Rehabilitation interventions to modify physical frailty in adults before lung transplantation: a systematic review protocol.

INTRODUCTION: Lung transplantation is the gold-standard treatment for end-stage lung disease for a small group of patients meeting strict acceptance criteria after optimal medical management has failed. Physical frailty is prevalent in lung transplant candidates and has been linked to worse outcomes both on the waiting list and postoperatively. Exercise has been proven to be beneficial in optimising exercise capacity and quality of life in lung transplant candidates, but its impact on physical frailty is unknown. This review aims to assess the effectiveness of exercise interventions in modifying physical frailty for adults awaiting lung transplantation. METHODS AND ANALYSIS: This protocol was prospectively registered on the PROSPERO database. We will search four databases plus trial registries to identify primary studies of adult candidates for lung transplantation undertaking exercise interventions and assessing outcomes pertaining to physical frailty. Studies must include at least 10 participants. Article screening will be performed by two researchers independently at each stage. Extraction will be performed by one reviewer and checked by a second. The risk of bias in studies will be assessed by two independent reviewers using tools appropriate for the research design of each study; where appropriate, we will use Cochrane Risk of Bias 2 or ROBINS-I. At each stage of the review process, discrepancies will be resolved through a consensus or consultation with a third reviewer. Meta-analyses of frailty outcomes will be performed if possible and appropriate as will prespecified subgroup and sensitivity analyses. Where we are unable to perform meta-analysis, we will conduct narrative synthesis following Synthesis without Meta-analysis guidance. The review will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. ETHICS AND DISSEMINATION: No ethical issues are predicted due to the nature of this study. Dissemination will occur via conference abstracts, professional networks, peer-reviewed journals and patient support groups. PROSPERO REGISTRATION NUMBER: CRD42022363730.

Inpatient-level care at home delivered by virtual wards and hospital at home: a systematic review and meta-analysis of complex interventions and their components.

BACKGROUND: Technology-enabled inpatient-level care at home services, such as virtual wards and hospital at home, are being rapidly implemented. This is the first systematic review to link the components of these service delivery innovations to evidence of effectiveness to explore implications for practice and research. METHODS: For this review (registered here https://osf.io/je39y ), we searched Cochrane-recommended multiple databases up to 30 November 2022 and additional resources for randomised and non-randomised studies that compared technology-enabled inpatient-level care at home with hospital-based inpatient care. We classified interventions into care model groups using three key components: clinical activities, workforce, and technology. We synthesised evidence by these groups quantitatively or narratively for mortality, hospital readmissions, cost-effectiveness and length of stay. RESULTS: We include 69 studies: 38 randomised studies (6413 participants; largely judged as low or unclear risk of bias) and 31 non-randomised studies (31,950 participants; largely judged at serious or critical risk of bias). The 69 studies described 63 interventions which formed eight model groups. Most models, regardless of using low- or high-intensity technology, may have similar or reduced hospital readmission risk compared with hospital-based inpatient care (low-certainty evidence from randomised trials). For mortality, most models had uncertain or unavailable evidence. Two exceptions were low technology-enabled models that involve hospital- and community-based professionals, they may have similar mortality risk compared with hospital-based inpatient care (low- or moderate-certainty evidence from randomised trials). Cost-effectiveness evidence is unavailable for high technology-enabled models, but sparse evidence suggests the low technology-enabled multidisciplinary care delivered by hospital-based teams appears more cost-effective than hospital-based care for those with chronic obstructive pulmonary disease (COPD) exacerbations. CONCLUSIONS: Low-certainty evidence suggests that none of technology-enabled care at home models we explored put people at higher risk of readmission compared with hospital-based care. Where limited evidence on mortality is available, there appears to be no additional risk of mortality due to use of technology-enabled at home models. It is unclear whether inpatient-level care at home using higher levels of technology confers additional benefits. Further research should focus on clearly defined interventions in high-priority populations and include comparative cost-effectiveness evaluation. TRIAL REGISTRATION: https://osf.io/je39y .

Digital technologies to prevent falls in people living with dementia or mild cognitive impairment: a rapid systematic overview of systematic reviews.

OBJECTIVE: Falls are a common cause of potentially preventable death, disability and loss of independence with an annual estimated cost of £4.4bn. People living with dementia (PlwD) or mild cognitive impairment (MCI) have an increased fall risk. This overview evaluates evidence for technologies aiming to reduce falls and fall risk for PlwD or MCI. METHODS: In October 2022, we searched five databases for evidence syntheses. We used standard methods to rapidly screen, extract data, assess risk of bias and overlap, and synthesise the evidence for each technology type. RESULTS: We included seven systematic reviews, incorporating 22 relevant primary studies with 1,412 unique participants. All reviews had critical flaws on AMSTAR-2: constituent primary studies were small, heterogeneous, mostly non-randomised and assessed as low or moderate quality. Technologies assessed were: wearable sensors, environmental sensor-based systems, exergaming, virtual reality systems. We found no evidence relating to apps. Review evidence for the direct impact on falls was available only from environmental sensors, and this was inconclusive. For wearables and virtual reality technologies there was evidence that technologies may differentiate PlwD who fell from those who did not; and for exergaming that balance may be improved. CONCLUSIONS: The evidence for technology to reduce falls and falls risk for PlwD and MCI is methodologically weak, based on small numbers of participants and often indirect. There is a need for higher-quality RCTs to provide robust evidence for effectiveness of fall prevention technologies. Such technologies should be designed with input from users and consideration of the wider implementation context.

Conducting a systematic review and evaluation of commercially available mobile applications (apps) on a health-related topic: the TECH approach and a step-by-step methodological guide.

OBJECTIVES: To provide an overview of the methodological considerations for conducting commercial smartphone health app reviews (mHealth reviews), with the aim of systematising the process and supporting high-quality evaluations of mHealth apps. DESIGN: Synthesis of our research team's experiences of conducting and publishing various reviews of mHealth apps available on app stores and hand-searching the top medical informatics journals (eg, The Lancet Digital Health, npj Digital Medicine, Journal of Biomedical Informatics and the Journal of the American Medical Informatics Association) over the last five years (2018-2022) to identify other app reviews to contribute to the discussion of this method and supporting framework for developing a research (review) question and determining the eligibility criteria. RESULTS: We present seven steps to support rigour in conducting reviews of health apps available on the app market: (1) writing a research question or aims, (2) conducting scoping searches and developing the protocol, (3) determining the eligibility criteria using the TECH framework, (4) conducting the final search and screening of health apps, (5) data extraction, (6) quality, functionality and other assessments and (7) analysis and synthesis of findings. We introduce the novel TECH approach to developing review questions and the eligibility criteria, which considers the Target user, Evaluation focus, Connectedness and the Health domain. Patient and public involvement and engagement opportunities are acknowledged, including co-developing the protocol and undertaking quality or usability assessments. CONCLUSION: Commercial mHealth app reviews can provide important insights into the health app market, including the availability of apps and their quality and functionality. We have outlined seven key steps for conducting rigorous health app reviews in addition to the TECH acronym, which can support researchers in writing research questions and determining the eligibility criteria. Future work will include a collaborative effort to develop reporting guidelines and a quality appraisal tool to ensure transparency and quality in systematic app reviews.

