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The article focuses on the consequences of exchange in the non-expansion states. Topics discussed include laws for regulating divorce, employment and child custody like disputes in the non-expansion states, resolution of disputes related to the income of people below poverty line, and the laws for the regulation Medicaid policies.

This Article evaluates the consequences of an early 2013 repeal of the enacted Health Care Reform. We consider the Act's significant provisions that will have taken effect by 2013. For implemented provisions, we review their current effect on coverage, costs, and care. We then evaluate the practical consequence of the loss of those provisions. For provisions that have not yet taken effect, but will before 2013, we evaluate their projected effects in considering the consequences of repeal. Finally, for provisions that will not take effect before 2014, but where significant funds and effort will be expended prior to 2014, we evaluate those costs in considering the consequences of repeal. We conclude that the loss of many provisions would cause a significant impact. However, not all segments of the population would be equally affected by a pre-2014 repeal. Americans with basic coverage stand to lose the most. For example, changes such as the extension of dependent coverage and restrictions on annual limits have greatly increased the value of basic coverage for those who have it. Medicare recipients would similarly stand to lose from a 2013 repeal. But for those unable to afford basic comprehensive coverage, a 2013 repeal would comparatively have less effect-though a repeal after 2014 would significantly impact this group. [ABSTRACT FROM AUTHOR]

The article focuses on how New York can implement a one-cent-per-ounce tax on sugar sweetened beverages (SSBs) and soda. Topics include why previous attempts to tax SSBs have failed, why lawmakers should refrain from framing the charges as sin taxes, and the redistribution of the revenue collected from soda tax.

Scurvy is not just a disease of the past, but of the present as well. Yet, the possibility of scurvy is often overlooked in assessing a client's mental health status. Prompt recognition and treatment of scurvy can prevent unnecessary diagnostic testing, as well as a delay in treatment. The author presents a case history of a 55-year-old man with scurvy, delusions, and depression. The client's history, course of illness, treatment, and plan of care are discussed. [ABSTRACT FROM AUTHOR]

Emerging drug candidates more often fall in the beyond-rule-of-five chemical space. Among them, proteolysis targeting chimeras (PROTACs) have gained great attention in the past decade. Although physicochemical properties of small molecules accomplishing Lipinski's rule-of-five can now be easily predicted through models generated by large data collections, for PROTACs the knowledge is still limited and heterogeneous, hampering their prediction. Here, the kinetic solubility and the coefficient of distribution at pH 7.4 (LogD 7.4 ) of 44 PROTACs, designed and synthesized to cover a wide chemical space, were measured. Their generally low solubility and high lipophilicity required an optimization of the experimental methods. Concerning the LogD 7.4 , several in silico prediction tools were tested, which were quite accurate for classical small molecules but provided dissimilar outcomes for PROTACs. Finally, in silico models for the prediction of PROTACs' kinetic solubility and LogD 7.4 were proposed by combining in-house generated experimental data with 3D description of PROTACs' structures.

Selective degradation of disease-causing proteins using proteolysis targeting chimeras (PROTACs) has gained great attention, thanks to its several advantages over traditional therapeutic modalities. Despite the advances made so far, the structural chemical complexity of PROTACs poses challenges in their synthetic approaches. PROTACs are typically prepared through a convergent approach, first synthesizing two fragments separately (target protein and E3 ligase ligands) and then coupling them to produce a fully assembled PROTAC. The amidation reaction represents the most common coupling exploited in PROTACs synthesis. Unfortunately, the overall isolated yields of such synthetic procedures are usually low due to one or more purification steps to obtain the final PROTAC with acceptable purity. In this work, we focused our attention on the optimization of the final amidation step for the synthesis of an anti-SARS-CoV-2 PROTAC by investigating different amidation coupling reagents and a range of alternative solvents, including ionic liquids (ILs). Among the ILs screened, [OMIM][ClO 4 ] emerged as a successful replacement for the commonly used DMF within the HATU-mediated amidation reaction, thus allowing the synthesis of the target PROTAC under mild and sustainable conditions in very high isolated yields. With the optimised conditions in hand, we explored the scalability of the synthetic approach and the substrate scope of the reaction by employing different E3 ligase ligand (VHL and CRBN)-based intermediates containing linkers of different lengths and compositions or by using different target protein ligands. Interestingly, in all cases, we obtained high isolated yields and complete conversion in short reaction times.

