Effectiveness of a complex psychosocial intervention to reduce metabolic syndrome in psychiatric outpatients with severe/persistent mental illness.

The prevalence of metabolic syndrome among individuals with severe mental illness is considerably higher than in the general population, contributing to the 15-20-year shorter life expectancy of this client population. The aim of this pilot study was to evaluate the effectiveness of a novel, complex psychosocial program to reduce metabolic syndrome. Members of both the intervention (n = 78) and control (n = 31) group were psychiatric outpatients with severe/persistent mental illness struggling with one or more symptoms of metabolic syndrome. Beyond the default elements of similar programs such as diet and exercise, the intervention covered medication use, sleep hygiene, stress management, as well as addressing spiritual needs, mindfulness, addictions, and self-care. Assessment of metabolic indicators were completed at baseline, at the end of the 11-week intervention, and 6 months post-intervention. The trajectory of change over time was significantly more favorable in the treatment than in the control group in terms of waist circumference (p = 0.013, η2 = 0.093) and a positive trend emerged in relation to blood glucose level (p = 0.082, η2 = 0.057). However, no statistically reliable difference was observed between the intervention and the control group regarding the other outcome variables (body mass index, systolic and diastolic blood pressure, serum triglyceride level, serum HDL cholesterol level, overall metabolic syndrome severity). These findings suggest that to produce more robust benefits, psychosocial interventions targeting the metabolic health of individuals with complex mental health needs should be either longer in duration if resources permit or narrower in focus (diet and exercise mainly) if resources are scarce. Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-021-02269-3.

Chemical, biological, radiological, and nuclear mass casualty medicine: a review of lessons from the Salisbury and Amesbury Novichok nerve agent incidents.

On March 4, 2018, two casualties collapsed on a park bench in Salisbury, Wiltshire, UK. They were later discovered to have been the victims of an attempted murder using the Soviet-era Novichok class of nerve agent. The casualties, along with three further critically ill patients, were cared for in Salisbury District Hospital's Intensive Care Unit. Before the COVID-19 pandemic, the Salisbury and Amesbury incidents were the longest-running major incidents in the history of the UK National Health Service. This narrative review seeks to reflect on the lessons learned from these chemical incidents, with a particular focus on hospital and local organisational responses.

A study on episodic memory reconsolidation that tells us more about consolidation.

Awake quiescence immediately after encoding is conducive to episodic memory consolidation. Retrieval can render episodic memories labile again, but reconsolidation can modify and restrengthen them. It remained unknown whether awake quiescence after retrieval supports episodic memory reconsolidation. We sought to examine this question via an object-location memory paradigm. We failed to probe the effect of quiescence on reconsolidation, but we did observe an unforeseen "delayed" effect of quiescence on consolidation. Our findings reveal that the beneficial effect of quiescence on episodic memory consolidation is not restricted to immediately following encoding but can be achieved at a delayed stage and even following a period of task engagement.

Dissociation of glucocerebrosidase dimer in solution by its co-factor, saposin C.

Mutations in the gene for the lysosomal enzyme glucocerebrosidase (GCase) cause Gaucher disease and are the most common risk factor for Parkinson disease (PD). Analytical ultracentrifugation of 8 µM GCase shows equilibrium between monomer and dimer forms. However, in the presence of its co-factor saposin C (Sap C), only monomer GCase is seen. Isothermal calorimetry confirms that Sap C associates with GCase in solution in a 1:1 complex (Kd = 2.1 ± 1.1 µM). Saturation cross-transfer NMR determined that the region of Sap C contacting GCase includes residues 63-66 and 74-76, which is distinct from the region known to enhance GCase activity. Because α-synuclein (α-syn), a protein closely associated with PD etiology, competes with Sap C for GCase binding, its interaction with GCase was also measured by ultracentrifugation and saturation cross-transfer. Unlike Sap C, binding of α-syn to GCase does not affect multimerization. However, adding α-syn reduces saturation cross-transfer from Sap C to GCase, confirming displacement. To explore where Sap C might disrupt multimeric GCase, GCase x-ray structures were analyzed using the program PISA, which predicted stable dimer and tetramer forms. For the most frequently predicted multimer interface, the GCase active sites are partially buried, suggesting that Sap C might disrupt the multimer by binding near the active site.

