Bicyclo[1.1.0]butyl Radical Cations: Synthesis and Application to [2π + 2σ] Cycloaddition Reactions.

As the chemistry that surrounds the field of strained hydrocarbons, such as bicyclo[1.1.0]butane, continues to expand, it becomes increasingly advantageous to develop alternative reactivity modes that harness their unique properties to access new regions of chemical space. Herein, we report the use of photoredox catalysis to promote the single-electron oxidation of bicyclo[1.1.0]butanes. The synthetic utility of the resulting radical cations is highlighted by their ability to undergo highly regio- and diastereoselective [2π + 2σ] cycloaddition reactions. The most notable feature of this transformation is the breadth of alkene classes that can be employed, including nonactivated alkenes, which have so far been elusive for previous strategies. A rigorous mechanistic investigation, in conjunction with DFT computation, was undertaken in order to better understand the physical nature of bicyclo[1.1.0]butyl radical cations and thus provides a platform from which further studies into the synthetic applications of these intermediates can be built upon.

Continuity of Care Advocate Model (CCAM): Healthcare Workers' Perspectives on Quality Stroke Care at an Acute Unit, Rehabilitation Center and Community Rehabilitation Program in Singapore.

Physicians, nurses, social workers, and allied health professionals including physiotherapists and occupational therapists play important roles as they work closely with stroke survivors to improve functional independence in daily activities and quality of life. Yet, in Singapore little is known about their perspectives on what constitute quality stroke care based on their clinical experiences. In this project, our qualitative interviews with 15 healthcare workers at a major stroke center in the country yielded a Continuity of Care Advocate Model (CCAM) to help us better understand our participants' experience-based perspectives on quality stroke care. We found that CCAM, constructed based on the perspectives of HCWs across a stroke care continuum, is a holistic model of quality stroke care which prioritizes support for patients and their families throughout the patient's health trajectory. We conclude by discussing how this model is aligned with and differs from current research on definitions of care continuity.

Frailty scoring in vascular and endovascular surgery: A systematic review.

One in 10 independently living adults aged 65 years old and older is considered frail, and frailty is associated with poor postoperative outcomes. This systematic review aimed to examine the association between frailty assessments and postoperative outcomes in patients with vascular disease. Electronic databases - MEDLINE, Embase, and the Cochrane Library - were searched from inception until January 2022, resulting in 648 articles reviewed for potential inclusion and 16 studies selected. Demographic data, surgery type, frailty measure, and postoperative outcomes predicted by frailty were extracted from the selected studies. The risk of bias was assessed using the Newcastle-Ottawa Scale. The selected studies (mean age: 56.1-76.3 years) had low-to-moderate risk of bias and included 16 vascular (elective and nonelective) surgeries and eight frailty measures. Significant associations (p < 0.05) were established between mortality (30-day, 90-day, 1-year, 5-year), 30-day morbidity, nonhome discharge, adverse events, failure to rescue, patient requiring care after discharge, and amputation following critical limb ischaemia. The strongest evidence was found between 30-day mortality and frailty. Composite 30-day morbidity and mortality, functional status at discharge, length of stay, spinal cord deficit, and access site complications were found to be nonsignificantly associated with frailty. With frailty being significantly associated with several adverse postoperative outcomes, preoperative frailty assessments can potentially be clinically useful in helping practitioners predict and guide the pre-, peri-, and postoperative management of frail with vascular disease.

Explicit and implicit mentalization of patients with first-episode schizophrenia: a study of self-referential gaze perception with eye movement analysis using hidden Markov models.

Mentalizing impairment is one of the core features of schizophrenia, and bias judgement of others' gaze as self-directing is common to schizophrenia patients. In this case-control study, 30 patients with first-episode schizophrenia (FES) and 30 matched healthy controls were assigned gaze perception tasks with variable stimulus presentation times (300 ms and no time limit) to determine the presence of self-referential gaze perception (SRGP) bias. The eye movement pattern during the task were tracked and data were analysed using hidden Markov models (HMMs). The SRGP involves reporting of others' gaze intent and was used as a measurement of explicit mentalizing process. Eye movement measurement represents automated visual attention pattern and was considered as a measurement of implicit mentalizing process. The patients with FES had significantly more SRGP bias than the controls in the 300 ms condition but not in the no-time-limit condition. Social cognitive function was related to SRGP bias in the patient group. Two distinct eye movement patterns were identified: eye-focused and nose-focused. Significant group differences in eye movement patterns in the 300 ms condition were found with more controls had eye-focused pattern. Social anxiety symptoms were related to the nose-focused pattern, positive psychotic symptoms were related to the eye-focused pattern, and depressive symptoms were related to less consistent eye movement patterns. No significant relationship was found between SRGP bias and eye movement patterns. The dissociation between explicit and implicit mentalizing processes with different cognitive and symptom dimensions associated with the two processes suggests the presence of different mechanisms.

