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The well-written Psychiatric Times article concluded, 'it is urgent for the field of psychiatry to reconcile the significant differences in remission rates for patients with [major depressive disorder; MDD] as [...]

NMDA receptors (NMDARs) play subunit-specific roles in synaptic function and are implicated in neuropsychiatric and neurodegenerative disorders. However, the in vivo consequences and therapeutic potential of pharmacologically enhancing NMDAR function via allosteric modulation are largely unknown. We examine the in vivo effects of GNE-0723, a positive allosteric modulator of GluN2A-subunit-containing NMDARs, on brain network and cognitive functions in mouse models of Dravet syndrome (DS) and Alzheimer's disease (AD). GNE-0723 use dependently potentiates synaptic NMDA receptor currents and reduces brain oscillation power with a predominant effect on low-frequency (12-20 Hz) oscillations. Interestingly, DS and AD mouse models display aberrant low-frequency oscillatory power that is tightly correlated with network hypersynchrony. GNE-0723 treatment reduces aberrant low-frequency oscillations and epileptiform discharges and improves cognitive functions in DS and AD mouse models. GluN2A-subunit-containing NMDAR enhancers may have therapeutic benefits in brain disorders with network hypersynchrony and cognitive impairments.

Students in chemistry often demonstrate difficulty with the principle of resonance. Despite many attempts to mitigate this difficulty, there have been few attempts to examine the root cause of these issues. In this study, students were assessed for their perception of Kekule structures based on perceptual learning theory, which is grounded in cognitive mechanisms of visual perception. The data from this assessment shows that students are perceiving inappropriate clues from this representation, which infers that the image itself might be an impediment to learning about resonance. Employment of a meta-representational competence approach was used to address these misperceptions.

TGF-β1 signaling is a critical driver of collagen accumulation and fibrotic disease but also a vital suppressor of inflammation and epithelial cell proliferation. The nature of this multifunctional cytokine has limited the development of global TGF-β1 signaling inhibitors as therapeutic agents. We conducted phenotypic screens for small molecules that inhibit TGF-β1-induced epithelial-mesenchymal transition without immediate TGF-β1 receptor (TβR) kinase inhibition. We identified trihydroxyphenolic compounds as potent blockers of TGF-β1 responses (IC50 ~50 nM), Snail1 expression, and collagen deposition in vivo in models of pulmonary fibrosis and collagen-dependent lung cancer metastasis. Remarkably, the functional effects of trihydroxyphenolics required the presence of active lysyl oxidase-like 2 (LOXL2), thereby limiting effects to fibroblasts or cancer cells, the major LOXL2 producers. Mechanistic studies revealed that trihydroxyphenolics induce auto-oxidation of a LOXL2/3-specific lysine (K731) in a time-dependent reaction that irreversibly inhibits LOXL2 and converts the trihydrophenolic to a previously undescribed metabolite that directly inhibits TβRI kinase. Combined inhibition of LOXL2 and TβRI activities by trihydrophenolics resulted in potent blockade of pathological collagen accumulation in vivo without the toxicities associated with global inhibitors. These findings elucidate a therapeutic approach to attenuate fibrosis and the disease-promoting effects of tissue stiffness by specifically targeting TβRI kinase in LOXL2-expressing cells.

After influenza infection, lineage-negative epithelial progenitors (LNEPs) exhibit a binary response to reconstitute epithelial barriers: activating a Notch-dependent ΔNp63/cytokeratin 5 (Krt5) remodelling program or differentiating into alveolar type II cells (AEC2s). Here we show that local lung hypoxia, through hypoxia-inducible factor (HIF1α), drives Notch signalling and Krt5pos basal-like cell expansion. Single-cell transcriptional profiling of human AEC2s from fibrotic lungs revealed a hypoxic subpopulation with activated Notch, suppressed surfactant protein C (SPC), and transdifferentiation toward a Krt5pos basal-like state. Activated murine Krt5pos LNEPs and diseased human AEC2s upregulate strikingly similar core pathways underlying migration and squamous metaplasia. While robust, HIF1α-driven metaplasia is ultimately inferior to AEC2 reconstitution in restoring normal lung function. HIF1α deletion or enhanced Wnt/β-catenin activity in Sox2pos LNEPs blocks Notch and Krt5 activation, instead promoting rapid AEC2 differentiation and migration and improving the quality of alveolar repair.

