OBJECTIVE:This systematic review and meta-analysis evaluates the current evidence on the management of intermittent claudication (IC), a prevalent manifestation of peripheral arterial disease (PAD). METHODS:We conducted comprehensive searches of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus. We addressed six questions developed by a guideline committee from the Society for Vascular Surgery, addressing pharmacological treatments, exercise regimens, endovascular interventions, and predictors of major adverse cardiovascular, limb-related events, and mortality. RESULTS:The search resulted in 5333 citations, from which we included 73 studies (46 randomized trials). In patients with PAD and IC who had one or more high-risk comorbidities, low-dose rivaroxaban and aspirin were associated with lower risk of major adverse limb events and major adverse cardiovascular events than aspirin alone. In patients who have undergone surgical or endovascular interventions for PAD, the addition of low-dose rivaroxaban to aspirin may improve limb outcomes. Of note, rivaroxaban trials excluded patients at high risk of bleeding. Single antiplatelet agents showed no significant efficacy differences head-to-head in ambulatory patients with IC and had a lower bleeding risk compared with combination therapy or anticoagulation. Home exercise programs were feasible and may be an alternative to supervised exercise in ambulatory patients with IC and in those who had revascularization. Several comorbidities increased the risk of adverse outcomes after revascularization for IC, such as advanced age, diabetes, coronary artery disease, chronic obstructive pulmonary disease, previous interventions, congestive heart failure, infrapopliteal artery involvement, and longer lesion lengths. In patients with IC undergoing endovascular intervention for superficial femoral artery disease, plain balloon angioplasty was associated with worse outcomes than drug elution or stent implantation for intermediate or longer lesions (ie, >5 cm). CONCLUSIONS:This systematic review summarizes the current evidence base for the management of IC, offering insights into the relative benefits and risks of various therapeutic strategies. The findings underscore the need for individualized patient care, considering both the potential benefits and risks associated with different interventions.

BACKGROUND: The management of patients who are receiving chronic oral anticoagulation therapy and require an elective surgery or an invasive procedure is a common clinical scenario.RESEARCH QUESTION: What is the best available evidence to support the development of American College of Chest Physicians guidelines on the perioperative management of pa-tients who are receiving long-term vitamin K agonist (VKA) or direct oral anticoagulant (DOAC) and require elective surgery or procedures?STUDY DESIGN AND METHODS: A literature search including multiple databases from database inception through July 16, 2020, was performed. Meta-analyses were conducted when appropriate.RESULTS: In patients receiving VKA (warfarin) undergoing elective noncardiac surgery, shorter (< 3 days) VKA interruption is associated with an increased risk of major bleeding. In patients who required VKA interruption, heparin bridging (mostly with low-molecular-weight heparin [LMWH]) was associated with a statistically significant increased risk of major bleed, repre-senting a very low certainty of evidence (COE). Compared with DOAC interruption 1 to 4 days before surgery, continuing DOACs may be associated with higher risk of bleeding demonstrated in some, but not all studies. In patients who needed DOAC interruption, bridging with LMWH may be associated with a statistically significant increased risk of bleeding, representing a low COE.INTERPRETATION: The certainty in the evidence supporting the perioperative management of anticoagulants remains limited. No high-quality evidence exists to support the practice of heparin bridging during the interruption of VKA or DOAC therapy for an elective surgery or procedure, or for the practice of interrupting VKA therapy for minor procedures, including cardiac device implantation, or continuation of a DOAC vs short-term interruption of a DOAC in the perioperative period.

CONTEXT:Hypercalcemia is a common complication of malignancy that is associated with high morbidity and mortality.OBJECTIVE:To support development of the Endocrine Society Clinical Practice Guideline for the treatment of hypercalcemia of malignancy in adults.METHODS:We searched multiple databases for studies that addressed 8 clinical questions prioritized by a guideline panel from the Endocrine Society. Quantitative and qualitative synthesis was performed. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess certainty of evidence.RESULTS:We reviewed 1949 citations, from which we included 21 studies. The risk of bias for most of the included studies was moderate. A higher proportion of patients who received bisphosphonate achieved resolution of hypercalcemia when compared to placebo. The incidence rate of adverse events was significantly higher in the bisphosphonate group. Comparing denosumab to bisphosphonate, there was no significant difference in the rate of patients who achieved resolution of hypercalcemia. Two-thirds of patients with refractory/recurrent hypercalcemia of malignancy who received denosumab following bisphosphonate therapy achieved resolution of hypercalcemia. Addition of calcitonin to bisphosphonate therapy did not affect the resolution of hypercalcemia, time to normocalcemia, or hypocalcemia. Only indirect evidence was available to address questions on the management of hypercalcemia in tumors associated with high calcitriol levels, refractory/recurrent hypercalcemia of malignancy following the use of bisphosphonates, and the use of calcimimetics in the treatment of hypercalcemia associated with parathyroid carcinoma. The certainty of the evidence to address all 8 clinical questions was low to very low.CONCLUSION:The evidence summarized in this systematic review addresses the benefits and harms of treatments of hypercalcemia of malignancy. Additional information about patients' values and preferences, and other important decisional and contextual factors is needed to facilitate the development of clinical recommendations.

