The implementation of evidence in clinical care. Exploring the gap between knowledge and practice.

Een conceptueel kader voor onderzoek Het beschikbaar maken van de resultaten van wetenschappelijke studies (evidentie of ‘evidence’) in de klinische praktijk zou rechtstreeks de kwaliteit van zorg verbeteren. Dit is echter niet het geval. Het concept ‘kwaliteit van zorg’ is complex en vraagt om een bredere benadering. In deze thesis stellen wij een theoretisch kader voor dat kan helpen om de brede waaier van determinanten en processen in kaart te brengen die een rol spelen bij het verbeteren van kwaliteit van zorg (hoofdstuk 2). Wanneer we dit theoretische kader bekijken vanuit een onderzoeksperspectief, tekenen zich drie soorten evidentie (wetenschappelijk bewijs) af: medische, contextuele en beleidsgerelateerde evidentie. Bij het nemen van beslissingen over patiënten dienen we te bouwen op degelijke kennis van de ziekte en de aanpak ervan (medische evidentie). We moeten echter ook de specifieke context van het arts-patiënt contact en het gezondheidszorgsysteem (contextuele evidentie) in rekening nemen en aandacht hebben voor een doelmatige (efficiëntie) en billijke (equity) verdeling van de beschikbare middelen (beleidsgerelateerde evidentie). Deze drie soorten evidentie zijn opgenomen in een ‘evidentie kader’ dat gebruikt kan worden bij het ontwikkelen en analyseren van onderzoek op het gebied van kwaliteitsbevordering in de eerstelijnsgezondheidszorg. De vier onderzoeksartikels in deze thesis exploreren het nut van dit ‘evidentie kader’ als instrument bij het onderzoeken van kwaliteitsverbetering in de gezondheidszorg, waarbij het gebruik maken van de resultaten van wetenschappelijk onderzoek voorop staat. Medische evidentie Medische evidentie verkrijgen we uit klinische studies en geeft ons informatie over de werkzaamheid (efficacy) van behandelingen of interventies. Hieronder verstaan we het effect bij geselecteerde populaties, in specifieke en gecontroleerde omstandigheden. Medische evidentie is de hoeksteen van evidence-based medicine (EBM) en dient daarom betrouwbaar en van goede kwaliteit te zijn. Evidentie op basis van systematische reviews en meta-analyses waarin de resultaten van individuele studies worden samengebracht, wordt beschouwd als krachtig bewijs bij het onderbouwen van aanbevelingen voor de klinische praktijk. De kwaliteit van deze syntheses is echter afhankelijk van de kwaliteit van de individuele studies die erin zijn opgenomen. Het kritisch beoordelen van deze studies is daarom een essentieel onderdeel van het beoefenen van EBM. Een slechte methodologische kwaliteit en selectieve beschikbaarheid van data zijn belangrijk en kunnen de validiteit van de reviews in gevaar brengen. In hoofdstuk 3 nemen we de beschikbare Cochrane reviews, een belangrijke bron van gesynthetiseerde medische evidentie, onder de loep. We bestudeerden een aselecte steekproef van alle Cochrane reviews, die referenties naar “unpublished data only” opnemen. Omdat deze gegevens niet zijn beoordeeld door redacteurs van tijdschriften of andere inhoudsdeskundigen, zijn zij een potentiële bron van vertekening voor de resultaten van de meta-analyse. Onze analyse toont dat het zoeken naar ongepubliceerde studies niet veel oplevert. Bovendien wordt 38% van de als ongepubliceerd aangeduide referenties (uiteindelijk) toch gepubliceerd, ofwel binnen de gerapporteerde zoekperiode, ofwel kort daarna. De methodologische