Effect of perioperative benzodiazepine use on intraoperative awareness and postoperative delirium: a systematic review and meta-analysis of randomised controlled trials and observational studies.

BACKGROUND: Benzodiazepine use is associated with delirium, and guidelines recommend avoiding them in older and critically ill patients. Their perioperative use remains common because of perceived benefits. METHODS: We searched CENTRAL, MEDLINE, CINAHL, PsycInfo, and Web of Science from inception to June 2021. Pairs of reviewers identified randomised controlled trials and prospective observational studies comparing perioperative use of benzodiazepines with other agents or placebo in patients undergoing surgery. Two reviewers independently abstracted data, which we combined using a random-effects model. Our primary outcomes were delirium, intraoperative awareness, and mortality. RESULTS: We included 34 randomised controlled trials (n=4354) and nine observational studies (n=3309). Observational studies were considered separately. Perioperative benzodiazepines did not increase the risk of delirium (n=1352; risk ratio [RR] 1.43; 95% confidence interval [CI]: 0.9-2.27; I2=72%; P=0.13; very low-quality evidence). Use of benzodiazepines instead of dexmedetomidine did, however, increase the risk of delirium (five studies; n=429; RR 1.83; 95% CI: 1.24-2.72; I2=13%; P=0.002). Perioperative benzodiazepine use decreased the risk of intraoperative awareness (n=2245; RR 0.26; 95% CI: 0.12-0.58; I2=35%; P=0.001; very low-quality evidence). When considering non-events, perioperative benzodiazepine use increased the probability of not having intraoperative awareness (RR 1.07; 95% CI: 1.01-1.13; I2=98%; P=0.03; very low-quality evidence). Mortality was reported by one randomised controlled trial (n=800; RR 0.90; 95% CI: 0.20-3.1; P=0.80; very low quality). CONCLUSIONS: In this systematic review and meta-analysis, perioperative benzodiazepine use did not increase postoperative delirium and decreased intraoperative awareness. Previously observed relationships of benzodiazepine use with delirium could be explained by comparisons with dexmedetomidine. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42019128144.

Association of primary and community care services with emergency visits and hospital admissions at the end of life in people with cancer: a retrospective cohort study.

OBJECTIVE: To examine the association between primary and community care use and measures of acute hospital use in people with cancer at the end of life. DESIGN: Retrospective cohort study. SETTING: We used Discover, a linked administrative and clinical data set from general practices, community and hospital records in North West London (UK). PARTICIPANTS: People registered in general practices, with a diagnosis of cancer who died between 2016 and 2019. PRIMARY AND SECONDARY OUTCOME MEASURES: ≥3 hospital admissions during the last 90 days, ≥1 admissions in the last 30 days and ≥1 emergency department (ED) visit in the last 2 weeks of life. RESULTS: Of 3581 people, 490 (13.7%) had ≥3 admissions in last 90 days, 1640 (45.8%) had ≥1 admission in the last 30 days, 1042 (28.6%) had ≥1 ED visits in the last 2 weeks; 1069 (29.9%) had more than one of these indicators. Contacts with community nurses in the last 3 months (≥13 vs <4) were associated with fewer admissions in the last 30 days (risk ratio (RR) 0.88, 95% CI 0.90 to 0.98) and ED visits in the last 2 weeks of life (RR 0.79, 95% CI 0.68 to 0.92). Contacts with general practitioners in the last 3 months (≥11 vs <4) was associated with higher risk of ≥3 admissions in the last 90 days (RR 1.63, 95% CI 1.33 to 1.99) and ED visits in the last 2 weeks of life (RR 1.27, 95% CI 1.10 to 1.47). CONCLUSIONS: Expanding community nursing could reduce acute hospital use at the end of life and improve quality of care.

Palliative Integration Into Ambulatory Oncology: An Advance Care Planning Quality Improvement Project.