Objectives. To evaluate the comparative effectiveness and harms of partial breast irradiation (PBI) compared with whole breast irradiation (WBI) for early-stage breast cancer, and how differences in effectiveness and harms may be influenced by patient, tumor, and treatment factors, including treatment modality, target volume, dose, and fractionation. We also evaluated the relative financial toxicity of PBI versus WBI. Data sources. MEDLINE®, Embase®, Cochrane Central Registrar of Controlled Trials, Cochrane Database of Systematic Reviews, Scopus, and various grey literature sources from database inception to June 30, 2022. Review methods. We included randomized clinical trials (RCTs) and observational studies that enrolled adult women with early-stage breast cancer who received one of six PBI modalities: multi-catheter interstitial brachytherapy, single-entry catheter brachytherapy (also known as intracavitary brachytherapy), 3-dimensional conformal external beam radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), proton radiation therapy, intraoperative radiotherapy (IORT). Pairs of independent reviewers screened and appraised studies. Results. Twenty-three original studies with 17,510 patients evaluated the comparative effectiveness of PBI, including 14 RCTs, 6 comparative observational studies, and 3 single-arm observational studies. PBI was not significantly different from WBI in terms of ipsilateral breast recurrence (IBR), overall survival, or cancer-free survival at 5 and 10 years (high strength of evidence [SOE]). Evidence for cosmetic outcomes was insufficient. Results were generally consistent when PBI modalities were compared with WBI, whether compared individually or combined. These PBI approaches included 3DCRT, IMRT, and multi-catheter interstitial brachytherapy. Compared with WBI, 3DCRT showed no difference in IBR, overall survival, or cancer-free survival at 5 and 10 years (moderate to high SOE); IMRT showed no difference in IBR or overall survival at 5 and 10 years (low SOE); multi-catheter interstitial brachytherapy showed no difference in IBR, overall survival, or cancer-free survival at 5 years (low SOE). Compared with WBI, IORT was associated with a higher IBR rate at 5, 10, and over 10 years (high SOE), with no difference in overall survival, cancer-free survival, or mastectomy-free survival (low to high SOE). There were significantly fewer acute adverse events (AEs) with PBI compared with WBI, with no apparent difference in late AEs (moderate SOE). Data about quality of life were limited. Head-to-head comparisons between the different PBI modalities showed insufficient evidence to estimate an effect on main outcomes. There were no significant differences in IBR or other outcomes according to patient, tumor, and treatment characteristics; however, data for subgroups were insufficient to draw conclusions. Eight studies addressed concepts closely related to financial toxicity. Compared with conventionally fractionated WBI, accelerated PBI was associated with lower transportation costs and days away from work. PBI was also associated with less subjective financial difficulty at various time points after radiotherapy. Conclusions. Clinical trials that compared PBI with WBI demonstrate no significant difference in the risk of IBR. PBI is associated with fewer acute AEs and may be associated with less financial toxicity. The current evidence supports the use of PBI in appropriately selected patients with early-stage breast cancer. Further investigation is needed to evaluate the outcomes of PBI in patients with various clinical and tumor characteristics, and to define optimal radiation treatment dose and technique for PBI.

A 66-year-old male with end-stage liver disease (ESLD) secondary to non-alcoholic fatty liver disease (NAFLD), complicated by hepatocellular carcinoma (HCC), underwent deceased donor liver transplantation from a Coronavirus disease 2019 (COVID-19) positive donor. He presented a month later with fever, diarrhea and pancytopenia which led to hospitalization. The hospital course was notable for respiratory failure, attributed to invasive aspergillosis, as well as a diffuse rash. A bone marrow biopsy revealed hypocellular marrow without specific findings. In the following days, laboratory parameters raised concern for secondary hemophagocytic lymphohistiocytosis (HLH). Clinical concern also grew for solid organ transplant graft-versus-host-disease (SOT-GVHD) based on repeat marrow biopsy with elevated donor-derived CD3+ T cells on chimerism. After, a multidisciplinary discussion, the patient was started on ruxolitinib, in addition to high dose steroids, to address both SOT-GVHD and secondary HLH. Patient developed symptoms concerning for hemorrhagic stroke and was transitioned to comfort care. Although GVHD has been studied extensively in hematopoietic stem cell transplant (HSCT) patients, it is a rare entity in SOT with a lack of guidelines for management. Additionally, whether COVID-19 may play a role in development of SOT-GVDH has not been explored.

Background: Early-stage breast cancer is among the most common cancer diagnoses. Adjuvant radiotherapy is an essential component of breast-conserving therapy, and several options exist for tailoring its extent and duration. This study assesses the comparative effectiveness of partial-breast irradiation (PBI) compared with whole-breast irradiation (WBI). Methods: A systematic review was completed to identify relevant randomized clinical trials and comparative observational studies. Independent reviewers working in pairs selected studies and extracted data. Randomized trial results were pooled using a random effects model. Prespecified main outcomes were ipsilateral breast recurrence (IBR), cosmesis, and adverse events (AEs). Results: Fourteen randomized clinical trials and 6 comparative observational studies with 17 234 patients evaluated the comparative effectiveness of PBI. PBI was not statistically significantly different from WBI for IBR at 5 years (RR = 1.34, 95% CI = 0.83 to 2.18; high strength of evidence [SOE]) and 10 years (RR = 1.29, 95% CI = 0.87 to 1.91; high SOE). Evidence for cosmetic outcomes was insufficient. Statistically significantly fewer acute AEs were reported with PBI compared with WBI, with no statistically significant difference in late AEs. Data from subgroups according to patient, tumor, and treatment characteristics were insufficient. Intraoperative radiotherapy was associated with higher IBR at 5, 10, and over than 10 years (high SOE) compared with WBI. Conclusions: Ipsilateral breast recurrence was not statistically significantly different between PBI and WBI. Acute AEs were less frequent with PBI. This evidence supports the effectiveness of PBI among selected patients with early-stage, favorable-risk breast cancer who are similar to those represented in the included studies.