The development of next-generation sequencing (NGS) technology allows to sequence whole exomes or genome. However, data analysis is still the biggest bottleneck for its wide implementation. Most laboratories still depend on manual procedures for data handling and analyses, which translates into a delay and decreased efficiency in the delivery of NGS results to doctors and patients. Thus, there is high demand for developing an automatic and an easy-to-use NGS data analyses system. We developed comprehensive, automatic genetic analyses controller named Mobile Genome Express (MGE) that works in smartphones or other mobile devices. MGE can handle all the steps for genetic analyses, such as: sample information submission, sequencing run quality check from the sequencer, secured data transfer and results review. We sequenced an Actrometrix control DNA containing multiple proven human mutations using a targeted sequencing panel, and the whole analysis was managed by MGE, and its data reviewing program called ELECTRO. All steps were processed automatically except for the final sequencing review procedure with ELECTRO to confirm mutations. The data analysis process was completed within several hours. We confirmed the mutations that we have identified were consistent with our previous results obtained by using multi-step, manual pipelines.

Next-generation sequencing (NGS) is becoming a standard for genetic analyses of clinical samples. DNAs retrieved from formalin-fixed, paraffin-embedded (FFPE) tissue specimens are commonly degraded, and specimens such as core biopsies are sometimes too small to obtain enough DNA for NGS applications. Thus, it is important to measure both the DNA quantity and quality accurately from clinical samples. However, there is no standard method for DNA quantity and quality analyses for NGS library preparation. We tested four different methods (PicoGreen, Qubit® fluorometry, TaqMan and SYBR-Green-based qPCR assay) and compared each to RNase P TaqMan as a reference control. We found that SYBR-Green-based qPCR assay provides a consistent and accurate DNA quantification while keeping its cost relatively low and the throughput high. We designed a dual-probe SYBR-Green qPCR assay for DNA quantity and quality assessment for targeted NGS library preparation. This assay provides a Dscore (degradation score) of the interrogated DNA by analyzing two different sizes of amplicons. We show an example of a clinical sample with a very high Dscore (high degradation). With a regular DNA quantification, without considering the degradation status, no correct NGS libraries were obtained. However, after optimizing the library condition by considering its poor DNA quality, a reasonably good library and sequencing results were obtained. In summary, we developed and presented a new DNA quantity and quality analysis qPCR assay for the targeted NGS library preparation. This assay may be mostly efficient for the clinical samples with high degradation and poor DNA quality.

Abstract Historically, few publications exist where patient engagement in clinical studies is a driving force in study design and implementation. The Patient Centered Outcomes Research Institute (PCORI), established in 2010, employed a new model of integrating stakeholder perspectives into healthcare research. This manuscript aims to share the experience of a Patient Engagement Group (PEG) that has engaged in hepatitis C (HCV) clinical research alongside investigators conducting two studies funded by PCORI and to inspire others to get more involved in research that can impact our healthcare and health policies. There are many gaps in treating infectious diseases. Traditionally, treatment and research have been strictly clinical/medical approaches with little focus on the biopsychosocial aspects of individual patients. Our PEG reflected on its own personal experiences regarding how research design can affect study implementation by including patients who are normally excluded. We considered barriers to treatment, out of pocket costs, access to insurance, and patient race/ethnicity. Common themes were discovered, and four major topics were discussed. In addition, measures used in the two studies to collect patient data were considered, tested, and implemented by the group. We describe in detail how we were formed and how we have worked together with researchers on two PCORI funded projects over the past 7 years. We formulated and implemented guidelines and responsibilities for operating as a PEG as well as appointing a chair, co-chair, and primary author of this manuscript. Written from the perspective of a PEG whose members experienced HCV treatment and cure, we provide lessons learned, and implications for further research to include patients. PEGs like ours who are included as active partners in research can provide useful input to many areas including how patients are treated during clinical trials, how they interact with research teams, and how the clinical benefits of drugs or devices are defined and evaluated. PCORI believes engagement impacts research to be more patient-centered, useful, and trustworthy, and will ultimately lead to greater use and interest of research results by the patient and the broader healthcare community.

Judgments of learning are most accurate when made at a delay from the initial encoding of the assessed material. A wealth of evidence suggests that this is because a delay encourages participants to base their predictions on cues retrieved from long-term memory, which are generally the most diagnostic of later memory performance. We investigated the hypothesis that different types of study techniques affect delayed JOL accuracy by influencing the accessibility of cues stored in long-term memory. In two experiments, we measured the delayed-JOL accuracy of participants who encoded semantically unrelated and weakly related word pairs through one of three study techniques: reading the pairs twice (study practice), generating keywords (elaborative encoding), or taking a cued-recall test with feedback (retrieval practice). We also measured the accessibility, utilization, and diagnostic quality of two long-term memory cues at the time of the delayed JOL: (a) retrieval of the target, and (b) noncriterial cues (retrieval of contextual details pertaining to the encoding of the target). We found that the accessibility of targets was positively associated with delayed-JOL accuracy. Further, we provide evidence that when study techniques enhance the accessibility of targets, they likewise enhance delayed-JOL accuracy.

