Enantioselective synthesis of ß-aryl-γ-lactam derivatives via Heck-Matsuda desymmetrization of N-protected 2,5-dihydro-1H-pyrroles.

We report herein an enantioselective palladium-catalyzed Heck-Matsuda reaction for the desymmetrization of N-protected 2,5-dihydro-1H-pyrroles with aryldiazonium salts, using the chiral N,N-ligand (S)-PyraBox. This strategy has allowed straightforward access to a diversity of 4-aryl-γ-lactams via Heck arylation followed by a sequential Jones oxidation. The overall method displays a broad scope and good enantioselectivity, favoring the (R) enantiomer. The applicability of the protocol is highlighted by the efficient enantioselective syntheses of the selective phosphodiesterase-4-inhibitor rolipram and the commercial drug baclofen as hydrochloride.

Analyzing the association between social vulnerability indexes and surgically underserved areas in the Inland Empire.

Background: The United States lacks equitable surgical access, prompting us to investigate whether there is an inverse relationship between Social Vulnerability Indices and the number of surgeons in a census tract, using the Inland Empire as a model. Methods: The Centers for Disease Control's (CDC) SVI 2018 database, composed of 823 census tracts, was compared against demographics of 1008 surgeons, from the American Medical Association's (AMA) 2018 Physician Masterfile. Analysis was performed via Spearman's bivariate and multiple regression. Results: An inverse relationship exists between surgeon number and overall social vulnerability (ρ = -0.266 [95 % CI -0.330 to -0.199], p < .001), and between surgeon number and each category of social vulnerability: Socioeconomic (ρ = -0.345 [95 % CI -0.0405 to -0.281], p < .001), Household Composition and Disability (ρ = -0.121 [95 % CI -0.190 to -0.051], p < .001), Minority Status and Language (ρ = -0.0317 [95 % CI -0.379 to -0.252], p < .001), and Housing Type and Transportation (ρ = -0.093 [95 % CI -0.153 to -0.023], p = .005). Multiple regression analysis revealed that the following were associated with a higher number of surgeons: higher "Per Capita Income" (B = 0.000151 [95 % CI 0.000079 to 0.000223], t(820) = 4.104, p < .001), larger Daytime Population (B = 0.000143 [95 % CI 0.000072 to 0.000214]; t(820) = 3.956, p < .001), larger Total Population (B = -0.013 [95 % CI -0.022 to -0.003]; t(820) = -2.672, p = .008), and smaller number of Persons aged 17 and younger (B = -0.005 [95 % CI -0.008 to -0.001]; t(820) = -2.794, p = .005). Conclusions: This study concludes that social vulnerability is predictive of, and significantly linked to, differences in surgical access and continues to advocate for research into understanding the surgeon's role in both individual and population health. Key message: Our work demonstrates that the number of surgeons in a census tract is inversely proportional to the census tract's overall Social Vulnerability Indices. Thus, this research can serve to educate the public, physicians, and other healthcare providers about the importance of incorporating social determinants of health into the construction of healthcare policy and practice, as well as the importance of continued funding for local and national social service programs as a means to alleviate specific health inequities, such as language and transportation.

"They Just Helped Save My Life:" Client Perspectives on the Los Angeles County Full Service Partnership (FSP) Program for Serious Mental Illness.

The purpose of this qualitative study was to elicit client perspectives on the Los Angeles County Full Service Partnership (FSP) program - an adaptation of Assertive Community Treatment (ACT). Semi-structured interviews were conducted with 20 FSP clients. Qualitative data were analyzed using thematic analysis. Two major themes were identified from the interview data: (1) Clients' acknowledgement of the material benefits of the FSP program; and (2) FSP's impact on restoring and stabilizing clients' social and treatment relationships. Interviewees greatly valued the material (i.e., basic needs, housing assistance) and relational (i.e., relationships with providers, restored personal relationships) aspects of the program, but did not ascribe the same degree of value to mental health treatment. Interviewees' emphases on material and relational aspects reflect the status of assertive mental health treatment as an intervention on intermediary determinants of health in the lives of persons diagnosed with serious mental illness.

Experimental Demonstration of the Thin-Film Liquid-Metal Jet as a Charge Stripper.

For high-power heavy ion accelerators, the development of a suitable charge stripper, which can handle intense beams, is essential. This Letter describes the first experimental demonstration of a heavy ion liquid lithium charge stripper. A 10-20 µm thick liquid lithium jet flowing at >50 m/s was formed and confirmed stable when bombarded by various heavy ion beams, while increasing the charge state of the incoming beams to the desired charge state range. This demonstration proved the existing power limitation with the conventional strippers can be overcome by the liquid-metal stripper, opening completely new possibilities in high-power accelerator development.

