Economic Evaluation of Clinical, Nutritional and Rehabilitation Interventions on Oropharyngeal Dysphagia after Stroke: A Systematic Review.

BACKGROUND: Post-stroke oropharyngeal dysphagia (PS-OD) and its complications increase healthcare costs, suggesting that its appropriate management is cost-effective. We aimed to assess the efficiency of healthcare interventions in PS-OD management. METHODS: A systematic review was conducted following PRISMA recommendations. Four databases were searched from inception through 30 June 2021. Outcome measures were cost-effectiveness and cost-savings of healthcare interventions. English and Spanish literature were included. Narrative and tables were used to present and synthesise evidence. Quality was evaluated using the CHEERS Statement. RESULTS: A total of 244 studies were identified, and 10 were included. Screening and diagnosis of PS-OD studies found: (1) adjusted reduction in hospitalisation costs when assessed during the first admission day; (2) non-significant reduction in hospitalisation costs with OD management after thrombolysis; and (3) videofluoroscopy as the most cost-effective screening method (compared to bedside evaluation and a combination of both). Two studies showed cost-effective rehabilitation programmes, including OD management. Pelczarska et al. showed an incremental cost-utility ratio of texture-modified diets using a gum-based thickener of 20,977 PLN (4660€) following a dynamic model, and Kotecki et al. commercially prepared thickened fluids that were 44% to 59% less expensive than in situ prepared fluids. Elia et al. showed home enteral nutrition was cost-effective (£12,817/QALY), and Beavan et al. showed higher nutrient intake and low increase in hospitalisation costs using looped-nasogastric tubes (£5.20 for every 1% increase). Heterogeneity between studies precluded a quantitative synthesis. CONCLUSIONS: Included studies suggest that healthcare interventions aiming to prevent OD complications are cost-effective. However, studies assessing novel strategies are needed.

The management of polypharmacy in people living with HIV.

Antiretroviral therapy (ART) has modified the prognosis of HIV which has evolved into a chronic condition. People living with HIV (PLWH) are living longer presenting an increased number of comorbidities leading to polypharmacy. Literature on the prevalence, associated factors, drug-drug interactions (DDIs), effects on ART-outcomes, geriatric conditions, and nutritional status together with health-interventions aimed to reduce it is presented in this review. A literature search was conducted on the MEDLINE database for all relevant English- and Spanish-language studies since 2006. Studies providing data of interest were identified and ordered in groups: (i) prevalence and associated factors (n = 37), (ii) DDIs (n = 19), (iii) Effects on ART-outcomes (n = 12), (iv) Effects on health conditions (n = 13), and (V) Health-interventions to assess and/or reduce it (n = 9). Polypharmacy occurs in 9-91% of PLWH (2.6-19.5% affected by severe polypharmacy). Main factors associated with polypharmacy are older age, a higher number of comorbidities, frailty, deteriorated renal function, and previous hospitalizations. DDIs were present in 19.15-84% of cases (1.3-12.2% for the most severe types). Mainly involved non-ART drugs were antihypertensives, statins, antithrombotic agents, corticosteroids, divalent cations, and antiacids. Polypharmacy can affect ART selection, adherence, and outcomes and has been related to some geriatric conditions such as falls, frailty, and poor nutritional status. Potentially prescribing issues are present in up to 87.9% of cases according to the STOPP-START and Beers criteria and some pharmacist-led interventions have been shown to reduce it. Considering these findings, polypharmacy should be considered a clinical concern in this population and treatment-optimization programs are needed to reduce its burden.

Risk factors for nosocomial bloodstream infections in COVID-19 affected patients: protocol for a case-control study.

BACKGROUND: Nosocomial bloodstream infection (nBSI) is an important clinical concern among COVID-19 hospitalised patients. It can cause sepsis and septic shock leading to high morbidity, mortality, and the emergence of antibiotic resistance. The aim of this case-control study is to identify the risk factors associated with the nBSI development in COVID-19 hospitalised patients and its incidence. METHODS AND ANALYSIS: A retrospective case-control study will be performed. Cases will include nBSI episodes of adult patients (≥18 years) admitted to Hospital Universitari Germans Trias i Pujol, Barcelona, Spain, from April to December 2020 with a diagnosis of SARS-CoV-2 pneumonia. Patients transferred from other hospitals will be excluded. Controls will include hospitalisation episodes of COVID-19 patients without nBSI. We will recruit a minimum of 74 nBSI episodes (cases) and 74 controls (according to sample size calculation). We will collect data on sociodemographics, clinical status at admission, hospital admission, in-hospital mortality, and exposure data (use of antivirals, glucocorticoids or immunomodulatory agents, length of hospitalisation, and use of medical devices such as intravenous catheters). A bivariate and a subsequent multivariate regression analysis will be performed to assess the independent effect of the associated risk factors after adjusting for confounders. The nBSI incidence rate will be estimated according to the number of nBSI episodes in admitted COVID-19 patients among the total person-month of follow-up. ETHICS AND DISSEMINATION: The protocol of this study was approved by the Ethical Committee for Drug Investigation of the Hospital Universitari Germans Trias i Pujol. The results of this case-control study will be published in a peer reviewed journal.

BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells.

Although the BCL6 transcriptional repressor is frequently expressed in human follicular lymphomas (FL), its biological role in this disease remains unknown. Herein, we comprehensively identify the set of gene promoters directly targeted by BCL6 in primary human FLs. We noted that BCL6 binds and represses NOTCH2 and NOTCH pathway genes. Moreover, BCL6 and NOTCH2 pathway gene expression is inversely correlated in FL. Notably, BCL6 upregulation is associated with repression of NOTCH2 and its target genes in primary human and murine germinal center (GC) cells. Repression of NOTCH2 is an essential function of BCL6 in FL and GC B cells because inducible expression of Notch2 abrogated GC formation in mice and killed FL cells. Indeed, BCL6-targeting compounds or gene silencing leads to the induction of NOTCH2 activity and compromises survival of FL cells, whereas NOTCH2 depletion or pathway antagonists rescue FL cells from such effects. Moreover, BCL6 inhibitors induced NOTCH2 expression and suppressed growth of human FL xenografts in vivo and primary human FL specimens ex vivo These studies suggest that established FLs are thus dependent on BCL6 through its suppression of NOTCH2Significance: We show that human FLs are dependent on BCL6, and primary human FLs can be killed using specific BCL6 inhibitors. Integrative genomics and functional studies of BCL6 in primary FL cells point toward a novel mechanism whereby BCL6 repression of NOTCH2 drives the survival and growth of FL cells as well as GC B cells, which are the FL cell of origin. Cancer Discov; 7(5); 506-21. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 443.

Factors associated with physical or sexual intimate partner violence perpetration by men attending substance misuse treatment in Catalunya: A mixed methods study.

BACKGROUND: Prevalence of intimate partner violence perpetration is higher among male substance misusers than men in the general population. Previous studies have included few risk factors, limiting their capacity to inform interventions. AIM: The aim of this study was to examine factors associated with intimate partner violence by male substance misusers. METHODS: Two hundred and thirty-five men in treatment for substance misuse completed surveys that included the Revised Conflict Tactics Scale and the Psychological Maltreatment of Women Inventory (PMWI). Variables significant in bivariate analyses were entered into multiple logistic regression analyses. Seventeen in-depth interviews were conducted with perpetrators and analysed using a framework approach. RESULTS: Just over a third of the men (34%) had been violent in the last year to their current/most recent partner. After excluding the men's own domestic victimisation from the multivariate model, perpetratation of such violence was significantly and independently associated with lower level of education, having higher PMWI dominance-isolation and emotional-verbal subscale scores and parents who had separated/divorced, and at a lower level of significance, childhood physical abuse, hazardous drinking and cocaine as the principal drug for which treatment was sought. Interview data suggested that perpetrators 'blamed' alcohol or cocaine use, jealousy, control and provocation or 'fighting back' for their behaviour. CONCLUSIONS: Intimate partner violence is common among men attending substance misuse treatment. Integrated interventions should that address both intimate partner violence and substance misuse should be considered. Areas for intervention would include reducing dominating-isolating behaviours and emotional-verbal abuse, improving communication skills, challenging gender-specific roles and believing that substance use 'causes' violent behaviour.

BCL6 is critical for the development of a diverse primary B cell repertoire.

BCL6 protects germinal center (GC) B cells against DNA damage-induced apoptosis during somatic hypermutation and class-switch recombination. Although expression of BCL6 was not found in early IL-7-dependent B cell precursors, we report that IL-7Ralpha-Stat5 signaling negatively regulates BCL6. Upon productive VH-DJH gene rearrangement and expression of a mu heavy chain, however, activation of pre-B cell receptor signaling strongly induces BCL6 expression, whereas IL-7Ralpha-Stat5 signaling is attenuated. At the transition from IL-7-dependent to -independent stages of B cell development, BCL6 is activated, reaches expression levels resembling those in GC B cells, and protects pre-B cells from DNA damage-induced apoptosis during immunoglobulin (Ig) light chain gene recombination. In the absence of BCL6, DNA breaks during Ig light chain gene rearrangement lead to excessive up-regulation of Arf and p53. As a consequence, the pool of new bone marrow immature B cells is markedly reduced in size and clonal diversity. We conclude that negative regulation of Arf by BCL6 is required for pre-B cell self-renewal and the formation of a diverse polyclonal B cell repertoire.

Kaiso contributes to DNA methylation-dependent silencing of tumor suppressor genes in colon cancer cell lines.

Aberrant CpG methylation of tumor suppressor gene regulatory elements is associated with transcriptional silencing and contributes to malignant transformation of different tissues. It is presumed that methylated DNA sequences recruit repressor machinery to actively shutdown gene expression. The Kaiso protein is a transcriptional repressor expressed in human and murine colorectal tumors that can bind to methylated clusters of CpG dinucleotides. We show here that Kaiso represses methylated tumor suppressor genes and can bind in a methylation-dependent manner to the CDKN2A in human colon cancer cell lines. The contribution of Kaiso to epigenetic silencing was underlined by the fact that Kaiso depletion induced tumor suppressor gene expression without affecting DNA methylation levels. As a consequence, colon cancer cells became susceptible to cell cycle arrest and cell death mediated by chemotherapy. The data suggest that Kaiso is a methylation-dependent "opportunistic" oncogene that silences tumor suppressor genes when they become hypermethylated. Because Kaiso inactivation sensitized colon cancer cell lines to chemotherapy, it is possible that therapeutic targeting of Kaiso could improve the efficacy of current treatment regimens.