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction Immune checkpoint inhibitor (ICI) myocarditis is a life-threatening condition characterized by lymphocytic myocardial infiltration[1]. Complete heart block (CHB) occurs in 15% of cases and is often fatal[2-4]. The nature and optimal management of this often-malignant condition is poorly understood[5]. Purpose This case series assesses prognostic factors associated with survival at 90 days among people with ICI myocarditis and CHB. Methods The electronic patient record system was used to identify patients admitted with ICI myocarditis. A two-physician review was used to assess the presence of ICI-associated CHB. Wilcoxon rank sum and Spearman’s rank correlation were used for categorical and quantitative variables respectively. Data was analysed using STATA/IC 16.1. The primary outcome was person-day survival 90 days after presenting symptom onset. Results Six patients were included in the final analysis. Mean survival was 47 person days. All had metastatic disease and presented 15 to 32 days after the first ICI infusion. All had muscle weakness. Other common self-symptoms were shortness of breath (4), blurred vision (4), double vision (3), collapse (3), and leg swelling (1). Proximal myopathy (2), fatigable myopathy (1), ptosis (3), and peripheral oedema (1) were present on examination. Raised troponin T and white blood cell count (WBC) were associated with 90-day survival (see Table 1). Nt-pro BNP, AST, and CK levels were raised in all patients. Two patients were tested for anti-striated muscle antibody titres, and both were strongly positive. Increase in QRS duration compared to baseline ECG was associated with lower survival at 90 days. Only one patient had CHB on admission. Steroid dose, IVIG, and plasmapheresis weren’t associated with survival. One patient declined device therapy. One declined permanent pacemaker (PPM) after insertion of transvenous pacemaker (TVP). Both died within 2 weeks. Three people underwent insertion of a transvenous pacemaker (TVP) followed by PPM insertion (table 2). All three eventually died within 100 days. One person received isoproterenol and immunosuppression as a bridge to PPM and survived. One patient was managed initially with TVP but subsequently declined PPM insertion. TVP removal resulted in CHB recurrence, and they died shortly after discharge. One person declined device therapy and died while receiving comfort care. Lead malfunction was frequent. One patient experienced bradycardia arrest with failure of a TVP lead to capture, while another experienced lead dislodgement. Conclusion CHB secondary to ICI is often fatal. It should be considered in patients presenting with symptoms of myositis, raised troponin and increased QRS duration. Despite a small sample size, this study identifies several prognostic factors which can guide both patients and physicians with decision-making. Larger studies are needed to better understand the role of device therapy in this population.

The management of patients who are receiving chronic oral anticoagulation therapy and require an elective surgery or an invasive procedure is a common clinical scenario.What is the best available evidence to support the development of American College of Chest Physicians guidelines on the perioperative management of patients who are receiving long-term vitamin K agonist (VKA) or direct oral anticoagulant (DOAC) and require elective surgery or procedures?A literature search including multiple databases from database inception through July 16, 2020, was performed. Meta-analyses were conducted when appropriate.In patients receiving VKA (warfarin) undergoing elective noncardiac surgery, shorter (< 3 days) VKA interruption is associated with an increased risk of major bleeding. In patients who required VKA interruption, heparin bridging (mostly with low-molecular-weight heparin [LMWH]) was associated with a statistically significant increased risk of major bleed, representing a very low certainty of evidence (COE). Compared with DOAC interruption 1 to 4 days before surgery, continuing DOACs may be associated with higher risk of bleeding demonstrated in some, but not all studies. In patients who needed DOAC interruption, bridging with LMWH may be associated with a statistically significant increased risk of bleeding, representing a low COE.The certainty in the evidence supporting the perioperative management of anticoagulants remains limited. No high-quality evidence exists to support the practice of heparin bridging during the interruption of VKA or DOAC therapy for an elective surgery or procedure, or for the practice of interrupting VKA therapy for minor procedures, including cardiac device implantation, or continuation of a DOAC vs short-term interruption of a DOAC in the perioperative period.

Objective:To summarize the available evidence about the perioperative management of patients who are receiving long-term antiplatelet therapy and require elective surgery/procedures.Methods:This systematic review supports the development of the American College of Chest Physicians guideline on the perioperative management of antiplatelet therapy. A literature search of MEDLINE, EMBASE, Scopus and Cochrane databases was conducted from each database's inception to July 16, 2020. Meta-analyses were conducted when possible.Results:In patients receiving long-term antiplatelet therapy and undergoing elective noncardiac surgery, the available evidence did not show a significant difference in major bleeding between a shorter vs longer antiplatelet interruption, with low certainty of evidence (COE). Compared with patients who received placebo perioperatively, aspirin continuation was associated with increased risk of major bleeding (relative risk [RR], 1.31; 95% CI, 1.15-1.50; high COE) and lower risk of major thromboembolism (RR, 0.74; 95% CI, 0.58-0.94; moderate COE). During antiplatelet interruption, bridging with low-molecular-weight heparin was associated with increased risk of major bleeding compared with no bridging (RR, 1.86; 95% CI, 1.24-2.79; very low COE). Continuation of antiplatelets during minor dental and ophthalmologic procedures was not associated with a statistically significant difference in the risk of major bleeding (very low COE).Conclusion:This systematic review summarizes the current evidence about the perioperative management of antiplatelet therapy and highlights the urgent need for further research, particularly with the increasing prevalence of patients taking 1 or more antiplatelet agents.

