In vitro production of infectious Plasmodium falciparum sporozoites.

An effective vaccine is needed for the prevention and elimination of malaria. The only immunogens that have been shown to have a protective efficacy of more than 90% against human malaria are Plasmodium falciparum (Pf) sporozoites (PfSPZ) manufactured in mosquitoes (mPfSPZ)1-7. The ability to produce PfSPZ in vitro (iPfSPZ) without mosquitoes would substantially enhance the production of PfSPZ vaccines and mosquito-stage malaria research, but this ability is lacking. Here we report the production of hundreds of millions of iPfSPZ. iPfSPZ invaded human hepatocytes in culture and developed to mature liver-stage schizonts expressing P. falciparum merozoite surface protein 1 (PfMSP1) in numbers comparable to mPfSPZ. When injected into FRGhuHep mice containing humanized livers, iPfSPZ invaded the human hepatocytes and developed to PfMSP1-expressing late liver stage parasites at 45% the quantity of cryopreserved mPfSPZ. Human blood from FRGhuHep mice infected with iPfSPZ produced asexual and sexual erythrocytic-stage parasites in culture, and gametocytes developed to PfSPZ when fed to mosquitoes, completing the P. falciparum life cycle from infectious gametocyte to infectious gametocyte without mosquitoes or primates.

Reactions of Heterometallic Phosphinidene-Bridged MoMn and MoRe Complexes with Sulfur and Selenium: From Chalcogenophosphinidene- to Trithiophosphonate-Bridged Derivatives.

Reactions of [MoReCp(µ-PR*)(CO)6] with S8 were strongly dependent on experimental conditions (R* = 2,4,6-C6H2tBu3). When using 1 equiv of sulfur, complex [MoReCp(µ-η2:κ1S-SPR*)(CO)6] was slowly formed at 313 K, with a thiophosphinidene ligand unexpectedly bridging the dimetal center in the novel µ-κ1S:η2 coordination mode, as opposed to the µ-κ1P:η2 mode usually found in related complexes. The latter underwent fast decarbonylation at 363 K to give [MoReCp(µ-η2:η2-SPR*)(CO)5], with a six-electron donor thiophosphinidene ligand rearranged into the rare µ-η2:η2 coordination mode. Depending on reaction conditions, reactions with excess sulfur involved the addition of two or three S atoms to the phosphinidene ligand to give new complexes identified as the dithiophosphinidene-bridged complex [MoReCp(µ-η2:κ2S,S'-S2PR*)(CO)5], its dithiophosphonite-bridged isomer [MoReCp(µ-κ2S,S':κ2S,S'-S2PR*)(CO)5], or the trithiophosphonate-bridged derivative [MoReCp(µ-κ2S,S':κ2S,S'-S3PR*)(CO)5], all of them displaying novel coordination modes of their PRS2 and PRS3 ligands, as determined by X-ray diffraction studies. In contrast, the related MoMn complex yielded [MoMnCp(µ-η2:η2-SPR*)(CO)5] under most conditions. A similar output was obtained in reactions with gray selenium for either MoRe or MoMn phosphinidene complexes, which under different conditions only gave the pentacarbonyl complexes [MoMCp(µ-η2:η2-SePR*)(CO)5] (M = Re, Mn), these providing a new coordination mode for selenophosphinidene ligands.

P-C, P-N, and M-N Bond Formation Processes in Reactions of Heterometallic Phosphinidene-Bridged MoMn and MoRe Complexes with Diazoalkanes and Organic Azides to Build Three- to Five-Membered Phosphametallacycles.