Advance care planning (ACP) is essential to ensuring that patient-centered end-of-life goals are respected if a health crisis occurs. Advanced practitioner barriers to ACP include insufficient time and limited confidence in discussions. The purpose of this quality improvement project was to increase advanced cancer patients' electronic health record (EHR) documented surrogate decision maker and ACP documentation by 25% over 8 weeks. A secondary aim was to decrease patients' decisional conflict scores (DCS) related to life-sustaining treatment preferences after a clinical nurse specialist (CNS)-led ACP session. Using the define, measure, analyze, improve, and control (DMAIC) process of quality improvement methodology, an interprofessional team led by a palliative CNS fostered practice change by (a) incorporating a patient self-administered Supportive Care and Communication Questionnaire (SCCQ) to standardize the ACP assessment, (b) creating an EHR nursing and provider documentation template, (c) offering advanced cancer patients a palliative CNS consultation for ACP review and advance directive completion, and (d) evaluating patients' DCS through the four-item SURE tool. Of 126 participants provided with the SCCQ, 90 completed the document, resulting in a 71% return rate. Among the completed SCCQs, 37% (n = 33) requested a CNS consultation, with 76% (n = 25) returning for the ACP session. The CNS intervention yielded an average reduction of 1.4 points in SURE tool findings, a statistically significant decrease determined by a paired sample t-test. The project's interprofessional collaboration promoted a system-wide standardized ACP process throughout ambulatory, acute, and post-hospital settings.

Identification of palliative care needs among people with dementia and its association with acute hospital care and community service use at the end-of-life: A retrospective cohort study using linked primary, community and secondary care data.

BACKGROUND: Hospital admissions among people dying with dementia are common. It is not known whether identification of palliative care needs could help prevent unnecessary admissions. AIM: To examine the proportion of people with dementia identified as having palliative care needs in their last year of life, and the association between identification of needs and primary, community and hospital services in the last 90 days. DESIGN: Retrospective cohort study using Discover, an administrative and clinical dataset from 365 primary care practices in London with deterministic individual-level data linkage to community and hospital records. SETTING/PARTICIPANTS: People diagnosed with dementia and registered with a general practitioner in North West London (UK) who died between 2016 and 2019. The primary outcome was multiple non-elective hospital admissions in the last 90 days of life. Secondary outcomes included contacts with primary and community care providers. We examined the association between identification of palliative care needs with outcomes. RESULTS: Among 5804 decedents with dementia, 1953 (33.6%) were identified as having palliative care needs, including 1141 (19.7%) identified before the last 90 days of life. Identification of palliative care needs before the last 90 days was associated with a lower risk of multiple hospital admissions (Relative Risk 0.70, 95% CI 0.58-0.85) and more contacts with the primary care practice, community nurses and palliative care teams in the last 90 days. CONCLUSIONS: Further investigation of the mechanisms underlying the association between identification of palliative care needs and reduced hospital admissions could help reduce reliance on acute care for this population.

Evaluating a digital tool for supporting breast cancer patients: a randomized controlled trial protocol (ADAPT).

BACKGROUND: There are a growing number of mHealth tools for breast cancer patients but a lack of scientific evidence for their effects. Recent studies have shown a mix of positive and negative impacts on users. Here we will assess the impact of OWise Breast Cancer, a mobile application for self-monitoring symptoms and managing care, on the process of self-management. METHODS: This randomized controlled trial with early stage breast cancer patients will assess the effect of OWise use on patient activation at 3 months from diagnosis measured by the PAM-13 questionnaire. We will also assess differences in changes in health-related quality of life, psychological distress, health status, and National Health Service (NHS) health resource utilization over the first year from diagnosis. Participants will be randomly allocated (1:1) to standard care or standard care plus OWise. Participants will complete questionnaires before starting anti-cancer treatment and at 3, 6, and 12 months from diagnosis. Clinical and patient-reported outcome data will be linked to health resource utilization data from Discover, an integrated care record of primary, secondary, and social care in North West London. We will measure contamination in the control group and adjust the sample size to mitigate the dilution of effect estimates. A per-protocol analysis will be conducted as a sensitivity analysis to assess robustness of the primary results. DISCUSSION: This study aims to generate evidence for the effectiveness of OWise at improving patient activation for women with early-stage breast cancer. The results will show the impact of using the tool at the patient level and the NHS health system level. The outcomes of the study will have implications for the application of OWise across the NHS for breast cancer patients and expansion into other tumor types. Assessing publicly available mHealth tools poses a challenge to trialists due to the risk of contamination. Here we apply various methods to measure, mitigate, and assess the effects of contamination. TRIAL REGISTRATION: The study was registered at clincaltrials.gov (NCT03866655) on 7 March 2019.