Ductal carcinoma in situ is very rare in male patients, accounting for approximately 5%–7% of all male breast cancers. We present a case of a man in his early 70s who presented with bloody nipple discharge and gynaecomastia and was subsequently diagnosed with ductal carcinoma in situ (DCIS). We discuss his management with surgical resection and the consideration of adjuvant treatment. We also review the existing literature on the presentation, diagnosis and management of DCIS in men. [ABSTRACT FROM AUTHOR]

TGF-[beta]1 signaling is a critical driver of collagen accumulation and fibrotic disease but also a vital suppressor of inflammation and epithelial cell proliferation. The nature of this multifunctional cytokine has limited the development of global TGF-[beta]1 signaling inhibitors as therapeutic agents. We conducted phenotypic screens for small molecules that inhibit TGF-[beta]1induced epithelial-mesenchymal transition without immediate TGF-[beta]1 receptor (TpR) kinase inhibition. We identified trihydroxyphenolic compounds as potent blockers of TGF-[beta]1 responses ([IC.sub.50]~50 nM), Snail1 expression, and collagen deposition in vivo in models of pulmonary fibrosis and collagen-dependent lung cancer metastasis. Remarkably, the functional effects of trihydroxyphenolics required the presence of active lysyl oxidase-like 2 (LOXL2), thereby limiting effects to fibroblasts or cancer cells, the major LOXL2 producers. Mechanistic studies revealed that trihydroxyphenolics induce autooxidation of a LOXL2/3-specific lysine (K731) in a time-dependent reaction that irreversibly inhibits LOXL2 and converts the trihydrophenolic to a previously undescribed metabolite that directly inhibits TpRI kinase. Combined inhibition of LOXL2 and TpRI activities by trihydrophenolics resulted in potent blockade of pathological collagen accumulation in vivo without the toxicities associated with global inhibitors. These findings elucidate a therapeutic approach to attenuate fibrosis and the disease-promoting effects of tissue stiffness by specifically targeting TpRI kinase in LOXL2-expressing cells., Introduction Tissue fibrosis is a major cause of human morbidity and mortality worldwide (1, 2). TGF-[beta]1 signaling through its heterotetrameric receptor complex of 2 receptor types, TpRII and TpRI, is [...]

Histone acetylation is a key component in the consolidation of long-term fear memories. Histone acetylation is fueled by acetyl-coenzyme A (acetyl-CoA), and recently, nuclear-localized metabolic enzymes that produce this metabolite have emerged as direct and local regulators of chromatin. In particular, acetyl-CoA synthetase 2 (ACSS2) mediates histone acetylation in the mouse hippocampus. However, whether ACSS2 regulates long-term fear memory remains to be determined. Here, we show that Acss2 knockout is well tolerated in mice, yet the Acss2-null mouse exhibits reduced acquisition of long-term fear memory. Loss of Acss2 leads to reductions in both histone acetylation and expression of critical learning and memory-related genes in the dorsal hippocampus, specifically following fear conditioning. Furthermore, systemic administration of blood-brain barrier-permeable Acss2 inhibitors during the consolidation window reduces fear-memory formation in mice and rats and reduces anxiety in a predator-scent stress paradigm. Our findings suggest that nuclear acetyl-CoA metabolism via ACSS2 plays a critical, previously unappreciated, role in the formation of fear memories. [ABSTRACT FROM AUTHOR]

Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain. Recent evidence suggests that adult hippocampal neurogenesis (AHN) persists throughout life in mammals, including humans. These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory. Importantly, studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases. Alzheimer’s disease (AD) is one of the most common forms of dementia affecting millions of people. Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus. Therefore, there has been growing interest in identifying how hippocampal neurogenesis is affected in AD. However, the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood. In this review, we summarized the recent literature on AHN and its impairments in AD. [ABSTRACT FROM AUTHOR]

Background Although engagement of infectious disease physicians has been demonstrated to improve clinical outcomes in a variety of disease states, the extent of infectious disease (ID) physician engagement in quality improvement (QI) or their knowledge of QI has not been assessed. Methods A 12-question, web-based survey was distributed to members of the Infectious Diseases Society of America (IDSA) between August and October 2019 to assess knowledge of and engagement in QI. The survey link was sent to IDSA members who self-identified patient care as their primary professional activity. Results Responses were received from 200 individuals (5.4% response rate, which is just below the standard IDSA survey response rate of 6%), consisting of 175 adult infectious disease physicians (IDPs). Most respondents were employed in a hospital or clinic (41%), private or group practice (25%), or university/medical center (24%). Fifty-eight percent of respondents currently participate in QI projects, while 38% serve on QI oversight committees. Among respondents, 27% reported not being engaged in QI. Infection prevention/hospital epidemiology (77%), stewardship (72%), and antimicrobial resistance (56%) were the most commonly reported measure types. Respondents reported barriers that limited participation in QI, including cost (61%), lack of time (56%), lack of data collection resources (48%), and lack of an ID-specific registry (46%). IDPs report significant interest in additional training in QI and new quality measures. Conclusions Although IDPs participate in QI, there are gaps in QI knowledge and measurement systems. The low response rate of our survey also suggests a lack of engagement in QI among IDPs. Closing these gaps will benefit ID in a value-driven health care economy. [ABSTRACT FROM AUTHOR]

