Effect of inpatient rehabilitation treatment ingredients on functioning, quality of life, length of stay, discharge destination, and mortality among older adults with unplanned admission: an overview review.

BACKGROUND: To synthesise the evidence for the effectiveness of inpatient rehabilitation treatment ingredients (versus any comparison) on functioning, quality of life, length of stay, discharge destination, and mortality among older adults with an unplanned hospital admission. METHODS: A systematic search of Cochrane Library, MEDLINE, Embase, PsychInfo, PEDro, BASE, and OpenGrey for published and unpublished systematic reviews of inpatient rehabilitation interventions for older adults following an unplanned admission to hospital from database inception to December 2020. Duplicate screening for eligibility, quality assessment, and data extraction including extraction of treatment components and their respective ingredients employing the Treatment Theory framework. Random effects meta-analyses were completed overall and by treatment ingredient. Statistical heterogeneity was assessed with the inconsistency-value (I2). RESULTS: Systematic reviews (n = 12) of moderate to low quality, including 44 non-overlapping relevant RCTs were included. When incorporated in a rehabilitation intervention, there was a large effect of endurance exercise, early intervention and shaping knowledge on walking endurance after the inpatient stay versus comparison. Early intervention, repeated practice activities, goals and planning, increased medical care and/or discharge planning increased the likelihood of discharge home versus comparison. The evidence for activities of daily living (ADL) was conflicting. Rehabilitation interventions were not effective for functional mobility, strength, or quality of life, or reduce length of stay or mortality. Therefore, we did not explore the potential role of treatment ingredients for these outcomes. CONCLUSION: Benefits observed were often for subgroups of the older adult population e.g., endurance exercise was effective for endurance in older adults with chronic obstructive pulmonary disease, and early intervention was effective for endurance for those with hip fracture. Future research should determine whether the effectiveness of these treatment ingredients observed in subgroups, are generalisable to older adults more broadly. There is a need for more transparent reporting of intervention components and ingredients according to established frameworks to enable future synthesis and/or replication. TRIAL REGISTRATION: PROSPERO Registration CRD42018114323 .

Prognostic factors of depression and depressive symptoms after hip fracture surgery: systematic review.

BACKGROUND: Patients with hip fracture and depression are less likely to recover functional ability. This review sought to identify prognostic factors of depression or depressive symptoms up to 1 year after hip fracture surgery in adults. This review also sought to describe proposed underlying mechanisms for their association with depression or depressive symptoms. METHODS: We searched for published (MEDLINE, Embase, PsychInfo, CINAHL and Web of Science Core Collection) and unpublished (OpenGrey, Greynet, BASE, conference proceedings) studies. We did not impose any date, geographical, or language limitations. Screening (Covidence), extraction (Checklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies, adapted for use with prognostic factors studies Checklist), and quality appraisal (Quality in Prognosis Studies tool) were completed in duplicate. Results were summarised narratively. RESULTS: In total, 37 prognostic factors were identified from 12 studies included in this review. The quality of the underlying evidence was poor, with all studies at high risk of bias in at least one domain. Most factors did not have a proposed mechanism for the association. Where factors were investigated by more than one study, the evidence was often conflicting. CONCLUSION: Due to conflicting and low quality of available evidence it is not possible to make clinical recommendations based on factors prognostic of depression or depressive symptoms after hip fracture. Further high-quality research investigating prognostic factors is warranted to inform future intervention and/or stratified approaches to care after hip fracture. TRIAL REGISTRATION: Prospero registration: CRD42019138690 .

Irish Policy-makers' Perceptions of Barriers and Facilitators to Hand Hygiene Compliance

Aim To examine the barriers to, and facilitators of, hand hygiene (HH) practices as perceived by national and hospital-level HH policy-makers in Ireland; and identify the extent to which the issues identified are addressed in national HH guidelines. Methods Semi-structured interviews were conducted with 12 national-and hospital-level Irish HH policy-makers. Four national Irish HH policy documents were reviewed. Results The policy-makers identified a range of barriers and facilitators of HH compliance. These were found to fit into six themes, with a number of suggestions for how to improve HH compliance. All of the policy documents referenced the World Health Organization's five moments, but lacked guidance on how to improve HH compliance beyond recommending audit and feedback. Conclusion Policy-makers identified potential areas for targeting in future interventions. The varied extent to which the issues identified in the interviews were addressed in the guidelines, policies, and standards suggest that revision of such documents is required.