Background: To support the development of guidelines on the management of carotid disease, a writing committee from the Society for Vascular Surgery has commissioned this systematic review. Methods: We searched multiple data bases for studies addressing five questions: medical management vs carotid revascularization (CEA) in asymptomatic patients, CEA vs carotid artery stenting (CAS) in symptomatic low surgical risk patients, the optimal timing of revascularization after acute stroke, screening high-risk patients for carotid disease, and the optimal sequence of interventions in patients with combined coronary and carotid disease. Studies were selected and appraised by pairs of independent reviewers. Meta-analyses were performed when feasible. Results: Medical management compared with carotid interventions in asymptomatic patients was associated with better early outcome during the first 30 days. However, CEA was associated with significantly lower long-term rate of stroke/death at 5 years. In symptomatic low-risk surgical patients, CEA was associated with a lower risk of stroke, but a significant increase in myocardial infarction compared with CAS during the first 30 days. When the long-term outcome of transfemoral CAS vs CEA in symptomatic patients were examined using preplanned pooled analysis of individual patient data from four randomized trials, the risk of death or stroke within 120 days of the index procedure was 5.5% for CEA and 8.7% for CAS, which lends support that, over the long term, CEA has a superior outcome compared with transfemoral CAS. When managing acute stroke, the comparison of CEA during the first 48 hours to that between day 2 and day 14 did not reveal a statistically significant difference on outcomes during the first 30 days. Registry data show good results with CEA performed in the first week, but not within the first 48 hours. A single risk factor, aside from peripheral artery disease, was associated with low carotid screening yield. Multiple risk factors greatly increase the yield of screening. Evidence on the timing of interventions in patients with combined carotid and coronary disease was sparse and imprecise. Patients without carotid symptoms, who had the carotid intervention first, compared with a combined carotid intervention and coronary artery bypass grafting, had better outcomes. Conclusions: This updated evidence summary supports the Society for Vascular Surgery clinical practice guidelines for commonly raised clinical scenarios. CEA was superior to medical therapy in the long-term prevention of stroke/death over medical therapy. CEA was also superior to transfemoral CAS in minimizing long-term stroke/death for symptomatic low risk surgical patients. CEA should optimally be performed between 2 and 14 days from the onset of acute stroke. Having multiple risk factors increases the value of carotid screening.

Surveillance Reports The three surveillance reports posted above include literature searches updated since the systematic review was posted in December 2020, putting newly identified studies in the context of what is known. No additional surveillance reports are planned.

Overall, based on reviewed evidence, in patients with chronic (mainly neuropathic) pain with short-term treatment (4 weeks to <6 months):• Comparable THC to CBD ratio oral spray is probably associated with small improvements in pain severity and function.There may be a large increased risk of dizziness and sedation, and a moderate increased risk of nausea.• Synthetic THC (high THC to CBD ratio) may be associated with moderate improvement in pain severity but with increased risk of sedation, and potential increased risk of nausea.Synthetic THC is probably associated with a large increased risk of dizziness.• Extracted whole-plant high THC to CBD ratio products may be associated with large increases in risk of withdrawal due to adverse events and dizziness.• Evidence on whole-plant cannabis, low THC to CBD ratio products (topical or oral CBD), other cannabinoids (cannabidivarin), and comparisons with other active interventions or between different cannabis-related products (one new observational study) was insufficient to draw conclusions.• Other key adverse event outcomes (i.e., psychosis, cannabis use disorder, cognitive deficits) and outcomes on the impact on opioid use were not reported.• No evidence on other plant-based compounds, such as kratom, met criteria for this review.Table 2 presents the conclusions from the systematic review, findings from ongoing literature surveillance, and an assessment of new studies on conclusions.Table 2. Assessment of systematic review conclusions

BACKGROUND:The American College of Chest Physicians Clinical Practice Guideline on the Perioperative Management of Antithrombotic Therapy addresses 43 Patients-Interventions-Comparators-Outcomes (PICO) questions related to the perioperative management of patients who are receiving long-term oral anticoagulant or antiplatelet therapy and require an elective surgery/procedure. This guideline is separated into four broad categories, encompassing the management of patients who are receiving: (1) a vitamin K antagonist (VKA), mainly warfarin; (2) if receiving a VKA, the use of perioperative heparin bridging, typically with a low-molecular-weight heparin; (3) a direct oral anticoagulant (DOAC); and (4) an antiplatelet drug.METHODS:Strong or conditional practice recommendations are generated based on high, moderate, low, and very low certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology for clinical practice guidelines.RESULTS:A multidisciplinary panel generated 44 guideline recommendations for the perioperative management of VKAs, heparin bridging, DOACs, and antiplatelet drugs, of which two are strong recommendations: (1) against the use of heparin bridging in patients with atrial fibrillation; and (2) continuation of VKA therapy in patients having a pacemaker or internal cardiac defibrillator implantation. There are separate recommendations on the perioperative management of patients who are undergoing minor procedures, comprising dental, dermatologic, ophthalmologic, pacemaker/internal cardiac defibrillator implantation, and GI (endoscopic) procedures.CONCLUSIONS:Substantial new evidence has emerged since the 2012 iteration of these guidelines, especially to inform best practices for the perioperative management of patients who are receiving a VKA and may require heparin bridging, for the perioperative management of patients who are receiving a DOAC, and for patients who are receiving one or more antiplatelet drugs. Despite this new knowledge, uncertainty remains as to best practices for the majority of perioperative management questions.