We study how career and wage incentives affect labor productivity through self-selection and incentive effect channels using a two-stage field experiment in Malawi. First, recent secondary school graduates were hired with either career or wage incentives. After employment, half of the workers with career incentives randomly received wage incentives, and half of the workers with wage incentives randomly received career incentives. Career incentives attract higher-performing workers than wage incentives do, but they do not increase productivity conditional on selection. Wage incentives increase productivity for those recruited through career incentives. Observable characteristics are limited in explaining selection effects of entry-level workers. [ABSTRACT FROM AUTHOR]

The University of Arkansas for Medical Sciences (UAMS), like many rural states, faces clinical and research obstacles to which digital innovation is seen as a promising solution. To implement digital technology, a mobile health interest group was established to lay the foundation for an enterprise-wide digital health innovation platform. To create a foundation, an interprofessional team was established, and a series of formal networking events was conducted. Three online digital health training models were developed, and a full-day regional conference was held featuring nationally recognized speakers and panel discussions with clinicians, researchers, and patient advocates involved in digital health programs at UAMS. Finally, an institution-wide survey exploring the interest in and knowledge of digital health technologies was distributed. The networking events averaged 35–45 attendees. About 100 individuals attended the regional conference with positive feedback from participants. To evaluate mHealth knowledge at the institution, a survey was completed by 257 UAMS clinicians, researchers, and staff. It revealed that there are opportunities to increase training, communication, and collaboration for digital health implementation. The inclusion of the mobile health working group in the newly formed Institute for Digital Health and Innovation provides a nexus for healthcare providers and researches to facilitate translational research. [ABSTRACT FROM AUTHOR]

TGF-β1 signaling is a critical driver of collagen accumulation and fibrotic disease but also a vital suppressor of inflammation and epithelial cell proliferation. The nature of this multifunctional cytokine has limited the development of global TGF-β1 signaling inhibitors as therapeutic agents. We conducted phenotypic screens for small molecules that inhibit TGF-β1-induced epithelial-mesenchymal transition without immediate TGF-β1 receptor (TβR) kinase inhibition. We identified trihydroxyphenolic compounds as potent blockers of TGF-β1 responses (IC50 ~50 nM), Snail1 expression, and collagen deposition in vivo in models of pulmonary fibrosis and collagen-dependent lung cancer metastasis. Remarkably, the functional effects of trihydroxyphenolics required the presence of active lysyl oxidase-like 2 (LOXL2), thereby limiting effects to fibroblasts or cancer cells, the major LOXL2 producers. Mechanistic studies revealed that trihydroxyphenolics induce auto-oxidation of a LOXL2/3-specific lysine (K731) in a time-dependent reaction that irreversibly inhibits LOXL2 and converts the trihydrophenolic to a previously undescribed metabolite that directly inhibits TβRI kinase. Combined inhibition of LOXL2 and TβRI activities by trihydrophenolics resulted in potent blockade of pathological collagen accumulation in vivo without the toxicities associated with global inhibitors. These findings elucidate a therapeutic approach to attenuate fibrosis and the disease-promoting effects of tissue stiffness by specifically targeting TβRI kinase in LOXL2-expressing cells. [ABSTRACT FROM AUTHOR]

Background: Maternity care is an integral part of family medicine, and the quality and cost-effectiveness of maternity care provided by family physicians is well documented. Considering the population health perspective, increasing the number of family physicians competent to provide maternity care is imperative, as is working to overcome the barriers discouraging maternity care practice. A standard that clearly defines maternity care competency and a systematic set of tools to assess competency levels could help overcome these barriers. National discussions between 2012 and 2014 revealed that tools for competency assessment varied widely. These discussions resulted in the formation of a workgroup, culminating in a Family Medicine Maternity Care Summit in October 2014. This summit allowed for expert consensus to describe three scopes of maternity practice, draft procedural and competency assessment tools for each scope, and then revise the tools, guided by the Family Medicine and OB/GYN Milestones documents from the respective residency review committees. The summit group proposed that achievement of a specified number of procedures completed should not determine competency; instead, a standardized competency assessment should take place after a minimum number is performed. The traditionally held required numbers for core procedures were reassessed at the summit, and the resulting consensus opinion is proposed here. Several ways in which these evaluation tools can be disseminated and refined through the creation of a learning collaborative across residency programs is described. The summit group believed that standardization in training will more clearly define the competencies of family medicine maternity care providers and begin to reduce one of the barriers that may discourage family physicians from providing maternity care. [ABSTRACT FROM AUTHOR]