The lived experience of US parents of children with autism spectrum disorders: a systematic review and meta-synthesis.

Current US statistics indicate that 1 in 68 children is diagnosed with an autistic spectrum disorder (Centers for Disease Control (2014) Prevalence of autism spectrum disorder among children aged 8 years-autism and developmental disabilities monitoring network, 11 Sites, United States, 2010. Morbidity and Mortality Weekly Report (MMWR)). The lived experience of parents with children diagnosed with autism spectrum disorder is important to know since quantitative studies have indicated that higher rates of mental disorders exist in this population as compared to parents of typically developing children (Yirmiya and Shaked (2005) Psychiatric disorders in parents of children with autism: a meta-analysis. Journal of Child Psychology and Psychiatry 46: 69-83). This study was a meta-synthesis of the qualitative literature in this area embedded within a systematic review. A comprehensive search and review yielded 14 studies. A total of six major themes were identified: (a) emotional stress and strain; (b) adaptation; (c) impact on the family; (d) services; (e) stigmatization; and (f) appreciating the little things. Implications of these results are discussed.

Helicobacter pylori hydrogenase accessory protein HypA and urease accessory protein UreG compete with each other for UreE recognition.

BACKGROUND: The gastric pathogen Helicobacter pylori relies on nickel-containing urease and hydrogenase enzymes in order to colonize the host. Incorporation of Ni(2+) into urease is essential for the function of the enzyme and requires the action of several accessory proteins, including the hydrogenase accessory proteins HypA and HypB and the urease accessory proteins UreE, UreF, UreG and UreH. METHODS: Optical biosensing methods (biolayer interferometry and plasmon surface resonance) were used to screen for interactions between HypA, HypB, UreE and UreG. RESULTS: Using both methods, affinity constants were found to be 5nM and 13nM for HypA-UreE and 8µM and 14µM for UreG-UreE. Neither Zn(2+) nor Ni(2+) had an effect on the kinetics or stability of the HypA-UreE complex. By contrast, addition of Zn(2+), but not Ni(2+), altered the kinetics and greatly increased the stability of the UreE-UreG complex, likely due in part to Zn(2+)-mediated oligomerization of UreE. Finally our results unambiguously show that HypA, UreE and UreG cannot form a heterotrimeric protein complex in vitro; instead, HypA and UreG compete with each other for UreE recognition. GENERAL SIGNIFICANCE: Factors influencing the pathogen's nickel budget are important to understand pathogenesis and for future drug design.

The Trajectory of Pediatric Cancer Data and Collection in the United States.

The past several years have been marked by substantial growth in pediatric cancer data and collection across the world. In the United States, multiple projects and standard setters have laid a foundation for the growth of this data, and the need for an overview and explanation of a few of the programs directly relevant to cancer registrars has become apparent. This article will discuss 3 initiatives that highlight many of the efforts and intricacies involved with the collection of pediatric cancer data in the cancer registry world: the National Childhood Cancer Registry, the Toronto Pediatric Cancer Stage Guidelines, and the Pediatric Site-Specific Data Items Work Group.

Harnessing the Power of Cancer Registries to Advance Our Understanding of Pediatric Cancer.

In 2020, the North American Association of Central Cancer Registries (NAACCR) was awarded a contract with the National Cancer Institute (NCI) to begin coordination of a new National Childhood Cancer Registry (NCCR), which would build on the existing infrastructure among both Surveillance, Epidemiology, and End Results (SEER) and National Program of Cancer Registries central registries. NCI and NAACCR planned to use the NCCR to securely match children across registries and with external data sources such as genomic data, medical and pharmacy claims, and other novel sources for residential history, financial toxicity and social determinants of health to build a robust database for pediatric cancer reporting and research. These linkages will enable researchers to address issues surrounding late effects of cancer treatment, recurrence, subsequent malignant neoplasms, and other critical outcomes.

Corrigendum: A reversible cell penetrating peptide-cargo linkage allows dissection of cell penetrating peptide-and cargo- dependent effects on internalization and identifies new functionalities of putative endolytic peptides.

[This corrects the article DOI: 10.3389/fphar.2022.1070464.].

Palliative medicine in the intensive care unit: needs, delivery, quality.

