Postpartum management of perineal injury - A critical narrative review of level 1 evidence.

BACKGROUND: Injury to the perineum is a common sequalae of vaginal birth. Lack of appropriateperineal wound care in the postnatal period is associated with increased pain and morbidity in theshort, medium, and long term. Women and maternity healthcare providers require high-levelevidence-based information to inform postnatal perineal wound care. OBJECTIVES: To review the high-level evidence informing postpartum management of perineal trauma. DESIGN: A systematic search of the literature regarding the postnatal management of perineal injury to produce a critical narrative review of the available level I evidence regarding the postnatal management of perineal trauma up to six months postpartum was undertaken. Systematic reviews were identified from searching the following databases: CINAHL, Cochrane Library, MEDLINE, PUBMED, and SCOPUS. Papers were selected if they met the following criteria: systematic reviews/level I evidence related to postnatal management of any form of perineal injury up to six months post birth, written in English, and published from January 2010 to 30th May 2021. A synthesis of the results was developed. FINDINGS: Nineteen systematic reviews met criteria for inclusion. The systematic reviews fell into one of the following categories of perineal trauma management: use of medication for pain relief, the decision to suture, suture techniques/materials, cryotherapy, use of antibiotics, ultrasound, physiotherapy treatment and complementary therapies. CONCLUSION: There is an overall lack of focused high-quality research to inform management of perineal injuries beyond the acute postnatal period. Clinical trials that include women's satisfaction and wellbeing as outcome measures are limited. IMPLICATIONS FOR PRACTICE: It is vital that women are provided with evidence-based postnatal care strategies to enhance perineal healing and resumption of normal activities. Future clinical trials for the management of perineal trauma should incorporate women's satisfaction as an outcome measure.Further research examining the follow-up care for the medium-long term for women experiencing ongoing sequalae of symptoms in the community setting is required to support clinical practice recommendations.

Zinc Status Alters Alzheimer's Disease Progression through NLRP3-Dependent Inflammation.

Alzheimer's disease is a devastating neurodegenerative disease with a dramatically increasing prevalence and no disease-modifying treatment. Inflammatory lifestyle factors increase the risk of developing Alzheimer's disease. Zinc deficiency is the most prevalent malnutrition in the world and may be a risk factor for Alzheimer's disease potentially through enhanced inflammation, although evidence for this is limited. Here we provide epidemiological evidence suggesting that zinc supplementation was associated with reduced risk and slower cognitive decline, in people with Alzheimer's disease and mild cognitive impairment. Using the APP/PS1 mouse model of Alzheimer's disease fed a control (35 mg/kg zinc) or diet deficient in zinc (3 mg/kg zinc), we determined that zinc deficiency accelerated Alzheimer's-like memory deficits without modifying amyloid ß plaque burden in the brains of male mice. The NLRP3-inflammasome complex is one of the most important regulators of inflammation, and we show here that zinc deficiency in immune cells, including microglia, potentiated NLRP3 responses to inflammatory stimuli in vitro, including amyloid oligomers, while zinc supplementation inhibited NLRP3 activation. APP/PS1 mice deficient in NLRP3 were protected against the accelerated cognitive decline with zinc deficiency. Collectively, this research suggests that zinc status is linked to inflammatory reactivity and may be modified in people to reduce the risk and slow the progression of Alzheimer's disease.SIGNIFICANCE STATEMENT Alzheimer's disease is a common condition mostly affecting the elderly. Zinc deficiency is also a global problem, especially in the elderly and also in people with Alzheimer's disease. Zinc deficiency contributes to many clinical disorders, including immune dysfunction. Inflammation is known to contribute to the risk and progression of Alzheimer's disease; thus, we hypothesized that zinc status would affect Alzheimer's disease progression. Here we show that zinc supplementation reduced the prevalence and symptomatic decline in people with Alzheimer's disease. In an animal model of Alzheimer's disease, zinc deficiency worsened cognitive decline because of an enhancement in NLRP3-driven inflammation. Overall, our data suggest that zinc status affects Alzheimer's disease progression, and that zinc supplementation could slow the rate of cognitive decline.