To examine whether the recent price patterns and transaction costs of Bitcoin represent a general characteristic of decentralized virtual currencies, we analyze virtual currencies in online games that have been voluntarily managed by individuals since 1990s. We find that matured game currencies have price stability similar to that of small size equities or gold, and their transaction costs are sometimes lower than real currencies. Assuming that virtual currencies with a longer history can provide an estimate for Bitcoin’s prospects, we project that Bitcoin will be less influenced by speculative trades and become a low cost alternative to real currencies. [ABSTRACT FROM AUTHOR]

An organic solvent-stable alkaline hydrolase (PA27) from Pseudomonas aeruginosa MH38 was expressed, characterized, and immobilized for biotechnological applications. Recombinant PA27 was expressed in Escherichia coli as a 27 kDa soluble protein and was purified by standard procedures. PA27 was found to be stable at pH 8-11 and below 50 °C. It maintained more than 80% of its activity under alkaline conditions (pH 8.0-11.0). Furthermore, PA27 exhibited remarkable stability in benzene and n-hexane at concentrations of 30% and 50%. Based on these properties, immobilization of PA27 for biotechnological applications was explored. Scanning electron microscopy revealed a very smooth spherical structure with numerous large pores. Interestingly, immobilized PA27 displayed improved thermal/chemical stabilities and high reusability. Specifically, immobilized PA27 has improved thermal stability, maintaining over 90% of initial activity after 1 h of incubation at 80 °C, whereas free PA27 had only 35% residual activity. Furthermore, immobilized PA27 showed higher residual activity than the free enzyme biocatalysts against detergents, urea, and phenol. Immobilized PA27 could be recycled 20 times with retention of ∼60% of its initial activity. Furthermore, macroscopic hydrogel formation of PA27 was also investigated. These characteristics make PA27 a great candidate for an industrial biocatalyst with potential applications. [ABSTRACT FROM AUTHOR]

Simple Summary: We conducted a retrospective cohort study to evaluate the association between broad-spectrum antibiotic use and disease progression in early-stage melanoma patients who underwent surgery. We used healthcare claims data (2008–2018) and identified individuals with melanoma diagnosis and surgery within 90 days of diagnosis. We studied the relationship between melanoma progression (a proxy measure created using cancer therapies, surgery, and metastasis) within 2 years of melanoma surgery and antibiotic use in three time windows separately: (i) 3 months prior to surgery, (ii) 1 month after surgery, and (iii) 3 months after surgery. We found that prescriptions for antibiotics in 3 months prior to surgery were not associated with melanoma progression; in contrast, antibiotic use in post-1- and post-3-months windows was associated with reduced risk of progression. Our study is exploratory and limited to early-stage melanoma patients with surgery. Animal studies and a few clinical studies have reported mixed findings on the association between antibiotics and cancer incidence. Antibiotics may inhibit tumor cell growth, but could also alter the gut-microbiome-modulated immune system and increase the risk of cancer. Studies that assess how antibiotics affect the progression of cancer are limited. We evaluated the association between broad-spectrum antibiotic use and melanoma progression. We conducted a retrospective cohort study using IQVIA PharMetrics® Plus data (2008–2018). We identified patients with malignant melanoma who underwent wide local excision or Mohs micrographic surgery within 90 days of first diagnosis. Surgery date was the index date. Patients were excluded if they had any other cancer diagnosis or autoimmune disorders in 1 year before the index date ("baseline"). Exposure to broad-spectrum antibiotics was identified in three time windows using three cohorts: 3 months prior to the index date, 1 month after the index date, and 3 months after the index date. The covariates were patients' demographic and clinical characteristics identified in the 1-year baseline period. The patients were followed from the index date until cancer progression, loss of enrollment, or the end of 2 years after the index date. Progression was defined as: (i) any hospice care after surgery, (ii) a new round of treatment for melanoma (surgery, chemotherapy, immunotherapy, targeted therapy, or radiotherapy) 180 days after prior treatment, or (iii) a metastasis diagnosis or a diagnosis of a new nonmelanoma primary cancer at least 180 days after first melanoma diagnosis or prior treatment. A high-dimensional propensity score approach with inverse weighting was used to adjust for the patients' baseline differences. Cox proportional hazard regression was used for estimating the association. The final samples included 3930, 3831, and 3587 patients (mean age: 56 years). Exposure to antibiotics was 16% in the prior-3-months, 22% in the post-1-month, and 22% in the post-3-months. In the pre-3-months analysis, 9% of the exposed group and 9% of the unexposed group had progressed. Antibiotic use was not associated with melanoma progression (HR: 0.81; 95% CI: 0.57–1.14). However, antibiotic use in subsequent 1 month and subsequent 3 months was associated with 31% reduction (HR: 0.69; 95% CI: 0.51–0.92) and 32% reduction (HR: 0.68; 95% CI: 0.51–0.91) in progression, respectively. In this cohort of patients with likely early-stage melanoma cancer, antibiotic use in 1 month and 3 months after melanoma surgery was associated with a lower risk of melanoma progression. Future studies are warranted to validate the findings. [ABSTRACT FROM AUTHOR]