Reactions of the heterometallic MoRe complex [MoReCp(µ-PR*)(CO)6] and its MoMn analogue with some small molecules having N-N multiple bonds, such as diazoalkanes and organic azides, were investigated (R* = 2,4,6-C6H2tBu3). Reactions with excess ethyl diazoacetate proceeded slowly and with concomitant denitrogenation to give complexes [MoMCp(µ-η2P,C:κ2P,O-PR*CHCO2Et)(CO)5], which display a bridging phosphaalkene ligand in a novel µ-η2:κ2 coordination mode, while reactions with other diazoalkanes resulted only in the decomposition of the organic reagent. The MoRe complex reacted with benzyl- or p-tolyl azide at room temperature to give the green complexes [MoReCp(µ-η2P,N:κP,N'2-PR*N3R)(CO)6] [R = Bn, p-tol], which display bridging phosphatriazadiene ligands in a novel 6-electron donor coordination mode as a result of a formal [2 + 1] cycloaddition of the terminal N atom of the azide to the Mo-P double bond of the parent complex, followed by coordination of the distal NR nitrogen to the rhenium center. Denitrogenation was only observed for the p-tolyl azide derivative, which upon heating at 333 K yielded [MoReCp{µ-κP:κN-PR*N(p-tol)}(CO)6], a molecule displaying a bridging phosphaimine ligand in a rare κP:κN coordination mode. Analogous reactions of the MoMn phosphinidene complex proceeded similarly at 273 K to give the phosphatriazadiene-bridged derivatives [MoMnCp(µ-η2P,N:κ2P,N'-PR*N3R)(CO)6], but these were thermally unstable and degraded at room temperature to give the mononuclear triazenylphosphanyl complexes [Mn2(κP,N-PR*NHNNR)(CO)3] as major products, along with small amounts of the phosphaimine-bridged complex [MoMnCp{µ-κP:κN-PR*N(p-tol)}(CO)6] in the case of the p-tolyl azide derivative. The structure of the new complexes was analyzed in light of spectroscopic data and single-crystal diffraction studies on selected examples of each type of complex.

The odyssey of complex neurogenetic disorders: From undetermined to positive.

The genetic and phenotypic heterogeneity of neurogenetic diseases forces patients and their families into a "diagnostic odyssey." An increase in the variability of genetic disorders and the corresponding gene-disease associations suggest the need to periodically re-evaluate the significance of variants of undetermined pathogenicity. Here, we report the diagnostic and clinical utility of Targeted Gene Panel Sequencing (TGPS) and Whole Exome Sequencing (WES) in 341 patients with suspected neurogenetic disorders from centers in Buenos Aires and Cincinnati over the last 4 years, focusing on the usefulness of reinterpreting variants previously classified as of uncertain significance. After a mean of ±2years (IC 95:0.73-3.27), approximately 30% of the variants of uncertain significance were reclassified as pathogenic. The use of next generation sequencing methods has facilitated the identification of both germline and mosaic pathogenic variants, expanding the diagnostic yield. These results demonstrate the high clinical impact of periodic reanalysis of undetermined variants in clinical neurology.

Argentinian clinical genomics in a leukodystrophies and genetic leukoencephalopathies cohort: Diagnostic yield in our first 9 years.

INTRODUCTION AND OBJECTIVES: Leukodystrophies and genetic leukoencephalopathies constitute a vast group of pathologies of the cerebral white matter. The large number of etiopathogenic genes and the frequent unspecificity on the clinical-radiological presentation generate remarkable difficulties in the diagnosis approach. Despite recent and significant developments, molecular diagnostic yield is still less than 50%. Our objective was to develop and explore the usefulness of a new diagnostic procedure using standardized molecular diagnostic tools, and next-generation sequencing techniques. MATERIALS AND METHODS: A prospective, observational, analytical study was conducted in a cohort of 46 patients, evaluated between May 2008 and December 2016, with a suspected genetic leukoencephalopathy or leukodystrophy. A diagnostic procedure was set up using classical monogenic tools in patients with characteristic phenotypes, and next-generation techniques in nonspecific ones. RESULTS: Global diagnostic procedure yield was 57.9%, identifying the etiological pathogenesis in 22 of the 38 studied subjects. Analysis by subgroups, Sanger method, and next-generation sequencing showed a yield of 64%, and 46.1% respectively. The most common pathologies were adrenoleukodystrophy, cerebral autosomal-dominant arteriopathy with subcortical infarcts (CADASIL), and vanishing white matter disease. CONCLUSIONS: Our results confirm the usefulness of the proposed diagnostic procedure expressed in a high diagnostic yield and suggest a more optimal cost-effectiveness in an etiological analysis phase.