To date, Proteolysis Targeting Chimera (PROTAC) technology has been successfully applied to mediate proteasomal-induced degradation of several pharmaceutical targets mainly related to oncology, immune disorders, and neurodegenerative diseases. On the other hand, its exploitation in the field of antiviral drug discovery is still in its infancy. Recently, we described two indomethacin (INM)-based PROTACs displaying broad-spectrum antiviral activity against coronaviruses. Here, we report the design, synthesis, and characterization of a novel series of INM-based PROTACs that recruit either Von-Hippel Lindau (VHL) or cereblon (CRBN) E3 ligases. The panel of INM-based PROTACs was also enlarged by varying the linker moiety. The antiviral activity resulted very susceptible to this modification, particularly for PROTACs hijacking VHL as E3 ligase, with one piperazine-based compound (PROTAC 6) showing potent anti-SARS-CoV-2 activity in infected human lung cells. Interestingly, degradation assays in both uninfected and virus-infected cells with the most promising PROTACs emerged so far (PROTACs 5 and 6) demonstrated that INM-PROTACs do not degrade human PGES-2 protein, as initially hypothesized, but induce the concentration-dependent degradation of SARS-CoV-2 main protease (M pro ) both in M pro -transfected and in SARS-CoV-2-infected cells. Importantly, thanks to the target degradation, INM-PROTACs exhibited a considerable enhancement in antiviral activity with respect to indomethacin, with EC 50 values in the low-micromolar/nanomolar range. Finally, kinetic solubility as well as metabolic and chemical stability were measured for PROTACs 5 and 6. Altogether, the identification of INM-based PROTACs as the first class of SARS-CoV-2 M pro degraders demonstrating activity also in SARS-CoV-2-infected cells represents a significant advance in the development of effective, broad-spectrum anti-coronavirus strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Textured implants and expanders are associated with an increased risk of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). As a result, plastic surgeons are utilizing smooth expanders, but many perceive these produce undesirable outcomes including infection, seroma, and lateral displacement., Objectives: The aim of this study was to compare clinical outcomes of smooth and textured expanders., Methods: Breast reconstruction patients from January 2018 to May 2021 were retrospectively reviewed. Included patients underwent placement of tissue expanders at the time of mastectomy. Primary outcomes included postoperative seroma, infection, malposition, days to final reconstruction, explantation, and the need for capsulorrhaphy., Results: In total, 233 patients were reviewed, of whom 167 met both inclusion and exclusion criteria. There was no statistically significant difference in poor outcomes comparing smooth and textured expanders. Days to final reconstruction was lower with smooth expanders per breast (P = .0424). The subpectoral group was associated with an increased likelihood of undergoing capsulorrhaphy (P = .004). Prepectoral placement was associated with more seromas (P = .0176) and infections (P = .0245). Demographic factors included older age as a protective factor for undergoing capsulorrhaphy (odds ratio [OR] = 0.962, P = .038), obesity increased the risk of infection (OR = 5.683, P = .0279) and malposition (OR = 6.208, P = .0222), and radiation was associated with malposition (OR = 3.408, P = .0246)., Conclusions: There was no significant difference in poor outcomes between smooth and textured expanders. Patient demographics and anatomical plane placement had greater effects on infection, seroma, and the need for capsulorrhaphy compared with tissue expander texturing., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