Virtual wards: a rapid evidence synthesis and implications for the care of older people.

BACKGROUND: Virtual wards are being rapidly developed within the National Health Service in the UK, and frailty is one of the first clinical pathways. Virtual wards for older people and existing hospital at home services are closely related. METHODS: In March 2022, we searched Medline, CINAHL, the Cochrane Database of Systematic Reviews and medRxiv for evidence syntheses which addressed clinical-effectiveness, cost-effectiveness, barriers and facilitators, or staff, patient or carer experience for virtual wards, hospital at home or remote monitoring alternatives to inpatient care. RESULTS: We included 28 evidence syntheses mostly relating to hospital at home. There is low to moderate certainty evidence that clinical outcomes including mortality (example pooled RR 0.77, 95% CI 0.60-0.99) were probably equivalent or better for hospital at home. Subsequent residential care admissions are probably reduced (example pooled RR 0.35, 95% CI 0.22-0.57). Cost-effectiveness evidence demonstrated methodological issues which mean the results are uncertain. Evidence is lacking on cost implications for patients and carers. Barriers and facilitators operate at multiple levels (organisational, clinical and patient). Patient satisfaction may be improved by hospital at home relative to inpatient care. Evidence for carer experience is limited. CONCLUSIONS: There is substantial evidence for the clinical effectiveness of hospital at home but less evidence for virtual wards. Guidance for virtual wards is lacking on key aspects including team characteristics, outcome selection and data protection. We recommend that research and evaluation is integrated into development of virtual ward models. The issue of carer strain is particularly relevant.

Predictive model-based interventions to reduce outpatient no-shows: a rapid systematic review.

OBJECTIVE: Outpatient no-shows have important implications for costs and the quality of care. Predictive models of no-shows could be used to target intervention delivery to reduce no-shows. We reviewed the effectiveness of predictive model-based interventions on outpatient no-shows, intervention costs, acceptability, and equity. MATERIALS AND METHODS: Rapid systematic review of randomized controlled trials (RCTs) and non-RCTs. We searched Medline, Cochrane CENTRAL, Embase, IEEE Xplore, and Clinical Trial Registries on March 30, 2022 (updated on July 8, 2022). Two reviewers extracted outcome data and assessed the risk of bias using ROB 2, ROBINS-I, and confidence in the evidence using GRADE. We calculated risk ratios (RRs) for the relationship between the intervention and no-show rates (primary outcome), compared with usual appointment scheduling. Meta-analysis was not possible due to heterogeneity. RESULTS: We included 7 RCTs and 1 non-RCT, in dermatology (n = 2), outpatient primary care (n = 2), endoscopy, oncology, mental health, pneumology, and an magnetic resonance imaging clinic. There was high certainty evidence that predictive model-based text message reminders reduced no-shows (1 RCT, median RR 0.91, interquartile range [IQR] 0.90, 0.92). There was moderate certainty evidence that predictive model-based phone call reminders (3 RCTs, median RR 0.61, IQR 0.49, 0.68) and patient navigators reduced no-shows (1 RCT, RR 0.55, 95% confidence interval 0.46, 0.67). The effect of predictive model-based overbooking was uncertain. Limited information was reported on cost-effectiveness, acceptability, and equity. DISCUSSION AND CONCLUSIONS: Predictive modeling plus text message reminders, phone call reminders, and patient navigator calls are probably effective at reducing no-shows. Further research is needed on the comparative effectiveness of predictive model-based interventions addressed to patients at high risk of no-shows versus nontargeted interventions addressed to all patients.

Rapid evidence synthesis to enable innovation and adoption in health and social care.

BACKGROUND: The rapid identification and adoption of effective innovations in healthcare is a known challenge. The strongest evidence base for innovations can be provided by evidence synthesis, but this is frequently a lengthy process and even rapid versions of this can be time-consuming and complex. In the UK, the Accelerated Access Review and Academic Health Science Network (AHSN) have provided the impetus to develop a consistently rapid process to support the identification and adoption of high-value innovations in the English NHS. METHODS: The Greater Manchester Applied Research Collaboration (ARC-GM) developed a framework for a rapid evidence synthesis (RES) approach, which is highly integrated within the innovation process of the Greater Manchester AHSN and the associated healthcare and research ecosystem. The RES uses evidence synthesis approaches and draws on the GRADE Evidence to Decision framework to provide rapid assessments of the existing evidence and its relevance to specific decision problems. We implemented this in a real-time context of decision-making around adoption of innovative health technologies. RESULTS: Key stakeholders in the Greater Manchester decision-making process for healthcare innovations have found that our approach is both timely and flexible; it is valued for its combination of rigour and speed. Our RES approach rapidly and systematically identifies, appraises and contextualises relevant evidence, which can then be transparently incorporated into decisions about the wider adoption of innovations. The RES also identifies limitations in existing evidence for innovations and this can inform subsequent evaluations. There is substantial interest from other ARCs and AHSNs in implementing a similar process. We are currently exploring methods to make completed RES publicly available. We are also exploring methods to evaluate the impact of using RES as more implementation decisions are made. CONCLUSIONS: The RES framework we have implemented combines transparency and consistency with flexibility and rapidity. It therefore maximises utility in a real-time decision-making context for healthcare innovations.

Reconstructive surgery for treating pressure ulcers.

BACKGROUND: There are several possible interventions for managing pressure ulcers (sometimes referred to as pressure injuries), ranging from pressure-relieving measures, such as repositioning, to reconstructive surgery. The surgical approach is usually reserved for recalcitrant wounds (where the healing process has stalled, or the wound is not responding to treatment) or wounds with full-thickness skin loss and exposure of deeper structures such as muscle fascia or bone. Reconstructive surgery commonly involves wound debridement followed by filling the wound with new tissue. Whilst this is an accepted means of ulcer management, the benefits and harms of different surgical approaches, compared with each other or with non-surgical treatments, are unclear. This is an update of a Cochrane Review published in 2016. OBJECTIVES: To assess the effects of different types of reconstructive surgery for treating pressure ulcers (category/stage II or above), compared with no surgery or alternative reconstructive surgical approaches, in any care setting. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was January 2022. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) that assessed reconstructive surgery in the treatment of pressure ulcers. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the studies, extracted study data, assessed the risk of bias and undertook GRADE assessments. We would have involved a third review author in case of disagreement. MAIN RESULTS: We identified one RCT conducted in a hospital setting in the USA. It enrolled 20 participants aged between 20 and 70 years with stage IV ischial or sacral pressure ulcers (involving full-thickness skin and tissue loss). The study compared two reconstructive techniques for stage IV pressure ulcers: conventional flap surgery and cone of pressure flap surgery, in which a large portion of the flap tip is de-epithelialised and deeply inset to obliterate dead space. There were no clear data for any of our outcomes, although we extracted some information on complete wound healing, wound dehiscence, pressure ulcer recurrence and wound infection. We graded the evidence for these outcomes as very low-certainty. The study provided no data for any other outcomes. AUTHORS' CONCLUSIONS: Currently there is very little randomised evidence on the role of reconstructive surgery in pressure ulcer management, although it is considered a priority area. More rigorous and robust research is needed to explore this intervention.