Efficient Synthesis and Multisite Reactivity of a Phosphinidene-Bridged Mo-Re Complex. A Platform Combining Nucleophilic and Electrophilic Features.

The heterometallic complex [MoReCp(µ-PR*)(CO)6] (3) was prepared in 60% overall yield from syn-[MoCp(PHR*)(CO)2] via a three-step procedure involving complexes syn-[MoCp(PClR*)(CO)2] and [MoReCp(µ-PR*)(CO)7] as intermediate species (R* = 2,4,6-C6H2tBu3). The PR* ligand in 3 displays a novel asymmetric interaction with the dimetal center, involving a double bond with one atom (Mo) and a dative single bond with the other one (Re). Compound 3 underwent thermal isomerization involving a C-H bond cleavage to yield the hydride [MoReCp(µ-H){µ-P(CH2CMe2)C6H2tBu2}(CO)6] and reacted with I2 to give [MoReCpI2(µ-PR*)(CO)6], which displays a symmetrical phosphinidene bridge. Its reaction with methyl propiolate at 293 K proceeded with [2 + 2] cycloaddition of the alkyne and decarbonylation to yield the phosphapropenylidene-bridged complex [MoReCp{µ-κ2P,C:η3-PR*CHC(CO2Me)}(CO)5] as the major product, whereas its reaction with excess CN(4-C6H4OMe) at 273 K proceeded with formal [2 + 1] cycloaddition of the isocyanide and further isocyanide addition at the Re site to yield the complex [MoReCp{µ-η2P,C:κ1P-PR*CN(4-C6H4OMe)}(CO)6{CN(4-C6H4OMe)}], which displays an azaphosphaallene ligand in a novel bridging coordination mode.

P-N and N-Mo Bond Formation Processes in the Reactions of a Pyramidal Phosphinidene-Bridged Dimolybdenum Complex with Diazoalkanes and Organic Azides.

The reactivity of the complex [Mo2Cp(µ-κ1:κ1,η5-PC5H4)(CO)2(η6-HMes*)(PMe3)] (1) toward different diazoalkanes and organic azides was investigated. The pyramidal phosphinidene ligand in 1 displayed a strong nucleophilicity, enabling these reactions to proceed rapidly even below room temperature. Thus, 1 reacted rapidly at 253 K with different diazoalkanes N2CRR' (R,R' = H,H, Ph,Ph, H,CO2Et) to give the corresponding P:P-bridged phosphadiazadiene derivatives as major products which, however, could not be isolated. Reaction of the latter with [H(OEt2)2](BAr'4) yielded the corresponding cationic derivatives [Mo2Cp{µ-κ1P:κ1P,η5-P(NHNCRR')C5H4}(η6-HMes*)(CO)2(PMe3)](BAr'4), which were isolated in ca. 70% yield. The related species [Mo2Cp{µ-κ1P:κ1P,η5-P(NMeNCHCO2Et)C5H4}(η6-HMes*)(CO)2(PMe3)](BAr'4) was isolated upon reaction of the ethyl diazoacetate derivative with MeI and subsequent anion exchange with Na(BAr'4). Reaction of 1 with aryl azides (4-C6H4Me)N3 and (4-C6H4F)N3 proceeded rapidly at low temperature to give possibly the corresponding P:P-bridged phosphaimine derivatives as major products, which could be neither isolated. Protonation of these products with [H(OEt2)2](BAr'4) gave the corresponding aminophosphanyl complexes [Mo2Cp{µ-κ1P:κ1P,η5-P(NHR)C5H4}(η6-HMes*)(CO)2(PMe3)](BAr'4), isolated in ca. 75% yield. In contrast, the result of reactions of 1 with benzyl azide was strongly dependent on temperature, including the temperature in the subsequent methylation step that gave isolable cationic derivatives. By a careful choice of experimental conditions, different complexes having methylated phosphatriazadiene ligands were isolated, such as [Mo2Cp{µ-κ1P:κ1P,η5-P(NNNMeCH2Ph)C5H4}(η6-HMes*)(CO)2(PMe3)](BAr'4) and the metallacyclic derivatives syn- and anti-[Mo2Cp{µ-κ2P,N:κ1P,η5-P(NMeNNCH2Ph)C5H4}(η6-HMes*)(CO)(PMe3)](BAr'4). Density functional theory calculations, along with NMR monitoring experiments, revealed that the formation of the latter products stemmed from different and kinetically favored phosphatriazadiene intermediates, thermodynamically disfavored with respect to the denitrogenation process, otherwise yielding phosphaimine derivatives.