kwaliteit van deze ongepubliceerde studies, in het bijzonder de data van geneesmiddelenfabrikanten of abstracts van symposia en congressen, was over het algemeen slecht of niet te beoordelen. Daarom lijkt het niet de moeite om uitgebreid te zoeken naar meestal moeilijk te lokaliseren ongepubliceerde studies. In plaats daarvan kan overwogen worden om Cochrane reviewers te adviseren om te investeren in het regelmatig actualiseren van hun reviews. Het overdragen van medische evidentie is een volgende stap in het beoefenen van evi-dence-based practice. Met behulp van verschillende soorten interventies heeft men getracht om de kloof tussen evidentie en praktijk te overbruggen, maar een ideale oplossing bestaat niet. In vele Europese landen, waaronder België, zijn Lokale Kwaliteitsgroepen (LOK’s) opgestart, kleine groepen van collega’s (bijvoorbeeld huisartsen in een zelfde regio). Zij zijn bedoeld als instrument ter verbetering van de zorgkwaliteit en maken deel uit van nationale systemen voor accreditering en permanente navorming in de gezondheidszorg. Onderzoek naar de impact van dergelijke groepen op de kwaliteit van de patiëntenzorg is echter schaars. In een pragmatische, op cluster niveau gerandomiseerde studie, evalueerden wij het effect van een eenmalige door de LOK-groep zelf geleide bijeenkomst over een nieuwe praktijkrichtlijn voor de aanpak van acute rhinosinusitus op het voorschrijven van antibiotica (hoofdstuk 4). Door niet in te grijpen in het groepsproces trachtten we de toestand in de dagelijkse praktijk zoveel mogelijk te benaderen. We stelden vast dat een eenmalige interventie geen significant effect heeft op de hoeveelheid voorgeschreven antibiotica (56.9% van de patiënten kreeg een antibioticum in de negen interventiegroepen en 58.3% in de negen controlegroepen). Er was evenmin een verschil tussen beide groepen in de proportie voorgeschreven eerste keuze antibiotica (34.5% versus 29.4%). Deze studie suggereert dat meer aandacht voor de context van de praktijk en meer inzicht in het proces van zelfreflectie en leren nodig zijn om het toepassen van EBM met behulp van lokale kwaliteitsgroepen te optimaliseren. Contextuele evidentie Medische evidentie geeft informatie over de werkzaamheid (efficacy) van een interventie in een gecontroleerde setting bij een zorgvuldig geselecteerde groep patiënten. Echter, in de realiteit zijn patiënten in de eerstelijn een mengeling van personen met verschillende biopsy-chologische, culturele en sociaaleconomische achtergronden, die zich aanmelden met een klacht in plaats van een diagnose, en die vaak meer dan één aandoening hebben. Zij raadplegen artsen die elk hun eigen specifieke vaardigheden (bijvoorbeeld met betrekking tot communicatie), overtuigingen en empathische talenten hebben. Bovendien worden patiënten in de dagelijkse praktijk minder intensief opgevolgd dan in een klinische studie en zijn ze ook veel minder trouw aan de voorgeschreven behandeling. Al deze factoren vormen de context van de patiëntenzorg en dragen bij tot de werkzaamheid van interventies in het dagelijkse leven, namelijk de doeltreffendheid (effectiveness). Informatie over contextuele evidentie helpt ons om de kloof tussen werkzaamheid en doeltreffendheid te begrijpen. Informatie over de doeltreffendheid is wat clinici werkelijk nodig hebben. Het geeft een antwoord op hun belang-rijkste vraag: “Hoe werkt het bij mijn patiënten in mijn praktijk?” Waarom behandelen artsen een ongecompliceerde