PROteolysis TArgeting Chimeras (PROTACs) are tripartite molecules consisting of a linker connecting a ligand for a protein of interest to an E3 ligase recruiter, whose rationale relies on proteasome-based protein degradation. PROTACs have expanded as a therapeutic strategy to open new avenues for unmet medical needs. Leveraging our expertise, we undertook a series of in vitro experiments aimed at elucidating PROTAC metabolism. In particular, we focused on PROTACs recruiting the von Hippel-Lindau (VHL) E3 ligase. After high-resolution mass spectrometry measurements, a characteristic metabolite with mass reduction of 200 units was detected and successively confirmed as a product deriving from the cleavage of the VHL ligand moiety. Subsequently, we identified hepatic and extrahepatic prolyl endopeptidases as the main putative metabolic enzymes involved. Finally, we designed and synthesized analogs of the VHL ligands that we further exploited for the synthesis of novel VHL-directed PROTACs with an improved metabolic stability in in vitro applications.

Gambling disorders are a serious public health problem. This manuscript will provide a comprehensive overview on this topic. Gambling disorder involves repeated patterns of gambling behaviors, that result in significant distress or impairment in a person's interpersonal relationships, employment, educational/career opportunities, and finances over a period of 12 months. Gambling is defined as an activity that involves risking something of value with the hopes of acquiring something of greater value. Comparable to substance use disorders, individuals with a gambling disorder may be unsuccessful in exercising control over their problematic behavior, engage in the behavior despite negative consequences, and have preoccupations/cravings to gamble. Gambling disorder has higher comorbidity rates of mental disorders including depression, anxiety, substance use, and personality disorders. Gamblers rarely seek treatment. Treatments must be tailored to the individual which may include psychological interventions, cognitive behavioral therapy, gamblers anonymous, and psychopharmacological agents such as selective serotonin reuptake inhibitors, mood stabilizers, and opioid antagonists to treat clinical symptoms.

Background: The Caprini score is a validated scale that calculates a patient's 30-day venous thromboembolism (VTE) risk based on their comorbidities. The American Society of Plastic Surgeons published VTE prophylaxis recommendations in 2011 based on the Caprini score, but these recommendations are vague and up to physician interpretation. The purpose of this study is to evaluate postoperative outcomes after the application of strict guidelines using the Caprini score with specific VTE chemoprophylaxis benchmarks on plastic surgery patients., Methods: A retrospective cohort analysis was performed on all plastic surgery patients who underwent surgery between July 2019 and July 2021. Patients between July 2019 and June 2020 were not subjected to any specific VTE prophylaxis protocol, while patients from July 2020 to July 2021 were subjected to the newly created VTE prophylaxis protocol. Every patient received a calculated Caprini score at their preoperative history and physical. The primary outcomes measured include hematoma, deep vein thrombosis (DVT) and pulmonary embolism (PE)., Results: Four hundred forty-one patients with 541 procedures were included in this study, with 275 patients in the "before" group and 166 patients in the "after" group. A total of 78.6% of patients received chemoprophylaxis in the "before" group compared with 20% in the "after" group. There was no significant difference in postoperative complications between the two groups including PE or DVT ( P = 0.2684 and 0.2696, respectively), with a trend toward hematoma formation in the "before" group ( P = 0.1358). After the application of evidence-based VTE guidelines, the patients stayed fewer days in the hospital (0.4 vs 0.7 days, P = 0.0085) and were less likely to be readmitted (2.4% vs 6.5%, P = 0.0333). The average cost per patient in the "before" group was $9.11 with a total cost of $3022.90. The average cost per patient in the "after" group was $4.23 with a total cost of $867.94 ( P = 0.032)., Conclusions: Our strict application of the Caprini score significantly and safely limited the number of patients receiving postoperative VTE chemoprophylaxis and showed no significant difference in postoperative hematoma, DVT, or PE., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The current article is a comprehensive overview of electroconvulsive therapy (ECT) for treatment-resistant depression (TRD), especially with suicidality and psychosis. Common misconceptions and stigma associated with ECT are discussed. Major depressive disorder, one of the most prevalent lifetime mental disorders, is often associated with significant impairments that impacts one's ability to function. Antidepressants may be efficacious in treating depression; however, approximately one third of individuals do not respond to psychotropic medications. Therefore, other treatment options, such as ECT, must be considered for those who do not respond to medications, have psychosis, or are suicidal. [ Journal of Psychosocial Nursing and Mental Health Services, 61 (6), 11-17.].