The accuracy of pulse oximetry in measuring oxygen saturation by levels of skin pigmentation: a systematic review and meta-analysis.

BACKGROUND: During the COVID-19 pandemic, there have been concerns regarding potential bias in pulse oximetry measurements for people with high levels of skin pigmentation. We systematically reviewed the effects of skin pigmentation on the accuracy of oxygen saturation measurement by pulse oximetry (SpO2) compared with the gold standard SaO2 measured by CO-oximetry. METHODS: We searched Ovid MEDLINE, Ovid Embase, EBSCO CINAHL, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform (up to December 2021) for studies with SpO2-SaO2 comparisons and measuring the impact of skin pigmentation or ethnicity on pulse oximetry accuracy. We performed meta-analyses for mean bias (the primary outcome in this review) and its standard deviations (SDs) across studies included for each subgroup of skin pigmentation and ethnicity and used these pooled mean biases and SDs to calculate accuracy root-mean-square (Arms) and 95% limits of agreement. The review was registered with the Open Science Framework ( https://osf.io/gm7ty ). RESULTS: We included 32 studies (6505 participants): 15 measured skin pigmentation and 22 referred to ethnicity. Compared with standard SaO2 measurement, pulse oximetry probably overestimates oxygen saturation in people with the high level of skin pigmentation (pooled mean bias 1.11%; 95% confidence interval 0.29 to 1.93%) and people described as Black/African American (1.52%; 0.95 to 2.09%) (moderate- and low-certainty evidence). The bias of pulse oximetry measurements for people with other levels of skin pigmentation or those from other ethnic groups is either more uncertain or suggests no overestimation. Whilst the extent of mean bias is small or negligible for all subgroups evaluated, the associated imprecision is unacceptably large (pooled SDs > 1%). When the extent of measurement bias and precision is considered jointly, pulse oximetry measurements for all the subgroups appear acceptably accurate (with Arms < 4%). CONCLUSIONS: Pulse oximetry may overestimate oxygen saturation in people with high levels of skin pigmentation and people whose ethnicity is reported as Black/African American, compared with SaO2. The extent of overestimation may be small in hospital settings but unknown in community settings. REVIEW PROTOCOL REGISTRATION: https://osf.io/gm7ty.

Negative pressure wound therapy for surgical wounds healing by primary closure.

BACKGROUND: Indications for the use of negative pressure wound therapy (NPWT) are broad and include prophylaxis for surgical site infections (SSIs). Existing evidence for the effectiveness of NPWT on postoperative wounds healing by primary closure remains uncertain. OBJECTIVES: To assess the effects of NPWT for preventing SSI in wounds healing through primary closure, and to assess the cost-effectiveness of NPWT in wounds healing through primary closure. SEARCH METHODS: In January 2021, we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries and references of included studies, systematic reviews and health technology reports. There were no restrictions on language, publication date or study setting. SELECTION CRITERIA: We included trials if they allocated participants to treatment randomly and compared NPWT with any other type of wound dressing, or compared one type of NPWT with another. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed trials using predetermined inclusion criteria. We carried out data extraction, assessment using the Cochrane risk of bias tool, and quality assessment according to Grading of Recommendations, Assessment, Development and Evaluations methodology. Our primary outcomes were SSI, mortality, and wound dehiscence. MAIN RESULTS: In this fourth update, we added 18 new randomised controlled trials (RCTs) and one new economic study, resulting in a total of 62 RCTs (13,340 included participants) and six economic studies. Studies evaluated NPWT in a wide range of surgeries, including orthopaedic, obstetric, vascular and general procedures. All studies compared NPWT with standard dressings. Most studies had unclear or high risk of bias for at least one key domain. Primary outcomes Eleven studies (6384 participants) which reported mortality were pooled. There is low-certainty evidence showing there may be a reduced risk of death after surgery for people treated with NPWT (0.84%) compared with standard dressings (1.17%) but there is uncertainty around this as confidence intervals include risk of benefits and harm; risk ratio (RR) 0.78 (95% CI 0.47 to 1.30; I2 = 0%). Fifty-four studies reported SSI; 44 studies (11,403 participants) were pooled. There is moderate-certainty evidence that NPWT probably results in fewer SSIs (8.7% of participants) than treatment with standard dressings (11.75%) after surgery; RR 0.73 (95% CI 0.63 to 0.85; I2 = 29%). Thirty studies reported wound dehiscence; 23 studies (8724 participants) were pooled. There is moderate-certainty evidence that there is probably little or no difference in dehiscence between people treated with NPWT (6.62%) and those treated with standard dressing (6.97%), although there is imprecision around the estimate that includes risk of benefit and harms; RR 0.97 (95% CI 0.82 to 1.16; I2 = 4%). Evidence was downgraded for imprecision, risk of bias, or a combination of these. Secondary outcomes There is low-certainty evidence for the outcomes of reoperation and seroma; in each case, confidence intervals included both benefit and harm. There may be a reduced risk of reoperation favouring the standard dressing arm, but this was imprecise: RR 1.13 (95% CI 0.91 to 1.41; I2 = 2%; 18 trials; 6272 participants). There may be a reduced risk of seroma for people treated with NPWT but this is imprecise: the RR was 0.82 (95% CI 0.65 to 1.05; I2 = 0%; 15 trials; 5436 participants). For skin blisters, there is low-certainty evidence that people treated with NPWT may be more likely to develop skin blisters compared with those treated with standard dressing (RR 3.55; 95% CI 1.43 to 8.77; I2 = 74%; 11 trials; 5015 participants). The effect of NPWT on haematoma is uncertain (RR 0.79; 95 % CI 0.48 to 1.30; I2 = 0%; 17 trials; 5909 participants; very low-certainty evidence). There is low-certainty evidence of little to no difference in reported pain between groups. Pain was measured in different ways and most studies could not be pooled; this GRADE assessment is based on all fourteen trials reporting pain; the pooled RR for the proportion of participants who experienced pain was 1.52 (95% CI 0.20, 11.31; I2 = 34%; two studies; 632 participants). Cost-effectiveness Six economic studies, based wholly or partially on trials in our review, assessed the cost-effectiveness of NPWT compared with standard care. They considered NPWT in five indications: caesarean sections in obese women; surgery for lower limb fracture; knee/hip arthroplasty; coronary artery bypass grafts; and vascular surgery with inguinal incisions. They calculated quality-adjusted life-years or an equivalent, and produced estimates of the treatments' relative cost-effectiveness. The reporting quality was good but the evidence certainty varied from moderate to very low. There is moderate-certainty evidence that NPWT in surgery for lower limb fracture was not cost-effective at any threshold of willingness-to-pay and that NPWT is probably cost-effective in obese women undergoing caesarean section. Other studies found low or very low-certainty evidence indicating that NPWT may be cost-effective for the indications assessed. AUTHORS' CONCLUSIONS: People with primary closure of their surgical wound and treated prophylactically with NPWT following surgery probably experience fewer SSIs  than people treated with standard dressings but there is probably no difference in wound dehiscence (moderate-certainty evidence). There may be a reduced risk of death after surgery for people treated with NPWT compared with standard dressings but there is uncertainty around this as confidence intervals include risk of benefit and harm (low-certainty evidence). People treated with NPWT may experience more instances of skin blistering compared with standard dressing treatment (low-certainty evidence). There are no clear differences in other secondary outcomes where most evidence is low or very low-certainty. Assessments of cost-effectiveness of NPWT produced differing results in different indications. There is a large number of ongoing studies, the results of which may change the findings of this review. Decisions about use of NPWT should take into account surgical indication and setting and consider evidence for all outcomes.