Pain Prevalence in two Italian Hospitals. An observational study.

Introduction: Pain is the most common and distressing medical symptom in hospitalized patients in all wards. Pain prevalence among hospitalized patients is an indicator of the quality of health care. Objective: The aim of this study is to describe pain prevalence in two Italian hospitals. Material and method: This is an observational study. It involved hospitalized patients of both sexes, able and unable to self-report. Descriptive analysis and multivariate analysis were applied. Results: A sample of 754 inpatients were included. In Terni Ho-spital (n = 255), pain prevalence was 80.8%. The mean pain severity was 5.2 (sd ± 3.33). At Rome's San Camillo Hospital (n=499), pain prevalence was 46.9%. Acute pain is more prevalent in women (OR= 0.65; CI 95% 0.43-0.99) and increases with age (OR= 0.97; CI 95% 0.96-0.99). Chronic pain is more prevalent in men (OR= 2.34; CI 95% 1.41-3.97) and increases with age (OR= 1.04; CI 95% 1.03-1.06). Discussion and conclusion.: San Camillo Hospital presents data showing reduced pain prevalence, and describing pain even in patients unable to self-report. It is reasonable to believe that pain control by the staff at San Camillo is better, even though both hospitals are equally important regional institutions.

Overview of Ten Child Mental Health Clinical Outcome Measures: Testing of Psychometric Properties with Diverse Client Populations in the U.S.

While many standardized assessment measures exist to track child mental health treatment outcomes, the degree to which such tools have been adequately tested for reliability and validity across race, ethnicity, and class is uneven. This paper examines the corpus of published tests of psychometric properties for the ten standardized measures used in U.S. child outpatient care, with focus on breadth of testing across these domains. Our goal is to assist care providers, researchers, and legislators in understanding how cultural mismatch impacts measurement accuracy and how to select tools appropriate to the characteristics of their client populations. We also highlight avenues of needed research for measures that are in common use. The list of measures was compiled from (1) U.S. state Department of Mental Health websites; (2) a survey of California county behavioral health agency directors; and (3) exploratory literature scans of published research. Ten measures met inclusion criteria; for each one a systematic review of psychometrics literature was conducted. Diversity of participant research samples was examined as well as differences in reliability and validity by gender, race or ethnicity, and socio-economic class. All measures showed adequate reliability and validity, however half lacked diverse testing across all three domains and all lacked testing with Asian American/Pacific Islander and Native American children. ASEBA, PSC, and SDQ had the broadest testing.

Interleukin-10 suppression enhances T-cell antitumor immunity and responses to checkpoint blockade in chronic lymphocytic leukemia.

T-cell dysfunction is a hallmark of B-cell Chronic Lymphocytic Leukemia (CLL), where CLL cells downregulate T-cell responses through regulatory molecules including programmed death ligand-1 (PD-L1) and Interleukin-10 (IL-10). Immune checkpoint blockade (ICB) aims to restore T-cell function by preventing the ligation of inhibitory receptors like PD-1. However, most CLL patients do not respond well to this therapy. Thus, we investigated whether IL-10 suppression could enhance antitumor T-cell activity and responses to ICB. Since CLL IL-10 expression depends on Sp1, we utilized a novel, better tolerated analogue of the Sp1 inhibitor mithramycin (MTMox32E) to suppress CLL IL-10. MTMox32E treatment inhibited mouse and human CLL IL-10 production and maintained T-cell effector function in vitro. In the Eµ-Tcl1 mouse model, treatment reduced plasma IL-10 and CLL burden and increased CD8+ T-cell proliferation, effector and memory cell prevalence, and interferon-γ production. When combined with ICB, suppression of IL-10 improved responses to anti-PD-L1 as shown by a 4.5-fold decrease in CLL cell burden compared to anti-PD-L1 alone. Combination therapy also produced more interferon-γ+, cytotoxic effector KLRG1+, and memory CD8+ T-cells, and fewer exhausted T-cells. Since current therapies for CLL do not target IL-10, this provides a novel strategy to improve immunotherapies.

A pilot study of enhanced operation fit: The feasibility of a camp-based health intervention for ethnically diverse families of children with intellectual and developmental disabilities.