Detecção de beta-lactamase por Staphylococcus coagulase-negativo isolados de queijo mussarela fatiados e fatiadores de frios / Beta-lactamase detection in coagulase-negative Staphylococci isolated from sliced mozzarella cheese and cold-cut slicers

A resistência de bactérias a antimicrobianos é considerada um problema de saúde pública, sendo a resistência aos beta-lactâmicos uma das mais importantes. O objetivo do presente estudo foi detectar a produção da enzima β-lactamase por isolados de Staphylococcus coagulase-negativo (SCN), provenientes de queijos Mussarela fatiados e equipamentos de fatiamento de frios. Os testes foram realizados utilizando discos impregnados com cefalosporina cromógena para detecção da β-lactamase. Dos 103 isolados de Staphylococcus spp. analisados, 55 (53%) produziram β-lactamase e 48 (47%) não produziram. Portanto, é possível inferir que SCN isolados neste estudo, podem inativar antimicrobianos β-lactâmicos e assim, exercer influência negativa na saúde pública, devido ao potencial em transferir genes de resistência antimicrobiana para outras bactérias.

Produção de biofilme por Staphylococcus coagulase negativa isolados de queijos e equipamentos / Biofilm production by coagulase-negative Staphylococci isolated from cheese and equipments

Biofilme é uma comunidade organizada de microrganismos que se forma em superfícies mal higienizadas, constituindo um mecanismo de defesa microbiana para permanência no ambiente. O objetivo do presente estudo foi investigar a capacidade de formação de biofilme de espécies de Staphylococcus coagulase negativa (SCN) isoladas de queijo Mussarela fatiado e de fatiadores de frios de estabelecimentos do município de Garanhuns-PE. De 103 isolados de SCN 56 (54,4%) foram negativos para produção de biofilme e 47 (45,6%) positivos, com a maior frequência de detecção nas espécies S. saprophyticus e S. cohnii subsp. urealyticum. Os resultados apontam para o potencial risco de contaminação cruzada de outros alimentos, uma vez que cepas bacterianas produtoras de biofilmes podem colonizar e persistir em superfícies de diversos equipamentos.

Blood-based detection of RAS mutations to guide anti-EGFR therapy in colorectal cancer patients: concordance of results from circulating tumor DNA and tissue-based RAS testing.

An accurate blood-based RAS mutation assay to determine eligibility of metastatic colorectal cancer (mCRC) patients for anti-EGFR therapy would benefit clinical practice by better informing decisions to administer treatment independent of tissue availability. The objective of this study was to determine the level of concordance between plasma and tissue RAS mutation status in patients with mCRC to gauge whether blood-based RAS mutation testing is a viable alternative to standard-of-care RAS tumor testing. RAS testing was performed on plasma samples from newly diagnosed metastatic patients, or from recurrent mCRC patients using the highly sensitive digital PCR technology, BEAMing (beads, emulsions, amplification, and magnetics), and compared with DNA sequencing data of respective FFPE (formalin-fixed paraffin-embedded) tumor samples. Discordant tissue RAS results were re-examined by BEAMing, if possible. The prevalence of RAS mutations detected in plasma (51%) vs. tumor (53%) was similar, in accord with the known prevalence of RAS mutations observed in mCRC patient populations. The positive agreement between plasma and tumor RAS results was 90.4% (47/52), the negative agreement was 93.5% (43/46), and the overall agreement (concordance) was 91.8% (90/98). The high concordance of plasma and tissue results demonstrates that blood-based RAS mutation testing is a viable alternative to tissue-based RAS testing.

A multisite blinded study for the detection of BRAF mutations in formalin-fixed, paraffin-embedded malignant melanoma.

Melanoma patients with BRAF mutations respond to treatment with vemurafenib, thus creating a need for accurate testing of BRAF mutation status. We carried out a blinded study to evaluate various BRAF mutation testing methodologies in the clinical setting. Formalin-fixed, paraffin-embedded melanoma samples were macrodissected before screening for mutations using Sanger sequencing, single-strand conformation analysis (SSCA), high resolution melting analysis (HRM) and competitive allele-specific TaqMan® PCR (CAST-PCR). Concordance of 100% was observed between the Sanger sequencing, SSCA and HRM techniques. CAST-PCR gave rapid and accurate results for the common V600E and V600K mutations, however additional assays are required to detect rarer BRAF mutation types found in 3-4% of melanomas. HRM and SSCA followed by Sanger sequencing are effective two-step strategies for the detection of BRAF mutations in the clinical setting. CAST-PCR was useful for samples with low tumour purity and may also be a cost-effective and robust method for routine diagnostics.