acute keelpijn nog altijd met antibiotica, terwijl er een richtlijn beschikbaar is die aanbeveelt om er geen voor te schrijven? In een observationeel onderzoek bij patiënten die hun huisarts raadpleegden voor een acute keelpijn, exploreerden we de contextuele evidentie (hoofdstuk 5). Artsen vermelden vaak dat zij onder druk van hun patiënten antibiotica voorschrijven. Ons onderzoek stelt dit argument in vraag. Een voorschrift voor een antibioticum was niet noodzakelijkerwijs de belangrijkste zorg van de patiënt. Goede pijnstilling zou wel eens een belangrijker reden kunnen zijn om hulp te zoeken. Het is mogelijk dat patiënten die een antibioticum verwachten eigenlijk iets tegen de pijn willen en onterecht denken dat een antibioticum het beste medicijn hiervoor is. Door met patiënten te praten over hun wensen en mogelijke misvattingen en door aandacht te geven aan hun ideeën over hun eigen gezondheid, zouden deze obstakels uit de weg geruimd kunnen worden en de weg kunnen open staan naar rationeler en meer evidence-based voorschrijven van antibiotica. Beleidsgerelateerde evidentie Beleidsmakers zijn vooral geïnteresseerd in de doelmatigheid (efficiency) en de billijkheid (equity) van interventies. Beleidsmaatregelen, waaronder terugbetalingsregelingen voor geneesmiddelen, kunnen krachtige drijfveren zijn van voorschrijfgedrag van artsen zeker op korte termijn. Dergelijke maatregelen zijn meestal geïnspireerd door kostenbeheersing en het is niet altijd duidelijk of dit principe overeenkomt met het principe van rationeel evidence-based voorschrijven. Onze analyse van de Belgische federale databank (Farmanet) toont dat de voorgeschreven volumes van zuurremmers inderdaad reageren op de verschillende terugbetalingsregelingen (hoofdstuk 6). Echter, deze maatregelen maken geen onderscheid tussen rationeel en irrationeel gebruik van zuurremmers en kunnen dus niet beschouwd worden als afdoende maatregel ter verbetering van de kwaliteit. Anderzijds zien we geen impact op de voorgeschreven volumes van het in dezelfde periode verspreide consensusrapport van het RIZIV over het doelmatige gebruik van zuurremmers. Onze analyse toont ook dat terugbetalingsregelingen soms een onbedoeld effect hebben. Dit alles suggereert dat het ontwerpen en evalueren van beleidsmaatregelen een gestructureerde procedure en evidence-based methode zouden moeten volgen. Medische en contextuele evidentie dienen het uitgangspunt te zijn van alle beleid en de referentie voor argumenten van alle betrokken partijen. Beleidsmakers dienen vervolgens de doelmatigheid en billijkheid te beoordelen en dit alles te plaatsen in de maatschappelijke en politieke prioriteiten. Een dialoog tussen beleidsmakers, onderzoekers, richtlijnontwikkelaars, gezondheidsprofessionals en patiënten zou een effectieve manier kunnen zijn om zowel kostenbeheersing als kwaliteit van zorg na te streven. De vier onderzoeksartikels in dit proefschrift illustreren dat het voorgestelde ‘evidentie ka-der’ nuttig kan zijn bij het onderzoeken van de determinanten van kwaliteit van zorg. Aandacht voor medische, contextuele en beleidsgerelateerde evidentie levert belangrijke informatie. Deze kan bruikbaar zijn bij het onderzoeken en ontwikkelen van strategieën en interventies, die het toepassen van de resultaten van wetenschappelijk onderzoek in de praktijk kunnen bevorderen. Op deze wijze kan een bijdrage geleverd worden aan het verbeteren van de kwaliteit van patiëntenzorg

