Determinants of welfare benefit use of immigrant groups - longitudinal evidence from Germany.

While recent literature in Germany has compared predictors of welfare use between EU and non-EU immigrants, refugees have yet to be added to the analysis. Using survey data of approximately 4,000 immigrants living in Germany, I examine the determinants of basic unemployment benefits receipt for intra-EU immigrants, refugees, and third country immigrants. In particular, I investigate how education affects the likelihood of welfare use for each immigrant group. Even after controlling for human capital factors, sociodemographic characteristics, and factors related to migration such as legal status and age at migration, refugees remain significantly more likely to receive benefits. Results demonstrate that higher education significantly decreases the likelihood of welfare receipt for EU and third country immigrants, but much less so for refugees. These findings may indicate that refugees' education is not being used to its full potential in the labor market or that they face additional challenges hindering their labor market integration. A further and unanticipated finding is that immigrants who hold permanent residency or German citizenship are less likely to receive unemployment benefits, pointing either to positive effects of a secure residency or selection into permanent residency and citizenship among those with the greatest labor market success. Overall, this research shows that challenges beyond human capital deficiencies and sociodemographic characteristics must be considered when studying immigrants' receipt of social benefits, that not all educational credentials are valued equally, and that the experiences of refugees differ in significant ways from those of other immigrant groups.

Mechanistic insights on novel small molecule allosteric activators of cGMP-dependent protein kinase PKG1α.

cGMP-dependent protein kinase (PKG) represents a compelling drug target for treatment of cardiovascular diseases. PKG1 is the major effector of beneficial cGMP signaling which is involved in smooth muscle relaxation and vascular tone, inhibition of platelet aggregation and signaling that leads to cardioprotection. In this study, a novel piperidine series of activators previously identified from an ultrahigh-throughput screen were validated to directly bind partially activated PKG1α and subsequently enhance its kinase activity in a concentration-dependent manner. Compounds from initial optimization efforts showed an ability to activate PKG1α independent of the endogenous activator, cGMP. We demonstrate these small molecule activators mimic the effect of cGMP on the kinetic parameters of PKG1α by positively modulating the KM of the peptide substrate and negatively modulating the apparent KM for ATP with increase in catalytic efficiency, kcat. In addition, these compounds also allosterically modulate the binding affinity of cGMP for PKG1α by increasing the affinity of cGMP for the high-affinity binding site (CNB-A) and decreasing the affinity of cGMP for the low-affinity binding site (CNB-B). We show the mode of action of these activators involves binding to an allosteric site within the regulatory domain, near the CNB-B binding site. To the best of our knowledge, these are the first reported non-cGMP mimetic small molecules shown to directly activate PKG1α. Insights into the mechanism of action of these compounds will enable future development of cardioprotective compounds that function through novel modes of action for the treatment of cardiovascular diseases.

Discovery of the First Non-cGMP Mimetic Small Molecule Activators of cGMP-Dependent Protein Kinase 1 α (PKG1α).

PKG1α is a central node in cGMP signaling. Current therapeutics that look to activate this pathway rely on elevation of cGMP levels and subsequent activation of PKG1α. Direct activation of PKG1α could potentially drive additional efficacy without associated side effects of blanket cGMP elevation. We undertook a high-throughput screen to identify novel activators. After triaging through numerous false positive hits, attributed to compound mediated oxidation and activation of PKG1α, a piperidine series of compounds was validated. The hit 1 was a weak activator with EC50 = 47 µM. The activity could be improved to single digit micromolar, as seen in compounds 21 and 25 (7.0 and 3.7 µM, respectively). Several compounds were tested in a pVASP cell-based assay, and for compounds with moderate permeability, good agreement was observed between the biochemical and functional assays. These compounds will function as efficient tools to further interrogate PKG1α biology.

Occupational Therapy for the Long Haul of Post-COVID Syndrome: A Case Report.

Prolonged symptoms from the novel coronavirus disease 2019 (COVID-19), otherwise known as long COVID, postacute sequelae of COVID-19 (PASC), or post-COVID syndrome, are affecting an increasingly high number of patients after severe, moderate, and mild acute COVID-19 infections. Using evidence-based practice strategies, this case report describes occupational therapy evaluation and treatment approaches, plan of care, and associated outcomes for one client experiencing long COVID symptoms in the outpatient setting.