Drugs must satisfy several protocols and tests before being approved for the market. Among them, forced degradation studies aim to evaluate drug stability under stressful conditions in order to predict the formation of harmful degradation products (DPs). Recent advances in LC-MS instrumentation have facilitated the structure elucidation of degradants, although a comprehensive data analysis still represents a bottle-neck due to the massive amount of data that can be easily generated. MassChemSite has been recently described as a promising informatics solution for LC-MS/MS and UV data analysis of forced degradation experiments and for the automated structural identification of DPs. Here, we applied MassChemSite to investigate the forced degradation of three poly(ADP-ribose) polymerase inhibitors (olaparib, rucaparib, and niraparib) under basic, acidic, neutral, and oxidative stress conditions. Samples were analyzed by UHPLC with online DAD coupled to high-resolution mass spectrometry. The kinetic evolution of the reactions and the influence of solvent on the degradation process were also assessed. Our investigation confirmed the formation of three DPs of olaparib and the wide degradation of the drug under the basic condition. Intriguingly, base-catalyzed hydrolysis of olaparib was greater when the content of aprotic-dipolar solvent in the mixture decreased. For the other two compounds, whose stability has been much less studied previously, six new degradants of rucaparib were identified under oxidative degradation, while niraparib emerged as stable under all stress conditions tested., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

The field of targeted protein degradation, through the control of the ubiquitin-proteasome system (UPS), is progressing considerably; to exploit this new therapeutic modality, the proteolysis targeting chimera (PROTAC) technology was born. The opportunity to use PROTACs engaging of new E3 ligases that can hijack and control the UPS system could greatly extend the applicability of degrading molecules. To this end, here we show a potential application of the ELIOT (E3 LIgase pocketOme navigaTor) platform, previously published by this group, for a scaffold-repurposing strategy to identify new ligands for a novel E3 ligase, such as TRIM33. Starting from ELIOT, a case study of the cross-relationship using GRID Molecular Interaction Field (MIF) similarities between TRIM24 and TRIM33 binding sites was selected. Based on the assumption that similar pockets could bind similar ligands and considering that TRIM24 has 12 known co-crystalised ligands, we applied a scaffold-repurposing strategy for the identification of TRIM33 ligands exploiting the scaffold of TRIM24 ligands. We performed a deeper computational analysis to identify pocket similarities and differences, followed by docking and water analysis; selected ligands were synthesised and subsequently tested against TRIM33 via HTRF binding assay, and we obtained the first-ever X-ray crystallographic complexes of TRIM33α with three of the selected compounds.

Background: Immediate breast reconstruction (IBR) is offered as part of the standard-of-care to females undergoing mastectomy. Racial disparity in IBR has been previously reported with a longstanding call for its elimination, though unknown if this goal is achieved. The aim of this study was to examine the current association between race and IBR and to investigate whether racial disparity is diminishing. Methods: Data was extracted from the National Cancer Database (NCDB) from 2004 to 2016. All variables in the database were controlled so that the comparison would be made solely between Black and White females. We also analyzed the trend in racial disparity to see if there has been a change from 2004 to 2016 after several calls for healthcare equality. Results: After propensity score matching, 69,084 White females were compared to 69,084 Black females. There was a statistically significant difference between the rate of IBR and race (23,386 [33.9%] in White females vs 20,850 [30.2%] in Black females, P -value  < .001). Despite a twofold increase in the rate of IBR in both White and Black females, a persistent gap of about 4% was observed over the study period, which translates to more than 2,500 Black females not receiving IBR. Conclusions: Using the NCDB database, a racial disparity was identified for IBR between White and Black females from 2004 and 2016. Unfortunately, the gap between the groups remained constant over this 13-year period., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2021 The Author(s).)