BACKGROUND: 15%-20% of critical care patients die during their hospital admission. This service evaluation assesses quality of palliative care in intensive care units (ICUs) compared with national standards. METHODS: Retrospective review of records for all patients who died in four ICUs (irrespective of treatment limitation) between 1 June and 31 July 2019. Descriptive statistics reported for patient characteristics, length of stay, admission route, identification triggers and palliative care delivery. RESULTS: Forty-five patients died, two records were untraced, thus N=43. The dying process was recognised in 88% (n=38). Among those where dying was recognised (N=35), 97% (34) had documented family discussion before death, 9% (3) were offered religious/spiritual support, 11% (4) had review of hydration/nutrition and 6% (2) had documented preferred place of death. Prescription of symptom control medications was complete in 71% (25) opioids, 34% (12) haloperidol, 54% (19) midazolam and 43% (15) hyoscine. Combining five triggers-length of stay >10 days prior to ICU admission 7% (3), multiorgan failure ≥3 systems 33% (14), stage IV malignancy 5% (2), post-cardiac arrest 23% (10) and intracerebral haemorrhage requiring mechanical ventilation 12% (5)-identified 60% (26) of patients. Referral to the palliative care team was seen in 14% (5), and 8% (3) had specialist palliative care team review. CONCLUSIONS: Recognition of dying was high but occurred close to death. Family discussions were frequent, but religious/spiritual needs, hydration/nutrition and anticipatory medications were less often considered. The ICUs delivered their own palliative care in conjunction with specialist palliative care input. Combining five triggers could increase identification of palliative care needs, but a larger study is needed.

A reversible cell penetrating peptide-cargo linkage allows dissection of cell penetrating peptide- and cargo-dependent effects on internalization and identifies new functionalities of putative endolytic peptides.

Cell penetrating peptides (CPPs) are a promising technology for therapeutic delivery of macromolecular cargos. CPPs have generally used covalent linkages to cargo, ensuring a common fate as one molecule. Conversely, our CPP-adaptor, TAT-CaM, noncovalently binds calmodulin binding sequence (CBS)-containing cargos in calcium rich media then dissociates in the calcium-poor endosomal environment following internalization, enhancing endosomal escape relative to standard CPPs. In this study, we report cell entry of positively charged protein cargos that were not increased by TAT-CaM while cargos based on the negatively charged maltose binding protein (MBP) displayed little intrinsic internalization but were internalized by TAT-CaM. In addition, association of positively charged proteins with negatively charged nucleic acids reduced internalization. This evidence points to the dominant role cargo charge plays in apparent CPP effectiveness. There has been little systematic investigation as to how interaction between CPPs and cargos impacts internalization efficiency. Our adaptors provide a tool that allows combinatorial assays to detect emergent properties. Toward this end we added 4 endolytic peptide (EP) sequences between cargo CBS and MBP moieties to create 4 new cargos and between TAT and CaM to create 4 new adaptors. The new cargos were assayed for internalization alone and with a panel of CPP-adaptors to identify combinations that displayed increased internalization efficiency or other properties. Among the most important results, addition of the EP LAH4 improved adaptor performance and provided some CPP capability to cargos. MBP-LAH4-CBS was internalized more effectively by most adaptors, suggesting this sequence has general stimulatory ability. Two other EPs, Aurein 1.2 and HA2, also provided some CPP capability to their MBP cargos but were unexpectedly antagonistic to internalization by most adaptors due to retention of adaptor/cargo complexes on the cell surface. We thus identified LAH4 as stimulator of internalization in both adaptors and cargos and uncovered new functionality for Aurein 1.2 and HA2, which may be related to their identification as EPs. Future experiments will test new endolytic capabilities made possible with combinatorial approaches.

In vitro evaluation of antimicrobial resistance selection in Neisseria gonorrhoeae.

