and action.

A wealth of behavioral data has shown that the visual properties of objects automatically potentiate motor actions linked with them, but how deeply are these affordances embedded in visual processing? In the study reported here, we used electrophysiological measures to examine the time course of affordance resulting from the leftward or rightward orientation of the handles of common objects. Participants were asked to categorize those objects using a left- or right-handed motor response. Lateralized readiness potentials showed rapid motor preparation in the hand congruent with the affordance provided by the object only 100 to 200 ms after stimulus presentation and up to 400 ms before the actual response. Examination of event-related potentials also revealed an effect of handle orientation and response-hand congruency on the visual P1 and N1 components. Both of these results suggest that activity in the early sensory pathways is modulated by the action associations of objects and the intentions of the viewer.

Effectiveness of supported employment for veterans with spinal cord injuries: results from a randomized multisite study.

OBJECTIVE: To examine whether supported employment (SE) is more effective than treatment as usual (TAU) in returning veterans to competitive employment after spinal cord injury (SCI). DESIGN: Prospective, randomized, controlled, multisite trial of SE versus TAU for vocational issues with 12 months of follow-up data. SETTING: SCI centers in the Veterans Health Administration. PARTICIPANTS: Subjects (N=201) were enrolled and completed baseline interviews. In interventional sites, subjects were randomly assigned to the SE condition (n=81) or the TAU condition (treatment as usual-interventional site [TAU-IS], n=76). In observational sites where the SE program was not available, 44 subjects were enrolled in a nonrandomized TAU condition (treatment as usual-observational site [TAU-OS]). INTERVENTIONS: The intervention consisted of an SE vocational rehabilitation program called the Spinal Cord Injury Vocational Integration Program, which adhered as closely as possible to principles of SE as developed and described in the individual placement and support model of SE for persons with mental illness. MAIN OUTCOME MEASURES: The primary study outcome measurement was competitive employment in the community. RESULTS: Subjects in the SE group were 2.5 times more likely than the TAU-IS group and 11.4 times more likely than the TAU-OS group to obtain competitive employment. CONCLUSIONS: To the best of our knowledge, this is the first and only controlled study of a specific vocational rehabilitation program to report improved employment outcomes for persons with SCI. SE, a well-prescribed method of integrated vocational care, was superior to usual practices in improving employment outcomes for veterans with SCI.

Detecting and coping with disruptive shocks in Arctic marine systems: a resilience approach to place and people.

It seems inevitable that the ongoing and rapid changes in the physical environment of the marine Arctic will push components of the region's existing social-ecological systems-small and large-beyond tipping points and into new regimes. Ongoing changes include warming, freshening, acidification, and alterations to food web structure. In anticipation we pose three distinct but interrelated challenges: (1) to explore existing connectivities within components of the marine system; (2) to seek indicators (if they exist) of approaching regime change through observation and modeling; and (3) to build functional resilience into existing systems through adaptation-oriented policy and to have in hand transformative options when tipping points are crossed and new development trajectories are required. Each of the above challenges is scale dependent, and each requires a much deeper understanding than we currently have of connectivity within existing systems and their response to external forcing. Here, we argue from a global perspective the need to understand the Arctic's role in an increasingly nonlinear world; then describe emerging evidence from new observations on the connectivity of processes and system components from the Canada Basin and subarctic seas surrounding northern North America; and finally posit an approach founded in "resilience thinking" to allow northern residents living in small coastal communities to participate in the observation, adaption and-if necessary-transformation of the social-ecological system with which they live.

Bioinformational trends in grape and wine biotechnology.

The creative destruction caused by the coronavirus pandemic is yielding immense opportunity for collaborative innovation networks. The confluence of biosciences, information sciences, and the engineering of biology, is unveiling promising bioinformational futures for a vibrant and sustainable bioeconomy. Bioinformational engineering, underpinned by DNA reading, writing, and editing technologies, has become a beacon of opportunity in a world paralysed by uncertainty. This article draws on lessons from the current pandemic and previous agricultural blights, and explores bioinformational research directions aimed at future-proofing the grape and wine industry against biological shocks from global blights and climate change.

Vitamin B(12) deficiency as a cause of delirium in a patient with spinal cord injury.

A man with spinal cord injury (SCI) and multiple medical comorbidities had new-onset delirium during his 14th month of hospitalization. Diagnostic workup did not elicit an obvious etiology for mental status changes. Delirium persisted despite psychiatry intervention, and he was unable to be weaned from the ventilator because of prolonged agitation. Routine anemia workup revealed a possible untreated vitamin B(12) deficiency, although laboratory values were inconclusive. Empiric treatment with cyanocobalamin injections was initiated, and his delirium remarkably resolved after 3 weeks of treatment. We provide a concise review of the etiologies and varied clinical presentations of vitamin B(12) deficiency. As illustrated in this case, classic laboratory findings may not appear, and neurologic impairments from SCI can obscure the physical signs of deficiency, making diagnosis difficult. Empiric treatment may be indicated in cases of neuropsychiatric abnormalities not explained by other causes.

Tipping toward sustainability: emerging pathways of transformation.

This article explores the links between agency, institutions, and innovation in navigating shifts and large-scale transformations toward global sustainability. Our central question is whether social and technical innovations can reverse the trends that are challenging critical thresholds and creating tipping points in the earth system, and if not, what conditions are necessary to escape the current lock-in. Large-scale transformations in information technology, nano- and biotechnology, and new energy systems have the potential to significantly improve our lives; but if, in framing them, our globalized society fails to consider the capacity of the biosphere, there is a risk that unsustainable development pathways may be reinforced. Current institutional arrangements, including the lack of incentives for the private sector to innovate for sustainability, and the lags inherent in the path dependent nature of innovation, contribute to lock-in, as does our incapacity to easily grasp the interactions implicit in complex problems, referred to here as the ingenuity gap. Nonetheless, promising social and technical innovations with potential to change unsustainable trajectories need to be nurtured and connected to broad institutional resources and responses. In parallel, institutional entrepreneurs can work to reduce the resilience of dominant institutional systems and position viable shadow alternatives and niche regimes.