Proteolysis targeting chimeras (PROTACs) represent an emerging class of compounds for innovative therapeutic application. Their bifunctional nature induces the formation of a ternary complex (target protein/PROTAC/E3 ligase) which allows target protein ubiquitination and subsequent proteasomal-dependent degradation. To date, despite great efforts being made to improve their biological efficacy PROTACs rational design still represents a challenging task, above all for the modulation of their physicochemical and pharmacokinetics properties. Considering the pivotal role played by the linker moiety, recently the insertion of a piperazine moiety into the PROTAC linker has been widely used, as this ring can in principle improve rigidity and increase solubility upon protonation. Nevertheless, the p K a of the piperazine ring is significantly affected by the chemical groups located nearby, and slight modifications in the linker could eliminate the desired effect. In the present study, the p K a values of a dataset of synthesized small molecule compounds including PROTACs and their precursors have been evaluated in order to highlight how a fine modulation of piperazine-containing linkers can impact the protonation state of these molecules or similar heterobifunctional ones. Finally, the possibility of predicting the trend through in silico approaches was also evaluated., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Two years after its emergence, SARS-CoV-2 still represents a serious and global threat to human health. Antiviral drug development usually takes a long time and, to increase the chances of success, chemical variability of hit compounds represents a valuable source for the discovery of new antivirals. In this work, we applied a platform of variably oriented virtual screening campaigns to seek for novel chemical scaffolds for SARS-CoV-2 main protease (M pro ) inhibitors. The study on the resulting 30 best hits led to the identification of a series of structurally unrelated M pro inhibitors. Some of them exhibited antiviral activity in the low micromolar range against SARS-CoV-2 and other human coronaviruses (HCoVs) in different cell lines. Time-of-addition experiments demonstrated an antiviral effect during the viral replication cycle at a time frame consistent with the inhibition of SARS-CoV-2 M pro activity. As a proof-of-concept, to validate the pharmaceutical potential of the selected hits against SARS-CoV-2, we rationally optimized one of the hit compounds and obtained two potent SARS-CoV-2 inhibitors with increased activity against M pro both in vitro and in a cellular context, as well as against SARS-CoV-2 replication in infected cells. This study significantly contributes to the expansion of the chemical variability of SARS-CoV-2 M pro inhibitors and provides new scaffolds to be exploited for pan-coronavirus antiviral drug development., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Yellow fever virus (YFV) is a mosquito-borne flavivirus, endemic in 47 countries in Africa and South America, which causes febrile symptoms that can evolve in 15% of the patients to serious hemorrhagic conditions, liver injury, and multiorgan failure. Although a highly effective vaccine (YF-17D vaccine) is available, to date, no antiviral drugs have been approved for the prevention and treatment of YFV infections., Areas Covered: This review article focuses on the description of viral targets that have been considered within YFV and flavivirus drug discovery studies and on the most relevant candidates reported so far that elicit broad-spectrum inhibition against relevant strains and mutants of YFV., Expert Opinion: Considering the growing interest on (re)emerging vector-borne viral infections, it is expected that flavivirus drug discovery will quickly deliver potential candidates for clinical evaluation. Due to similarity among flaviviral targets, several candidates identified against different flaviviruses have shown broad-spectrum activity, thus exhibiting anti-YFV activity, as well. In this regard, it would be desirable to routinely include the assessment of antiviral activity against different YFV strains. On the other hand, the development of host targeting agents are still at an initial stage and deserve further focused efforts.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19 disease, has rapidly imposed an urgent need to identify effective drug candidates. In this context, the high resolution and non-redundant beta-Coronavirus protein cavities database is pivotal to help virtual screening protocols. Furthermore, the cross-relationship among cavities can lead to highlighting multitarget therapy chances. Here, we first collect all protein cavities on SARS-CoV-2, SARS-CoV, and MERS-CoV X-ray structures, and then, we compute a similarity map by using molecular interaction fields (MIFs). All the results come together in CROMATIC (CROss-relationship MAp of CaviTIes from Coronaviruses). CROMATIC encloses both a comprehensive and a non-redundant version of the cavities collection and a similarity map revealing, on the one hand, cavities that are conserved among the three Coronaviruses and, on the other hand, unexpected similarities among cavities that can represent a key starting point for multitarget therapy strategies. Similarity analysis was also performed for the available structures of SARS-CoV-2 spike variants, linking sequence mutations to three-dimensional interaction alterations. The CROMATIC repository is freely available to the scientific community at https://github.com/moldiscovery/sars-cromatic.