Approaches to enabling rapid evaluation of innovations in health and social care: a scoping review of evidence from high-income countries.

OBJECTIVE: The COVID-19 pandemic increased the demand for rapid evaluation of innovation in health and social care. Assessment of rapid methodologies is lacking although challenges in ensuring rigour and effective use of resources are known. We mapped reports of rapid evaluations of health and social care innovations, categorised different approaches to rapid evaluation, explored comparative benefits of rapid evaluation, and identified knowledge gaps. DESIGN: Scoping review. DATA SOURCES: MEDLINE, EMBASE and Health Management Information Consortium (HMIC) databases were searched through 13 September 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included publications reporting primary research or methods for rapid evaluation of interventions or services in health and social care in high-income countries. DATA EXTRACTION AND SYNTHESIS: Two reviewers developed and piloted a data extraction form. One reviewer extracted data, a second reviewer checked 10% of the studies; disagreements and uncertainty were resolved through consensus. We used narrative synthesis to map different approaches to conducting rapid evaluation. RESULTS: We identified 16 759 records and included 162 which met inclusion criteria.We identified four main approaches for rapid evaluation: (1) Using methodology designed specifically for rapid evaluation; (2) Increasing rapidity by doing less or using less time-intensive methodology; (3) Using alternative technologies and/or data to increase speed of existing evaluation method; (4) Adapting part of non-rapid evaluation.The COVID-19 pandemic resulted in an increase in publications and some limited changes in identified methods. We found little research comparing rapid and non-rapid evaluation. CONCLUSIONS: We found a lack of clarity about what 'rapid evaluation' means but identified some useful preliminary categories. There is a need for clarity and consistency about what constitutes rapid evaluation; consistent terminology in reporting evaluations as rapid; development of specific methodologies for making evaluation more rapid; and assessment of advantages and disadvantages of rapid methodology in terms of rigour, cost and impact.

Development of standard definitions and grading for Maternal and Fetal Adverse Event Terminology.

OBJECTIVE: Adverse event (AE) monitoring is central to assessing therapeutic safety. The lack of a comprehensive framework to define and grade maternal and fetal AEs in pregnancy trials severely limits understanding risks in pregnant women. We created AE terminology to improve safety monitoring for developing pregnancy drugs, devices and interventions. METHOD: Existing severity grading for pregnant AEs and definitions/indicators of 'severe' and 'life-threatening' conditions relevant to maternal and fetal clinical trials were identified through a literature search. An international multidisciplinary group identified and filled gaps in definitions and severity grading using Medical Dictionary for Regulatory Activities (MedDRA) terms and severity grading criteria based on Common Terminology Criteria for Adverse Event (CTCAE) generic structure. The draft criteria underwent two rounds of a modified Delphi process with international fetal therapy, obstetric, neonatal, industry experts, patients and patient representatives. RESULTS: Fetal AEs were defined as being diagnosable in utero with potential to harm the fetus, and were integrated into MedDRA. AE severity was graded independently for the pregnant woman and her fetus. Maternal (n = 12) and fetal (n = 19) AE definitions and severity grading criteria were developed and ratified by consensus. CONCLUSIONS: This Maternal and Fetal AE Terminology version 1.0 allows systematic consistent AE assessment in pregnancy trials to improve safety.

Beds, overlays and mattresses for preventing and treating pressure ulcers: an overview of Cochrane Reviews and network meta-analysis.

BACKGROUND: Pressure ulcers (also known as pressure injuries, pressure sores and bed sores) are localised injuries to the skin or underlying soft tissue, or both, caused by unrelieved pressure, shear or friction. Specific kinds of beds, overlays and mattresses are widely used with the aim of preventing and treating pressure ulcers. OBJECTIVES: To summarise evidence from Cochrane Reviews that assess the effects of beds, overlays and mattresses on reducing the incidence of pressure ulcers and on increasing pressure ulcer healing in any setting and population. To assess the relative effects of different types of beds, overlays and mattresses for reducing the incidence of pressure ulcers and increasing pressure ulcer healing in any setting and population. To cumulatively rank the different treatment options of beds, overlays and mattresses in order of their effectiveness in pressure ulcer prevention and treatment. METHODS: In July 2020, we searched the Cochrane Library. Cochrane Reviews reporting the effectiveness of beds, mattresses or overlays for preventing or treating pressure ulcers were eligible for inclusion in this overview. Two review authors independently screened search results and undertook data extraction and risk of bias assessment using the ROBIS tool. We summarised the reported evidence in an overview of reviews. Where possible, we included the randomised controlled trials from each included review in network meta-analyses. We assessed the relative effectiveness of beds, overlays and mattresses for preventing or treating pressure ulcers and their probabilities of being, comparably, the most effective treatment. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We include six Cochrane Reviews in this overview of reviews, all at low or unclear risk of bias. Pressure ulcer prevention: four reviews (of 68 studies with 18,174 participants) report direct evidence for 27 pairwise comparisons between 12 types of support surface on the following outcomes: pressure ulcer incidence, time to pressure ulcer incidence, patient comfort response, adverse event rates, health-related quality of life, and cost-effectiveness. Here we focus on outcomes with some evidence at a minimum of low certainty. (1) Pressure ulcer incidence: our overview includes direct evidence for 27 comparisons that mostly (19/27) have very low-certainty evidence concerning reduction of pressure ulcer risk. We included 40 studies (12,517 participants; 1298 participants with new ulcers) in a network meta-analysis involving 13 types of intervention. Data informing the network are sparse and this, together with the high risk of bias in most studies informing the network, means most network contrasts (64/78) yield evidence of very low certainty. There is low-certainty evidence that, compared with foam surfaces (reference treatment), reactive air surfaces (e.g. static air overlays) (risk ratio (RR) 0.46, 95% confidence interval (CI) 0.29 to 0.75), alternating pressure (active) air surfaces (e.g. alternating pressure air mattresses, large-celled ripple mattresses) (RR 0.63, 95% CI 0.42 to 0.93), and reactive gel surfaces (e.g. gel pads used on operating tables) (RR 0.47, 95% CI 0.22 to 1.01) may reduce pressure ulcer incidence. The ranking of treatments in terms of effectiveness is also of very low certainty for all interventions. It is unclear which treatment is best for preventing ulceration. (2) Time to pressure ulcer incidence: four reviews had direct evidence on this outcome for seven comparisons. We included 10 studies (7211 participants; 699 participants with new ulcers) evaluating six interventions in a network meta-analysis. Again, data from most network contrasts (13/15) are of very low certainty. There is low-certainty evidence that, compared with foam surfaces (reference treatment), reactive air surfaces may reduce the hazard of developing new pressure ulcers (hazard ratio (HR) 0.20, 95% CI 0.04 to 1.05). The ranking of all support surfaces for preventing pressure ulcers in terms of time to healing is uncertain. (3) Cost-effectiveness: this overview includes direct evidence for three comparisons. For preventing pressure ulcers, alternating pressure air surfaces are probably more cost-effective than foam surfaces (moderate-certainty evidence). Pressure ulcer treatment: two reviews (of 12 studies with 972 participants) report direct evidence for five comparisons on: complete pressure ulcer healing, time to complete pressure ulcer healing, patient comfort response, adverse event rates, and cost-effectiveness. Here we focus on outcomes with some evidence at a minimum of low certainty. (1) Complete pressure ulcer healing: our overview includes direct evidence for five comparisons. There is uncertainty about the relative effects of beds, overlays and mattresses on ulcer healing. The corresponding network meta-analysis (with four studies, 397 participants) had only three direct contrasts and a total of six network contrasts. Again, most network contrasts (5/6) have very low-certainty evidence. There was low-certainty evidence that more people with pressure ulcers may heal completely using reactive air surfaces than using foam surfaces (RR 1.32, 95% CI 0.96 to 1.80). We are uncertain which surfaces have the highest probability of being the most effective (all very low-certainty evidence). (2) Time to complete pressure ulcer healing: this overview includes direct evidence for one comparison: people using reactive air surfaces may be more likely to have healed pressure ulcers compared with those using foam surfaces in long-term care settings (HR 2.66, 95% CI 1.34 to 5.17; low-certainty evidence). (3) Cost-effectiveness: this overview includes direct evidence for one comparison: compared with foam surfaces, reactive air surfaces may cost an extra 26 US dollars for every ulcer-free day in the first year of use in long-term care settings (low-certainty evidence). AUTHORS' CONCLUSIONS: Compared with foam surfaces, reactive air surfaces may reduce pressure ulcer risk and may increase complete ulcer healing. Compared with foam surfaces, alternating pressure air surfaces may reduce pressure ulcer risk and are probably more cost-effective in preventing pressure ulcers. Compared with foam surfaces, reactive gel surfaces may reduce pressure ulcer risk, particularly for people in operating rooms and long-term care settings. There are uncertainties for the relative effectiveness of other support surfaces for preventing and treating pressure ulcers, and their efficacy ranking. More high-quality research is required; for example, for the comparison of reactive air surfaces with alternating pressure air surfaces. Future studies should consider time-to-event outcomes and be designed to minimise any risk of bias.