Stroke in Hemodialysis Patients Randomized to Different Intravenous Iron Strategies: A Prespecified Analysis from the PIVOTAL Trial.

Background: People with kidney failure treated with hemodialysis (HD) are at increased risk of stroke compared with similarly aged people with normal kidney function. One concern is that treatment of renal anemia might increase stroke risk. We studied risk factors for stroke in a prespecified secondary analysis of a randomized, controlled trial of intravenous iron treatment strategies in HD. Methods: We analyzed data from the Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial, focusing on variables associated with risk of stroke. The trial randomized 2141 adults who had started HD <12 months earlier and who were receiving an erythropoiesis-stimulating agent (ESA) to high-dose IV iron administered proactively or low-dose IV iron administered reactively in a 1:1 ratio. Possible stroke events were independently adjudicated. We performed analyses to identify variables associated with stroke during follow-up and assessed survival following stroke. Results: During a median 2.1 years of follow-up, 69 (3.2%) patients experienced a first postrandomization stroke. Fifty-seven (82.6%) were ischemic strokes, and 12 (17.4%) were hemorrhagic strokes. There were 34 postrandomization strokes in the proactive arm and 35 postrandomization strokes in the reactive arm (hazard ratio, 0.90; 95% confidence interval, 0.56 to 1.44; P=0.66). In multivariable models, women, diabetes, history of prior stroke at baseline, higher baseline systolic BP, lower serum albumin, and higher C-reactive protein were independently associated with stroke events during follow-up. Hemoglobin, total iron, and ESA dose were not associated with risk of stroke. Fifty-eight percent of patients with a stroke event died during follow-up compared with 23% without a stroke. Conclusions: In patients on HD, stroke risk is broadly associated with risk factors previously described to increase cardiovascular risk in this population. Proactive intravenous iron does not increase stroke risk.Clinical Trial registry name and registration number: Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL), 2013-002267-25.

Intravenous Iron Dosing and Infection Risk in Patients on Hemodialysis: A Prespecified Secondary Analysis of the PIVOTAL Trial.

BACKGROUND: Experimental and observational studies have raised concerns that giving intravenous (IV) iron to patients, such as individuals receiving maintenance hemodialysis, might increase the risk of infections. The Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial randomized 2141 patients undergoing maintenance hemodialysis for ESKD to a high-dose or a low-dose IV iron regimen, with a primary composite outcome of all-cause death, heart attack, stroke, or hospitalization for heart failure. Comparison of infection rates between the two groups was a prespecified secondary analysis. METHODS: Secondary end points included any infection, hospitalization for infection, and death from infection; we calculated cumulative event rates for these end points. We also interrogated the interaction between iron dose and vascular access (fistula versus catheter). RESULTS: We found no significant difference between the high-dose IV iron group compared with the lose-dose group in event rates for all infections (46.5% versus 45.5%, respectively, which represented incidences of 63.3 versus 69.4 per 100 patient years, respectively); rates of hospitalization for infection (29.6% versus 29.3%, respectively) also did not differ. We did find a significant association between risk of a first cardiovascular event and any infection in the previous 30 days. Compared with patients undergoing dialysis with an arteriovenous fistula, those doing so via a catheter had a higher incidence of having any infection, hospitalization for infection, or fatal infection, but IV iron dosing had no effect on these outcomes. CONCLUSIONS: The high-dose and low-dose IV iron groups exhibited identical infection rates. Risk of a first cardiovascular event strongly associated with a recent infection.

Intravenous Iron in Patients Undergoing Maintenance Hemodialysis.