Dopamine (DA) is a behaviorally and clinically diverse neuromodulator that controls CNS function. DA plays major roles in many behaviors including locomotion, learning, habit formation, perception, and memory processing. Reflecting this, DA dysregulation produces a wide variety of cognitive symptoms seen in neuropsychiatric diseases such as Parkinson's, Schizophrenia, addiction, and Alzheimer's disease. Here, we review recent advances in the DA systems neuroscience field and explore the advancing hypothesis that DA's behavioral function is linked to disease deficits in a neural circuit-dependent manner. We survey different brain areas including the basal ganglia's dorsomedial/dorsolateral striatum, the ventral striatum, the auditory striatum, and the hippocampus in rodent models. Each of these regions have different reported functions and, correspondingly, DA's reflecting role in each of these regions also has support for being different. We then focus on DA dysregulation states in Parkinson's disease, addiction, and Alzheimer's Disease, emphasizing how these afflictions are linked to different DA pathways. We draw upon ideas such as selective vulnerability and region-dependent physiology. These bodies of work suggest that different channels of DA may be dysregulated in different sets of disease. While these are great advances, the fine and definitive segregation of such pathways in behavior and disease remains to be seen. Future studies will be required to define DA's necessity and contribution to the functional plasticity of different striatal regions. [ABSTRACT FROM AUTHOR]

Multi-drug resistant bacterial infections are a serious threat to global public health. Changes in treatment modalities and prudent use of antibiotics can assist in reducing the threat, but new approaches are also required for untreatable cases. The use of predatory bacteria, such as Bdellovibriobacteriovorus, is among the novel approaches being considered as possible therapeutics for antibiotic resistant and/or unidentified bacterial infections. Previous studies have examined the feasibility of using predatory bacteria to reduce colony-forming units (CFUs) in the lungs of rats exposed to lethal doses of Klebsiella pneumoniae; here we apply the approach to the Tier 1 select agent Yersinia pestis, and show that three doses of B. bacteriovorus introduced every six hours reduces the number of CFUs of Y. pestis in the lungs of inoculated mice by 86% after 24 h of infection. These experiments further demonstrate that predatory bacteria may serve to combat Gram negative bacterial infections, including those considered potential bioweapon agents, in the future. [ABSTRACT FROM AUTHOR]

Objective: To compare rates and risk factors of severe COVID-19-related outcomes between American Indian/Alaska Native (AI/AN) and non-Hispanic White people (NHW). Methods: Aggregate Social Vulnerability Index (SVI), COVID-19-related risk factor, hospitalization, and mortality data were obtained from 16 states for January 1, 2020-March 31, 2021. Generalized estimating equation Poisson regression models calculated age-adjusted cumulative incidences, incidence ratios (IR), and 95% confidence intervals (CI) comparing AI/AN and NHW persons by age, sex, and county-level SVI status. Results: Race data were missing for 42.7% of COVID-19 cases, 24.7% of hospitalizations, and 10.1% of deaths. Risk of AI/AN COVID-19 mortality was 2.6 times that of NHW persons (IR 2.6, 95% CI: 1.7 - 3.4); risk of COVID-19-related hospitalization among AI/AN persons was 3.5 times that of NHW (IR: 3.5, 95% CI: 2.7 - 4.3). Severe COVID-19 outcomes were significantly higher for AI/AN persons compared to NHW persons across all age and sex groups. There was no statistically significant difference in COVID-19 outcomes by SVI status. Associations between severe COVID-19 outcomes and co-morbid risk factors were inconsistent. Conclusions: Results describe increased risk of severe COVID-19 outcomes for AI/AN persons compared to NHW persons despite quality issues in public health surveillance data. Data linkages and improved ascertainment reduce race/ethnicity misclassification and improve data quality. COVID-19-related health burdens among AI/AN persons warrant improved access for AI/AN communities to medical countermeasures and healthcare resources. [ABSTRACT FROM AUTHOR]