Background: Most hypospadias patients undergo 1 surgical procedure and go on to live normal lives. However, there is a small subset of patients who have remaining functional complications after their repair. Patients presenting with diffuse scarring of the urethral plate and a shortage of penile skin for closure are referred to as "hypospadias cripples." We present our experience using tissue expanders in the treatment of reoperative hypospadias with skin deficiency., Methods: We retrospectively reviewed hospital records from 2009 to 2019. Five hypospadias cripple patients were encountered. A multidisciplinary team involving plastic surgery and pediatric urology collaborated a 3-stage reconstructive plan:Stage 1-Scar excision and buccal mucosal graft harvestStage 2-Dorsal tissue expander placementStage 3-Tissue expander explantation, creation of neourethra, and skin closure., Results: Successful skin closures were achieved in all patients. There were no cases of expander explanation. Average time between tissue expander placement and final reconstruction ranged from 3 to 4 months. Complications included 2 cases of penile cellulitis, 1 with an associated abscess, and 2 limited urethrocutaneous fistulas, which were addressed with an additional operative procedure., Conclusions: The 3-stage approach is advantageous in treating hypospadias cripple patients. This population can benefit greatly from tissue expander placement after buccal result with an acceptable complication rate. Using a multidisciplinary approach is beneficial in treating these complex patients., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Indomethacin (INM), a well-known non-steroidal anti-inflammatory drug, has recently gained attention for its antiviral activity demonstrated in drug repurposing studies against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Although the mechanism of action of INM is not yet fully understood, recent studies have indicated that it acts at an early stage of the coronaviruses (CoVs) replication cycle. In addition, a proteomic study reported that the anti-SARS-CoV-2 activity of INM could be also ascribed to its ability to inhibit human prostaglandin E synthase type 2 (PGES-2), a host protein which interacts with the SARS-CoV-2 NSP7 protein. Although INM does not potently inhibit SARS-CoV-2 replication in infected Vero E6 cells, here we have explored for the first time the application of the Proteolysis Targeting Chimeras (PROTACs) technology in order to develop more potent INM-derived PROTACs with anti-CoV activity. In this study, we report the design, synthesis, and biological evaluation of a series of INM-based PROTACs endowed with antiviral activity against a panel of human CoVs, including different SARS-CoV-2 strains. Two PROTACs showed a strong improvement in antiviral potency compared to INM. Molecular modelling studies support human PGES-2 as a potential target of INM-based antiviral PROTACs, thus paving the way toward the development of host-directed anti-CoVs strategies. To the best of our knowledge, these PROTACs represent the first-in-class INM-based PROTACs with antiviral activity and also the first example of the application of PROTACs to develop pan-coronavirus agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Objective: To develop a valid and reliable instrument for measuring attitudes toward osteopathic medicine., Methods: Participants included 5,669 first-year students from 33 U.S. colleges of osteopathic medicine, who completed an online survey at the beginning of the 2019-2020 academic year. Using data from the nationwide Project in Osteopathic Medical Education and Empathy, we developed a 13-item instrument: Attitudes Toward Osteopathic Medicine Scale (ATOMS) and demonstrated the validity and reliability of its scores. The social desirability response bias was controlled in statistical analyses., Results: The corrected item-total score correlations were all positive and statistically significant, and the effect sizes of item discrimination indices were large. Cronbach's coefficient alpha reliability was 0.83. Construct validity, corroborating face and content validity of the ATOMS, was supported by three components, emerged from factor analysis: "Perspectives on Osteopathic Medicine," "Osteopathic Diagnosis and Treatment," and "Holistic-Integrative Care." Correlations between ATOMS scores and scores of cognitive empathy, emotional empathy; orientation toward interprofessional collaboration; lifelong learning; and burnout were statistically significant in the expected direction, providing validity evidence for the ATOMS. Using the method of contrasted groups, significant differences in the ATOMS scores were found by gender, ethnicity, academic background, and career interest in the expected direction, supporting the validity of the ATOMS scores. National norms were developed to assess individual scores alongside national percentile ranks., Conclusions: The ATOMS, developed in a nationwide study, supported by strong psychometric evidence for measuring orientation toward osteopathic medicine, has implications for the assessment of osteopathic medical education, patient outcomes, and admission decisions.