BACKGROUND: Intravenous iron is a standard treatment for patients undergoing hemodialysis, but comparative data regarding clinically effective regimens are limited. METHODS: In a multicenter, open-label trial with blinded end-point evaluation, we randomly assigned adults undergoing maintenance hemodialysis to receive either high-dose iron sucrose, administered intravenously in a proactive fashion (400 mg monthly, unless the ferritin concentration was >700 µg per liter or the transferrin saturation was ≥40%), or low-dose iron sucrose, administered intravenously in a reactive fashion (0 to 400 mg monthly, with a ferritin concentration of <200 µg per liter or a transferrin saturation of <20% being a trigger for iron administration). The primary end point was the composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death, assessed in a time-to-first-event analysis. These end points were also analyzed as recurrent events. Other secondary end points included death, infection rate, and dose of an erythropoiesis-stimulating agent. Noninferiority of the high-dose group to the low-dose group would be established if the upper boundary of the 95% confidence interval for the hazard ratio for the primary end point did not cross 1.25. RESULTS: A total of 2141 patients underwent randomization (1093 patients to the high-dose group and 1048 to the low-dose group). The median follow-up was 2.1 years. Patients in the high-dose group received a median monthly iron dose of 264 mg (interquartile range [25th to 75th percentile], 200 to 336), as compared with 145 mg (interquartile range, 100 to 190) in the low-dose group. The median monthly dose of an erythropoiesis-stimulating agent was 29,757 IU in the high-dose group and 38,805 IU in the low-dose group (median difference, -7539 IU; 95% confidence interval [CI], -9485 to -5582). A total of 320 patients (29.3%) in the high-dose group had a primary end-point event, as compared with 338 (32.3%) in the low-dose group (hazard ratio, 0.85; 95% CI, 0.73 to 1.00; P<0.001 for noninferiority; P=0.04 for superiority). In an analysis that used a recurrent-events approach, there were 429 events in the high-dose group and 507 in the low-dose group (rate ratio, 0.77; 95% CI, 0.66 to 0.92). The infection rate was the same in the two groups. CONCLUSIONS: Among patients undergoing hemodialysis, a high-dose intravenous iron regimen administered proactively was superior to a low-dose regimen administered reactively and resulted in lower doses of erythropoiesis-stimulating agent being administered. (Funded by Kidney Research UK; PIVOTAL EudraCT number, 2013-002267-25 .).

Fatigue interventions in long term, physical health conditions: A scoping review of systematic reviews.

OBJECTIVE: Fatigue is prominent across many long term physical health conditions. This scoping review aimed to map the fatigue intervention literature, to ascertain if certain interventions may be effective across conditions, and if novel interventions tested in specific long term conditions may be promising for other conditions. METHODS: Scoping review methodological frameworks were used. Electronic bibliographic databases were searched (inception to November 2016) for systematic reviews of fatigue interventions in long term conditions. Inclusion criteria were: long term physical health condition; review focus on fatigue management; objective and systematic review process; primary review outcome is fatigue. Articles focussing on surgical interventions or treatments thought to trigger fatigue were excluded. A narrative synthesis was performed. RESULTS: Of 115 full texts screened, 52 reviews were included. Interventions were categorised as pharmacological and non-pharmacological (exercise, psychological/behavioural and complementary medicine). Pharmacological interventions did not consistently demonstrate benefit, except for anti-TNFs and methylphenidate which may be effective at reducing fatigue. Non-pharmacological interventions such as graded exercise and fatigue-specific psychological interventions may be effective, but heterogeneous intervention components limit conclusions. 'Complementary medicine' interventions (e.g. Chinese herbal medicines) showed promise, but the possibility of publication bias must be considered. CONCLUSIONS: Further research is necessary to inform clinical practice. The reported effectiveness of some interventions across inflammatory health conditions, such as anti-TNFs, aerobic exercise, and psychologically based approaches such as CBT, highlights a potential transdiagnostic avenue for fatigue management. More novel strategies that may be worth exploring include expressive writing and mindfulness, although the mechanisms for these in relation to fatigue are unclear. More work is needed to identify transdiagnostic mechanisms of fatigue and to design interventions based on these.