Objective To determine whether endometrial hCG infusion at the time of human blastocyst transfer impacts implantation rates. Design Randomized double-blinded placebo-controlled trial. Setting Academic. Patient(s) Infertile couples with the female partner less than 43 years old (n = 300) undergoing fresh or frozen ET of one or two blastocysts. Intervention(s) Patients undergoing ET were randomized into either a treatment or a control group. The treatment group received an infusion of 500 IU of hCG diluted in ET media. The control group received a sham infusion of ET media. Infusions were done using a separate catheter less than 3 minutes before actual ET. Main Outcome Measure(s) Sustained implantation rate: ongoing viable gestation (primary outcome) and ongoing pregnancy rate (secondary outcome). Result(s) A total of 473 blastocysts were transferred into 300 patients. There were no differences between the two groups in sustained implantation rate (48.1% in the hCG group, 44.2% in the control group) or ongoing pregnancy rate (58.8% in the hCG group, 52.0% in the control group). Conclusion(s) Endometrial infusion of hCG at the time of blastocyst ET does not improve sustained implantation rates. Clinical Trial Registration Number NCT01643993 . [ABSTRACT FROM AUTHOR]

Ductal carcinoma in situ is very rare in male patients, accounting for approximately 5%-7% of all male breast cancers. We present a case of a man in his early 70s who presented with bloody nipple discharge and gynaecomastia and was subsequently diagnosed with ductal carcinoma in situ (DCIS). We discuss his management with surgical resection and the consideration of adjuvant treatment. We also review the existing literature on the presentation, diagnosis and management of DCIS in men., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Reanalyse the patient-level data set of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study with fidelity to the original research protocol and related publications., Design: The study was open label and semirandomised examining the effectiveness of up to four optimised and increasingly aggressive, antidepressant therapies in depressed adults. Patients who failed to gain adequate relief from their level 1 trial on the SSRI citalopram could receive up to three additional treatment trials in levels 2-4., Setting: 41 North American psychiatry and primary care treatment centres., Participants: 4041 adults screened positive for major depressive disorder. In contrast to most clinical trials, STAR*D enrolled patients seeking care (vs recruited) and included patients with a wide range of common comorbid medical and psychiatric conditions to enhance the generalisability of findings to real-world clinical practice., Interventions: STAR*D evaluated the relative effectiveness of 13 antidepressants therapies in treatment levels 2-4 for depressed patients who failed to gain adequate benefit from their level 1 medication trial., Main Outcome Measures: According to the STAR*D protocol, the primary outcome was remission, defined as a score <8 on the blinded Hamilton Rating Scale for Depression (HRSD). Response was a secondary outcome defined as ≥50% reduction in HRSD scores. STAR*D's protocol specifically excluded all non-blinded clinic-administered assessments from use as research outcome measures., Results: STAR*D investigators did not use the protocol-stipulated HRSD to report cumulative remission and response rates in their summary article and instead used a non-blinded clinic-administered assessment. This inflated their report of outcomes, as did their inclusion of 99 patients who scored as remitted on the HRSD at study outset as well as 125 who scored as remitted when initiating their next-level treatment. These patients should have been excluded from data analysis. In contrast to the STAR*D-reported 67% cumulative remission rate after up to four antidepressant treatment trials, the rate was 35.0% when using the protocol-stipulated HRSD and inclusion in data analysis criteria., Conclusion: STAR*D's cumulative remission rate was approximately half of that reported., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Supplemental material is available for this article. Keywords: Mammography, Breast, Machine Learning © RSNA, 2023., Competing Interests: Disclosures of conflicts of interest: J.J.J. No relevant relationships. B.L.V. No relevant relationships. A.B. No relevant relationships. T.K. No relevant relationships. T.S. No relevant relationships. R.C. No relevant relationships. R.D. No relevant relationships. M.M. No relevant relationships. G.O. No relevant relationships. G.S. No relevant relationships. M.W. No relevant relationships. C.R.M. No relevant relationships. M.S.N. No relevant relationships. I.B. No relevant relationships. J.G. NSF and NIH grants; Nightingale Foundation grant; ACR AI Advisory group; SIIM director at large; HL7 board member; trainee editorial board member lead and associate editor for Radiology: Artificial Intelligence. H.T. Kheiron Medical Technologies, academic-industry collaboration; consultant for Arterys, Sirona Medical, and BioData Consortium; owner of Lightbox AI., (© 2023 by the Radiological Society of North America, Inc.)