TAP-mediated processing of exoerythrocytic antigens is essential for protection induced with radiation-attenuated Plasmodium sporozoites.

MHC class I dependent CD8(+) T cells are essential for protection induced by radiation-attenuated Plasmodium sporozoites (RAS) in murine malaria models. Apart from the mechanism of activation of CD8(+) T cells specific for the circumsporozoite protein, the major sporozoite antigen (Ag), CD8(+) T cells specific for other exoerythrocytic Ags that have been shown to mediate protection have not been thoroughly investigated. Specifically, mechanisms of processing and presentation of exoerythrocytic Ags, which includes liver stage (LS) Ags, remain poorly understood. We hypothesize that as exogenous proteins, LS Ags are processed by mechanisms involving either the TAP-dependent phagosomal-to-cytosol or TAP-independent vacuolar pathway of cross-presentation. We used TAP-deficient mice to investigate whether LS Ag mediated induction of naïve CD8(+) T cells and their recall during sporozoite challenge occur by the TAP-dependent or TAP-independent pathways. On the basis of functional attributes, CD8(+) T cells were activated via the TAP-independent pathway during immunizations with Plasmodium berghei RAS; however, IFN-γ(+) CD8(+) T cells previously induced by P. berghei RAS in TAP-deficient mice failed to be recalled against sporozoite challenge and the mice became parasitemic. On the basis of these observations, we propose that TAP-associated Ag processing is indispensable for sterile protection induced with P. berghei RAS.

Mosquito bite immunization with radiation-attenuated Plasmodium falciparum sporozoites: safety, tolerability, protective efficacy and humoral immunogenicity.

BACKGROUND: In this phase 1 clinical trial, healthy adult, malaria-naïve subjects were immunized with radiation-attenuated Plasmodium falciparum sporozoites (PfRAS) by mosquito bite and then underwent controlled human malaria infection (CHMI). The PfRAS model for immunization against malaria had previously induced >90 % sterile protection against homologous CHMI. This study was to further explore the safety, tolerability and protective efficacy of the PfRAS model and to provide biological specimens to characterize protective immune responses and identify protective antigens in support of malaria vaccine development. METHODS: Fifty-seven subjects were screened, 41 enrolled and 30 received at least one immunization. The true-immunized subjects received PfRAS via mosquito bite and the mock-immunized subjects received mosquito bites from irradiated uninfected mosquitoes. Sera and peripheral blood mononuclear cells (PBMCs) were collected before and after PfRAS immunizations. RESULTS: Immunization with PfRAS was generally safe and well tolerated, and repeated immunization via mosquito bite did not appear to increase the risk or severity of AEs. Local adverse events (AEs) of true-immunized and mock-immunized groups consisted of erythaema, papules, swelling, and induration and were consistent with reactions from mosquito bites seen in nature. Two subjects, one true- and one mock-immunized, developed large local reactions that completely resolved, were likely a result of mosquito salivary antigens, and were withdrawn from further participation as a safety precaution. Systemic AEs were generally rare and mild, consisting of headache, myalgia, nausea, and low-grade fevers. Two true-immunized subjects experienced fever, malaise, myalgia, nausea, and rigours approximately 16 h after immunization. These symptoms likely resulted from pre-formed antibodies interacting with mosquito salivary antigens. Ten subjects immunized with PfRAS underwent CHMI and five subjects (50 %) were sterilely protected and there was a significant delay to parasitaemia in the other five subjects. All ten subjects developed humoral immune responses to whole sporozoites and to the circumsporozoite protein prior to CHMI, although the differences between protected and non-protected subjects were not statistically significant for this small sample size. CONCLUSIONS: The protective efficacy of this clinical trial (50 %) was notably less than previously reported (>90 %). This may be related to differences in host genetics or the inherent variability in mosquito biting behavior and numbers of sporozoites injected. Differences in trial procedures, such as the use of leukapheresis prior to CHMI and of a longer interval between the final immunization and CHMI in these subjects compared to earlier trials, may also have reduced protective efficacy. This trial has been retrospectively registered at ISRCTN ID 17372582, May 31, 2016.