Psychometric evaluation of a measure of factors influencing hand hygiene behaviour to inform intervention.

BACKGROUND: Although the hand hygiene (HH) procedure is simple, the related behaviour is complex and is not readily understood, explained or changed. There is a need for practical tools to provide data that can guide healthcare managers and practitioners not only on the 'what' (the standards that must be met), but also the 'how' (guidance on how to achieve the standards). AIM: To develop a valid questionnaire to evaluate attitudes to the factors that influence engagement in HH behaviour that can be readily completed, administered and analysed by healthcare professionals to identify appropriate intervention strategies. Construct validity was assessed using confirmatory factor analysis, predictive validity was assessed through comparison with self-reported HH behaviour, and convergent validity was assessed through direct unit-level observation of HH behaviour. METHODS: The Capability, Opportunity, Motivation-Behaviour (COM-B) model was used to design a 25-item questionnaire that was distributed to intensive care unit (ICU) personnel in Ireland. Direct observation of HH behaviour was carried out at two ICUs. FINDINGS: In total, 292 responses to the survey (response rate 41.0%) were included in the analysis. Confirmatory factor analysis resulted in a 17-item questionnaire. Multiple regression revealed that a model including capability, opportunity and motivation was a significant predictor of self-reported behavioural intention [F(3,209)=22.58, P<0.001]. However, the opportunity factor was not found to make a significant contribution to the regression model. CONCLUSION: The COM-B HH questionnaire is reliable and valid, and provides data to support the development and evaluation of HH interventions that meet the needs of specific healthcare units.

Computerised cognitive behavioural therapy for alcohol use disorder: a pilot randomised control trial.

BACKGROUND: Cognitive behavioural therapy (CBT) has been used in the treatment of alcohol use disorder (AUD), generally in individual or group therapy, but not via computer. Aim This study examined the effectiveness of an interactive, personalised, computer-based CBT therapy in a randomised control trial. METHODS: We studied a group of 55 patients with AUD, randomised to either 5-hour-long computerised CBT sessions or a placebo cognitive-stimulating session, together with a 4-week inpatient rehabilitation treatment, and followed them for 3 months. RESULTS: There was a high degree of patient adherence to the protocol. Both groups did well, with a significant fall in alcohol outcome measures including number of drinks per drinking day, and number of drinking days, and an increase in abstinence rates in both groups to an equivalent level. The CBT group attended alcoholics anonymous groups more frequently, and had significant alterations in their alcohol self-efficacy outcomes, which correlated with their drinking outcomes. We concluded that computerised CBT is a potentially useful clinical tool that warrants further investigation in different treatment settings for AUD.

Apoptosis and proliferation in nongenotoxic carcinogenesis: species differences and role of PPARalpha.

Peroxisome proliferators (PPs) are nongenotoxic rodent hepatocarcinogens that cause liver enlargement and hepatocarcinogenesis associated with peroxisome proliferation, induction of hepatocyte DNA synthesis and suppression of apoptosis. Acyl CoA oxidase (ACO) is a key enzyme of peroxisomal beta-oxidation and its transcriptional activation by PPs is often used as marker for the rodent response. PPs activate the peroxisome proliferator activated receptor-alpha, PPARalpha. Recent data suggest a role for tumour necrosis factor alpha (TNFalpha). This cytokine appears to be permissive for a PPARalpha-dependent growth response to PPs. Humans and guinea pigs appear to be nonresponsive to the adverse effects of PPs noted in rodents. These species differences can be attributed to reduced quantity of full length functional PPARalpha in human liver and evidence supports the presence of a truncated form of PPARalpha, hPPARalpha8/14 in human liver. In addition, species differences could be attributed to qualitative differences in the PPARalpha-mediated response because the promoter for human ACO differs in sequence and activity from the rat equivalent. These data contribute to our understanding of how chemicals may cause tumours in rodents and how this response may differ in humans.

Species differences in sequence and activity of the peroxisome proliferator response element (PPRE) within the acyl CoA oxidase gene promoter.