Educating Nurses on Intravenous Lidocaine for Postoperative Pain Management.

As healthcare practitioners continue to search for multimodal analgesic therapies to reduce postoperative opioid requirements, surgical ward nurses need to stay up to date on the status of emerging therapies. One of these is intravenous lidocaine for postoperative pain management. Unfortunately, there is a lack of resources to assist surgical ward nurses who are unfamiliar with lidocaine infusions for pain. This article aims to review the pharmacology of intravenous lidocaine for pain management, describe an experience of a university-affiliated Veterans Affairs hospital with implementation of intravenous lidocaine on the surgical ward, and suggest practical tools that can be used to develop protocols and educational content for nurses managing intravenous lidocaine infusions in the postoperative period.

Development of a Study Protocol for Evaluation of a Novel Measure to Incorporate Information Freshness into Network Analysis of Online Resources for COVID-19.

We proposed a novel measure, Degree of Connectivity with Integration of Freshness (DCIF), to incorporate information freshness into analysis of online resource networks. We conducted a pilot study to apply this new measure to a dataset of online information resources related to COVID-19 risk assessment. Among the 52 nodes, we recorded statistically significant difference between the numerical values of DCIF and the traditional structural measure Degree of Connectivity (DC). Manual reviews of 18 selected nodes showed that DCIF outperformed DC in 11 of them, suggesting potential promise of the proposed new measure. We finalized the protocol for manual review based on the pilot and started a full-scale study. The proposed new measure has the potential to provide quantitative assessment on information freshness for timely and effective dissemination of clinical evidence. Further research is required to address the limitations of this pilot study and to examine the generalization of the findings.

High-Fat Diet-Induced DeSUMOylation of E4BP4 Promotes Lipid Droplet Biogenesis and Liver Steatosis in Mice.

Dysregulated lipid droplet accumulation has been identified as one of the main contributors to liver steatosis during nonalcoholic fatty liver disease (NAFLD). However, the underlying molecular mechanisms for excessive lipid droplet formation in the liver remain largely unknown. In the current study, hepatic E4 promoter-binding protein 4 (E4BP4) plays a critical role in promoting lipid droplet formation and liver steatosis in a high-fat diet (HFD)-induced NAFLD mouse model. Hepatic E4bp4 deficiency (E4bp4-LKO) protects mice from HFD-induced liver steatosis independently of obesity and insulin resistance. Our microarray study showed a markedly reduced expression of lipid droplet binding genes, such as Fsp27, in the liver of E4bp4-LKO mice. E4BP4 is both necessary and sufficient to activate Fsp27 expression and lipid droplet formation in primary mouse hepatocytes. Overexpression of Fsp27 increased lipid droplets and triglycerides in E4bp4-LKO primary mouse hepatocytes and restored hepatic steatosis in HFD-fed E4bp4-LKO mice. Mechanistically, E4BP4 enhances the transactivation of Fsp27 by CREBH in hepatocytes. Furthermore, E4BP4 is modified by SUMOylation, and HFD feeding induces deSUMOylation of hepatic E4BP4. SUMOylation of five lysine residues of E4BP4 is critical for the downregulation of Fsp27 and lipid droplets by cAMP signaling in hepatocytes. Taken together, this study revealed that E4BP4 drives liver steatosis in HFD-fed mice through its regulation of lipid droplet binding proteins. Our study also highlights the critical role of deSUMOylation of hepatic E4BP4 in promoting NAFLD.

Physicians' Perspectives on HL7 Information Policy Sensitive Value Set: A Validation Study through Health Concept Categorization.