Neurogenetics in Argentina: diagnostic yield in a personalized research based clinic.

As a whole neurogenetic diseases are a common group of neurological disorders. However, the recognitionand molecular diagnosis of these disorders is not always straightforward. Besides, there is a paucity of informationregarding the diagnostic yield that specialized neurogenetic clinics could obtain. We performed a prospective,observational, analytical study of the patients seen in a neurogenetic clinic at a tertiary medicalcentre to assess the diagnostic yield of a comprehensive diagnostic evaluation that included a personalizedclinical assessment along with traditional and next-generation sequencing diagnostic tests. We included a cohortof 387 patients from May 2008 to June 2014. For sub-group analysis we selected a sample of patientswhose main complaint was the presence of progressive ataxia, to whom we applied a systematic moleculardiagnostic algorithm. Overall, a diagnostic mutation was identified in 27·4% of our cohort. However, if weonly considered those patients where a molecular test could be performed, the success rate rises to 45%. Weobtained diagnostic yields of 23·5 and 57·5% in the global group of ataxic patients and in the subset of ataxicpatients with a positive family history, respectively. Thus, about a third of patients evaluated in a neurogeneticclinic could be successfully diagnosed.

Attachment styles and associated psychosocial factors in patients at ultra-high risk for psychosis: A systematic review.

BACKGROUND: Patients with an ultra-high risk of psychosis (UHR) are more likely to transition to psychosis. Attachment style has also been associated with psychosis and other symptoms. AIMS: To review attachment styles in UHR patients and to analyze related psychosocial factors. Ours is the first systematic review of attachment in this population. METHOD: We performed a systematic review of attachment and related psychosocial factors in UHR patients following the PRISMA methodology. RESULTS: We identified five studies. The results revealed high rates of insecure attachment in this population (more than 80%). The UHR sample presented high levels of depression, anxiety, social anxiety, emotional reactivity, trauma, and poor mentalization. Premorbid social adjustment was a predictor of improvement in disorganization and negative symptoms. The rate of transition to psychosis was 10%. Attachment patterns accounted for 16.8% of the variance. This vulnerability for psychosis was also associated with poor mentalization. CONCLUSION: Early detection of patients with UHR and insecure attachment is crucial, since early intervention to address symptoms, mentalization, and attachment is feasible and may lead to an improvement in the remaining associated psychosocial related factors (secure style: better global functioning and less affective and anxious symptoms). PROSPERO ID440957.

Plasma brain-derived neurotrophic factor levels, learning capacity and cognition in patients with first episode psychosis.

BACKGROUND: Cognitive impairments are seen in first psychotic episode (FEP) patients. The neurobiological underpinnings that might underlie these changes remain unknown. The aim of this study is to investigate whether Brain Derived Neurotrophic Factor (BDNF) levels are associated with cognitive impairment in FEP patients compared with healthy controls. METHODS: 45 FEP patients and 45 healthy controls matched by age, gender and educational level were selected from the Basque Country area of Spain. Plasma BDNF levels were assessed in healthy controls and in patients. A battery of cognitive tests was applied to both groups, with the patients being assessed at 6 months after the acute episode and only in those with a clinical response to treatment. RESULTS: Plasma BDNF levels were altered in patients compared with the control group. In FEP patients, we observed a positive association between BDNF levels at six months and five cognitive domains (learning ability, immediate and delayed memory, abstract thinking and processing speed) which persisted after controlling for medications prescribed, drug use, intelligence quotient (IQ) and negative symptoms. In the healthy control group, BDNF levels were not associated with cognitive test scores. CONCLUSION: Our results suggest that BDNF is associated with the cognitive impairment seen after a FEP. Further investigations of the role of this neurotrophin in the symptoms associated with psychosis onset are warranted.