In rats and mice, peroxisome proliferators (PP) cause liver enlargement, hepatocarcinogenesis and peroxisome proliferation associated with induction of enzymes such as acyl CoA oxidase (ACO). However, humans appear to be non-responsive to the adverse effects of PPs such as ACO induction. PPs activate the peroxisome proliferator activated receptor alpha (PPARalpha) that binds to DNA at peroxisome proliferator response elements (PPREs) within the promoters of PP-responsive genes. When the human ACO promoter was cloned previously (Varanasi et al., 1996. Journal of Biological Chemistry, 271, 2147-2155), it was reported to contain a PPRE (5' AGGTCA C TGGTCA 3') that bound PPARalpha and could be activated in vitro by Wyeth-14,643 (at >1 mM) or DEHP (at > 1.5 mM). In contrast, when we cloned the ACO gene promoter from a human liver biopsy, it was non-responsive to PPs and differed at three positions (5' AGGTCA G CTGTCA 3') from that reported previously (Woodyatt et al., 1999. Carcinogenesis, 20, 369-375). Subsequent to this, Varanasi et al. re-sequenced their constructs and obtained the same sequence as we have described (Varanasi et al., 1998. Journal of Biological Chemistry, 273, 30832). However, the observation that the errant sequence (5' AGGTCA C TGGTCA 3') was able to bind PPARalpha still remained since it appears that this sequence was used by Varanasi et al. (1996) to design oligonucleotides for their DNA binding analyses. Thus, if the 5' AGGTCA C TGGTCA 3' sequence did exist in some individuals, it could be active. To address this, we used site-directed mutagenesis to create a promoter fragment that contained the errant sequence. This reporter gene was transfected into NIH3T3 cells together with a plasmid expressing mPPARalpha, and assessed for its ability to drive PP-mediated gene transcription using a non-toxic concentration of Wyeth-14,643 (100 microM). This human ACO promoter was also inactive, unlike the equivalent rat ACO promoter fragment used as a positive control. Next, we used site directed mutagenesis to convert the PPRE found in the active rat ACO promoter (3' AGGACA A AGGTCA 5') to our inactive human sequence (AGGTCA G CTGTCA). This human PPRE was unable to drive PP-induced gene transcription even in the context of the rat ACO promoter suggesting that the activity of the rat promoter is conferred principally by the PPRE sequence, even though it may be enhanced by flanking sequences. These data confirm that neither the native nor the errant human ACO gene PPRE can respond to PPs. The absence of a responsive PPRE contributes to our understanding of the lack of response of humans to some of the adverse effects of the PP class of non-genotoxic hepatocarcinogens.

The peroxisome proliferator (PP) response element upstream of the human acyl CoA oxidase gene is inactive among a sample human population: significance for species differences in response to PPs.

Peroxisome proliferators (PP) cause peroxisome proliferation, associated with rodent hepatocyte growth perturbation and hepatocarcinogenesis. However, in humans this class of non-genotoxic carcinogens does not appear to have the same adverse effects. The peroxisome proliferator-activated receptor alpha (PPARalpha) mediates the effects of PPs in rodents via peroxisome proliferator response elements (PPREs) upstream of PP-responsive genes such as acyl coenzyme A oxidase (ACO). When the human ACO promoter was cloned previously, it was found to be active and to contain a consensus PPRE (-1918 AGGTCA C TGGTCA -1906). To confirm and extend those original findings, we isolated a 2 kb genomic fragment of the ACO gene promoter from a human liver biopsy and used it to create a beta-galactosidase reporter gene plasmid. The human ACO promoter reporter plasmid was added to both Hepalclc7 and NIH 3T3 cells together with a plasmid expressing mPPARa and assessed for its ability to drive PP-mediated gene transcription. The human ACO promoter fragment was inactive, unlike the equivalent rat ACO promoter fragment used as a positive control. The PPRE within our cloned fragment of the human ACO promoter differed at three positions (5'-AGGTCA G CTGTCA-3') from the previously published active human ACO promoter. Next, we studied the frequency of the inactive versus the active human PPRE within the human population. Using a PCR strategy, we isolated and analysed genomic DNA fragments from 22 unrelated human individuals and from the human hepatoma cell line HepG2. In each case, the PPRE contained the inactive sequence. These data show that the human ACO gene promoter found in a sample human population is inactive. This may explain at the genomic level the lack of response of humans to some of the adverse effects of the PP class of non-genotoxic hepatocarcinogens.