Involvement of chromatin and histone deacetylation in SV40 T antigen transcription regulation.

Simian Virus 40 (SV40) large T antigen (T Ag) is a multifunctional viral oncoprotein that regulates viral and cellular transcriptional activity. However, the mechanisms by which such regulation occurs remain unclear. Here we show that T antigen represses CBP-mediated transcriptional activity. This repression is concomitant with histone H3 deacetylation and is TSA sensitive. Moreover, our results demonstrate that T antigen interacts with HDAC1 in vitro in an Rb-independent manner. In addition, the overexpression of HDAC1 cooperates with T antigen to antagonize CBP transactivation function and correlates with chromatin deacetylation of the TK promoter. Finally, decreasing HDAC1 levels with small interfering RNA (siRNA) partially abolishes T antigen-induced repression. These findings highlight the importance of the histone acetylation/deacetylation balance in the cellular transformation mediated by oncoviral proteins.

The histone acetyltransferases CBP/p300 are degraded in NIH 3T3 cells by activation of Ras signalling pathway.

The CBP [CREB (cAMP-response-element-binding protein)-binding protein]/p300 acetyltransferases function as transcriptional co-activators and play critical roles in cell differentiation and proliferation. Accumulating evidence shows that alterations of the CBP/p300 protein levels are linked to human tumours. In the present study, we show that the levels of the CBP/p300 co-activators are decreased dramatically by continuous PDGF (platelet-derived growth factor) and Ras signalling pathway activation in NIH 3T3 fibroblasts. This effect occurs by reducing the expression levels of the CBP/p300 genes. In addition, CBP and p300 are degraded by the 26 S proteasome pathway leading to an overall decrease in the levels of the CBP/p300 proteins. Furthermore, we provide evidence that Mdm2 (murine double minute 2), in the presence of active H-Ras or N-Ras, induces CBP/p300 degradation in NIH 3T3 cells. These findings support a novel mechanism for modulating other signalling transduction pathways that require these common co-activators.

Role of histone modifications in marking and activating genes through mitosis.

The global inhibition of transcription at the mitotic phase of the cell cycle occurs together with the general displacement of transcription factors from the mitotic chromatin. Nevertheless, the DNase- and potassium permanganate-hypersensitive sites are maintained on potentially active promoters during mitosis, helping to mark active genes at this stage of the cell cycle. Our study focuses on the role of histone acetylation and H3 (Lys-4) methylation in the maintenance of the competency of these active genes during mitosis. To this end we have analyzed histone modifications across the promoters and coding regions of constitutively active, inducible, and inactive genes in mitotic arrested cells. Our results show that basal histone modifications are maintained during mitosis at promoters and coding regions of the active and inducible RNA polymerase II-transcribed genes. In addition we have demonstrated that, together with H3 acetylation and H3 (Lys-4) methylation, H4 (Lys-12) acetylation at the coding regions contributes to the formation of a stable mark on active genes at this stage of the cell cycle. Finally, analysis of cyclin B1 gene activation during mitosis revealed that the former occurs with a strong increase of H3 (Lys-4) trimethylation but not H3 or H4 acetylation, suggesting that histone methyltransferases are active during this stage. These data demonstrate a critical role of histone acetylation and H3 (Lys-4) methylation during mitosis in marking and activating genes during the mitotic stage of the cell cycle.

Mechanisms of P/CAF auto-acetylation.

P/CAF is a histone acetyltransferase enzyme which was originally identified as a CBP/p300-binding protein. In this manuscript we report that human P/CAF is acetylated in vivo. We find that P/CAF is acetylated by itself and by p300 but not by CBP. P/CAF acetylation can be an intra- or intermolecular event. The intermolecular acetylation requires the N-terminal domain of P/CAF. The intramolecular acetylation targets five lysines (416-442) at the P/CAF C-terminus, which are in the nuclear localisation signal (NLS). Finally, we show that acetylation of P/CAF leads to an increment of its histone acetyltransferase (HAT) activity. These findings identify a new post-translation modification on P/CAF which may regulate its function.

The SV40 T antigen modulates CBP histone acetyltransferase activity.

Histone acetyltransferases (HATs) play a key role in transcription control, cell proliferation and differentiation by modulating chromatin structure; however, little is known about their own regulation. Here we show that expression of the viral oncoprotein SV40 T antigen increases histone acetylation and global cellular HAT activities. In addition, it enhances CREB-binding protein HAT activity and modulates its transcriptional activity. Finally, we show that inhibition of cellular histone deacetylases by trichostatin A increases the SV40 infectivity rate. These findings highlight the importance of histone acetylation in the regulation of the cell cycle by oncoviral proteins.