Stress testing is one of the most important parts of the drug development process, helping to foresee stability problems and to identify degradation products. One of the processes involving stress testing is represented by forced degradation studies, which can predict the impact of certain conditions of pH, moisture, heat, or other negative effects due to transportation or packaging issues on drug potency and purity, ensuring patient safety. Regulatory agencies have been working on a standardization of laboratory procedures since the past two decades. One of the results of those years of intensive research is the International Conference on Harmonization (ICH) guidelines, which clearly define which forced degradation studies should be performed on new drugs, which become a routine work in pharmaceutical laboratories. Since used techniques based on high-performance liquid chromatography coupled with high-resolution mass spectrometry have been developed years ago and are now mastered by pharmaceutical scientists, automation of data analysis, and thus data processing, is becoming a hot topic nowadays. In this work, we present MassChemSite and WebChembase as a tandem to automatize the routine analysis studies without missing information quality, using as a case study the degradation of lansoprazole under acidic, oxidative, basic, and neutral stress conditions.

Influenza (flu) virus is a serious threat to global health with the potential to generate devastating pandemics. The availability of broad spectrum antiviral drugs is an unequaled weapon during pandemic events, especially when a vaccine is still not available. One of the most promising targets for the development of new antiflu therapeutics is the viral RNA-dependent RNA polymerase (RdRP). The assembly of the flu RdRP heterotrimeric complex from the individual polymerase acidic protein (PA), polymerase basic protein 1 (PB1), and polymerase basic protein 2 (PB2) subunits is a prerequisite for RdRP functions, such as mRNA synthesis and genome replication. In this Review, we report the known protein-protein interactions (PPIs) occurring by RdRP that could be disrupted by small molecules and analyze their benefits and drawbacks as drug targets. An overview of small molecules able to interfere with flu RdRP functions exploiting the PPI inhibition approach is described. In particular, an update on the most recent inhibitors targeting the well-consolidated RdRP PA-PB1 subunit heterodimerization is mainly reported, together with pioneer inhibitors targeting other virus-virus or virus-host interactions involving RdRP subunits. As demonstrated by the PA-PB1 interaction inhibitors discussed herein, the inhibition of flu RdRP functions by PPI disrupters clearly represents a valid means to identify compounds endowed with a broad spectrum of action and a reduced propensity to develop drug resistance, which are the main issues of antiviral drugs.