Amino acid residues in both the DNA-binding and ligand-binding domains influence transcriptional activity of the human peroxisome proliferator-activated receptor alpha.

We have investigated the basis of the lack of activity of a natural variant human peroxisome proliferator-activated receptor alpha, hPPARalpha6/29. A subcloning approach was used to change the four variant amino acids in the hPPARalpha6/29 sequence, individually and in combination, to those found in an active human PPARalpha. Individual amino acid "back mutations" were unable to confer on hPPARalpha6/29 the ability to be activated by peroxisome proliferators in a transient transfection assay. Although hPPARalpha6/29 was able to bind specifically to DNA in the presence of the retinoid X receptor alpha (RXRalpha), the complete restoration of receptor transcriptional activity required two separate back mutations of the hPPARalpha6/29 sequence, namely amino acid 123 in the DNA binding domain, and amino acid 444 close to the C-terminus. This suggests that sequences in the PPARalpha DNA binding domain influence other receptor functions besides DNA binding.

Peroxisome proliferator-activated receptors: structures and function.

We have been attempting to elucidate the molecular mechanisms through which peroxisome proliferators exert their pleiotropic effects, with particular emphasis on understanding why humans appear unresponsive to these compounds. There is a wealth of data to implicate the peroxisome proliferator-activated receptor alpha (PPAR alpha) in mediating these effects in rodent species; PPAR alpha is expressed in tissues that show physiological changes in response to PPs, is transcriptionally activated in vitro by a variety of PPs, and it has been recently demonstrated that mice lacking this receptor are refractory to the effects of clofibrate and Wy-14,643, at least in the short term. It is conceivable that differences in PPAR alpha between responsive rodent and unresponsive human subjects may provide the key to understanding the basis of this species variation in response, and with this in mind we have been studying the biology of PPAR alpha in humans and looking at interindividual variation. There is already published evidence, albeit on only two sequences, for structural and functional polymorphism in human PPAR alphas. We have extended these findings, and shown that: There is considerable variation in hPPAR alpha cDNAs obtained from different individuals, both at the gross structural level (lack of a coding exon) and of a more subtle nature (single base changes leading to amino acid substitutions). One such cDNA, the sequence of which differs at only three amino acids from that published, encodes a receptor that is incapable of transcriptional activation by potent PPs. The degree to which hPPAR alpha transcripts are expressed in human livers can vary by up to an order of magnitude between individuals. The tissue-specific expression profile of PPAR alpha in humans is very different from that in rat and mouse. In particular, the human liver contains generally low levels of PPAR alpha in contrast to the responsive rodents, in which potent PPs cause liver tumors. Taken together, these data suggest first that human and rodent PPAR alphas differ according to a number of molecular and biochemical criteria, and secondly that there is a degree of interindividual variation in PPAR alpha structure and function. Studies are ongoing to clarify this further, but human polymorphism may go some way towards explaining the apparent paradox that active PPAR alpha receptors can be isolated from an "unresponsive" species.

A human peroxisome-proliferator-activated receptor-gamma is activated by inducers of adipogenesis, including thiazolidinedione drugs.

We have cloned a human cognate of the mouse peroxisome-proliferator-activated receptor-gamma (hPPAR gamma) from a human placenta cDNA library. Sequence analysis reveals a high degree of similarity with the mouse receptor and, like other PPAR, hPPAR gamma forms heterodimers with the retinoid X receptor alpha (RXR alpha) and binds in vitro to DNA elements containing direct repeats of the sequence TGACCT. In common with mouse PPAR gamma, hPPAR gamma is expressed strongly in adipose tissue, but significant levels also are detectable in placenta, lung and ovary. In vitro trans-activation data suggest hPPAR gamma is only poorly activated by xenobiotic peroxisome proliferators, although certain fatty acids and eicosanoids are potent activators of this receptor. Both mouse and human PPAR gamma are capable of being activated by thiazolidinedione drugs, although the two receptors appear to differ in their sensitivity to these compounds. Taken together, these data suggest a high degree of structural and functional similarity between mouse and human PPAR gamma, and provide evidence for variation in human receptor structure which may result in differential sensitivity to activators.