Nasal decongestants in monotherapy for the common cold

Background : Many treatments for the common cold exist and are sold over-the-counter. Nevertheless, evidence on the effectiveness and safety of nasal decongestants is limited. Objectives : To assess the efficacy, and short-and long-termsafety, of nasal decongestants used inmonotherapy to alleviate symptoms of the common cold in adults and children. Search methods : We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 6, June 2016), which contains the Cochrane Acute Respiratory Infections (ARI) Specialised Register, MEDLINE (1946 to July 2016), Embase (2010 to 15 July 2016), CINAHL (1981 to 15 July 2016), LILACS (1982 to July 2016), Web of Science (1955 to July 2016) and clinical trials registers. Selection criteria : Randomised controlled trials (RCTs) and cluster-RCTs investigating the effectiveness and adverse effects of nasal decongestants compared with placebo for treating the common cold in adults and children. We excluded quasi-RCTs. Data collection and analysis : Three review authors independently extracted and summarised data on subjective measures of nasal congestion, overall patient wellbeing score, objective measures of nasal airway resistance, adverse effects and general recovery. One review author acted as arbiter in cases of disagreement. We categorised trials as single and multi-dose and analysed data both separately and together. We also analysed studies using an oral or topical nasal decongestant separately and together. Main results : We included 15 trials with 1838 participants. Fourteen studies included adult participants only (aged 18 years and over). In six studies the intervention was a single dose and in nine studies multiple doses were used. Nine studies used pseudoephedrine and three studies used oxymetazoline. Other decongestants included phenylpropanolamine, norephedrine and xylometazoline. Phenylpropanolamine (or norephedrine) is no longer available on the market therefore we did not include the results of these studies in the meta-analyses. Eleven studies used oral decongestants; four studies used topical decongestants. Participants were included after contracting the common cold. The duration of symptoms differed among studies; in 10 studies participants had symptoms for less than three days, in three studies symptoms were present for less than five days, one study counted the number of colds over one year, and one study experimentally induced the common cold. In the single-dose studies, the effectiveness of a nasal decongestant was measured on the same day, whereas the follow-up in multi-dose studies ranged between one and 10 days. Most studies were conducted in university settings (N = eight), six at a specific university common cold centre. Three studies were conducted at a university in collaboration with a hospital and two in a hospital only setting. In two studies the setting was unclear. There were large differences in the reporting of outcomes and the reporting of methods in most studies was limited. Therefore, we judged most studies to be at low or unclear risk of bias. Pooling was possible for a limited number of studies only; measures of effect are expressed as standardised mean differences (SMDs). A positive SMD represents an improvement in congestion. There is no defined minimal clinically important difference for measures of subjective improvement in nasal congestion, therefore we used the SMDs as a guide to assess whether an effect was small (0.2 to 0.49), moderate (0.5 to 0.79) or large (>= 0.8). Single-dose decongestant versus placebo: 10 studies compared a single dose of nasal decongestant with placebo and their effectiveness was tested between 15 minutes and 10 hours after dosing. Seven of 10 studies reported subjective symptom scores for nasal congestion; none reported overall patient well-being. However, pooling was not possible due to the large diversity in the measurement and reporting of symptoms of congestion. Two studies recorded adverse events. Both studies used an oral decongestant and each of them showed that there was no statistical difference between the number of adverse events in the treatment group versus the placebo group. Multi-dose decongestant versus placebo: nine studies compared multiple doses of nasal decongestants with placebo, but only five reported on the primary outcome, subjective symptom scores for nasal congestion. Only one study used a topical decongestant; none reported overall patient well-being. Subjective measures of congestion were significantly better for the treatment group compared with placebo approximately three hours after the last dose (SMD 0.49, 95% confidence interval (CI) 0.07 to 0.92; P = 0.02; GRADE: low-quality evidence). However, the SMD of 0.49 only indicates a small clinical effect. Pooling was based on two studies, one oral and one topical, therefore we were unable to assess the effects of oral and topical decongestants separately. Seven studies reported adverse events (six oral and one topical decongestant); meta-analysis showed that there was no statistical difference between the number of adverse events in the treatment group (125 per 1000) compared to the placebo group (126 per 1000). The odds ratio (OR) for adverse events in the treatment group was 0.98 (95% CI 0.68 to 1.40; P = 0.90; GRADE: low-quality evidence). The results remained the same when we only considered studies using an oral decongestant (OR 0.95, 95% CI 0.65 to 1.39; P = 0.80; GRADE: low-quality evidence). Authors' conclusions : We were unable to draw conclusions on the effectiveness of single-dose nasal decongestants due to the limited evidence available. For multiple doses of nasal decongestants, the current evidence suggests that these may have a small positive effect on subjective measures of nasal congestion in adults with the common cold. However, the clinical relevance of this small effect is unknown and there is insufficient good-quality evidence to draw any firm conclusions. Due to the small number of studies that used a topical nasal decongestant, we were also unable to draw conclusions on the effectiveness of oral versus topical decongestants. Nasal decongestants do not seem to increase the risk of adverse events in adults in the short term. The effectiveness and safety of nasal decongestants in children and the clinical relevance of their small effect in adults is yet to be determined