Gonococcal infections represent an urgent public-health threat as >50% of cases caused by Neisseria gonorrhoeae strains display reduced susceptibility to at least one antimicrobial agent. We evaluated the pharmacodynamics of a number of antimicrobials against N. gonorrhoeae in order to assess the likelihood of mutant selection by these agents. The mutant prevention concentration (MPC) and mutant selection window (MSW) were determined for azithromycin, ceftriaxone, doxycycline, ertapenem, gentamicin, ciprofloxacin, levofloxacin and moxifloxacin against a wild-type strain of N. gonorrhoeae (ATCC 49226) and a gyrA mutant of ATCC 49226. Pharmacokinetic parameters, including peak concentration (Cmax), half-life (t1/2) and area under the plasma concentration-time curve over 24 h (AUC), associated with each agent were used to calculate the time within the MSW (TMSW, percentage of the dosing interval that antimicrobial concentrations fall within the MSW), Cmax/MPC ratio and AUC/MPC ratio for each antimicrobial agent. Concentrations of ceftriaxone (500 mg), ertapenem, ciprofloxacin, levofloxacin and moxifloxacin surpass the MPC for both strains. Results of pharmacodynamic analyses suggest that ertapenem, ciprofloxacin, levofloxacin and moxifloxacin may be most likely to prevent mutant selection in N. gonorrhoeae. Use of ceftriaxone, azithromycin, doxycycline or gentamicin for gonorrhoea is expected to lead to the ongoing emergence of resistance to these agents. There is a clear need to develop novel treatment regimens for gonococcal infections in order to limit the dissemination of resistance in N. gonorrhoeae.

A real-time assay for cell-penetrating peptide-mediated delivery of molecular cargos.

Cell-penetrating peptides (CPPs) are capable of transporting molecules to which they are tethered across cellular membranes. Unsurprisingly, CPPs have attracted attention for their potential drug delivery applications, but several technical hurdles remain to be overcome. Chief among them is the so-called 'endosomal escape problem,' i.e. the propensity of CPP-cargo molecules to be endocytosed but remain entrapped in endosomes rather than reaching the cytosol. Previously, a CPP fused to calmodulin that bound calmodulin binding site-containing cargos was shown to efficiently deliver cargos to the cytoplasm, effectively overcoming the endosomal escape problem. The CPP-adaptor, "TAT-CaM," evinces delivery at nM concentrations and more rapidly than we had previously been able to measure. To better understand the kinetics and mechanism of CPP-adaptor-mediated cargo delivery, a real-time cell penetrating assay was developed in which a flow chamber containing cultured cells was installed on the stage of a confocal microscope to allow for observation ab initio. Also examined in this study was an improved CPP-adaptor that utilizes naked mole rat (Heterocephalus glaber) calmodulin in place of human and results in superior internalization, likely due to its lesser net negative charge. Adaptor-cargo complexes were delivered into the flow chamber and fluorescence intensity in the midpoint of baby hamster kidney cells was measured as a function of time. Delivery of 400 nM cargo was observed within seven minutes and fluorescence continued to increase linearly as a function of time. Cargo-only control experiments showed that the minimal uptake which occurred independently of the CPP-adaptor resulted in punctate localization consistent with endosomal entrapment. A distance analysis was performed for cell-penetration experiments in which CPP-adaptor-delivered cargo showing wider dispersions throughout cells as compared to an analogous covalently-bound CPP-cargo. Small molecule endocytosis inhibitors did not have significant effects upon delivery. The real-time assay is an improvement upon static endpoint assays and should be informative in a broad array of applications.

The synthesis and evaluation of flavone and isoflavone chimeras of novobiocin and derrubone.

The natural products novobiocin and derrubone have both demonstrated Hsp90 inhibition and structure-activity relationships have been established for each scaffold. Given these compounds share several key structural features, we hypothesized that incorporation of elements from each could provide insight to structural features important for Hsp90 inhibition. Thus, chimeric analogues of novobiocin and derrubone were constructed and evaluated. These studies confirmed that the functionality present at the 3-position of the isoflavone plays a critical role in determining Hsp90 inhibition and suggests that the bicyclic ring system present in both novobiocin and derrubone do not share similar modes of binding.

Unintended Consequences of Expanding Electronic Pathology Reporting: The Inverse Relationship Between Data Completeness and Data Quality.

