Applying Topical Anesthetic on Pediatric Lacerations in the Emergency Department: A Quality Improvement Project.

OBJECTIVES: Caring for pediatric lacerations in the emergency department (ED) is typically painful because of irrigation and suturing. To improve this painful experience, we aimed to increase the use of a topical anesthetic, Eutectic Mixture of Local Anesthetics (EMLA) on eligible pediatric lacerations with an attainable, sustainable, and measurable goal of 60%. The baseline rate of applying topical anesthetic to eligible lacerations was 23% in our ED. We aimed to increase the use of topical anesthetics on eligible pediatric lacerations to a measurable goal of 60% within 3 months of implementing our intervention. METHODS: We conducted a prospective, single-center, interrupted time series, ED quality improvement project from November 2019 to July 2020. A multidisciplinary team of physicians and nurses performed a cause-and-effect analysis identifying 2 key drivers: early placement of EMLA and physician buy-in on which we built our Plan, Do, Study, and Act (PDSA) cycles. We collected data on number of eligible patients receiving EMLA, as well as patient and physician feedback via phone calls within 2 days after encounter. Balancing measures included ED length of stay (LOS), patient and physician satisfaction with EMLA, and adverse effects of EMLA. RESULTS: We needed 3 PDSA cycles to reach our goal of 60% in 3 months, which was also maintained for 5 months. The PDSA cycles used educational interventions, direct provider feedback about noncompliance, and patient satisfaction results obtained via phone calls. Balancing measures were minimally impacted: 75% good patient satisfaction, no adverse events but an increase in LOS of patients who received EMLA compared with those who did not (1.79 ± 0.66 vs 1.41 ± 0.83 hours, P < 0.001). The main reasons for dissatisfaction for physicians were the increased LOS and the preference for procedural sedation or intranasal medications. CONCLUSIONS: With a few simple interventions, our aim of applying EMLA to 60% of eligible pediatric lacerations was attained and maintained.

A systematic review and meta-analysis of revascularization outcomes of infrainguinal chronic limb-threatening ischemia.

BACKGROUND: The optimal strategy for revascularization in infrainguinal chronic limb-threatening ischemia (CLTI) remains debatable. Comparative trials are scarce, and daily decisions are often made using anecdotal or low-quality evidence. METHODS: We searched multiple databases through May 7, 2017, for prospective studies with at least 1-year follow-up that evaluated patient-relevant outcomes of infrainguinal revascularization procedures in adults with CLTI. Independent pairs of reviewers selected articles and extracted data. Random-effects meta-analysis was used to pool outcomes across studies. RESULTS: We included 44 studies that enrolled 8602 patients. Periprocedural outcomes (mortality, amputation, major adverse cardiac events) were similar across treatment modalities. Overall, patients with infrapopliteal disease had higher patency rates of great saphenous vein graft at 1 and 2 years (primary: 87%, 78%; secondary: 94%, 87%, respectively) compared with all other interventions. Prosthetic bypass outcomes were notably inferior to vein bypass in terms of amputation and patency outcomes, especially for below knee targets at 2 years and beyond. Drug-eluting stents demonstrated improved patency over bare-metal stents in infrapopliteal arteries (primary patency: 73% vs 50% at 1 year), and was at least comparable to balloon angioplasty (66% primary patency). Survival, major amputation, and amputation-free survival at 2 years were broadly similar between endovascular interventions and vein bypass, with prosthetic bypass having higher rates of limb loss. Overall, the included studies were at moderate to high risk of bias and the quality of evidence was low. CONCLUSIONS: There are major limitations in the current state of evidence guiding treatment decisions in CLTI, particularly for severe anatomic patterns of disease treated via endovascular means. Periprocedural (30-day) mortality, amputation, and major adverse cardiac events are broadly similar across modalities. Patency rates are highest for saphenous vein bypass, whereas both patency and limb salvage are markedly inferior for prosthetic grafting to below the knee targets. Among endovascular interventions, percutaneous transluminal angioplasty and drug-eluting stents appear comparable for focal infrapopliteal disease, although no studies included long segment tibial lesions. Heterogeneity in patient risk, severity of limb threat, and anatomy treated renders direct comparison of outcomes from the current literature challenging. Future studies should incorporate both limb severity and anatomic staging to best guide clinical decision making in CLTI.