CONTEXT:Individuals with diabetes or newly recognized hyperglycemia account for over 30% of noncritically ill hospitalized patients. Management of hyperglycemia in these patients is challenging.OBJECTIVE:To support development of the Endocrine Society Clinical Practice Guideline for management of hyperglycemia in adults hospitalized for noncritical illness or undergoing elective surgical procedures.METHODS:We searched several databases for studies addressing 10 questions provided by a guideline panel from the Endocrine Society. Meta-analysis was conducted when feasible. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess certainty of evidence.RESULTS:We included 94 studies reporting on 135 553 patients. Compared with capillary blood glucose, continuous glucose monitoring increased the number of patients identified with hypoglycemia and decreased mean daily blood glucose (BG) (very low certainty). Data on continuation of insulin pump therapy in hospitalized adults were sparse. In hospitalized patients receiving glucocorticoids, combination neutral protamine hagedorn (NPH) and basal-bolus insulin was associated with lower mean BG compared to basal-bolus insulin alone (very low certainty). Data on NPH insulin vs basal-bolus insulin in hospitalized adults receiving enteral nutrition were inconclusive. Inpatient diabetes education was associated with lower HbA1c at 3 and 6 months after discharge (moderate certainty) and reduced hospital readmissions (very low certainty). Preoperative HbA1c level < 7% was associated with shorter length of stay, lower postoperative BG and a lower number of neurological complications and infections, but a higher number of reoperations (very low certainty). Treatment with glucagon-like peptide-1 agonists or dipeptidyl peptidase-4 inhibitors in hospitalized patients with type 2 diabetes and mild hyperglycemia was associated with lower frequency of hypoglycemic events than insulin therapy (low certainty). Caloric oral fluids before surgery in adults with diabetes undergoing surgical procedures did not affect outcomes (very low certainty). Counting carbohydrates for prandial insulin dosing did not affect outcomes (very low certainty). Compared with scheduled insulin (basal-bolus or basal insulin + correctional insulin), correctional insulin was associated with higher mean daily BG and fewer hypoglycemic events (low certainty).CONCLUSION:The certainty of evidence supporting many hyperglycemia management decisions is low, emphasizing importance of shared decision-making and consideration of other decisional factors.

OBJECTIVE:To evaluate the effectiveness and adverse events of autologous platelet-rich plasma (PRP) in individuals with lower-extremity diabetic ulcers, lower-extremity venous ulcers, and pressure ulcers.PATIENTS AND METHODS:We searched multiple databases from database inception to June 11, 2020, for randomized controlled trials and observational studies that compared PRP to any other wound care without PRP in adults with lower-extremity diabetic ulcers, lower-extremity venous ulcers, and pressure ulcers.RESULTS:We included 20 randomized controlled trials and five observational studies. Compared with management without PRP, PRP therapy significantly increased complete wound closure in lower-extremity diabetic ulcers (relative risk, 1.20; 95% CI, 1.09 to 1.32, moderate strength of evidence [SOE]), shortened time to complete wound closure, and reduced wound area and depth (low SOE). No significant changes were found in terms of wound infection, amputation, wound recurrence, or hospitalization. In patients with lower-extremity venous ulcers or pressure ulcers, the SOE was insufficient to estimate an effect on critical outcomes, such as complete wound closure or time to complete wound closure. There was no statistically significant difference in adverse events.CONCLUSION:Autologous PRP may increase complete wound closure, shorten healing time, and reduce wound size in individuals with lower-extremity diabetic ulcers. The evidence is insufficient to estimate an effect on wound healing in individuals with lower-extremity venous ulcers or pressure ulcers.TRIAL REGISTRATION:PROSPERO Identifier: CRD42020172817.

Importance Migraine is common and can be associated with significant morbidity, and several treatment options exist for acute therapy. Objective To evaluate the benefits and harms associated with acute treatments for episodic migraine in adults. Data Sources Multiple databases from database inception to February 24, 2021. Study Selection Randomized clinical trials and systematic reviews that assessed effectiveness or harms of acute therapy for migraine attacks. Data Extraction and Synthesis Independent reviewers selected studies and extracted data. Meta-analysis was performed with the DerSimonian-Laird random-effects model with Hartung-Knapp-Sidik-Jonkman variance correction or by using a fixed-effect model based on the Mantel-Haenszel method if the number of studies was small. Main Outcomes and Measures The main outcomes included pain freedom, pain relief, sustained pain freedom, sustained pain relief, and adverse events. The strength of evidence (SOE) was graded with the Agency for Healthcare Research and Quality Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Findings Evidence on triptans and nonsteroidal anti-inflammatory drugs was summarized from 15 systematic reviews. For other interventions, 115 randomized clinical trials with 28 803 patients were included. Compared with placebo, triptans and nonsteroidal anti-inflammatory drugs used individually were significantly associated with reduced pain at 2 hours and 1 day (moderate to high SOE) and increased risk of mild and transient adverse events. Compared with placebo, calcitonin gene-related peptide receptor antagonists (low to high SOE), lasmiditan (5-HT1F receptor agonist; high SOE), dihydroergotamine (moderate to high SOE), ergotamine plus caffeine (moderate SOE), acetaminophen (moderate SOE), antiemetics (low SOE), butorphanol (low SOE), and tramadol in combination with acetaminophen (low SOE) were significantly associated with pain reduction and increase in mild adverse events. The findings for opioids were based on low or insufficient SOE. Several nonpharmacologic treatments were significantly associated with improved pain, including remote electrical neuromodulation (moderate SOE), transcranial magnetic stimulation (low SOE), external trigeminal nerve stimulation (low SOE), and noninvasive vagus nerve stimulation (moderate SOE). No significant difference in adverse events was found between nonpharmacologic treatments and sham. Conclusions and Relevance There are several acute treatments for migraine, with varying strength of supporting evidence. Use of triptans, nonsteroidal anti-inflammatory drugs, acetaminophen, dihydroergotamine, calcitonin gene-related peptide antagonists, lasmiditan, and some nonpharmacologic treatments was associated with improved pain and function. The evidence for many other interventions, including opioids, was limited.