Wearable Adaptive Resistance Training Improves Ankle Strength, Walking Efficiency and Mobility in Cerebral Palsy: A Pilot Clinical Trial.

GOAL: To determine the efficacy of wearable adaptive resistance training for rapidly improving walking ability in children with cerebral palsy (CP). METHODS: Six children with spastic CP (five males, one female; mean age 14y 11mo; three hemiplegic, three diplegic; Gross Motor Function Classification System [GMFCS] levels I and II) underwent ten, 20-minute training sessions over four weeks with a wearable adaptive resistance device. Strength, speed, walking efficiency, timed up and go (TUG), and six-minute walk test (6MWT) were used to measure training outcomes. RESULTS: Participants showed increased average plantar flexor strength (17 ± 8%, p = 0.02), increased preferred walking speed on the treadmill (39 ± 25%, p = 0.04), improved metabolic cost of transport (33 ± 9%, p = 0.03), and enhanced performance on the timed up and go (11 ± 9%, p = 0.04) and six-minute walk test (13 ± 9%, p = 0.04). CONCLUSIONS: The observed increase in preferred walking speed, reduction in metabolic cost of transport, and improved performance on clinical tests of mobility highlights the potentially transformative nature of this novel therapy; the rate at which this intervention elicited improved function was 3 - 6 times greater than what has been reported previously.

Zeaxanthin-based dietary supplement and topical serum improve hydration and reduce wrinkle count in female subjects.

BACKGROUND: Dietary modification, through supplementation and elimination diets, has become an area of interest to help slow skin aging, reduce symptom severity or prevent reoccurrence of certain dermatologic conditions [Clinical Dermatology vol. 31 (2013) 677-700]. Free radical components (reactive oxygen species or ROS) or lipid peroxide (LPO) is involved in the pathogenesis and progression of accelerated skin aging when prolonged oxidative stress occurs. The use of antioxidant-related therapies such as nutraceuticals is of particular interest in restoring skin homeostasis. Antioxidant carotenoid zeaxanthin is concentrated in the eye and skin tissue and believed to decrease the formation of ROS associated with UV light exposure. With zeaxanthin, phytoceramides, and botanical extracts an oral and topical test product (with zeaxanthin, algae extracts, peptides, hyaluronate) have been developed to improve the appearance and condition of skin when used as directed. METHODS: Subjects were divided into three groups: two tests (skin formula 1 - oral product alone (ZO-1), skin formula 2- oral product with topical product (ZO-2 + ZT)), and one placebo control. The study consisted of a washout visit, baseline (randomization), week two (2), week four (4), week six (6), week eight (8), and week twelve (12). Key parameters measured were as follows: fine lines, deep lines, total wrinkles, wrinkle severity, radiance/skin color (L, a*, b*), discolorations, and skin pigment homogeneity. RESULTS: Thirty-one subjects completed the twelve-week study; no adverse events were recorded during the study. Statistically significant improvements from baseline mean hydration score were observed in active groups at weeks 2, 6, and 8. A statistically significant difference was observed between mean differences from baseline scores for total wrinkle count at week 4 for the combination active groups compared to placebo. A statistically significant difference from baseline scores for fine lines count was also observed at the week 4 visit compared to placebo for both active groups. Statistically significant differences from baseline scores for average wrinkles severity were seen for week 12 visit for both active groups compared to placebo. CONCLUSION: We have shown that the combination of zeaxanthin-based dietary supplement plus a topical formulation produces superior hydration to that of placebo. Additionally, we have shown that the combination of oral and topical combination vs. oral alone has superior abilities to improve parameters associated with facial lines and wrinkles compared to placebo, although the dietary supplement alone proved most effective in reducing wrinkle count and severity.

The relation of HIV testing and treatment to identity formation in Zambia.