A systematic review and meta-analysis of revascularization outcomes of infrainguinal chronic limb-threatening ischemia.

BACKGROUND: The optimal strategy for revascularization in infrainguinal chronic limb-threatening ischemia (CLTI) remains debatable. Comparative trials are scarce, and daily decisions are often made using anecdotal or low-quality evidence. METHODS: We searched multiple databases through May 7, 2017, for prospective studies with at least 1-year follow-up that evaluated patient-relevant outcomes of infrainguinal revascularization procedures in adults with CLTI. Independent pairs of reviewers selected articles and extracted data. Random-effects meta-analysis was used to pool outcomes across studies. RESULTS: We included 44 studies that enrolled 8602 patients. Periprocedural outcomes (mortality, amputation, major adverse cardiac events) were similar across treatment modalities. Overall, patients with infrapopliteal disease had higher patency rates of great saphenous vein graft at 1 and 2 years (primary: 87%, 78%; secondary: 94%, 87%, respectively) compared with all other interventions. Prosthetic bypass outcomes were notably inferior to vein bypass in terms of amputation and patency outcomes, especially for below knee targets at 2 years and beyond. Drug-eluting stents demonstrated improved patency over bare-metal stents in infrapopliteal arteries (primary patency: 73% vs 50% at 1 year), and was at least comparable to balloon angioplasty (66% primary patency). Survival, major amputation, and amputation-free survival at 2 years were broadly similar between endovascular interventions and vein bypass, with prosthetic bypass having higher rates of limb loss. Overall, the included studies were at moderate to high risk of bias and the quality of evidence was low. CONCLUSIONS: There are major limitations in the current state of evidence guiding treatment decisions in CLTI, particularly for severe anatomic patterns of disease treated via endovascular means. Periprocedural (30-day) mortality, amputation, and major adverse cardiac events are broadly similar across modalities. Patency rates are highest for saphenous vein bypass, whereas both patency and limb salvage are markedly inferior for prosthetic grafting to below the knee targets. Among endovascular interventions, percutaneous transluminal angioplasty and drug-eluting stents appear comparable for focal infrapopliteal disease, although no studies included long segment tibial lesions. Heterogeneity in patient risk, severity of limb threat, and anatomy treated renders direct comparison of outcomes from the current literature challenging. Future studies should incorporate both limb severity and anatomic staging to best guide clinical decision making in CLTI.

A systematic review and meta-analysis of revascularization outcomes of infrainguinal chronic limb-threatening ischemia.