Randomized Trial Comparing Proactive, High-Dose versus Reactive, Low-Dose Intravenous Iron Supplementation in Hemodialysis (PIVOTAL): Study Design and Baseline Data.

BACKGROUND: Intravenous (IV) iron supplementation is a standard maintenance treatment for hemodialysis (HD) patients, but the optimum dosing regimen is unknown. METHODS: PIVOTAL (Proactive IV irOn Therapy in hemodiALysis patients) is a multicenter, open-label, blinded endpoint, randomized controlled (PROBE) trial. Incident HD adults with a serum ferritin < 400 µg/L and transferrin saturation (TSAT) levels < 30% receiving erythropoiesis-stimulating agents (ESA) were eligible. Enrolled patients were randomized to a proactive, high-dose IV iron arm (iron sucrose 400 mg/month unless ferritin > 700 µg/L and/or TSAT ≥40%) or a reactive, low-dose IV iron arm (iron sucrose administered if ferritin <200 µg/L or TSAT < 20%). We hypothesized that proactive, high-dose IV iron would be noninferior to reactive, low-dose IV iron for the primary outcome of first occurrence of nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure or death from any cause. If noninferiority is confirmed with a noninferiority limit of 1.25 for the hazard ratio of the proactive strategy relative to the reactive strategy, a test for superiority will be carried out. Secondary outcomes include infection-related endpoints, ESA dose requirements, and quality-of-life measures. As an event-driven trial, the study will continue until at least 631 primary outcome events have accrued, but the expected duration of follow-up is 2-4 years. RESULTS: Of the 2,589 patients screened across 50 UK sites, 2,141 (83%) were randomized. At baseline, 65.3% were male, the median age was 65 years, and 79% were white. According to eligibility criteria, all patients were on ESA at screening. Prior stroke and MI were present in 8 and 9% of the cohort, respectively, and 44% of patients had diabetes at baseline. Baseline data for the randomized cohort were generally concordant with recent data from the UK Renal Registry. CONCLUSIONS: PIVOTAL will provide important information about the optimum dosing of IV iron in HD patients representative of usual clinical practice. TRIAL REGISTRATION: EudraCT number: 2013-002267-25.

Multidisciplinary team care for people with rheumatoid arthritis: a systematic review and meta-analysis.

The objective of this study was to systematically review the evidence from randomised controlled trials (RCTs) evaluating the effectiveness of multidisciplinary team (MDT) care for the management of disability, disease activity and quality of life (QoL) in adults with rheumatoid arthritis (RA). Data sources identified published (MEDLINE, PsychINFO, EMBASE, CINAHL, Web of Science, CENTRAL) and unpublished (OpenGrey) literature. Independent data extraction and quality assessment, using the Cochrane risk of bias tool, were conducted by two reviewers. The primary outcome was change in disability at 12 months; secondary outcomes included disability at other time points and disease activity and QoL at 12 months. Where possible, the pooled effect sizes were calculated for inpatient or outpatient MDT interventions. Four hundred and fifteen studies were retrieved. Twelve manuscripts, which reported 10 RCTs, representing 1147 participants were included. Only data from five high- or moderate-quality trials were pooled according to clinical setting. There was no difference in disability between inpatient MDT care and any comparison group [mean difference (95% confidence intervals) 0.04, -0.13 to 0.20] or between outpatient MDT care and comparison groups (0.09, -0.07 to 0.25) at 12 months. There was no difference in disability at 2 years or <12 months or disease activity and QoL at 12 months between MDT care and any comparison group. There is limited evidence evaluating the effect of MDT care on disability, disease activity or QoL in people with RA. There is likely to be no effect of MDT care on disability at 12 months or other time points.