BACKGROUND: Obesity rates are higher in children with intellectual and developmental disabilities (DD) compared to typically developing (TD) children. In TD children, family-based (FB) interventions for obesity are the most effective interventions. Research addressing obesity interventions for children with IDD is limited. METHOD: We adapted a community-based obesity intervention created for TD children for children with IDD and added a parent education component. The current study examined the feasibility of Enhanced-Operation Fit, a camp-based intervention created in order to reduce weight, and improve health behavior outcomes. Participants were 16 children (68.8% male; Mage  = 13.15, SDage  = 1.62) and their parents. RESULTS: Results indicated that incorporating a daily parent education group limited recruitment potential, but showed promising preliminary improvements in parent feeding and child eating behaviors. CONCLUSIONS: Health interventions for children with IDD are greatly needed and the current study may be a cost and time-efficient intervention to help address this public health crisis.

Novel phase I trial design to evaluate the addition of cediranib or selumetinib to preoperative chemoradiotherapy for locally advanced rectal cancer: the DREAMtherapy trial.

BACKGROUND: The DREAMtherapy (Dual REctal Angiogenesis MEK inhibition radiotherapy) trial is a novel intertwined design whereby two tyrosine kinase inhibitors (cediranib and selumetinib) were independently evaluated with rectal chemoradiotherapy (CRT) in an efficient manner to limit the extended follow-up period often required for radiotherapy studies. PATIENTS AND METHODS: Cediranib or selumetinib was commenced 10 days before and then continued with RT (45 Gy/25#/5 wks) and capecitabine (825 mg/m2 twice a day (BID)). When three patients in the cediranib 15-mg once daily (OD) cohort were in the surveillance period, recruitment to the selumetinib cohort commenced. This alternating schedule was followed throughout. Three cediranib (15, 20 and 30 mg OD) and two selumetinib cohorts (50 and 75 mg BID) were planned. Circulating and imaging biomarkers of inflammation/angiogenesis were evaluated. RESULTS: In case of cediranib, dose-limiting diarrhoea, fatigue and skin reactions were seen in the 30-mg OD cohort, and therefore, 20 mg OD was defined as the maximum tolerated dose. Forty-one percent patients achieved a clinical or pathological complete response (7/17), and 53% (9/17) had an excellent clinical or pathological response (ECPR). Significantly lower level of pre-treatment plasma tumour necrosis factor alpha (TNFα) was found in patients who had an ECPR. In case of selumetinib, the 50-mg BID cohort was poorly tolerated (fatigue and diarrhoea); a reduced dose cohort of 75-mg OD was opened which was also poorly tolerated, and further recruitment was abandoned. Of the 12 patients treated, two attained an ECPR (17%). CONCLUSIONS: This novel intertwined trial design is an effective way to independently investigate multiple agents with radiotherapy. The combination of cediranib with CRT was well tolerated with encouraging efficacy. TNFα emerged as a potential predictive biomarker of response and warrants further evaluation.

Selection of a Child Clinical Outcome Measure for Statewide Use in Publicly Funded Outpatient Mental Health Programs.

OBJECTIVE: This study describes the process of choosing a clinical outcome measure for a statewide performance outcome system for children receiving publicly funded mental health services in California. METHODS: The recommendation is based on a five-phase approach, including an environmental scan of measures used by state mental health agencies; a statewide provider survey; a scientific literature review; a modified Delphi panel; and final rating of candidate measures by using nine minimum criteria informed by stakeholder priorities, scientific evidence, and state statute. RESULTS: Only 10 states reported use of at least one standardized measure for outcome measurement. In California, the most frequently reported measures were the Child and Adolescent Needs and Strengths (CANS) (N=33), the Child Behavior Checklist (N=14), and the Eyberg Child Behavior Inventory (N=12). Based on modified Delphi panel ratings, only the Achenbach System of Empirically Based Assessment, the Strengths and Difficulties Questionnaire, and the Pediatric Symptom Checklist (PSC) were rated on average in the high-equivocal to high range on effective care, scientific acceptability, usability, feasibility, and overall utility. The PSC met all nine minimum criteria for recommendation for statewide use. In its final decision, the California Department of Health Care Services mandated use of the PSC and CANS. CONCLUSIONS: There is a lack of capacity to compare child clinical outcomes across states and California counties. Frequently used outcome measures were often not supported by scientific evidence or Delphi panel ratings. Policy action is needed to promote the selection of a common clinical outcome measure and measurement methodology for children receiving publicly funded mental health care.

Evaluation of the Mental Health Services Act in Los Angeles County: Implementation and Outcomes for Key Programs.