BACKGROUND: The optimal strategy for revascularization in infrainguinal chronic limb-threatening ischemia (CLTI) remains debatable. Comparative trials are scarce, and daily decisions are often made using anecdotal or low-quality evidence. METHODS: We searched multiple databases through May 7, 2017, for prospective studies with at least 1-year follow-up that evaluated patient-relevant outcomes of infrainguinal revascularization procedures in adults with CLTI. Independent pairs of reviewers selected articles and extracted data. Random-effects meta-analysis was used to pool outcomes across studies. RESULTS: We included 44 studies that enrolled 8602 patients. Periprocedural outcomes (mortality, amputation, major adverse cardiac events) were similar across treatment modalities. Overall, patients with infrapopliteal disease had higher patency rates of great saphenous vein graft at 1 and 2 years (primary: 87%, 78%; secondary: 94%, 87%, respectively) compared with all other interventions. Prosthetic bypass outcomes were notably inferior to vein bypass in terms of amputation and patency outcomes, especially for below knee targets at 2 years and beyond. Drug-eluting stents demonstrated improved patency over bare-metal stents in infrapopliteal arteries (primary patency: 73% vs 50% at 1 year), and was at least comparable to balloon angioplasty (66% primary patency). Survival, major amputation, and amputation-free survival at 2 years were broadly similar between endovascular interventions and vein bypass, with prosthetic bypass having higher rates of limb loss. Overall, the included studies were at moderate to high risk of bias and the quality of evidence was low. CONCLUSIONS: There are major limitations in the current state of evidence guiding treatment decisions in CLTI, particularly for severe anatomic patterns of disease treated via endovascular means. Periprocedural (30-day) mortality, amputation, and major adverse cardiac events are broadly similar across modalities. Patency rates are highest for saphenous vein bypass, whereas both patency and limb salvage are markedly inferior for prosthetic grafting to below the knee targets. Among endovascular interventions, percutaneous transluminal angioplasty and drug-eluting stents appear comparable for focal infrapopliteal disease, although no studies included long segment tibial lesions. Heterogeneity in patient risk, severity of limb threat, and anatomy treated renders direct comparison of outcomes from the current literature challenging. Future studies should incorporate both limb severity and anatomic staging to best guide clinical decision making in CLTI.

Bypass surgery versus endovascular interventions in severe or critical limb ischemia.

OBJECTIVE: Critical limb ischemia is associated with a significant morbidity and mortality. We systematically reviewed the evidence to compare bypass surgery with endovascular revascularization in patients with critical limb ischemia. METHODS: We systematically searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, CINAHL, and Scopus through October 2014 for comparative studies (randomized and nonrandomized). Predefined outcomes of interest were mortality, major amputation, patency, and wound healing. We pooled odds ratios (ORs) of the outcomes of interest using the random-effects model. RESULTS: Nine studies that enrolled 3071 subjects were included. There was no significant difference in mortality (OR, 0.72; 95% confidence interval [CI], 0.44-1.16) or amputation (OR, 1.2; 95% CI, 0.87-1.65). Bypass surgery was associated with higher primary patency (OR, 2.50; 95% CI, 1.25-4.99) and assisted primary patency (OR, 3.39; 95% CI, 1.53-7.51). The quality of evidence was low for mortality and amputation outcomes and moderate for patency outcomes. CONCLUSIONS: Low quality of evidence due to imprecision and heterogeneity suggests that bypass surgery and endovascular approaches may have similar effect on mortality and major amputations. However, better primary and primary assisted patency can be expected with surgery.

Reducing the risk of transfusion-transmitted cytomegalovirus infection: a systematic review and meta-analysis.

BACKGROUND: Leukoreduced (LR) or cytomegalovirus (CMV)-seronegative cellular blood components are commonly used to reduce the risk of transfusion-transmitted CMV infection in high-risk patients. STUDY DESIGN AND METHODS: We performed a systematic review and meta-analysis to evaluate the evidence for the use of LR cellular blood components with or without concurrent CMV testing of donor units in patients undergoing chemotherapy or solid organ and hematopoietic stem cell transplantation, in pregnant women, in very-low-birthweight infants, and in patients with primary immunodeficiency. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus from 1980 through February 2015. Studies were included if they had a comparison group. Two independent reviewers selected and appraised studies. Meta-analysis was performed when appropriate. RESULTS: Of 457 studies screened, 11 were eligible. One study was excluded from the meta-analysis because the comparison performed differed significantly from the others. Meta-analysis of five studies that compared leukoreduction to transfusing CMV-untested blood components showed no significant difference in clinical CMV infection (relative risk [RR], 0.26; 95% confidence interval [CI], 0.04-1.57) or laboratory CMV infection (RR, 0.33; 95% CI, 0.08-1.37). Meta-analysis of three studies that compared leukoreduction to transfusing CMV-seronegative cellular components showed no significant difference in laboratory CMV infection (RR, 2.18; 95% CI, 0.96-4.98). Meta-analysis of two studies that compared adding CMV testing to leukoreduction (vs. leukoreduction alone) showed no significant difference in clinical or laboratory CMV infection. The certainty in estimates was low for all comparisons. CONCLUSION: At present, the scientific evidence does not favor a single strategy for reducing the risk of transfusion-related CMV infection in high-risk patients.