BACKGROUND: In 2016, the New Jersey State Cancer Registry (NJSCR) began expanding electronic laboratory reporting. As a result, the number of electronic pathology reports (EPRs) submitted to NJSCR increased markedly from 2015 to 2017. EPRs are more likely to contain incomplete or missing race than North American Association of Central Cancer Registry (NAACCR) abstracts from hospitals and physician offices. NJSCR staff conduct follow-back for additional information for laboratory-only cases, but response rates are poor, the process is lengthy, and laboratory reports often do not include physician information. PURPOSE: To assess the impact of increased EPR on the quality of race data. METHODS: NJSCR data sets created 24 months after the end of the diagnosis year-with data that were more than 98% complete-were used to calculate the percent of EPR-only cases by primary site and the percent of cases with unknown race. We calculated the relative risk of unknown race by site, compared to all sites, and used Spearman's ρ to assess the correlation between EPR-only cases and unknown race. RESULTS: While the percent of cases with unknown race was within the standards for NAACCR Gold Certification (3%), it varied by cancer site. Sites less likely to be reported by hospitals had higher rates of unknown race in the 24-month data set: prostate, leukemia, melanoma, bladder. After follow-back and death clearance activities, ≥36 months after the diagnosis year, the percent of cases with unknown race is reduced, although the impact varies by cancer site. CONCLUSION: Race-specific incidence rates for certain cancer types may be artificially depressed in the 24-month data set due to the unavailability of race for the increasing number of laboratory-only cases. While follow-back activities help to improve the collection of race data over time, these new values are not available until a revised data set is released. The higher proportion of unknown or other race in the 24-month data set impacts the accuracy of reporting the burden and trends of cancer by race. In addition, cases with unknown race may be ineligible for inclusion in cancer surveillance research studies.

Remote Auditing of Reporting Facilities by the Central Registry: Challenging but Rewarding.

OBJECTIVE: Discuss the experience of the New Jersey State Cancer Registry's (NJSCR's) transition to remote auditing of reporting facilities. METHODS: We conducted remote audits from 2016-2019 for reporting years 2014-2017. Facilities were selected for audit if they (1) were <90% complete for the year; (2) had ≥10 electronic pathology records (HL7) without a corresponding hospital abstract; or (3) had not been audited in the past 5 years. HL7 records and disease index data were used to determine which cases were potentially unreported. Disease index data were linked to data from the NJSCR Surveillance, Epidemiology, and End Results Data Management System (SEER*DMS) via Match*Pro software. We describe the number of facilities audited and the number of unreported cases identified as a result of the audit process by reporting year and audit type. We also calculate the percent increase in cases reported by reporting year and describe salient challenges in the process. RESULTS: During 4 years of data collection for the reporting years 2014-2017, 101 audits were completed and 10,546 cases were identified as unreported, representing a 7.1% increase in the number of reportable cases among those facilities audited. Challenges for the central registry involved organizing and reviewing large volumes of electronic data and Excel worksheets, and communications with facilities in the process of changing affiliations, personnel, or encryption policies. CONCLUSIONS: The new process has improved the audit experience for central registry staff and increased the capture of cases being reported to NJSCR. Facilities also made improvements to casefinding, reporting, and communications to the NJSCR.

Synthesis and evaluation of Hsp90 inhibitors that contain the 1,4-naphthoquinone scaffold.

High-throughput screening of a library of diverse molecules has identified the 1,4-naphthoquinone scaffold as a new class of Hsp90 inhibitors. The synthesis and evaluation of a rationally-designed series of analogues containing the naphthoquinone core scaffold has provided key structure-activity relationships for these compounds. The most active inhibitors exhibited potent in vitro activity with low micromolar IC(50) values in anti-proliferation and Her2 degradation assays. In addition, 3g, 12, and 13a induced the degradation of oncogenic Hsp90 client proteins, a hallmark of Hsp90 inhibition. The identification of these naphthoquinones as Hsp90 inhibitors provides a new scaffold upon which improved Hsp90 inhibitors can be developed.

A collaborative care model for patients with Type-2 diabetes.

The research on diabetes has shown the need to move from a traditional medical model to a patient-team orientation. This has led to a number of collaborative programs targeting the patient and family's comprehensive needs. This paper details one collaborative care program for underserved patients with Type-2 diabetes set in rural, eastern North Carolina. Roles of the therapeutic team are incorporated along with a case example highlighting the bio-psychosocial-spiritual model in action. Sustainability, challenges, and strengths are included to facilitate a realistic appraisal of the program.