Compression bandages or stockings versus no compression for treating venous leg ulcers.

BACKGROUND: Leg ulcers are open skin wounds on the lower leg that can last weeks, months or even years. Most leg ulcers are the result of venous diseases. First-line treatment options often include the use of compression bandages or stockings. OBJECTIVES: To assess the effects of using compression bandages or stockings, compared with no compression, on the healing of venous leg ulcers in any setting and population. SEARCH METHODS: In June 2020 we searched the Cochrane Wounds Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions by language, date of publication or study setting. SELECTION CRITERIA: We included randomised controlled trials that compared any types of compression bandages or stockings with no compression in participants with venous leg ulcers in any setting. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed studies using predetermined inclusion criteria. We carried out data extraction, and risk-of-bias assessment using the Cochrane risk-of-bias tool. We assessed the certainty of the evidence according to GRADE methodology. MAIN RESULTS: We included 14 studies (1391 participants) in the review. Most studies were small (median study sample size: 51 participants). Participants were recruited from acute-care settings, outpatient settings and community settings, and a large proportion (65.9%; 917/1391) of participants had a confirmed history or clinical evidence of chronic venous disease, a confirmed cause of chronic venous insufficiency, or an ankle pressure/brachial pressure ratio of greater than 0.8 or 0.9. The average age of participants ranged from 58.0 to 76.5 years (median: 70.1 years). The average duration of their leg ulcers ranged from 9.0 weeks to 31.6 months (median: 22.0 months), and a large proportion of participants (64.8%; 901/1391) had ulcers with an area between 5 and 20 cm2. Studies had a median follow-up of 12 weeks. Compression bandages or stockings applied included short-stretch bandage, four-layer compression bandage, and Unna's boot (a type of inelastic gauze bandage impregnated with zinc oxide), and comparator groups used included 'usual care', pharmacological treatment, a variety of dressings, and a variety of treatments where some participants received compression (but it was not the norm). Of the 14 included studies, 10 (71.4%) presented findings which we consider to be at high overall risk of bias. Primary outcomes There is moderate-certainty evidence (downgraded once for risk of bias) (1) that there is probably a shorter time to complete healing of venous leg ulcers in people wearing compression bandages or stockings compared with those not wearing compression (pooled hazard ratio for time-to-complete healing 2.17, 95% confidence interval (CI) 1.52 to 3.10; I2 = 59%; 5 studies, 733 participants); and (2) that people treated using compression bandages or stockings are more likely to experience complete ulcer healing within 12 months compared with people with no compression (10 studies, 1215 participants): risk ratio for complete healing 1.77, 95% CI 1.41 to 2.21; I2 = 65% (8 studies with analysable data, 1120 participants); synthesis without meta-analysis suggests more completely-healed ulcers in compression bandages or stockings than in no compression (2 studies without analysable data, 95 participants). It is uncertain whether there is any difference in rates of adverse events between using compression bandages or stockings and no compression (very low-certainty evidence; 3 studies, 585 participants). Secondary outcomes Moderate-certainty evidence suggests that people using compression bandages or stockings probably have a lower mean pain score than those not using compression (four studies with 859 participants and another study with 69 ulcers): pooled mean difference -1.39, 95% CI -1.79 to -0.98; I2 = 65% (two studies with 426 participants and another study with 69 ulcers having analysable data); synthesis without meta-analysis suggests a reduction in leg ulcer pain in compression bandages or stockings, compared with no compression (two studies without analysable data, 433 participants). Compression bandages or stockings versus no compression may improve disease-specific quality of life, but not all aspects of general health status during the follow-up of 12 weeks to 12 months (four studies with 859 participants; low-certainty evidence). It is uncertain if the use of compression bandages or stockings is more cost-effective than not using them (three studies with 486 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: If using compression bandages or stockings, people with venous leg ulcers probably experience complete wound healing more quickly, and more people have wounds completely healed. The use of compression bandages or stockings probably reduces pain and may improve disease-specific quality of life. There is uncertainty about adverse effects, and cost effectiveness. Future research should focus on comparing alternative bandages and stockings with the primary endpoint of time to complete wound healing alongside adverse events including pain score, and health-related quality of life, and should incorporate cost-effectiveness analysis where possible. Future studies should adhere to international standards of trial conduct and reporting.

Bacteria and bioburden and healing in complex wounds: A prognostic systematic review.