Non-pharmacological treatment of depression: a systematic review and evidence map.

BACKGROUND: The comparative effectiveness of non-pharmacological treatments of depression remains unclear. METHODS: We conducted an overview of systematic reviews to identify randomised controlled trials (RCTs) that compared the efficacy and adverse effects of non-pharmacological treatments of depression. We searched multiple electronic databases through February 2016 without language restrictions. Pairs of reviewers determined eligibility, extracted data and assessed risk of bias. Meta-analyses were conducted when appropriate. RESULT: We included 367 RCTs enrolling ∼20 000 patients treated with 11 treatments leading to 17 unique head-to-head comparisons. Cognitive behavioural therapy, naturopathic therapy, biological interventions and physical activity interventions reduced depression severity as measured using standardised scales. However, the relative efficacy among these non-pharmacological interventions was lacking. The effect of these interventions on clinical response and remission was unclear. Adverse events were lower than antidepressants. LIMITATION: The quality of evidence was low to moderate due to inconsistency and unclear or high risk of bias, limiting our confidence in findings. CONCLUSIONS: Non-pharmacological therapies of depression reduce depression symptoms and should be considered along with antidepressant therapy for the treatment of mild-to-severe depression. A shared decision-making approach is needed to choose between non-pharmacological therapies based on values, preferences, clinical and social context.

Testing for germline mutations in sporadic pheochromocytoma/paraganglioma: a systematic review.

BACKGROUND: The presence of germline mutations in sporadic pheochromocytomas and paragangliomas (SPPs) may change the clinical management of both index patients and their family members. However, the frequency of germline mutations in SPPs is unknown. OBJECTIVE: To describe the frequency of germline mutations in SPPs and to determine the value of testing index patients and their family members for these mutations. METHODS: We searched databases through June 2012 for observational studies of patients with SPPs who underwent germline genetic testing. The criteria used to define sporadic tumours were (i) the absence of a family history of PCC/PG, (ii) the absence of syndromic features, (iii) the absence of bilateral disease and (iv) the absence of metastatic disease. RESULTS: We included 31 studies including 5031 patients (mean age 44). These patients received tests for any of these ten mutations: SDHAF2, RET, SDHD, SDHB, SDHC, VHL, TMEM127, MAX, Isocitrate Dehydrogenase Mutation (IDH) and NF1. The overall frequency of germline mutation in SPP was 551 of 5031 or 11%; when studies with patients fulfilling four criteria for sporadic tumours were used, the frequency was 171 of 1332 or 13%. The most common germline mutation was SDHB 167 of 3611 (4·6%). Little outcome data were available to assess the benefits of genetic testing in index cases and family members. CONCLUSIONS: The frequency of germline mutations in SPPs is approximately 11-13% and the most common mutations affect less than 1 in 20 patients. The value of testing for germline mutations in patients with SPPs and their family members is unknown, as the balance of potential benefits and harms remains unclear.

The natural history of untreated severe or critical limb ischemia.