Cannabis use and involuntary admission may mediate long-term adherence in first-episode psychosis patients: a prospective longitudinal study.

BACKGROUND: This study aimed to examine factors associated with treatment adherence in first-episode psychosis (FEP) patients followed up over 8 years, especially involuntary first admission and stopping cannabis use. METHODS: This prospective, longitudinal study of FEP patients collected data on symptoms, adherence, functioning, and substance use. Adherence to treatment was the main outcome variable and was categorized as 'good' or 'bad'. Cannabis use during follow-up was stratified as continued use, stopped use, and never used. Bivariate and logistic regression models identified factors significantly associated with adherence and changes in adherence over the 8-year follow-up period. RESULTS: Of the 98 FEP patients analyzed at baseline, 57.1% had involuntary first admission, 74.4% bad adherence, and 52% cannabis use. Good adherence at baseline was associated with Global Assessment of Functioning score (p = 0.019), Hamilton Depression Rating Scale score (p = 0.017) and voluntary admission (p < 0.001). Adherence patterns over 8 years included: 43.4% patients always bad, 26.1% always good, 25% improved from bad to good. Among the improved adherence group, 95.7% had involuntary first admission and 38.9% stopped cannabis use. In the subgroup of patients with bad adherence at baseline, involuntary first admission and quitting cannabis use during follow up were associated with improved adherence. CONCLUSIONS: The long-term association between treatment adherence and type of first admission and cannabis use in FEP patients suggest targets for intervention to improve clinical outcomes.

HIV nonnucleoside reverse transcriptase inhibitors and trimethoprim-sulfamethoxazole inhibit plasmodium liver stages.

BACKGROUND: Although nonnucleoside reverse transcriptase inhibitors (NNRTIs) are usually part of first-line treatment regimens for human immunodeficiency virus (HIV), their activity on Plasmodium liver stages remains unexplored. Additionally, trimethoprim-sulfamethoxazole (TMP-SMX), used for opportunistic infection prophylaxis in HIV-exposed infants and HIV-infected patients, reduces clinical episodes of malaria; however, TMP-SMX effect on Plasmodium liver stages requires further study. METHODS: We characterized NNRTI and TMP-SMX effects on Plasmodium liver stages in vivo using Plasmodium yoelii. On the basis of these results, we conducted in vitro studies assessing TMP-SMX effects on the rodent parasites P. yoelii and Plasmodium berghei and on the human malaria parasite Plasmodium falciparum. RESULTS: Our data showed NNRTI treatment modestly reduced P. yoelii liver stage parasite burden and minimally extended prepatent period. TMP-SMX administration significantly reduced liver stage parasite burden, preventing development of patent parasitemia in vivo. TMP-SMX inhibited development of rodent and P. falciparum liver stage parasites in vitro. CONCLUSIONS: NNRTIs modestly affect liver stage Plasmodium parasites, whereas TMP-SMX prevents patent parasitemia. Because drugs that inhibit liver stages target parasites when they are present in lower numbers, these results may have implications for eradication efforts. Understanding HIV drug effects on Plasmodium liver stages will aid in optimizing treatment regimens for HIV-exposed and HIV-infected infected patients in malaria-endemic areas.

Two-year evaluation of a multifamily psychoeducational program (PROTEC) in the family burden and prognosis of bipolar patients.