The wound microbiome may play an important role in the wound healing process. We conducted the first systematic prognosis review investigating whether aspects of the wound microbiome are independent prognostic factors for the healing of complex wounds. We searched Medline, Embase, CINAHL and the Cochrane Library to February 2019. We included longitudinal studies which assessed the independent association of aspects of wound microbiome with healing of complex wounds while controlling for confounding factors. Two reviewers extracted data and assessed risk of bias and certainty of evidence using the GRADE approach. We synthesised studies narratively due to the clinical and methodological heterogeneity of included studies and sparse data. We identified 28 cohorts from 21 studies with a total of 38,604 participants, including people with diabetes and foot ulcers, open surgical wounds, venous leg ulcers and pressure ulcers. Risk of bias varied from low (2 cohorts) to high (17 cohorts); the great majority of participants were in cohorts at high risk of bias. Most evidence related to the association of baseline clinical wound infection with healing. Clinical infection at baseline may be associated with less likelihood of wound healing in foot ulcers in diabetes (HR from cohort with moderate risk of bias 0.53, 95% CI 0.33 to 0.83) or slower healing in open surgical wounds (HR 0.65, 95% CI 0.51 to 0.83); evidence in other wounds is more limited. Most other associations assessed showed no clear relationship with wound healing; evidence was limited and often sparse; and we documented gaps in the evidence. There is low certainty evidence that a diagnosis of wound infection may be prognostic of poorer healing in foot ulcers in diabetes, and some moderate certainty evidence for this in open surgical wounds. Low certainty evidence means that more research could change these findings.

Intra-Cavity Lavage and Wound Irrigation for Prevention of Surgical Site Infection: Systematic Review and Network Meta-Analysis.

Background: Surgical site infections (SSIs) are costly and associated with poorer patient outcomes. Intra-operative surgical site irrigation and intra-cavity lavage may reduce the risk of SSIs through removal of dead or damaged tissue, metabolic waste, and site exudate. Irrigation with antibiotic or antiseptic solutions may further reduce the risk of SSI because of bacteriocidal properties. Randomized controlled trials (RCTs) have been conducted comparing irrigation solutions, but important comparisons (e.g., antibiotic vs. antiseptic irrigation) are absent. We use systematic review-based network meta-analysis (NMA) of RCTs to compare irrigation solutions for prevention of SSI. Methods: We used Cochrane methodology and included all RCTs of participants undergoing a surgical procedure with primary site closure, in which method of irrigation was the only systematic difference between groups. We used a random effects Bayesian NMA to create a connected network of comparisons. Results are presented as odds ratios (OR) of SSI, where OR <1 indicates a beneficial effect. Results: We identified 42 eligible RCTs with 11,726 participants. Most were at unclear or high risk of bias. The RCTs included groups given no irrigation or non-antibacterial, antiseptic, or antibiotic irrigation. There was substantial heterogeneity, and a random effects model was selected. Relative to non-antibacterial irrigation, mean OR of SSI was 0.439 (95% credible interval: 0.282, 0.667) for antibiotic irrigation and 0.573 (0.321, 0.953) for antiseptic agents. No irrigation was similar to non-antibacterial irrigation (OR 0.959 [0.555, 1.660]). Antibiotic and antiseptic irrigation were ranked as most effective for preventing SSIs; this conclusion was robust to potential bias. Conclusions: Our NMA found that antibiotic and antiseptic irrigation had the lowest odds of SSI. There was high heterogeneity, however, and studies were at high risk of bias. A large RCT directly comparing antibiotic irrigation with both antiseptic and non-antibacterial irrigation is needed to define the standard of care for SSI prevention by site irrigation.

Negative pressure wound therapy for surgical wounds healing by primary closure.

BACKGROUND: Indications for the use of negative pressure wound therapy (NPWT) are broad and include prophylaxis for surgical site infections (SSIs). Existing evidence for the effectiveness of NPWT on postoperative wounds healing by primary closure remains uncertain. OBJECTIVES: To assess the effects of NPWT for preventing SSI in wounds healing through primary closure, and to assess the cost-effectiveness of NPWT in wounds healing through primary closure. SEARCH METHODS: In June 2019, we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries and references of included studies, systematic reviews and health technology reports. There were no restrictions on language, publication date or study setting. SELECTION CRITERIA: We included trials if they allocated participants to treatment randomly and compared NPWT with any other type of wound dressing, or compared one type of NPWT with another type of NPWT. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed trials using predetermined inclusion criteria. We carried out data extraction, assessment using the Cochrane 'Risk of bias' tool, and quality assessment according to Grading of Recommendations, Assessment, Development and Evaluations methodology. MAIN RESULTS: In this third update, we added 15 new randomised controlled trials (RCTs) and three new economic studies, resulting in a total of 44 RCTs (7447 included participants) and five economic studies. Studies evaluated NPWT in the context of a wide range of surgeries including orthopaedic, obstetric, vascular and general procedures. Economic studies assessed NPWT in orthopaedic, obstetric and general surgical settings. All studies compared NPWT with standard dressings. Most studies had unclear or high risk of bias for at least one key domain. Primary outcomes Four studies (2107 participants) reported mortality. There is low-certainty evidence (downgraded twice for imprecision) showing no clear difference in the risk of death after surgery for people treated with NPWT (2.3%) compared with standard dressings (2.7%) (risk ratio (RR) 0.86; 95% confidence interval (CI) 0.50 to 1.47; I2 = 0%). Thirty-nine studies reported SSI; 31 of these (6204 participants), were included in meta-analysis. There is moderate-certainty evidence (downgraded once for risk of bias) that NPWT probably results in fewer SSI (8.8% of participants) than treatment with standard dressings (13.0% of participants) after surgery; RR 0.66 (95% CI 0.55 to 0.80 ; I2 = 23%). Eighteen studies reported dehiscence; 14 of these (3809 participants) were included in meta-analysis. There is low-certainty evidence (downgraded once for risk of bias and once for imprecision) showing no clear difference in the risk of dehiscence after surgery for NPWT (5.3% of participants) compared with standard dressings (6.2% of participants) (RR 0.88, 95% CI 0.69 to 1.13; I2 = 0%). Secondary outcomes There is low-certainty evidence showing no clear difference between NPWT and standard treatment for the outcomes of reoperation and incidence of seroma. For reoperation, the RR was 1.04 (95% CI 0.78 to 1.41; I2 = 13%; 12 trials; 3523 participants); for seroma, the RR was 0.72 (95% CI 0.50 to 1.05; I2 = 0%; seven trials; 729 participants). The effect of NPWT on occurrence of haematoma or skin blisters is uncertain (very low-certainty evidence); for haematoma, the RR was 0.67 (95% CI 0.28 to 1.59; I2 = 0%; nine trials; 1202 participants) and for blisters the RR was 2.64 (95% CI 0.65 to 10.68; I2 = 69%; seven trials; 796 participants). The overall effect of NPWT on pain is uncertain (very low-certainty evidence from seven trials (2218 participants) which reported disparate measures of pain); but moderate-certainty evidence suggests there is probably little difference between the groups in pain after three or six months following surgery for lower limb fracture (one trial, 1549 participants). There is also moderate-certainty evidence for women undergoing caesarean sections (one trial, 876 participants) and people having surgery for lower limb fractures (one trial, 1549 participants) that there is probably little difference in quality of life scores at 30 days or 3 or 6 months, respectively. Cost-effectiveness Five economic studies, based wholly or partially on trials included in our review, assessed the cost-effectiveness of NPWT compared with standard care. They considered NPWT in four indications: caesarean sections in obese women; surgery for lower limb fracture; knee/hip arthroplasty and coronary artery bypass graft surgery. They calculated quality-adjusted life-years for treatment groups and produced estimates of the treatments' relative cost-effectiveness. The reporting quality was good but the grade of the evidence varied from moderate to very low. There is moderate-certainty evidence that NPWT in surgery for lower limb fracture was not cost-effective at any threshold of willingness-to-pay and that NPWT is probably cost-effective in obese women undergoing caesarean section. Other studies found low or very low-certainty evidence indicating that NPWT may be cost-effective for the indications assessed. AUTHORS' CONCLUSIONS: People experiencing primary wound closure of their surgical wound and treated prophylactically with NPWT following surgery probably experience fewer SSI than people treated with standard dressings (moderate-certainty evidence). There is no clear difference in number of deaths or wound dehiscence between people treated with NPWT and standard dressings (low-certainty evidence). There are also no clear differences in secondary outcomes where all evidence was low or very low-certainty. In caesarean section in obese women and surgery for lower limb fracture, there is probably little difference in quality of life scores (moderate-certainty evidence). Most evidence on pain is very low-certainty, but there is probably no difference in pain between NPWT and standard dressings after surgery for lower limb fracture (moderate-certainty evidence). Assessments of cost-effectiveness of NPWT produced differing results in different indications. There is a large number of ongoing studies, the results of which may change the findings of this review. Decisions about use of NPWT should take into account surgical indication and setting and consider evidence for all outcomes.