BACKGROUND As the use of injectable skin fillers increase in popularity, an increase in the reported adverse events is expected. OBJECTIVE This systematic review supports the development of American Society for Dermatologic Surgery practice guideline on the management of adverse events of skin fillers. METHODS AND MATERIALS Several databases for studies on risk factors or treatments of injection-related visual compromise (IRVC), skin necrosis, inflammatory events, and nodules were searched. Meta-analysis was conducted when feasible. RESULTS The review included 182 studies. However, IRVC was very rare (1-2/1,000,000 patients) but had poor prognosis with improvement in 19% of cases. Skin necrosis was more common (approximately 5/1,000) with better prognosis (up to 77% of cases showing improvement). Treatments of IRVC and skin necrosis primarily depend on hyaluronidase injections. Risk of skin necrosis, inflammatory events, and nodules may be lower with certain fillers, brands, injection techniques, and volume. Treatment of inflammatory events and nodules with antibiotics, corticosteroids, 5-FU, and hyaluronidase was associated with high response rate (75%-80%). Most of the studies were small and noncomparative, making the evidence certainty very low. CONCLUSION Practitioners must have adequate knowledge of anatomy, elicit history of skin filler use, and establish preemptive protocols that prepare the clinical practice to manage complications.

Objectives To evaluate the effectiveness and comparative effectiveness of pharmacologic and nonpharmacologic therapies for the acute treatment of episodic migraine in adults. Data sources MEDLINE®, Embase®, Cochrane Central Registrar of Controlled Trials, Cochrane Database of Systematic Reviews, PsycINFO®, Scopus, and various grey literature sources from database inception to July 24, 2020. Comparative effectiveness evidence about triptans and nonsteroidal anti-inflammatory drugs (NSAIDs) was extracted from existing systematic reviews. Review methods We included randomized controlled trials (RCTs) and comparative observational studies that enrolled adults who received an intervention to acutely treat episodic migraine. Pairs of independent reviewers selected and appraised studies. Results Data on triptans were derived from 186 RCTs summarized in nine systematic reviews (101,276 patients; most studied was sumatriptan, followed by zolmitriptan, eletriptan, naratriptan, almotriptan, rizatriptan, and frovatriptan). Compared with placebo, triptans resolved pain at 2 hours and 1 day, and increased the risk of mild and transient adverse events (high strength of the body of evidence [SOE]). Data on NSAIDs were derived from five systematic reviews (13,214 patients; most studied was ibuprofen, followed by diclofenac and ketorolac). Compared with placebo, NSAIDs probably resolved pain at 2 hours and 1 day, and increased the risk of mild and transient adverse events (moderate SOE). For other interventions, we included 135 RCTs and 6 comparative observational studies (37,653 patients). Compared with placebo, antiemetics (low SOE), dihydroergotamine (moderate to high SOE), ergotamine plus caffeine (moderate SOE), and acetaminophen (moderate SOE) reduced acute pain. Opioids were evaluated in 15 studies (2,208 patients). Butorphanol, meperidine, morphine, hydromorphone, and tramadol in combination with acetaminophen may reduce pain at 2 hours and 1 day, compared with placebo (low SOE). Some opioids may be less effective than some antiemetics or dexamethasone (low SOE). No studies evaluated instruments for predicting risk of opioid misuse, opioid use disorder, or overdose, or evaluated risk mitigation strategies to be used when prescribing opioids for the acute treatment of episodic migraine. Calcitonin gene-related peptide (CGRP) receptor antagonists improved headache relief at 2 hours and increased the likelihood of being headache-free at 2 hours, at 1 day, and at 1 week (low to high SOE). Lasmiditan (the first approved 5-HT1F receptor agonist) restored function at 2 hours and resolved pain at 2 hours, 1 day, and 1 week (moderate to high SOE). Sparse and low SOE suggested possible effectiveness of dexamethasone, dipyrone, magnesium sulfate, and octreotide. Compared with placebo, several nonpharmacologic treatments may improve various measures of pain, including remote electrical neuromodulation (moderate SOE), magnetic stimulation (low SOE), acupuncture (low SOE), chamomile oil (low SOE), external trigeminal nerve stimulation (low SOE), and eye movement desensitization re-processing (low SOE). However, these interventions, including the noninvasive neuromodulation devices, have been evaluated only by single or very few trials. Conclusions A number of acute treatments for episodic migraine exist with varying degrees of evidence for effectiveness and harms. Use of triptans, NSAIDs, antiemetics, dihydroergotamine, CGRP antagonists, and lasmiditan is associated with improved pain and function. The evidence base for many other interventions for acute treatment, including opioids, remains limited.

The coronavirus disease 2019 (COVID-19) pandemic requires making rapid decisions based on sparse and rapidly changing evidence. Evidence synthesis programs conduct systematic reviews for guideline developers, health systems clinicians, and decision-makers that usually take an average 6 to 8 months to complete. We present a framework for evidence synthesis programs to respond to pandemics that has proven feasible and practical during the COVID-19 response in a large multistate health system employing more than 78,000 people. The framework includes four components: an approach for conducting rapid reviews, a repository of rapid reviews, a registry for all original studies about COVID-19, and twice-weekly prioritized update of new evidence sent to key stakeholders. As COVID-19 will not be our last pandemic, we share the details of this framework to allow replication in other institutions and re-implementation in future pandemics.