Los Angeles County used Mental Health Services Act (MHSA) funds to greatly expand access to Full-Service Partnership (FSP) services and offer new prevention and early intervention (PEI) services. This study examines the reach of key MHSA-funded activities and what the impact of those activities has been, with a focus on PEI programs for children and transition-age youth (TAY) and FSP programs for children, TAY, and adults. The evaluation found evidence that the Los Angeles County Department of Mental Health (LAC DMH) is reaching the highly vulnerable population it seeks to reach with its FSP and youth PEI programs. Furthermore, those reached by the programs experience improvements in their mental health and life circumstances. Refining data collection will enable more-thorough evaluation of processes of care and would inform the program's quality-improvement efforts.

Social interactions impact on the dopaminergic system and drive individuality.

Individuality is a striking feature of animal behavior. Individual animals differ in traits and preferences which shape their interactions and their prospects for survival. However, the mechanisms underlying behavioral individuation are poorly understood and are generally considered to be genetic-based. Here, we devised a large environment, Souris City, in which mice live continuously in large groups. We observed the emergence of individual differences in social behavior, activity levels, and cognitive traits, even though the animals had low genetic diversity (inbred C57BL/6J strain). We further show that the phenotypic divergence in individual behaviors was mirrored by developing differences in midbrain dopamine neuron firing properties. Strikingly, modifying the social environment resulted in a fast re-adaptation of both the animal's traits and its dopamine firing pattern. Individuality can rapidly change upon social challenges, and does not just depend on the genetic status or the accumulation of small differences throughout development.

Nicotinic receptors mediate stress-nicotine detrimental interplay via dopamine cells' activity.

Epidemiological studies report strong association between mood disorders and tobacco addiction. This high comorbidity requires adequate treatment but the underlying mechanisms are unknown. We demonstrate that nicotine exposure, independent of drug withdrawal effects, increases stress sensitivity, a major risk factor in mood disorders. Nicotine and stress concur to induce long-lasting cellular adaptations within the dopamine (DA) system. This interplay is underpinned by marked remodeling of nicotinic systems, causing increased ventral tegmental area (VTA) DA neurons' activity and stress-related behaviors, such as social aversion. Blocking ß2 or α7 nicotinic acetylcholine receptors (nAChRs) prevents, respectively, the development and the expression of social stress-induced neuroadaptations; conversely, facilitating α7 nAChRs activation specifically in the VTA promotes stress-induced cellular and behavioral maladaptations. Our work unravels a complex nicotine-stress bidirectional interplay and identifies α7 nAChRs as a promising therapeutic target for stress-related psychiatric disorders.

GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons.

Human mutations of the GRID1 gene encoding the orphan delta1 glutamate receptor-channel (GluD1) are associated with schizophrenia but the explicit role of GluD1 in brain circuits is unknown. Based on the known function of its paralog GluD2 in cerebellum, we searched for a role of GluD1 in slow glutamatergic transmission mediated by metabotropic receptor mGlu1 in midbrain dopamine neurons, whose dysfunction is a hallmark of schizophrenia. We found that an mGlu1 agonist elicits a slow depolarizing current in HEK cells co-expressing mGlu1 and GluD1, but not in cells expressing mGlu1 or GluD1 alone. This current is abolished by additional co-expression of a dominant-negative GluD1 dead pore mutant. We then characterized mGlu1-dependent currents in dopamine neurons from midbrain slices. Both the agonist-evoked and the slow postsynaptic currents are abolished by expression of the dominant-negative GluD1 mutant, pointing to the involvement of native GluD1 channels in these currents. Likewise, both mGlu1-dependent currents are suppressed in GRID1 knockout mice, which reportedly display endophenotypes relevant for schizophrenia. It is known that mGlu1 activation triggers the transition from tonic to burst firing of dopamine neurons, which signals salient stimuli and encodes reward prediction. In vivo recordings of dopamine neurons showed that their spontaneous burst firing is abolished in GRID1 knockout mice or upon targeted expression of the dominant-negative GluD1 mutant in wild-type mice. Our results de-orphanize GluD1, unravel its key role in slow glutamatergic transmission and provide insights into how GRID1 gene alterations can lead to dopaminergic dysfunctions in schizophrenia.

Mobile Health Interventions for Psychiatric Conditions in Children: A Scoping Review.

A scoping review was performed to determine what evidence exists to support the clinical use of mobile health (mHealth) interventions to address child psychiatric disorders. The review focused on children less than 18 years old who were diagnosed with a mental disorder, used an mHealth intervention, and included novel outcome data. Each study assessed feasibility of the intervention and concluded that the interventions were accepted and/or liked by patients. Of the 2 studies that examined effectiveness using a randomized controlled trial design, there were no statistically significant differences in clinical outcomes, but results were limited by small sample size.