Negative pressure wound therapy for surgical wounds healing by primary closure.

BACKGROUND: Indications for the use of negative pressure wound therapy (NPWT) are broad and include prophylaxis for surgical site infections (SSIs). Existing evidence for the effectiveness of NPWT on postoperative wounds healing by primary closure remains uncertain. OBJECTIVES: To assess the effects of NPWT for preventing SSI in wounds healing through primary closure, and to assess the cost-effectiveness of NPWT in wounds healing through primary closure. SEARCH METHODS: In June 2019, we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries and references of included studies, systematic reviews and health technology reports. There were no restrictions on language, publication date or study setting. SELECTION CRITERIA: We included trials if they allocated participants to treatment randomly and compared NPWT with any other type of wound dressing, or compared one type of NPWT with another type of NPWT. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed trials using predetermined inclusion criteria. We carried out data extraction, assessment using the Cochrane 'Risk of bias' tool, and quality assessment according to Grading of Recommendations, Assessment, Development and Evaluations methodology. MAIN RESULTS: In this third update, we added 15 new randomised controlled trials (RCTs) and three new economic studies, resulting in a total of 44 RCTs (7447 included participants) and five economic studies. Studies evaluated NPWT in the context of a wide range of surgeries including orthopaedic, obstetric, vascular and general procedures. Economic studies assessed NPWT in orthopaedic, obstetric and general surgical settings. All studies compared NPWT with standard dressings. Most studies had unclear or high risk of bias for at least one key domain. Primary outcomes Four studies (2107 participants) reported mortality. There is low-certainty evidence (downgraded twice for imprecision) showing no clear difference in the risk of death after surgery for people treated with NPWT (2.3%) compared with standard dressings (2.7%) (risk ratio (RR) 0.86; 95% confidence interval (CI) 0.50 to 1.47; I2 = 0%). Thirty-nine studies reported SSI; 31 of these (6204 participants), were included in meta-analysis. There is moderate-certainty evidence (downgraded once for risk of bias) that NPWT probably results in fewer SSI (8.8% of participants) than treatment with standard dressings (13.0% of participants) after surgery; RR 0.66 (95% CI 0.55 to 0.80 ; I2 = 23%). Eighteen studies reported dehiscence; 14 of these (3809 participants) were included in meta-analysis. There is low-certainty evidence (downgraded once for risk of bias and once for imprecision) showing no clear difference in the risk of dehiscence after surgery for NPWT (5.3% of participants) compared with standard dressings (6.2% of participants) (RR 0.88, 95% CI 0.69 to 1.13; I2 = 0%). Secondary outcomes There is low-certainty evidence showing no clear difference between NPWT and standard treatment for the outcomes of reoperation and incidence of seroma. For reoperation, the RR was 1.04 (95% CI 0.78 to 1.41; I2 = 13%; 12 trials; 3523 participants); for seroma, the RR was 0.72 (95% CI 0.50 to 1.05; I2 = 0%; seven trials; 729 participants). The effect of NPWT on occurrence of haematoma or skin blisters is uncertain (very low-certainty evidence); for haematoma, the RR was 0.67 (95% CI 0.28 to 1.59; I2 = 0%; nine trials; 1202 participants) and for blisters the RR was 2.64 (95% CI 0.65 to 10.68; I2 = 69%; seven trials; 796 participants). The overall effect of NPWT on pain is uncertain (very low-certainty evidence from seven trials (2218 participants) which reported disparate measures of pain); but moderate-certainty evidence suggests there is probably little difference between the groups in pain after three or six months following surgery for lower limb fracture (one trial, 1549 participants). There is also moderate-certainty evidence for women undergoing caesarean sections (one trial, 876 participants) and people having surgery for lower limb fractures (one trial, 1549 participants) that there is probably little difference in quality of life scores at 30 days or 3 or 6 months, respectively. Cost-effectiveness Five economic studies, based wholly or partially on trials included in our review, assessed the cost-effectiveness of NPWT compared with standard care. They considered NPWT in four indications: caesarean sections in obese women; surgery for lower limb fracture; knee/hip arthroplasty and coronary artery bypass graft surgery. They calculated quality-adjusted life-years for treatment groups and produced estimates of the treatments' relative cost-effectiveness. The reporting quality was good but the grade of the evidence varied from moderate to very low. There is moderate-certainty evidence that NPWT in surgery for lower limb fracture was not cost-effective at any threshold of willingness-to-pay and that NPWT is probably cost-effective in obese women undergoing caesarean section. Other studies found low or very low-certainty evidence indicating that NPWT may be cost-effective for the indications assessed. AUTHORS' CONCLUSIONS: People experiencing primary wound closure of their surgical wound and treated prophylactically with NPWT following surgery probably experience fewer SSI than people treated with standard dressings (moderate-certainty evidence). There is no clear difference in number of deaths or wound dehiscence between people treated with NPWT and standard dressings (low-certainty evidence). There are also no clear differences in secondary outcomes where all evidence was low or very low-certainty. In caesarean section in obese women and surgery for lower limb fracture, there is probably little difference in quality of life scores (moderate-certainty evidence). Most evidence on pain is very low-certainty, but there is probably no difference in pain between NPWT and standard dressings after surgery for lower limb fracture (moderate-certainty evidence). Assessments of cost-effectiveness of NPWT produced differing results in different indications. There is a large number of ongoing studies, the results of which may change the findings of this review. Decisions about use of NPWT should take into account surgical indication and setting and consider evidence for all outcomes.

Protease activity as a prognostic factor for wound healing in complex wounds.