American Journal of HematologyVolume 95, Issue 5 p. E114-E117 CORRESPONDENCEFree Access Pregnancy outcomes in myeloproliferative neoplasms: A Mayo Clinic report on 102 pregnancies Naseema Gangat, Naseema Gangat Division of Hematology, Mayo Clinic, Rochester, MinnesotaSearch for more papers by this authorMaansi Joshi, Maansi Joshi Division of Hematology, Mayo Clinic, Rochester, MinnesotaSearch for more papers by this authorSahrish Shah, Sahrish Shah Division of Hematology, Mayo Clinic, Rochester, MinnesotaSearch for more papers by this authorMeera Yogarajah, Meera Yogarajah Division of Hematology, Mayo Clinic, Rochester, MinnesotaSearch for more papers by this authorMrinal M. Patnaik, Mrinal M. Patnaik orcid.org/0000-0001-6998-662X Division of Hematology, Mayo Clinic, Rochester, MinnesotaSearch for more papers by this authorAnimesh Pardanani, Animesh Pardanani Division of Hematology, Mayo Clinic, Rochester, MinnesotaSearch for more papers by this authorAlexandra P. Wolanskyj-Spinner, Alexandra P. Wolanskyj-Spinner Division of Hematology, Mayo Clinic, Rochester, MinnesotaSearch for more papers by this authorAyalew Tefferi, Corresponding Author Ayalew Tefferi tefferi.ayalew@mayo.edu orcid.org/0000-0003-4605-3821 Division of Hematology, Mayo Clinic, Rochester, Minnesota Correspondence Ayalew Tefferi, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905.Search for more papers by this author Naseema Gangat, Naseema Gangat Division of Hematology, Mayo Clinic, Rochester, MinnesotaSearch for more papers by this authorMaansi Joshi, Maansi Joshi Division of Hematology, Mayo Clinic, Rochester, MinnesotaSearch for more papers by this authorSahrish Shah, Sahrish Shah Division of Hematology, Mayo Clinic, Rochester, MinnesotaSearch for more papers by this authorMeera Yogarajah, Meera Yogarajah Division of Hematology, Mayo Clinic, Rochester, MinnesotaSearch for more papers by this authorMrinal M. Patnaik, Mrinal M. Patnaik orcid.org/0000-0001-6998-662X Division of Hematology, Mayo Clinic, Rochester, MinnesotaSearch for more papers by this authorAnimesh Pardanani, Animesh Pardanani Division of Hematology, Mayo Clinic, Rochester, MinnesotaSearch for more papers by this authorAlexandra P. Wolanskyj-Spinner, Alexandra P. Wolanskyj-Spinner Division of Hematology, Mayo Clinic, Rochester, MinnesotaSearch for more papers by this authorAyalew Tefferi, Corresponding Author Ayalew Tefferi tefferi.ayalew@mayo.edu orcid.org/0000-0003-4605-3821 Division of Hematology, Mayo Clinic, Rochester, Minnesota Correspondence Ayalew Tefferi, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905.Search for more papers by this author First published: 05 February 2020 https://doi.org/10.1002/ajh.25748Citations: 9 Naseema Gangat and Maansi Joshi contributed equally to this project. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat To the Editor: Over the past five decades, 361 (12%) of 3023patients with myeloproliferative neoplasms (MPN), seen at the Mayo Clinic, were age 40 years or younger; specific diagnosis in approximately half of these patients was essential thrombocythemia (ET).1 True incidence of pregnancy in MPN is difficult to ascertain since most data is derived from retrospective series. However, it is known that among the MPNs, pregnancy occurs most frequently in ET, followed by polycythemia vera (PV) but is extremely rare in the context of primary myelofibrosis (PMF).2 In ET the live birth rate is highly variable ranging from 50% to 75% primarily due to first trimester fetal loss. Predictors of fetal loss including the role of the JAK2V617F mutation remain debatable.2-5 The current study aims to: (a) provide an accurate description of pregnancy outcomes including fetal and maternal complications in MPN, (b) evaluate trends in outcomes over the last decade, and (c) identify predictors of fetal loss, particularly the impact of driver mutations (JAK2, CALR, MPL) and treatments in ET. After institutional review board approval, we utilized our institutional MPN database to identify 152, 36, and 26 women aged <50 years with ET, PV and PMF, respectively. A comprehensive obstetric history of pregnancies occurring after MPN diagnosis was recorded. Fetal outcomes were characterized as live birth, first/second trimester loss, or stillbirth. Maternal complications included pre-eclampsia, placental abruption, thrombosis and hemorrhage occurring up to 6 weeks postpartum. Trends in pregnancy outcomes over the last decade were computed with the year 2008 as a cut-off. JMP Pro 13.0.0 software from SAS Institute, Cary, NC, USA, was used for all statistical analysis. A total of 95 pregnancies occurred in 55 of 152 (36%) women with ET; half (n = 27) had more than one pregnancy (two pregnancies (n = 17), three pregnancies (n = 7), four pregnancies (n = 3). Note, 21 women had pregnancies prior to ET diagnosis, of which eight (38%) experienced one or more fetal loss. Median age at first pregnancy post ET diagnosis was 29 years (range, 20-36 years), with median leukocyte count of 9 × 109/L (range, 3.9-19.8 × 109/L) and platelet count of 849 × 109/L (range; 252-1998 × 109/L). Seven women (13%) were active smokers, with diabetes mellitus, hypertension and hyperlipidemia in one woman each. International Prognostic Score of Thrombosis for Essential Thrombocythemia (IPSET-thrombosis) categories were computable for 40 women; low (n = 20), intermediate (n = 14), and high risk (n = 6). Among 34 women with known driver mutational status, 45% were JAK2V617F mutated (n = 18), 30% CALR mutated (n = 12) and the remainder triple negative. A group of 33(60%) women were on aspirin therapy during first pregnancy, additionally 13 patients were receiving cytoreductive therapy (interferon (n = 8), anagrelide (n = 3), with one woman each on hydroxyurea and radioactive phosphorus). Five women received anticoagulation with low molecular