Objective: To determine the utility of treating facial palsy with mirror book therapy in conjunction with facial physical rehabilitation., Methods: We randomly selected and reviewed the charts of 25 patients with idiopathic facial palsy. 10 of these patients received facial physical rehabilitation including manual therapy and postural exercises. 15 of these patients received mirror book therapy in conjunction with standard facial rehabilitation. Before and after treatment, patients in both groups were rated using the Facial Grading System (FGS) score, the Facial Disability Index--Physical (FDIP) score, and the Facial Disability Index--Social (FDIS) score. Differences in response to therapy were analyzed., Results: Patients in the facial physical rehabilitation group without mirror book therapy group showed on average a 20.8% increase in the FGS score, a 19% increase in the FDIP score, and a 14.6% increase in the FDIS score. Patients in the mirror book therapy group showed an average of 24.9% increase in the Facial Grading System (FGS) score, a 21.6% increase in the Facial Disability Index--Physical (FDIP) score, and a 24.5% increase in the Facial Disability Index--Social (FDIS) score., Conclusion: The addition of mirror book therapy to standard facial rehabilitation treatments does significantly improve outcomes in the treatment of idiopathic facial palsy.

Multi-drug resistant bacterial infections are a serious threat to global public health. Changes in treatment modalities and prudent use of antibiotics can assist in reducing the threat, but new approaches are also required for untreatable cases. The use of predatory bacteria, such as Bdellovibrio bacteriovorus , is among the novel approaches being considered as possible therapeutics for antibiotic resistant and/or unidentified bacterial infections. Previous studies have examined the feasibility of using predatory bacteria to reduce colony-forming units (CFUs) in the lungs of rats exposed to lethal doses of Klebsiella pneumoniae ; here we apply the approach to the Tier 1 select agent Yersinia pestis , and show that three doses of B. bacteriovorus introduced every six hours reduces the number of CFUs of Y. pestis in the lungs of inoculated mice by 86% after 24 h of infection. These experiments further demonstrate that predatory bacteria may serve to combat Gram negative bacterial infections, including those considered potential bioweapon agents, in the future.

Introduction: Recurrent head and neck carcinomas are notoriously difficult to treat. Salvage surgery, brachytherapy, and repeat external beam radiotherapy have all been utilized, achieving modest local control at the expense of elevated toxicity. We performed a retrospective review to evaluate the efficacy of single fraction stereotactic radiosurgery (SRS) for the treatment of recurrent head and neck carcinomas., Methods: Eighteen previously irradiated patients diagnosed with a locoregionally recurrent head and neck malignancy and treated with single fraction SRS from 2000 to 2016 were analyzed. Actuarial rates for local control (LC) and overall survival (OS) were calculated with Kaplan-Meier estimates., Results: Median follow-up was 16.1 months and SRS dose was 13.3 Gy. One-year rate of LC was 52.7% (95% confidence interval [CI] 29%-72%). Median OS was 25.4 months. Parotid gland primary had an increased risk of progressive disease (PD) following SRS (hazard ratio [HR] 4.24, p=0.02). Squamous cell histology was negatively associated with OS (HR 3.85, p=0.03). One patient experienced grade 2 radionecrosis., Conclusions: Single fraction SRS is an acceptable treatment for previously irradiated patients with recurrent head and neck primary malignancies. Dose escalation to optimize LC should be examined., Competing Interests: The authors have declared financial relationships, which are detailed in the next section.

An organic solvent-stable alkaline hydrolase (PA27) from Pseudomonas aeruginosa MH38 was expressed, characterized, and immobilized for biotechnological applications. Recombinant PA27 was expressed in Escherichia coli as a 27 kDa soluble protein and was purified by standard procedures. PA27 was found to be stable at pH 8-11 and below 50 °C. It maintained more than 80% of its activity under alkaline conditions (pH 8.0-11.0). Furthermore, PA27 exhibited remarkable stability in benzene and n-hexane at concentrations of 30% and 50%. Based on these properties, immobilization of PA27 for biotechnological applications was explored. Scanning electron microscopy revealed a very smooth spherical structure with numerous large pores. Interestingly, immobilized PA27 displayed improved thermal/chemical stabilities and high reusability. Specifically, immobilized PA27 has improved thermal stability, maintaining over 90% of initial activity after 1 h of incubation at 80 °C, whereas free PA27 had only 35% residual activity. Furthermore, immobilized PA27 showed higher residual activity than the free enzyme biocatalysts against detergents, urea, and phenol. Immobilized PA27 could be recycled 20 times with retention of ~60% of its initial activity. Furthermore, macroscopic hydrogel formation of PA27 was also investigated. These characteristics make PA27 a great candidate for an industrial biocatalyst with potential applications.