Healing mechanisms are disrupted in complex wounds. Proteases may persist longer in nonhealing wounds. We sought to investigate whether protease activity, protease inhibitor activity, or their combinations are independent prognostic factors for healing of complex wounds. We searched MEDLINE, EMBASE, CINAHL, and The Cochrane Library to March 2019. Study selection comprised longitudinal studies assessing the independent effect of proteases, their inhibitors or ratios of the two, on healing of complex wounds, while controlling for confounding factors. Two reviewers independently extracted data and assessed risk of bias. We conducted meta-analyses separately for proteases, inhibitors, and ratios. We graded the evidence certainty (quality). We identified eight eligible studies in 10 cohorts involving 343 participants. Risk of bias was moderate or high. Elevated protease activity may be associated with less wound healing (standardized mean difference [SMD]: -0.41, 95% CI -0.72 to -0.11; nine cohorts); and elevated protease inhibitor activity with more healing (SMD: 0.37, 95% CI 0.06-0.68; five cohorts), this is low certainty evidence. Increased protease: inhibitor ratios may be associated with less healing (SMD -0.47, 95% CI -0.94 to -0.01; four cohorts), but this evidence is of very low certainty. Heterogeneity in protease activity was unexplained by prespecified subgroup analyses for wound type or protease activity status, but partially explained by protease class. Posthoc analysis suggested elevated levels of a particular protease, MMP-1, may be associated with more healing and other proteases with less healing. This is low/very low certainty evidence. Limitations were small included studies at moderate or high risk of bias, and the use of posthoc analyses. Elevated protease activity and protease: inhibitor ratios may be associated with less healing, and elevated inhibitor levels with more healing. There may be important differences between MMP-1 and other proteases. High quality research is needed to explore these new findings further.

Negative pressure wound therapy for surgical wounds healing by primary closure.

BACKGROUND: Indications for the use of negative pressure wound therapy (NPWT) are broad and include prophylaxis for surgical site infections (SSIs). While existing evidence for the effectiveness of NPWT remains uncertain, new trials necessitated an updated review of the evidence for the effects of NPWT on postoperative wounds healing by primary closure. OBJECTIVES: To assess the effects of negative pressure wound therapy for preventing surgical site infection in wounds healing through primary closure. SEARCH METHODS: We searched the Cochrane Wounds Specialised Register, CENTRAL, Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase, and EBSCO CINAHL Plus in February 2018. We also searched clinical trials registries for ongoing and unpublished studies, and checked reference lists of relevant included studies as well as reviews, meta-analyses, and health technology reports to identify additional studies. There were no restrictions on language, publication date, or setting. SELECTION CRITERIA: We included trials if they allocated participants to treatment randomly and compared NPWT with any other type of wound dressing, or compared one type of NPWT with another type of NPWT. DATA COLLECTION AND ANALYSIS: Four review authors independently assessed trials using predetermined inclusion criteria. We carried out data extraction, 'Risk of bias' assessment using the Cochrane 'Risk of bias' tool, and quality assessment according to GRADE methodology. MAIN RESULTS: In this second update we added 25 intervention trials, resulting in a total of 30 intervention trials (2957 participants), and two economic studies nested in trials. Surgeries included abdominal and colorectal (n = 5); caesarean section (n = 5); knee or hip arthroplasties (n = 5); groin surgery (n = 5); fractures (n = 5); laparotomy (n = 1); vascular surgery (n = 1); sternotomy (n = 1); breast reduction mammoplasty (n = 1); and mixed (n = 1). In three key domains four studies were at low risk of bias; six studies were at high risk of bias; and 20 studies were at unclear risk of bias. We judged the evidence to be of low or very low certainty for all outcomes, downgrading the level of the evidence on the basis of risk of bias and imprecision.Primary outcomesThree studies reported mortality (416 participants; follow-up 30 to 90 days or unspecified). It is uncertain whether NPWT has an impact on risk of death compared with standard dressings (risk ratio (RR) 0.63, 95% confidence interval (CI) 0.25 to 1.56; very low-certainty evidence, downgraded once for serious risk of bias and twice for very serious imprecision).Twenty-five studies reported on SSI. The evidence from 23 studies (2533 participants; 2547 wounds; follow-up 30 days to 12 months or unspecified) showed that NPWT may reduce the rate of SSIs (RR 0.67, 95% CI 0.53 to 0.85; low-certainty evidence, downgraded twice for very serious risk of bias).Fourteen studies reported dehiscence. We combined results from 12 studies (1507 wounds; 1475 participants; follow-up 30 days to an average of 113 days or unspecified) that compared NPWT with standard dressings. It is uncertain whether NPWT reduces the risk of wound dehiscence compared with standard dressings (RR 0.80, 95% CI 0.55 to 1.18; very low-certainty evidence, downgraded twice for very serious risk of bias and once for serious imprecision).Secondary outcomesWe are uncertain whether NPWT increases or decreases reoperation rates when compared with a standard dressing (RR 1.09, 95% CI 0.73 to 1.63; 6 trials; 1021 participants; very low-certainty evidence, downgraded for very serious risk of bias and serious imprecision) or if there is any clinical benefit associated with NPWT for reducing wound-related readmission to hospital within 30 days (RR 0.86, 95% CI 0.47 to 1.57; 7 studies; 1271 participants; very low-certainty evidence, downgraded for very serious risk of bias and serious imprecision). It is also uncertain whether NPWT reduces incidence of seroma compared with standard dressings (RR 0.67, 95% CI 0.45 to 1.00; 6 studies; 568 participants; very low-certainty evidence, downgraded twice for very serious risk of bias and once for serious imprecision). It is uncertain if NPWT reduces or increases the risk of haematoma when compared with a standard dressing (RR 1.05, 95% CI 0.32 to 3.42; 6 trials; 831 participants; very low-certainty evidence, downgraded twice for very serious risk of bias and twice for very serious imprecision. It is uncertain if there is a higher risk of developing blisters when NPWT is compared with a standard dressing (RR 6.64, 95% CI 3.16 to 13.95; 6 studies; 597 participants; very low-certainty evidence, downgraded twice for very serious risk of bias and twice for very serious imprecision).Quality of life was not reported separately by group but was used in two economic evaluations to calculate quality-adjusted life years (QALYs). There was no clear difference in incremental QALYs for NPWT relative to standard dressing when results from the two trials were combined (mean difference 0.00, 95% CI -0.00 to 0.00; moderate-certainty evidence).One trial concluded that NPWT may be more cost-effective than standard care, estimating an incremental cost-effectiveness ratio (ICER) value of GBP 20.65 per QALY gained. A second cost-effectiveness study estimated that when compared with standard dressings NPWT was cost saving and improved QALYs. We rated the overall quality of the reports as very good; we did not grade the evidence beyond this as it was based on modelling assumptions. AUTHORS' CONCLUSIONS: Despite the addition of 25 trials, results are consistent with our earlier review, with the evidence judged to be of low or very low certainty for all outcomes. Consequently, uncertainty remains about whether NPWT compared with a standard dressing reduces or increases the incidence of important outcomes such as mortality, dehiscence, seroma, or if it increases costs. Given the cost and widespread use of NPWT for SSI prophylaxis, there is an urgent need for larger, well-designed and well-conducted trials to evaluate the effects of newer NPWT products designed for use on clean, closed surgical incisions. Such trials should initially focus on wounds that may be difficult to heal, such as sternal wounds or incisions on obese patients.