INTRODUCTION: Bipolar disorder causes a significant burden on the lives of patients and their families. The family is one of the targets for therapeutic intervention, related to the prognosis in patients with bipolar disorder. AIM: To assess the effectiveness of a multifamily psychoeducational program for people with bipolar disorder, in the family burden: objective and subjective and in the variables related to the course of the patients with bipolar disorder (symptoms, adherence, functionality, hospitalizations), comparing it with a control group (CG). MATERIALS AND METHODS: A total of 148 relatives of bipolar patients and 148 bipolar patients were recruited. The sample was randomized (experimental group [EG] and CG) and with single-blind evaluations (baseline, at 5 months and one year). Clinical and sociodemographic variables were collected from families and patients (family burden self-report scale, Strauss-Carpenter Scale, Global Assessment of Functioning, Morisky Green adherence Scale). Both, EG and CG received 8 multifamily sessions, applied exclusively on the relatives of patients with bipolar disorder, but in the EG a psychoeducational treatment was carried out and in the CG only playful and current topics were discussed. Bivariate and logistic regression models were used, among others. RESULTS: The caregivers and patients of the EG and CG did not differ in any of the baseline variables (sociodemographic and clinical) (P>.001). In the total sample, the baseline objective burden was light (mean 0.6±0.4) and the subjective ones was medium-moderate (mean 1.1±0.3). During the follow-up, in relation to the variables of the caregivers, there was a greater reduction in the objective burden in the EG compared to the CG (5 months P=.006; one year P=.002). It was found that the objective burden (P=.006) and the subjective burden (P=.003) were significantly reduced over a year in EG but not in the CG. During the follow-up, the patients whose caregivers belonged to the EG showed a greater increase in the frequency of social activity (P=.008), in the work activity (P=.002), and global functioning (P=.002), and reduced their symptoms (P≤.001). Longitudinal analyses, over a year, showed that patients in the EG had a greater improvement in functionality compared to patients in the CG (P=.001). After the intervention, adherence to pharmacological treatment improved more in EG than in the CG (P≤.001). Regarding hospitalizations, any patients in the CG were hospitalized during the 5 months after the intervention, while 27.8% of the patients in the CG were hospitalized (P≤.001); the difference between groups remained significant in the long term (one year: P≤.001; 2 years: P≤.001). There were no significant differences between groups in the pharmacological treatment of the patients in any of the evaluations. CONCLUSIONS: The multifamily psychoeducational intervention group improved the family burden after the intervention. Likewise, bipolar patients, whose families attended the EG, improved significantly, over a year, the functionality, the frequency of social contacts, the work status, the adherence to treatment, and reduced their symptoms. In addition, in the EG, the percentage of hospitalizations during the 2 years of follow-up was significantly reduced.

Cycloaddition and C-S Bond Cleavage Processes in Reactions of Heterometallic Phosphinidene-Bridged MoRe and MoMn Complexes with Alkynes and Phenyl Isothiocyanate.

Reactions of [MoReCp(µ-PMes*)(CO)6] with internal alkynes RC≡CR yielded the phosphapropenylidene-bridged complexes [MoReCp(µ-κ2P,C:η3-PMes*CRCR)(CO)5] (Mes* = 2,4,6-C6H2tBu3; R = CO2Me, Ph). Terminal alkynes HC≡CR1 gave mixtures of isomers [MoReCp(µ-κ2P,C:η3-PMes*CHCR1)(CO)5] and [MoReCp(µ-κ2P,C:η3-PMes*CR1CH)(CO)5], with the first isomer being major (R1 = CO2Me) or unique (R1 = tBu), indicating the relevance of steric repulsions during the [2 + 2] cycloaddition step between Mo=P and C≡C bonds in these reactions. Similar reactions were observed for [MoMnCp(µ-PMes*)(CO)6]. Addition of ligands to these complexes promoted rearrangement of the phosphapropenylidene ligand into the allyl-like µ-η3:κ1C mode, as shown by the reaction of [MoReCp(µ-κ2P,C:η3-PMes*CHC(CO2Me)}(CO)5] with CN(p-C6H4OMe) to give [MoReCp{µ-η3:κ1C-PMes*CHC(CO2Me)}(CO)5{CN(p-CH4OMe)}2]. The MoRe phosphinidene complex reacted with S=C=NPh to give as major products the phosphametallacyclic complex [MoReCp{µ-κ2P,S:κ2P,S-PMes*C(NPh)S}(CO)5] and its thiophosphinidene-bridged isomer [MoReCp(µ-η2:κ1S-SPMes*)(CO)5(CNPh)]. The first product follows from a [2 + 2] cycloaddition between Mo=P and C=S bonds, with specific formation of P-C bonds, whereas the second one would arise from the alternative cycloaddition involving the formation of P-S bonds, more favored on steric grounds. The prevalence of the µ-η2:κ1S coordination mode of the SPMes* ligand over the µ-η2:κ1p mode was investigated theoretically to conclude that steric congestion favors the first mode, while the kinetic barrier for interconversion between isomers is low in any case.