OBJECTIVE: Critical limb ischemia (CLI) is associated with high morbidity and mortality. Because most patients with CLI will eventually undergo some type of revascularization, the natural history of CLI is not well defined, although it is important to know when patients decide to pursue treatment. METHODS: We systematically searched multiple databases for controlled and uncontrolled studies of patients with CLI who did not receive revascularization with a minimum follow-up of ≥1 year. Predefined outcomes of interest were mortality, major amputation, and wound healing. Random-effects meta-analysis was used to pool cumulative incidence across studies. RESULTS: We identified 13 studies enrolling 1527 patients. During a median follow-up of 12 months, all-cause mortality rate was 22% (confidence interval [CI], 12%-33%) and major amputation rate was 22% (CI, 2%-42%). Worsened wound or ulcer was found at 35% (CI, 10%-62%). There was a trend toward improvement in mortality and amputation rate in studies done after 1997. The quality of evidence was low because of increased risk of bias and inconsistency. CONCLUSIONS: Mortality and major amputations are common in patients who have untreated CLI during a median follow-up of 1 year, although these outcomes have improved in recent times.

Nonrevascularization-based treatments in patients with severe or critical limb ischemia.

OBJECTIVE: The aim of this systematic review was to synthesize the existing evidence about various nonrevascularization-based therapies used to treat patients with severe or critical limb ischemia (CLI) who are not candidates for surgical revascularization. METHODS: We systematically searched multiple databases through November 2014 for controlled randomized and nonrandomized studies comparing the effect of medical therapies (prostaglandin E1 and angiogenic growth factors) and devices (pumps and spinal cord stimulators). We report odds ratios (ORs) and 95% confidence intervals (CIs) of the outcomes of interest pooling data across studies using the random effects model. RESULTS: We included 19 studies that enrolled 2779 patients. None of the nonrevascularization-based treatments were associated with a significant effect on mortality. Intermittent pneumatic compression (OR, 0.14; 95% CI, 0.04-0.55) and spinal cord stimulators (OR, 0.53; 95% CI, 0.36-0.79) were associated with reduced risk of amputation. A priori established subgroup analyses (combined vs single therapy; randomized vs nonrandomized) were not statistically significant. CONCLUSIONS: Very low-quality evidence, mainly due to imprecision and increased risk of bias, suggests that intermittent pneumatic compression and spinal cord stimulators may reduce the risk of amputations. Evidence supporting other medical therapies is insufficient.

RADIOTHERAPY VERSUS RADIOSURGERY IN TREATING PATIENTS WITH ACROMEGALY: A SYSTEMATIC REVIEW AND META-ANALYSIS.

OBJECTIVE: When patients with acromegaly have residual disease following surgery, adjuvant radiation therapy is considered. Both stereotactic radiosurgery (SRS) and conventional fractionated radiotherapy (RT) are utilized. We conducted a systematic review and meta-analysis to synthesize the existing evidence and compare outcomes for SRS and RT in patients with acromegaly. METHODS: We searched Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus through April 2014 for studies in which SRS or RT were used in patients with acromegaly. Outcomes evaluated were serum insulin-like growth factor-I (IGF-I) and growth hormone (GH) levels, biochemical remission, all-cause mortality, hypopituitarism, headaches, and secondary malignancies. We pooled outcomes using a random-effects model. RESULTS: The final search yielded 30 eligible studies assessing 2,464 patients. Compared to RT, SRS was associated with a nonsignificant increase in remission rate at the latest follow-up period (52% vs. 36%; P = .14) and a significantly lower follow-up IGF-I level (-409.72 µg/L vs. -102 µg/L, P = .002). SRS had a lower incidence of hypopituitarism than RT; however, the difference was not statistically significant (32% vs. 51%, respectively; P = .05). CONCLUSION: SRS may be associated with better biochemical remission, and it had a lower risk of hypopituitarism with at least 1 deficient axis when compared with RT; however, the confidence in such evidence is very low due to the noncomparative nature of the studies, high heterogeneity, and imprecision.

Comparative systematic review and meta-analysis of compression modalities for the promotion of venous ulcer healing and reducing ulcer recurrence.