Antihistamines for the common cold

Background : The common cold is an upper respiratory tract infection, most commonly caused by a rhinovirus. It affects people of all age groups and although in most cases it is self limiting, the common cold still causes significant morbidity. Antihistamines are commonly offered over the counter to relieve symptoms for patients affected by the common cold, however there is not much evidence of their efficacy. Objectives : To assess the effects of antihistamines on the common cold. Search methods : We searched CENTRAL (2015, Issue 6), MEDLINE (1948 to July week 4, 2015), EMBASE (2010 to August 2015), CINAHL (1981 to August 2015), LILACS (1982 to August 2015) and Biosis Previews (1985 to August 2015). Selection criteria We selected randomised controlled trials (RCTs) using antihistamines as monotherapy for the common cold. We excluded any studies with combination therapy or using antihistamines in patients with an allergic component in their illness. Data collection and analysis : Two authors independently assessed trial quality and extracted data. We collected adverse effects information from the included trials. Main results : We included 18 RCTs, which were reported in 17 publications (one publication reports on two trials) with 4342 participants (of which 212 were children) suffering from the common cold, both naturally occurring and experimentally induced. The interventions consisted of an antihistamine as monotherapy compared with placebo. In adults there was a short-term beneficial effect of antihistamines on severity of overall symptoms: on day one or two of treatment 45% had a beneficial effect with antihistamines versus 38% with placebo (odds ratio (OR) 0.74, 95% confidence interval (CI) 0.60 to 0.92). However, there was no difference between antihistamines and placebo in the mid term(three to four days) to long term(six to 10 days). When evaluating individual symptoms such as nasal congestion, rhinorrhoea and sneezing, there was some beneficial effect of the sedating antihistamines compared to placebo (e.g. rhinorrhoea on day three: mean difference (MD) -0.23, 95% CI -0.39 to -0.06 on a four-or five-point severity scale; sneezing on day three: MD 0.35, 95% CI -0.49 to -0.20 on a four-point severity scale), but this effect is clinically non-significant. Adverse events such as sedation were more commonly reported with sedating antihistamines although the differences were not statistically significant. Only two trials included children and the results were conflicting. The majority of the trials had a low risk of bias although some lacked sufficient trial quality information. Authors' conclusions : Antihistamines have a limited short-term (days one and two of treatment) beneficial effect on severity of overall symptoms but not in the mid to long term. There is no clinically significant effect on nasal obstruction, rhinorrhoea or sneezing. Although side effects are more common with sedating antihistamines, the difference is not statistically significant. There is no evidence of effectiveness of antihistamines in children

Participant demographics reported in "Table 1" of randomised controlled trials: a case of "inverse evidence"?

Introduction. Data supporting external validity of trial results allows clinicians to assess the applicability of a study's findings to their practice population. Socio-economic status (SES) of trial participants may be critical to external validity given the relationship between social and economic circumstances and health. We explored how this is documented in reports of RCTs in four major general medical journals. Methods. The contents lists of four leading general medical journals were hand searched to identify 25 consecutive papers reporting RCT results in each journal (n = 100). Data on demographic characteristics were extracted from each paper's Table 1 only (or equivalent). Results. Authors infrequently reported key demographic characteristics relating to SES of RCT participants. Age and gender of participants were commonly reported. Less than 10% reported occupational group, employment status, income or area based measures of disadvantage. Conclusions. Without adequate reporting of key indicators of SES in trial participants it is unclear if lower SES groups are under-represented. If such groups are systematically under-recruited into trials, this may limit the external validity and applicability of study findings to these groups. This is in spite of the higher health-care need in more disadvantaged populations. Under-representation of low SES groups could underestimate the reported effect of an intervention for those with a higher baseline risk. The marginal benefit identified in a trial with poor or no representation of lower SES participants could significantly underestimate the potential benefit to a low SES community. More transparency in this reporting and greater attention to the impact of SES on intervention outcomes in clinical trials is needed. This could be considered in the next revision of the CONSORT statement

Antibiotics for acute rhinosinusitis in adults.

