Structure-based design of a quadrivalent fusion glycoprotein vaccine for human parainfluenza virus types 1-4.

Parainfluenza virus types 1-4 (PIV1-4) are highly infectious human pathogens, of which PIV3 is most commonly responsible for severe respiratory illness in newborns, elderly, and immunocompromised individuals. To obtain a vaccine effective against all four PIV types, we engineered mutations in each of the four PIV fusion (F) glycoproteins to stabilize their metastable prefusion states, as such stabilization had previously enabled the elicitation of high-titer neutralizing antibodies against the related respiratory syncytial virus. A cryoelectron microscopy structure of an engineered PIV3 F prefusion-stabilized trimer, bound to the prefusion-specific antibody PIA174, revealed atomic-level details for how introduced mutations improved stability as well as how a single PIA174 antibody recognized the trimeric apex of prefusion PIV3 F. Nine combinations of six newly identified disulfides and two cavity-filling mutations stabilized the prefusion PIV3 F immunogens and induced 200- to 500-fold higher neutralizing titers in mice than were elicited by PIV3 F in the postfusion conformation. For PIV1, PIV2, and PIV4, we also obtained stabilized prefusion Fs, for which prefusion versus postfusion titers were 2- to 20-fold higher. Elicited murine responses were PIV type-specific, with little cross-neutralization of other PIVs. In nonhuman primates (NHPs), quadrivalent immunization with prefusion-stabilized Fs from PIV1-4 consistently induced potent neutralizing responses against all four PIVs. For PIV3, the average elicited NHP titer from the quadrivalent immunization was more than fivefold higher than any titer observed in a cohort of over 100 human adults, highlighting the ability of a prefusion-stabilized immunogen to elicit especially potent neutralization.

[From OPG to REMS: the role of a territorial health service in the implementation of security and non-custodial measures towards offenders with psychological problems]. / Dagli OPG alle REMS: il ruolo di un servizio sanitario territoriale nell'esecuzione delle misure di sicurezza detentive e non, nei confronti degli autori di reato con problemi psichici.

AIMS: Managing health care for people suffering from mental illness is undergoing deep changes in recent years in Italy. The purpose of this study is to describe the progressive process of overcoming the Forensic Hospitals in Italy (OPGs) and to identify the necessary care and rehabilitation pathways in this process, in the experience of the territorial health service in Salerno, Italy. METHODS: An analysis of the recent laws related to the ongoing process and an analysis of epidemiological and structural data referring to the time interval between 2010 and 2017 concerning the OPGs/Residential Services for the Execution of Security Measures (RSESM)/Mental Health System in Campania, Italy and in the territory of Salerno in particular. RESULTS: The acts governing the transition from OPG to RSESM include DPCM 1/4/2008 and subsequent "Conferenza Unificata" agreements, other laws and regional health organizational regulations. A thorough restructuring of the National Health Service is required. A substantial path in Campania has been completed, with the closure of OPGs, the realization of definitive RSESM, the Departments for Mental Health Care in prison, the Regional Technical Group for overcoming the OPGs, the territorial Services for overcoming the OPGs and for Mental Health in Prison. The result of these transformations is a deep change in the health care approach, as evidenced by the current changes in action in indicative parameters of care pathways and their outcomes. CONCLUSIONS: The new approach shows both improvement features and totally or partially unaddressed problematic features. As for the actual management issues, improvements in communication between Mental Health Care and the magistracy. The overall evaluation of the transformations in progress is positive. At this stage, it is crucial to identify and monitor indicators of the pathways of care and their outcomes and to implement synergies among the systems involved.

Tobacco smoking in treatment-resistant schizophrenia patients is associated with impaired cognitive functioning, more severe negative symptoms, and poorer social adjustment.

Tobacco smoking is common in schizophrenia patients. It has been reported that schizophrenia patients who are tobacco smokers have better cognitive performances compared to those who are nonsmokers. However, little is known on the effects of tobacco smoking in treatment-resistant schizophrenia (TRS) patients. The aim of this study was to compare cognitive performances, psychotic symptoms, and social adjustment in tobacco smoker TRS patients compared to nonsmoker TRS patients. Smoker and nonsmoker TRS patients did not differ in demographics and in mean daily antipsychotic dose. Smoker TRS patients had significantly higher scores than nonsmoker patients on the positive and negative syndrome scale (PANSS) and on the negative symptoms subscale. These patients also performed worse than nonsmoker patients on problem-solving cognitive domain. Social adjustment was not significantly different between the two groups. In both groups of patients, worse cognitive performances were mostly predicted by higher severity of negative symptoms. Worse performances on the verbal memory and problem-solving cognitive domains were correlated with social-functioning impairment in tobacco smoker TRS patients but not in nonsmoker ones. The results showed that tobacco smoking was not significantly associated with better cognitive performances in TRS patients, while it was significantly associated with higher negative symptoms. Even if a direct causative mechanism cannot be inferred and despite the fact that these patients may use tobacco to self-medicate, it could be speculated that these associations may, at least partially, be related to a tobacco-smoking-induced worsening of abnormal dopamine dysfunction, which has been suggested to occur in TRS patients.