The Health Level 7 (HL7) organization introduced the Information Sensitivity Policy Value Set with 45 sensitive data categories to facilitate the implementation of granular electronic consent technology. The goal is to allow patients to have control over the sharing of their sensitive medical records. This study represents the first attempt to explore physicians' viewpoints on these categories. Twelve physicians participated in a survey, leading to revisions in 21 HL7 categories. They later classified 600 clinical data items through a second survey using the updated categories. Participants' perspectives were documented, and data analysis included descriptive measures and heat maps. In the first survey, six participants suggested adding 19 new categories (e.g., personality disorder), and modifying 25 category definitions. Two new categories and sixteen revised category definitions were incorporated to support more patient-friendly content and inclusive language. Fifteen new category recommendations were addressed through a revision of category definitions (e.g., personality disorder described as a behavioral health condition). In the second survey, data categorizations led to recommendations for more categories from ten participants. Future revisions of the HL7 categories should incorporate physicians' viewpoints, validate the categories using patient data or/and include patients' perspectives, and develop patient-centric category specifications.

Acute medical units during the first wave of the COVID-19 pandemic: a cross-national exploratory study of impact and responses.

BACKGROUND: The COVID-19 pandemic represents one of the greatest ever challenges for healthcare. In the UK and beyond, acute medical units (AMUs) are the first point of assessment and care for the majority of medical inpatients. By their design and systems, they inevitably played an important role in the COVID-19 response but to date little has been published on how the COVID-19 pandemic has affected how AMUs have reorganised their resources, processes and structure. METHODS: This retrospective study in August 2020 of 10 AMUs across Europe and Australasia used a standardised questionnaire to investigate existing practice and structure of AMUs, the national context of local hospital experience, changes to practice during the COVID-19 pandemic and views regarding future practice. RESULTS: Changes to AMU structure, process and organisation are described in two contexts: preventing and controlling the spread of COVID-19 and adding value to the patient's acute care journey in the local context. We describe novel practices that have arisen and highlight areas of concern. CONCLUSIONS: The AMUs were able to adapt to meet the demands of acute care delivery during the first wave of the COVID-19 pandemic. Operational planning and prioritisation of resources must be optimised to ensure sustainability of these services for future waves.

Self-referential gaze perception of patients with schizophrenia and its relationship with symptomatology and cognitive functions.

Self-referential gaze perception (SRGP)-the perception that others' gaze is towards oneself-is a core experience in patients with schizophrenia, and may be related to common delusional themes such as delusions of reference. Studies exploring SRGP bias in schizophrenia are limited and results have been inconsistent, particularly regarding its relationship with symptomatology and cognition. Seventy-five patients with schizophrenia-spectrum disorders (25 with high level of reference delusion, 25 with low reference delusion and 25 in clinical remission) and 25 matched healthy controls were compared in a gaze perception task to judge whether averted gaze with varied ambiguity was directed at them. All subjects were assessed with delusion and reference ideations and cognitive functions. Psychotic symptoms were assessed in patients. Gaze perception analysis adopted both behavioural and psychophysical approaches. Group differences and predictors of SRGP in ambiguous and unambiguous conditions were investigated. Both groups of symptomatic patients displayed higher ambiguous SRGP rate, and the group with high reference delusions showed more unambiguous SRGP bias. Cognitive functions were negatively associated with SRGP rate while positive and negative symptoms were positively associated. Cognitive function was the only significant predictor for ambiguous-SRGP rate. Patients with psychotic symptoms have hypermentalization of gaze perception as towards oneself, whereas patients with delusions of reference have more profound bias in gaze perception. General cognition is implicated in SRGP rate. Future studies could investigate interventions with targeted psychopathological profiles by improving non-social cognitive functions to test the hypothesis that cognitive functioning is related to SRGP bias and delusional beliefs.

The Capital Investment Strategy for Radiation therapy in Ontario: A Framework to Ensure Access to Radiation Therapy.