Background: Empathy, which involves understanding another person's experiences and concerns, is an important component for developing physicians' overall competence. This longitudinal study was designed to test the hypothesis that medical students' empathy can be enhanced and sustained by Humanitude Care Methodology, which focuses on perception, emotion and speech., Methods: This six-year longitudinal observational study examined 115 students who entered Okayama University Medical School in 2013. The study participants were exposed to two empathy-enhancing programs: (1) a communication skills training program (involving medical interviews) and (2) a Humanitude training program aimed at enhancing their empathy. They completed the Jefferson Scale of Empathy (JSE) seven times: when they entered medical school, before participation in the first program (medical interview), immediately after the first program, before the second program (Humanitude exercise), immediately after the second program, and in the 5th and 6th year (last year) of medical school. A total of 79 students (69% of the cohort) completed all seven test administrations of the JSE., Results: The mean JSE scores improved significantly after participation in the medical interview program (p < 0.01) and the Humanitude training program (p = 0.001). However, neither program showed a sustained effect., Conclusions: The Humanitude training program as well as medical interview training program, had significant short-term positive effects for improving empathy among medical students. Additional reinforcements may be necessary for a long-term sustained effect.

Although second-line antiandrogen therapy (SAT) is the standard of care in men with castration-resistant prostate cancer (CRPC), resistance inevitably occurs. One major proposed mechanism of resistance to SAT involves the emergence of androgen receptor (AR) splice variant-7, AR-V7. Recently, we developed MTX-23 using the principle of proteolysis targeting chimera (PROTAC) to target both AR-V7 and AR-full length (AR-FL). MTX-23 has been designed to simultaneously bind AR's DNA binding domain (DBD) and the Von Hippel-Lindau (VHL) E3 ubiquitin ligase. Immunoblots demonstrated that MTX-23's degradation concentration 50% (DC 50 ) for AR-V7 and AR-FL was 0.37 and 2 μmol/L, respectively. Further studies revealed that MTX-23 inhibited prostate cancer cellular proliferation and increased apoptosis only in androgen-responsive prostate cancer cells. The antiproliferative effect of MTX-23 was partially reversed when either AR-V7 or AR-FL was overexpressed and was completely abrogated when both were overexpressed. To assess the potential therapeutic value of MTX-23, we next generated 12 human prostate cancer cell lines that are resistant to the four FDA-approved SAT agents-abiraterone, enzalutamide, apalutamide, and darolutamide. When resistant cells were treated with MTX-23, decreased cellular proliferation and reduced tumor growth were observed both in vitro and in mice. These results collectively suggest that MTX-23 is a novel PROTAC small molecule that may be effective against SAT-resistant CRPC by degrading both AR-V7 and AR-FL., (©2020 American Association for Cancer Research.)

Background and Objectives: Medical student distress and mental health needs are critical issues in undergraduate medical education. The imposter phenomenon (IP), defined as inappropriate feelings of inadequacy among high achievers is linked to psychological distress. We investigated the prevalence of IP among first-year medical school students and its association with personality measures that affect interpersonal relationships and well-being., Methods: Two hundred fifty-seven students at a large, urban, northeastern medical school completed the Clance Impostor Phenomenon Scale (CIPS), Jefferson Scale of Empathy, Self-Compassion Scale, and Zuckerman-Kuhlman Personality Questionnaire immediately before beginning their first year of medical school. At the end of their first year, 182 of these students again completed the CIPS., Results: Eighty-seven percent of the entering students reported high or very high degrees of IP. Students with higher IP scores had significantly lower mean scores on self-compassion, sociability self-esteem (P&lt;.0001 for all), and getting along with peers (P=.03). Lower IP scores were related to lower mean scores on neuroticism/anxiety and loneliness (P&lt;.001 for both). Women obtained a higher mean IP score than men. IP scores at the end of the school year increased significantly compared with the beginning of the year (P&lt;.001), both in frequency and intensity of IP., Conclusions: IP was common in matriculating first-year medical students and significantly increased at year's end. Higher IP scores were significantly associated with lower scores for self-compassion, sociability, self-esteem, and higher scores on neuroticism/anxiety.