OBJECTIVE: This was a systematic review of the literature to determine which compression method is superior in promoting ulcer healing and reducing recurrence in patients with lower extremity venous ulcer disease. METHODS: We conducted a comprehensive search of multiple databases for randomized and nonrandomized comparative studies from 1990 to December 2013. RESULTS: We identified 36 studies and two Cochrane systematic reviews. Many studies had moderate risk of bias. We found no overall difference between compression stockings vs compression bandages with respect to ulcer healing, time to ulcer healing, or ulcer recurrence outcomes. When we compared stockings vs short stretch bandages, stockings were superior with respect to ulcer healing. However, stockings compared with four-layer systems showed no difference in ulcer healing outcomes. When four-layer systems were compared with compression with less than four layers, there was also no significant difference in ulcer healing outcomes. Similarly, short stretch bandages were not superior to long stretch bandages with respect to ulcer healing, time to ulcer healing, or ulcer recurrence. One Cochrane review presented many additional comparisons and reported increased wound healing with compression compared with no compression, with multicomponent systems over single component systems, and compression systems with an elastic component over no elastic component. Another Cochrane review demonstrated a reduction in recurrence with compression in patients with healed ulcers. CONCLUSIONS: At least moderate-quality evidence supports compression over no compression, multicomponent systems over single component systems, and systems with an elastic component over those without. We did not find significant differences with respect to ulcer healing outcomes for other comparisons. Low-quality evidence supports the effect of compression on ulcer recurrence.

Systematic review and meta-analysis of surgical interventions versus conservative therapy for venous ulcers.

OBJECTIVE: This goal of this study was to systematically review the literature to determine if surgical intervention (open or endovascular) is superior to compression alone with respect to ulcer healing, ulcer recurrence, and time to ulcer healing in patients with lower extremity venous ulcer disease. METHODS: We conducted a comprehensive search of multiple databases for randomized controlled trials (RCTs) and comparative observational studies from 1990 to December 2013. The interventions of interest were any open or endovascular surgical interventions on the venous system in the lower extremity compared with compression alone. RESULTS: We included 11 studies (seven RCTs and four observational studies) with moderate to increased risk of bias. The meta-analysis of all studies demonstrated increased healing rate (pooled risk ratio [RR], 1.06; 95% confidence interval [CI], 1.00-1.13; I(2) = 10%) and lower risk of recurrence (RR, 0.54; 95% CI, 0.34-0.85; I(2) = 27%) with open surgical procedures compared with compression. However, the meta-analysis of only RCTs showed no difference, possibly due to imprecision. The meta-analysis of three RCTs showed no difference in time to ulcer healing, -0.41 (95% CI, -0.89 to 0.07). Two studies of endovascular surgical procedures compared with compression showed no significant difference in ulcer healing (RR, 1.65; 95% CI, 0.43-6.32). One study of open surgical venous ligation and stripping compared with endovenous laser also showed no significant difference in ulcer recurrence (RR, 0.83; 95% CI, 0.21-3.27). CONCLUSIONS: Open surgical interventions may improve lower extremity venous ulcer healing. The quality of this evidence is low because the analysis was dominated by the results of observational studies. The current evidence does not definitively support the superiority of endovascular surgical interventions compared with compression alone.

Patient engagement in research: a systematic review.

BACKGROUND: A compelling ethical rationale supports patient engagement in healthcare research. It is also assumed that patient engagement will lead to research findings that are more pertinent to patients' concerns and dilemmas. However; it is unclear how to best conduct this process. In this systematic review we aimed to answer 4 key questions: what are the best ways to identify patient representatives? How to engage them in designing and conducting research? What are the observed benefits of patient engagement? What are the harms and barriers of patient engagement? METHODS: We searched MEDLINE, EMBASE, PsycInfo, Cochrane, EBSCO, CINAHL, SCOPUS, Web of Science, Business Search Premier, Academic Search Premier and Google Scholar. Included studies were published in English, of any size or design that described engaging patients or their surrogates in research design. We conducted an environmental scan of the grey literature and consulted with experts and patients. Data were analyzed using a non-quantitative, meta-narrative approach. RESULTS: We included 142 studies that described a spectrum of engagement. In general, engagement was feasible in most settings and most commonly done in the beginning of research (agenda setting and protocol development) and less commonly during the execution and translation of research. We found no comparative analytic studies to recommend a particular method. Patient engagement increased study enrollment rates and aided researchers in securing funding, designing study protocols and choosing relevant outcomes. The most commonly cited challenges were related to logistics (extra time and funding needed for engagement) and to an overarching worry of a tokenistic engagement. CONCLUSIONS: Patient engagement in healthcare research is likely feasible in many settings. However, this engagement comes at a cost and can become tokenistic. Research dedicated to identifying the best methods to achieve engagement is lacking and clearly needed.