PURPOSE: Ontario Health (Cancer Care Ontario), formerly known as CCO, is the provincial governmental agency in Ontario, Canada responsible for developing radiation therapy-specific capital investment strategies, updated every 5 years, to ensure equitable access and to gain the highest value from these investments in infrastructure. These plans are informed by the changing landscape of health care delivery, technologic advancements affecting radiation therapy care, patient desire for care closer to home, and expected increases in utilization of radiation therapy services. In this article, we describe the development, model, and final recommendations of CCO's fifth radiation therapy capital investment strategy. METHODS AND MATERIALS: A panel of multidisciplinary provincial experts, in combination with 2 patient and family advisors, developed planning principles to guide the development of a patient-centered strategy. Adaption of the previously used model for radiation therapy planning was used. RESULTS: The development of the capital investment strategy took place from fall 2017 to fall 2018. The model included 3 main factors: patient demand (including utilization targets), machine throughput, and machine demand and supply. The final recommendation is for an investment of 26 new radiation therapy machines in the province by 2028. CONCLUSIONS: The strategy plans for continued province-wide access to quality radiation therapy care and ensures machines are added to the system at the right place and in the right time. Ongoing data collection throughout this period is necessary to ensure the strategy achieves its goals and to allow for planning of future strategies.

Copper-responsive magnetic resonance imaging contrast agents.

The design, synthesis, and evaluation of the Copper-Gad (CG) family, a new class of copper-activated magnetic resonance imaging (MRI) contrast agents, are presented. These indicators comprise a Gd(3+)-DO3A core coupled to various thioether-rich receptors for copper-induced relaxivity switching. In the absence of copper ions, inner-sphere water binding to the Gd(3+) chelate is restricted, resulting in low longitudinal relaxivity values (r(1) = 1.2-2.2 mM(-1) s(-1) measured at 60 MHz). Addition of Cu(+) to CG2, CG3, CG4, and CG5 and either Cu(+) or Cu(2+) to CG6 triggers marked enhancements in relaxivity (r(1) = 2.3-6.9 mM(-1) s(-1)). CG2 and CG3 exhibit the greatest turn-on responses, going from r(1) = 1.5 mM(-1) s(-1) in the absence of Cu(+) to r(1) = 6.9 mM(-1) s(-1) upon Cu(+) binding (a 360% increase). The CG sensors are highly selective for Cu(+) and/or Cu(2+) over competing metal ions at cellular concentrations, including Zn(2+) at 10-fold higher concentrations. (17)O NMR dysprosium-induced shift and nuclear magnetic relaxation dispersion measurements support a mechanism in which copper-induced changes in the coordination environment of the Gd(3+) core result in increases in q and r(1). T(1)-weighted phantom images establish that the CG sensors are capable of visualizing changes in copper levels by MRI at clinical field strengths.

Conceptual adequacy of the neuropathic pain symptom inventory in six countries.

BACKGROUND: Neuropathic pain results from a nerve lesion or nerve damage. Because it is a subjective experience, patient-reported outcomes may measure both the symptoms and impact on the patient's life. The purpose of this study was to determine whether the Neuropathic Pain Symptom Inventory (NPSI) adequately assesses neuropathic pain symptoms in patients with diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, and sciatica across multiple cultures. METHODS: From data collected from 132 subjects in 6 countries, qualitative research methods identified their most important symptoms (and verbal descriptions) associated with neuropathic pain. A core set of commonly described symptoms spanning multiple cultures was also described. Moderators using a semi-structured discussion guide conducted focus groups consisting of patients in the U.S., Brazil, Japan, China, Finland, and Spain to elicit concepts that were most important and relevant (concept elicitation phase). Study subjects ranked the importance of each neuropathic pain symptom, completed the NPSI, and commented on its ability to capture key symptoms (face and content validation phase). RESULTS: Descriptive terms for sensations of neuropathic pain were similar in all countries; burning, electric shocks, and pins and needles were among the most-common sensations. Individuals with neuropathic pain experienced all sensations that were included in the NPSI. They also tended to describe pins and needles and numbness interchangeably, perhaps reflecting the relative number of DPN subjects on study. CONCLUSION: Based on data from these focus groups, the NPSI is an acceptable instrument for assessing neuropathic pain.

Hypokalaemia in Sjögren's syndrome: the missing piece.