Targeting the PI3K/Akt cell survival pathway to induce cell death of HIV-1 infected macrophages with alkylphospholipid compounds.

BACKGROUND: HIV-1 infected macrophages and microglia are long-lived viral reservoirs persistently producing viral progenies. HIV-1 infection extends the life span of macrophages by promoting the stress-induced activation of the PI3K/Akt cell survival pathway. Importantly, various cancers also display the PI3K/Akt activation for long-term cell survival and outgrowth, and Akt inhibitors have been extensively searched as anti-cancer agents. This led us to investigate whether Akt inhibitors could antagonize long-term survival and cytoprotective phenotype of HIV-1 infected macrophages. PRINCIPAL FINDINGS: Here, we examined the effect of one such class of drugs, alkylphospholipids (ALPs), on cell death and Akt pathway signals in human macrophages and a human microglial cell line, CHME5, infected with HIV-1 BaL or transduced with HIV-1 vector, respectively. Our findings revealed that the ALPs, perifosine and edelfosine, specifically induced the death of HIV-1 infected primary human macrophages and CHME5 cells. Furthermore, these two compounds reduced phosphorylation of both Akt and GSK3ß, a downstream substrate of Akt, in the transduced CHME5 cells. Additionally, we observed that perifosine effectively reduced viral production in HIV-1 infected primary human macrophages. These observations demonstrate that the ALP compounds tested are able to promote cell death in both HIV-1 infected macrophages and HIV-1 expressing CHME5 cells by inhibiting the action of the PI3K/Akt pathway, ultimately restricting viral production from the infected cells. SIGNIFICANCE: This study suggests that Akt inhibitors, such as ALP compounds, may serve as potential anti-HIV-1 agents specifically targeting long-living HIV-1 macrophages and microglia reservoirs.

Ribonucleoside triphosphates as substrate of human immunodeficiency virus type 1 reverse transcriptase in human macrophages.

We biochemically simulated HIV-1 DNA polymerization in physiological nucleotide pools found in two HIV-1 target cell types: terminally differentiated/non-dividing macrophages and activated/dividing CD4(+) T cells. Quantitative tandem mass spectrometry shows that macrophages harbor 22-320-fold lower dNTP concentrations and a greater disparity between ribonucleoside triphosphate (rNTP) and dNTP concentrations than dividing target cells. A biochemical simulation of HIV-1 reverse transcription revealed that rNTPs are efficiently incorporated into DNA in the macrophage but not in the T cell environment. This implies that HIV-1 incorporates rNTPs during viral replication in macrophages and also predicts that rNTP chain terminators lacking a 3'-OH should inhibit HIV-1 reverse transcription in macrophages. Indeed, 3'-deoxyadenosine inhibits HIV-1 proviral DNA synthesis in human macrophages more efficiently than in CD4(+) T cells. This study reveals that the biochemical landscape of HIV-1 replication in macrophages is unique and that ribonucleoside chain terminators may be a new class of anti-HIV-1 agents specifically targeting viral macrophage infection.

Comparison of the PSC-17 and alternative mental health screens in an at-risk primary care sample.

OBJECTIVE: To validate the 17-item version of the Pediatric Symptom Checklist (PSC-17) as a screen for common pediatric mental disorders in primary care. METHOD: Patients were 269 children and adolescents (8-15 years old) whose parents completed the PSC-17 in primary care waiting rooms. Children were later assessed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL). The PSC-17's subscales were compared with K-SADS-PL diagnoses and measures of anxiety, depression, general psychopathology, functioning, and impairment. RESULTS: In receiver operating characteristics analyses, the PSC-17 subscales performed as well as competing screens (Child Depression Inventory, the parent and child Screens for Child Anxiety-Related Disorders) and Child Behavior Checklist subscales (Aggressive, Anxious-Depressed, Attention, Externalizing, Internalizing, and Total) in predicting diagnoses of attention-deficit/hyperactivity disorder, externalizing disorders, and depression (area under the curve > or =0.80). The instrument was less successful with anxiety (area under the curve = 0.68). None of the screens were highly sensitive, many were insensitive, and all would have low positive predictive value in low-risk primary care populations. CONCLUSIONS: The PSC-17 and its subscales are briefer than alternative questionnaires, but performed as well as those instruments in detecting common mental disorders in primary care. Continued research is needed to develop brief yet sensitive assessment instruments appropriate for primary care.