Efficacy of Pharmacological Therapies for the Prevention of Fractures in Postmenopausal Women: A Network Meta-Analysis.

BACKGROUND: Osteoporosis and osteopenia are associated with increased fracture incidence in postmenopausal women. We aimed to determine the comparative effectiveness of various available pharmacological therapies. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ISI Web of Science, and Scopus for randomized controlled trials that enrolled postmenopausal women with primary osteoporosis and evaluated the risk of hip, vertebral, or nonvertebral fractures. A network meta-analysis was conducted using the multivariate random effects method. RESULTS: We included 107 trials (193,987 postmenopausal women; mean age, 66 years; 55% white; median follow-up, 28 months). A significant reduction in hip fractures was observed with romosozumab, alendronate, zoledronate, risedronate, denosumab, estrogen with progesterone, and calcium in combination with vitamin D. A significant reduction in nonvertebral fractures was observed with abaloparatide, romosozumab, denosumab, teriparatide, alendronate, risedronate, zoledronate, lasofoxifene, tibolone, estrogen with progesterone, and vitamin D. A significant reduction in vertebral fractures was observed with abaloparatide, teriparatide, parathyroid hormone 1-84, romosozumab, strontium ranelate, denosumab, zoledronate, risedronate, alendronate, ibandronate, raloxifene, bazedoxifene, lasofoxifene, estrogen with progesterone, tibolone, and calcitonin. Teriparatide, abaloparatide, denosumab, and romosozumab were associated with the highest relative risk reductions, whereas ibandronate and selective estrogen receptor modulators had lower efficacy. The evidence for the treatment of fractures with vitamin D and calcium remains limited despite numerous large trials. CONCLUSIONS: This network meta-analysis provides comparative effective estimates for the various available treatments to reduce the risk of fragility fractures in postmenopausal women.

Treatment Options for Hirsutism: A Systematic Review and Network Meta-Analysis.

Background: Several pharmacologic treatments for hirsutism are used in practice; however, their relative efficacy is unclear. Methods: We searched MEDLINE, EMBASE, and CENTRAL through January 2017 for randomized controlled trials (RCTs) with follow-up of at least 6 months that evaluated antiandrogens, insulin sensitizers, and oral contraceptives in women with hirsutism. Independent pairs of reviewers selected and appraised trials. Random-effects network meta-analysis was used to compare individual drugs and classes. Results: We included 43 trials. Estrogen-progestin oral contraceptives pills (OCPs), antiandrogens, and insulin sensitizers were superior to placebo, with standardized mean reductions (95% confidence intervals) of -0.94 (-1.49 to -0.38), -1.29 (-1.80 to -0.79), and -0.62 (-1.00 to -0.23), respectively. Antiandrogen monotherapy, the combination of OCP and antiandrogen, the combination of OCPs and insulin sensitizer, and the combination of antiandrogen and insulin sensitizer were superior to insulin sensitizer monotherapy. The combination of OCPs and antiandrogen was superior to OCPs. Antiandrogen monotherapy with flutamide, finasteride, and spironolactone were each superior to placebo but similar to each other in efficacy. OCPs containing levonorgestrel, cyproterone acetate, or drospirenone were similar in effectiveness to other OCPs or had trivial differences. The certainty in comparisons with placebo was moderate and for head-to-head comparisons was low. Conclusions: Estrogen-progestin OCPs, antiandrogens, and insulin sensitizers are superior to placebo for the treatment of hirsutism.