A 58-year-old Chinese woman with well controlled type 1 diabetes mellitus presented with acute and progressive bilateral lower limb weakness. Investigations revealed severe hypokalaemia (1.3 mmol/L) and hypophosphataemia (<0.32 mmol/L) with rhabdomyolysis and electrocardiogram changes, without other concurrent biochemical abnormalities. Immediate intravenous and oral potassium and phosphate replacement was initiated with objective improvement in weakness with replenished electrolyte levels. Urine studies confirmed renal potassium wasting. Further history revealed frequent dental caries, xerostomia and recent weight loss. A computerised tomography scan showed atrophy of her salivary glands and a skin lesion biopsied by her GP in the past had been histologically characterised as anetoderma. The constellation of these findings and subsequent positive anti-SSA/SSB levels confirmed her diagnosis of primary Sjögren's syndrome (PSS). PSS has a wide spectrum of renal involvement and should be a differential diagnosis when investigating interstitial nephritis and electrolyte abnormalities, particularly in patients with coexisting autoimmune conditions.

Clinical validation of a novel diagnostic HIV-2 total nucleic acid qualitative assay using the Abbott m2000 platform: Implications for complementary HIV-2 nucleic acid testing for the CDC 4th generation HIV diagnostic testing algorithm.

BACKGROUND: The 2014 CDC 4th generation HIV screening algorithm includes an orthogonal immunoassay to confirm and discriminate HIV-1 and HIV-2 antibodies. Additional nucleic acid testing (NAT) is recommended to resolve indeterminate or undifferentiated HIV seroreactivity. HIV-2 NAT requires a second-line assay to detect HIV-2 total nucleic acid (TNA) in patients' blood cells, as a third of untreated patients have undetectable plasma HIV-2 RNA. OBJECTIVES: To validate a qualitative HIV-2 TNA assay using peripheral blood mononuclear cells (PBMC) from HIV-2-infected Senegalese study participants. STUDY DESIGN: We evaluated the assay precision, sensitivity, specificity, and diagnostic performance of an HIV-2 TNA assay. Matched plasma and PBMC samples were collected from 25 HIV-1, 30 HIV-2, 8 HIV-1/-2 dual-seropositive and 25 HIV seronegative individuals. Diagnostic performance was evaluated by comparing the outcome of the TNA assay to the results obtained by the 4th generation HIV screening and confirmatory immunoassays. RESULTS: All PBMC from 30 HIV-2 seropositive participants tested positive for HIV-2 TNA including 23 patients with undetectable plasma RNA. Of the 30 matched plasma specimens, one was HIV non-reactive. Samples from 50 non-HIV-2 infected individuals were confirmed as non-reactive for HIV-2 Ab and negative for HIV-2 TNA. The agreement between HIV-2 TNA and the combined immunoassay results was 98.8% (79/80). Furthermore, HIV-2 TNA was detected in 7 of 8 PBMC specimens from HIV-1/HIV-2 dual-seropositive participants. CONCLUSIONS: Our TNA assay detected HIV-2 DNA/RNA in PBMC from serologically HIV-2 reactive, HIV indeterminate or HIV undifferentiated individuals with undetectable plasma RNA, and is suitable for confirming HIV-2 infection in the HIV testing algorithm.

Development and novel therapeutics in hepatocellular carcinoma: a review.

This review summarizes the epidemiological trend, risk factors, prevention strategies such as vaccination, staging, current novel therapeutics, including the drugs under clinical trials, and future therapeutic trends for hepatocellular carcinoma (HCC). As HCC is the third most common cause of cancer-related death worldwide, its overall incidence remains alarmingly high in the developing world and is steadily rising across most of the developed and developing world. Over the past 15 years, the incidence of HCC has more than doubled and it increases with advancing age. Chronic infection with hepatitis B virus is the leading cause of HCC, closely followed by infection with hepatitis C virus. Other factors contributing to the development of HCC include alcohol abuse, tobacco smoking, and metabolic syndrome (including obesity, diabetes, and fatty liver disease). Treatment options have improved in the past few years, particularly with the approval of several molecular-targeted therapies. The researchers are actively pursuing novel therapeutic targets as well as predictive biomarker for treatment of HCC. Advances are being made in understanding the mechanisms underlying HCC, which in turn could lead to novel therapeutics. Nevertheless, there are many emerging agents still under clinical trials and yet to show promising results. Hence, future therapeutic options may include different combination of novel therapeutic interventions.