Background : Acute rhinosinusitis is an acute infection of the nasal passages and paranasal sinuses that lasts less than four weeks. Diagnosis of acute rhinosinusitis is generally based on clinical signs and symptoms in ambulatory care settings. Technical investigations are not routinely performed, nor are they recommended in most countries. Some trials show a trend in favour of antibiotics, but the balance of benefit versus harm is unclear. We merged two Cochrane Reviews for this update, which comprised different approaches with overlapping populations, resulting in different conclusions. For this review update, we maintained the distinction between populations diagnosed by clinical signs and symptoms, or imaging. Objectives : To assess the effects of antibiotics versus placebo or no treatment in adults with acute rhinosinusitis in ambulatory care settings. Search methods : We searched CENTRAL (2017, Issue 12), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (January 1950 to January 2018), Embase (January 1974 to January 2018), and two trials registers (January 2018). We also checked references from identified trials, systematic reviews, and relevant guidelines. Selection criteria : Randomised controlled trials of antibiotics versus placebo or no treatment in people with rhinosinusitis-like signs or symptoms or sinusitis confirmed by imaging. Data collection and analysis : Two review authors independently extracted data about cure and side effects and assessed the risk of bias. We contacted trial authors for additional information as required. Main results : We included 15 trials involving 3057 participants. Of the 15 included trials, 10 appeared in our 2012 review, and five (631 participants) are legacy trials from merging two reviews. No new studies were included from searches for this update. Overall, risk of bias was low. Without antibiotics, 46% of participants with rhinosinusitis, whether or not confirmed by radiography, were cured after 1 week and 64% after 14 days. Antibiotics can shorten time to cure, but only 5 to 11 more people per 100 will be cured faster if they receive antibiotics instead of placebo or no treatment: clinical diagnosis (odds ratio (OR) 1.25, 95% confidence interval (CI) 1.02 to 1.54; number needed to treat for an additional beneficial outcome (NNTB) 19, 95% CI 10 to 205; I-2 = 0%; 8 trials; high-quality evidence) and diagnosis confirmed by radiography (OR 1.57, 95% CI 1.03 to 2.39; NNTB 10, 95% CI 5 to 136; I-2 = 0%; 3 trials; moderate-quality evidence). Cure rates with antibiotics were higher when a fluid level or total opacification in any sinus was found on computed tomography (OR 4.89, 95% CI 1.75 to 13.72; NNTB 4, 95% CI 2 to 15; 1 trial; moderate-quality evidence). Purulent secretion resolved faster with antibiotics (OR 1.58, 95% CI 1.13 to 2.22; NNTB 10, 95% CI 6 to 35; I-2 = 0%; 3 trials; high-quality evidence). However, 13 more people experienced side effects with antibiotics compared to placebo or no treatment (OR 2.21, 95% CI 1.74 to 2.82; number needed to treat for an additional harmful outcome (NNTH) 8, 95% CI 6 to 12; I-2 = 16%; 10 trials; high-quality evidence). Five fewer people per 100 will experience clinical failure if they receive antibiotics instead of placebo or no treatment (Peto OR 0.48, 95% CI 0.36 to 0.63; NNTH 19, 95% CI 15 to 27; I-2 = 21%; 12 trials; high-quality evidence). A disease-related complication (brain abscess) occurred in one participant (of 3057) one week after receiving open antibiotic therapy (clinical failure, control group). Authors' conclusions :The potential benefit of antibiotics to treat acute rhinosinusitis diagnosed either clinically (low risk of bias, high-quality evidence) or confirmed by imaging (low to unclear risk of bias, moderate-quality evidence) is marginal and needs to be seen in the context of the risk of adverse effects. Considering antibiotic resistance, and the very low incidence of serious complications, we conclude there is no place for antibiotics for people with uncomplicated acute rhinosinusitis. We could not draw conclusions about children, people with suppressed immune systems, and those with severe sinusitis, because these populations were not included in the available trials

Withdrawal versus continuation of long-term antipsychotic drug use for behavioural and psychological symptoms in older people with dementia