Geographic variation in the altitudinal migration patterns, body size, oxidative status and exploratory behavior in a neotropical bird.

To cope with life in the mountains, populations of the same species can exhibit substantial variability in their altitudinal migration patterns and phenotypes in response to local weather conditions. Studying such variability can provide valuable insights into how local populations respond to environmental challenges, and this information can be useful for conservation efforts in mountain ecosystems. Here, we used δ2H values of feathers and blood to evaluate latitudinal variation in altitudinal migration patterns and its possible links with body size, oxidative status, and exploratory behavior in 72 individuals of rufous-collared sparrow (Zonotrichia capensis) that breed at low and high elevations in the center (~33°) and south (~38°) of Chile. Our results show that both altitudinal migration patterns and oxidative status were significantly influenced by the latitude of breeding sites, while exploratory behavior was associated with elevation. Notably, we found that fast-explorer birds inhabiting low elevations in central Chile displayed higher levels of oxidative damage than slow-explorer birds. These outcomes underscore the possibility of local adaptations in response to diverse local environmental conditions in the Andes. We discuss the implications of latitude, elevation, and environmental temperature in shaping the observed patterns and highlight the significance of identifying local adaptations in mountain birds for better predicting their response to climate change and other challenges stemming from anthropogenic activities.

E-H Bond Cleavage Processes in Reactions of Heterometallic Phosphinidene-Bridged MoRe and MoMn Complexes with Hydrogen and p-Block Element Hydrides.

Reactions of complexes [MoMCp(µ-PMes*)(CO)6] with H2 and several p-block element (E) hydrides mostly resulted in the cleavage of E-H bonds under mild conditions [M = Re (1a) and Mn (1b); Mes* = 2,4,6-C6H2tBu3]. The reaction with H2 (ca. 4 atm) proceeded even at 295 K to give the hydrides [MoMCp(µ-H)(µ-PHMes*)(CO)6]. The same result was obtained in the reactions with H3SiPh and, for 1a, upon reduction with Na(Hg) followed by protonation of the resulting anion [MoReCp(µ-PHMes*)(CO)6]-. The latter reacted with [AuCl{P(p-tol)3}] to yield the related heterotrimetallic cluster [MoReAuCp(µ-PHMes*)(CO)6{P(p-tol)3}]. The reaction of 1a with thiophenol gave the thiolate-bridged complex [MoReCp(µ-PHMes*)(µ-SPh)(CO)6], which evolved readily to the pentacarbonyl derivative [MoReCp(µ-PHMes*)(µ-SPh)(CO)5]. In contrast, no P-H bond cleavage was observed in reactions of complexes 1a,b with PHCy2, which just yielded the substituted derivatives [MoMCp(µ-PMes*)(CO)5(PHCy2)]. Reactions with HSnPh3 again resulted in E-H bond cleavage, but now with the stannyl group terminally bound to M, while 1a reacted with BH3·PPh3 to give the hydride-bridged derivatives [MoReCp(µ-H)(µ-PHMes*)(CO)5(PPh3)] and [MoReCp(µ-H){µ-P(CH2CMe2)C6H2tBu2}(CO)5(PPh3)], which follow from hydrogenation, C-H cleavage, and CO/PPh3 substitution steps. Density functional theory calculations on the PPh-bridged analogue of 1a revealed that hydrogenation likely proceeds through the addition of H2 to the Mo=P double bond of the complex, followed by rearrangement of the Mo fragment to drive the resulting terminal hydride into a bridging position.