Prevention of exacerbations in patients with stable non-cystic fibrosis bronchiectasis: a systematic review and meta-analysis of pharmacological and non-pharmacological therapies.

BACKGROUND: Several pharmacological and non-pharmacological therapies are used to treat stable bronchiectasis of non-cystic fibrosis (CF) aetiology. OBJECTIVE: We conducted a systematic review and meta-analysis to assess the evidence of the effectiveness of pharmacological and non-pharmacological treatment options in patients with stable non-CF bronchiectasis with a focus on reducing exacerbations. STUDY SELECTION: Multiple databases were searched through September 2017. Outcomes included the number of patients with exacerbation events, mean number of exacerbations, hospitalisations, mortality, quality of life measures, and safety and adverse effects. Meta-analysis was conducted using the random effects model. FINDINGS: 30 randomised controlled trials enrolled subjects with non-CF bronchiectasis using different interventions. Moderate-quality evidence supported the effect of long-term antibiotics (≥3 months) on lowering the number of patients experiencing exacerbation events (relative risk 0.77 (95% CI 0.68 to 0.89)), reducing number of exacerbations (incidence rate ratio 0.62 (95% CI 0.49 to 0.78)), improving forced expiratory volume (litre) in the first second (FEV1) (weighted mean difference (WMD); 0.02 (95% CI 0.00 to 0.04)), decreasing sputum purulence scores (numerical scale of 1-8) (WMD -0.90 (95% CI -1.58 to -0.22)) and improving quality of life scores assessed by the St George's Respiratory Questionnaire (WMD -6.07 (95% CI -10.7 to -1.43)). Bronchospasm increased with inhaled antibiotics while diarrhoea increased particularly with oral macrolide therapy. CONCLUSIONS: Moderate-quality evidence supports long-term antibiotic therapy for preventing exacerbations in stable non-CF bronchiectasis. However, data about the optimum agent, mode of therapy and length of treatment are limited. There is paucity of high-quality evidence to support the management of stable non-CF bronchiectasis including prevention of exacerbations.

Treatment Effect in Earlier Trials of Patients With Chronic Medical Conditions: A Meta-Epidemiologic Study.

OBJECTIVE: To determine whether the early trials in chronic medical conditions demonstrate an effect size that is larger than that in subsequent trials. METHODS: We identified randomized controlled trials (RCTs) evaluating a drug or device in patients with chronic medical conditions through meta-analyses (MAs) published between January 1, 2007, and June 23, 2015, in the 10 general medical journals with highest impact factor. We estimated the prevalence of having the largest effect size or heterogeneity in the first 2 published trials. We evaluated the association of the exaggerated early effect with several a priori hypothesized explanatory variables. RESULTS: We included 70 MAs that had included a total of 930 trials (average of 13 [range, 5-48] RCTs per MA) with average follow-up of 24 (range, 1-168) months. The prevalence of the exaggerated early effect (ie, proportion of MAs with largest effect or heterogeneity in the first 2 trials) was 37%. These early trials had an effect size that was on average 2.67 times larger than the overall pooled effect size (ratio of relative effects, 2.67; 95% CI, 2.12-3.37). The presence of exaggerated effect was not significantly associated with trial size; number of events; length of follow-up; intervention duration; number of study sites; inpatient versus outpatient setting; funding source; stopping a trial early; adequacy of random sequence generation, allocation concealment, or blinding; loss to follow-up or the test for publication bias. CONCLUSION: Trials evaluating treatments of chronic medical conditions published early in the chain of evidence commonly demonstrate an exaggerated treatment effect compared with subsequent trials. At the present time, this phenomenon remains unpredictable. Considering the increasing morbidity and mortality of chronic medical conditions, decision makers should act on early evidence with caution.