Background : Antipsychotic agents are often used to treat neuropsychiatric symptoms (NPS) in people with dementia although there is uncertainty about the effectiveness of their long-term use for this indication and concern that they may cause harm, including higher mortality. When behavioural strategies have failed and treatment with antipsychotic drugs is instituted, regular attempts to withdraw them have been recommended in guidelines. Physicians, nurses and families of older people with dementia may be reluctant to stop antipsychotics, fearing deterioration of NPS. This is an update of a Cochrane Review published in 2013. Objectives : To evaluate whether withdrawal of antipsychotic agents is successful in older people with dementia and NPS in primary care or nursing home settings, to list the different strategies for withdrawal of antipsychotic agents in older participants with dementia and NPS, and to measure the effects of withdrawal of antipsychotic agents on participants' behaviour and assess safety. Search methods : We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, clinical trials registries and grey literature sources up to 11 January 2018. Selection criteria : We included all randomised, controlled trials comparing an antipsychotic withdrawal strategy to continuation of antipsychotics in people with dementia who had been treated with an antipsychotic drug for at least three months. Data collection and analysis : We used standard methodological procedures according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of evidence for each outcome using the GRADE approach. Main results : We included 10 studies involving 632 participants. One new trial (19 participants) was added for this update. One trial was conducted in a community setting, eight in nursing homes and one in both settings. Different types of antipsychotics at varying doses were discontinued in the studies. Both abrupt and gradual withdrawal schedules were used. Reported data were predominantly from studies at low or unclear risk of bias. We included nine trials with 575 randomised participants that used a proxy outcome for overall success of antipsychotic withdrawal. Pooling data was not possible due to heterogeneity of outcome measures used. Based on assessment of seven studies, discontinuation may make little or no difference to whether or not participants complete the study (low-quality evidence). Two trials included only participants with psychosis, agitation or aggression who had responded to antipsychotic treatment. In these two trials, stopping antipsychotics was associated with a higher risk of leaving the study early due to symptomatic relapse or a shorter time to symptomatic relapse. We found low-quality evidence that discontinuation may make little or no difference to overall NPS, measured using various scales (7 trials, 519 participants). There was some evidence from subgroup analyses in two trials that discontinuation may reduce agitation for participants with less severe NPS at baseline, but may be associated with a worsening of NPS in participants with more severe NPS at baseline. None of the studies assessed withdrawal symptoms. Adverse effects of antipsychotics (such as falls) were not systematically assessed. Low-quality evidence showed that discontinuation may have little or no effect on adverse events (5 trials, 381 participants), quality of life (2 trials, 119 participants), or cognitive function (5 trials, 365 participants). There were insufficient data to determine whether discontinuation of antipsychotics has any effect on mortality (very low-quality evidence). Authors' conclusions : There is low-quality evidence that antipsychotics may be successfully discontinued in older people with dementia and NPS who have been taking antipsychotics for at least three months, and that discontinuation may have little or no important effect on behavioural and psychological symptoms. This is consistent with the observation that most behavioural complications of dementia are intermittent and often do not persist for longer than three months. Discontinuation may have little or no effect on overall cognitive function. Discontinuation may make no difference to adverse events and quality of life. Based on the trials in this review, we are uncertain whether discontinuation of antipsychotics leads to a decrease in mortality. People with psychosis, aggression or agitation who responded well to long-term antipsychotic drug use, or those with more severe NPS at baseline, may benefit behaviourally from continuation of antipsychotics. Discontinuation may reduce agitation for people with mild NPS at baseline. However, these conclusions are based on few studies or small subgroups and further evidence of benefits and harms associated with withdrawal of antipsychotic is required in people with dementia and mild and severe NPS. The overall conclusions of the review have not changed since 2013 and the number of available trials remains low

Complete sequence-based pathway analysis by differential on-chip DNA and RNA extraction from a single cell

Abstract We demonstrate on-chip, differential DNA and RNA extraction from a single cell using a microfluidic chip and a two-stage lysis protocol. This method enables direct use of the whole extract, without additional washing steps, reducing sample loss. Using this method, the tumor driving pathway in individual cells from a colorectal cancer cell line was determined by applying a Bayesian computational pathway model to sequences obtained from the RNA fraction of a single cell and, the mutations driving the pathway were determined by analyzing sequences obtained from the DNA fraction of the same single cell. This combined functional and mutational pathway assessment of a single cell could be of significant value for dissecting cellular heterogeneity in tumors and analyzing single circulating tumor cells