Química analítica cualitativa

En esta obra se exponen los fundamentos en los que se basa la química analítica moderna con particular dedicación al estudio de los equilibrios en disolución, explicados con ayuda de diagramas y métodos gráficos. Se tratan además, las propiedades analíticas consideradas como periódicas y los conceptos de sensibilidad y selectividad de las reacciones. Índice Extractado: La obra está dividida en 4 partes: Primera; Fundamentos de química analítica moderna - Segunda; Química analítica de los cationes - Tercera parte; Química analítica de los aniones - Cuarta parte; se integra el estudio de los problemas sólidos - Apéndices

Spatial Heterogeneity of Cx43 is an Arrhythmogenic Substrate of Polymorphic Ventricular Tachycardias during Compensated Cardiac Hypertrophy in Rats.

BACKGROUND: Ventricular remodeling increases the propensity of ventricular tachyarrhythmias and sudden death in patients. We studied the mechanism underlying these fatal arrhythmias, electrical and structural cardiac remodeling, as well as arrhythmogeneity during early, compensated hypertrophy in a rat model of chronic pressure overload. METHODS: Twenty-six Wistar rats were subjected to transverse aortic constriction (TAC) (n = 13) or sham operation (n = 13). Four weeks postoperative, echo- and electrocardiography was performed. Epicardial (208 or 455 sites) and transmural (30 sites) ventricular activation mapping was performed on Langendorff perfused hearts. Subsequently, hearts were processed for (immuno)histological and molecular analyses. RESULTS: TAC rats showed significant hypertrophy with preserved left ventricular (LV) function. Epicardial conduction velocity (CV) was similar, but more dispersed in TAC. Transmural CV was slowed in TAC (37.6 ± 2.9 cm s(-1)) compared to sham (58.5 ± 3.9 cm s(-1); P < 0.01). Sustained polymorphic ventricular tachycardias were induced from LV in 8/13 TAC and in 0/13 sham rats. During VT, electrical activation patterns showed variable sites of earliest epicardial activation and altering sites of functional conduction block. Wandering epicardial reentrant activation was sporadically observed. Collagen deposition was significantly higher in TAC compared to sham, but not different between arrhythmogenic and non-arrhythmogenic TAC animals. Connexin43 (Cx43) expression was heterogeneous with a higher prevalence of non-phosphorylated Cx43 in arrhythmogenic TAC animals. CONCLUSION: In TAC rats with compensated cardiac hypertrophy, dispersion of conduction correlated to arrhythmogenesis, an increased heterogeneity of Cx43, and a partial substitution with non-phosphorylated Cx43. These alterations may result in the increased vulnerability to polymorphic VTs.

The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.

Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.

Arrhythmogenic Remodeling in Murine Models of Deoxycorticosterone Acetate-Salt-Induced and 5/6-Subtotal Nephrectomy-Salt-Induced Cardiorenal Disease.

BACKGROUND: Renal failure is associated with adverse cardiac remodeling and sudden cardiac death. The mechanism leading to enhanced arrhythmogenicity in the cardiorenal syndrome is unclear. The aim of this study was to characterize electrophysiological and tissue alterations correlated with enhanced arrhythmogenicity in two distinct mouse models of renal failure. METHODS: Thirty-week-old 129Sv mice received a high-salt diet and deoxycorticosterone acetate (DOCA) for 8 weeks, followed by an additional period of high-salt diet for 27 weeks (DOCA-salt aged model). Adult CD-1 mice were submitted to 5/6-subtotal nephrectomy (SNx) and treated for 11 weeks with a high-salt diet (SNx-salt adult model). Vulnerability to arrhythmia as well as conduction velocities (CVs) of the hearts were determined ex vivo with epicardial mapping. Subsequently, the hearts were characterized for connexin 43 (Cx43) and fibrosis. RESULTS: DOCA-salt and SNx-salt mice developed renal dysfunction characterized by albuminuria. Heart, lung and kidney weights were increased in DOCA-salt mice. Both DOCA-salt and SNx-salt mice were highly susceptible to ventricular arrhythmias. DOCA-salt mice had a significant decrease in both longitudinal and transversal CV in the left ventricle. Histological analysis revealed a significant reduction in Cx43 expression as well as an increase in interstitial fibrosis in both DOCA-salt and SNx-salt mice. CONCLUSION: DOCA-salt and SNx-salt treatment induced renal dysfunction, which resulted in structural and electrical cardiac remodeling and enhanced arrhythmogenicity. The reduced Cx43 expression and increased fibrosis levels in these hearts are likely candidates for the formation of the arrhythmogenic substrate.