Why would many Zambians be reluctant to access lifesaving antiretroviral treatment? Does the process of accessing an HIV test in Zambia promote an identity that can change individuals' livelihood strategies? What happens to individuals when people access treatment? Voluntary testing and treatment centres and the HIV-prevention programmes that support them have come to embody explicit messages about 'health,' 'progress,' 'civilisation' and 'modernity,' and through this they compel individuals to take on a particular identity. In Zambia the pursuit of HIV testing and biomedical treatment forces individuals to locate themselves somewhat differently in relation to community support structures, placing their faith in the future on an uneasy foundation of a 'modern' identity. This is embodied in the deep-rooted suspicion that many Zambians have toward the international HIV/AIDS-response sector from which HIV and AIDS treatment programmes are derived. Drawing upon the notion of 'therapeutic citizenship' I examine why the 'AIDS industry' continues to symbolise such tension. I explore how individuals believe their identity will shift through participation in HIV testing and treatment options and how that might impact long-term and short-term livelihood strategies.

Phase I and pharmacokinetic study of the oral farnesyltransferase inhibitor lonafarnib administered twice daily to pediatric patients with advanced central nervous system tumors using a modified continuous reassessment method: a Pediatric Brain Tumor Consortium Study.

PURPOSE: A dose-escalation phase I and pharmacokinetic study of the farnesyltransferase inhibitor lonafarnib (SCH66336) was conducted in children with recurrent or progressive CNS tumors. Primary objectives were to estimate the maximum-tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs) and pharmacokinetics of lonafarnib. Farnesylation inhibition of HDJ-2 in peripheral blood was also measured. PATIENTS AND METHODS: Lonafarnib was administered orally twice daily at dose levels of 70, 90, 115, 150, and 200 mg/m2/dose bid. A modified continual reassessment method (CRM) was used to estimate the MTD based on actual dosages of lonafarnib administered and toxicities observed during the initial 4 weeks of treatment. RESULTS: Fifty-three children with progressive or recurrent brain tumors were enrolled, with a median age of 12.2 years (range, 3.9 to 19.5 years). Dose-limiting pneumonitis or myelosuppression was observed in three of three patients at the 200 mg/m2/dose level. A relatively constant DLT rate at the 70, 90, and 115 mg/m2/dose levels resulted in a recommended phase II dose of 115 mg/m2/dose. Significant diarrhea did not occur with prophylactic loperamide. Both radiographic response (one anaplastic astrocytoma) and stable disease (one medulloblastoma, two high-grade and four low-grade gliomas, one ependymoma, and one sarcoma) were noted, and seven patients remained on treatment for 1 year or longer. CONCLUSION: Although the estimated MTD by the CRM model was 98.5 mg/m2/dose, because of the relatively constant observed DLT rate at the lower four dose levels, the recommended phase II dose of lonafarnib is 115 mg/m2/dose administered twice daily by mouth with concurrent loperamide.

Phase I study of the farnesyltransferase inhibitor lonafarnib with weekly paclitaxel in patients with solid tumors.

PURPOSE: To establish the maximum tolerated dose of the farnesyltransferase inhibitor lonafarnib (Sarasar, Schering-Plough Corp., Kenilworth, NJ) in combination with weekly paclitaxel in patients with solid tumors. Tolerability, pharmacokinetics, safety, and dose-limiting toxicity were characterized. EXPERIMENTAL DESIGN: Patients were enrolled from January 2000 to May 2001. Lonafarnib was administered continuously orally twice daily at doses of 100, 125, and 150 mg in combination with paclitaxel at doses of 40, 60, or 80 mg/m(2) i.v. over 1 h weekly in 28-day cycles in a phase I design. Plasma samples for determinations of lonafarnib and paclitaxel concentrations were collected at selected time points. RESULTS: Twenty-seven patients were enrolled. The maximum tolerated dose (the dose level below where dose-limiting toxicity occurred and the recommended phase II dose) was lonafarnib 125 mg/m(2) twice daily and paclitaxel 80 mg/m(2) weekly. Dose-limiting toxicity was neutropenia with or without fever, which occurred in two of three patients treated at the lonafarnib 150 mg twice daily dose level. Diarrhea was a common side effect of lonafarnib but usually was mild to moderate in severity and could be controlled with standard medication without lonafarnib dose adjustment. Other reported adverse events included nausea, vomiting, fatigue, and taste changes. These adverse events were neither more frequent nor more severe than would be expected with paclitaxel alone. There were no apparent pharmacokinetic interactions between weekly paclitaxel and continuous twice-daily lonafarnib. CONCLUSIONS: The recommended dose of lonafarnib for phase II trials is 125 mg orally twice daily when combined with weekly paclitaxel 80 mg/m(2). The dose-limiting toxicity was neutropenia.