weight heparin. Live births for first pregnancy after ET diagnosis, were noted in 34 women (62%) with the remainder experiencing fetal loss predominantly in the first trimester. Maternal complications in 24% women included post-partum hemorrhage (n = 5), venous thromboembolism (n = 3), preeclampsia (n = 3) and placental abruption (n = 2). On the other hand only four (7%) fetal complications arose; two intrauterine growth retardation and pre-term births each. We recommend referring to Table 1 for details on clinical parameters and pregnancy outcomes in ET. Table 1. Clinical characteristics and pregnancy outcomes of 55 women with essential thrombocythemia (ET) Variables at first pregnancy post ET All first pregnancies post ET N = 55 Age in years, median (range) 29 (20-36) Hemoglobin (g/dL), median (range) 12.7 (9-16.6) Leukocyte count (× 109/L), median (range) 8.4 (3.9-19.8) Platelet count (× 109/L), median (range) 840 (252-1998) Driver mutations (N evaluable = 40[%] for JAK2) (N evaluable = 34 [%] for JAK2,CALR,MPL) JAK2V617F Mutated 18 (45) Wild type 22 (55) CALR 12 (35) Triple negative 4 (12) IPSET thrombosis (N evaluable = 40 [%]) Low risk 20 (50) Intermediate risk 14 (35) High risk 6 (15) Clinical features (N evaluable = 53 [%]) Splenomegaly 9 (17) Microvascular symptoms 8 (15) Cardiovascular risk factors 10 (19) (diabetes mellitus, hypertension tobacco use, hyperlipidemia) Thrombosis & hemorrhage (N evaluable = 50[%]) Thrombosis prior to pregnancy 13 (26) Thrombosis in first pregnancy 3 (6) Hemorrhage prior to pregnancy 4 (8) Hemorrhage in first pregnancy 5 (10) Preeclampsia 3 (6) Placental abruption 2 (4) Treatments (N evaluable = 53[%]) Aspirin alone 33(62) Aspirin + cytoreductive therapya 5 (9) Cytoreductive therapy 12 (23) Anticoagulation (LMWH) 5 (9) No treatment 9 (17) First pregnancy outcome post ET Live birth, n(%) 34 (62) Fetal loss, n (%) 21 (38) First trimester 19 (35) Second trimester 2 (4) Stillbirth 0 Maternal complicationsb, n (%) 13 (24) Thrombosis 3 (5) Hemorrhage 5 (9) Preeclampsia 3 (5) Placental abruption 2 (4) Fetal complicationsc, n (%) 4 (7) IUGR 2 (3.5) Preterm birth 2 (3.5) Cesarean section, n (%) 5 (9) All pregnancy outcomes post ET(N = 95) Live birth, n (%) 64 (67) Fetal loss, n (%) 31 (33) First trimester 27 (28) Second trimester 3 (3) Stillbirth 1 (1) Maternal complicationsb, n (%) 17 (18) Thrombosis 4 (4) Hemorrhage 7 (7) Preeclampsia 4 (4) Placental abruption 2 (2) Fetal complicationc, n (%) 5 (5) IUGR 3 (3) Preterm birth 2 (2) Cesarean section, n (%) 7 (7) Note: IPSET-thrombosis -International Prognostic Score of Thrombosis for Essential Thrombocythemia: Low risk score = 0-1; intermediate risk, score = 2; and high risk, score ≥ 3. Risk factors included: age, cardiovascular risk factors, previous thrombosis, and JAK2V617F mutation. Abbreviation: LMWH, low molecular weight heparin. a Cytoreductive therapy included Hydroxyurea, Interferon alpha, Anagrelide and P32 (radioactive phosphorus). b Maternal complications- (Thrombosis, hemorrhage, preeclampsia, placental abruption). c Fetal complications- (IUGR-intrauterine growth retardation, preterm birth). Twenty seven women underwent a second pregnancy, of which 22 (81%) were live births. First trimester loss occurred in five of 27 second pregnancies (19%); all of whom had experienced antecedent pregnancy fetal loss. Six of 10 (60%) of third pregnancies were fetal losses (first trimester (n = 4), second trimester (n = 1), still birth (n = 1)). It is noteworthy that five of six third pregnancy fetal losses coincided with first pregnancy (P = .58), and four with second pregnancy loss (P = .34). An encouraging trend in pregnancy outcomes over the preceding decade was observed with increasing live birth rates of 76% post 2008 as opposed to 63% prior to 2008 (P = .34). As expected, this trend aligned with a significant reduction in both maternal/fetal complications after 2008 (5% vs 34%) (P = .007). Subsequently, we interrogated pregnancies in ET to identify disease features predictive of fetal loss and learnt that first pregnancy fetal loss was highly predictive of second pregnancy loss (P = .004). On the other hand, aspirin use during pregnancy was a preventive measure with fetal loss rates with or without aspirin of 27% vs 60% respectively (P = .02). Other factors such as maternal age > 30 years (P = .8), leukocytosis (P = .85), thrombocytosis (P = .41), JAK2 mutation (P = .62), CALR mutation (P = .28), prior thrombosis (P = .3), IPSET thrombosis (P = .63), fetal loss prior to ET (P = .53), anticoagulation use,P = .88), or cytoreductive therapy (P = .72) did not impact outcomes. With regards to PV, 4 of 36 (11%) women; median age 29.7 years, median hemoglobin 17.4 g/dL, leukocyte count 12 × 109/L, and platelet count 703 × 109/L with one or more pregnancies were studied. Patient one had venous thrombosis after diagnosis that was managed with aspirin, enoxaparin and hydroxyurea. She experienced an uncomplicated first pregnancy save for emergent Cesarean section for fetal distress resulting in a live birth. Patient two had a successful pregnancy while on aspirin, despite a history of two spontaneous miscarriages. Patient three, without prior thrombosis or fetal loss, delivered a live fetus by Cesarean section complicated by post-partum pulmonary embolism, treated with aspirin, enoxaparin and phlebotomies. Her subsequent pregnancy was uncomplicated on aspirin and enoxaparin. Patient four without prior thrombosis or hemorrhage had an uneventful first pregnancy on aspirin. Two women with PMF aged 26 and 28 years with elevated platelet counts of 1205 × 109/L and 784 × 109/L respectively, CALR mutated had a successful pregnancy each while on aspirin. In summary, the largest analysis of pregnancies in MPN from a single institution highlights substantial progress in pregnancy complications over the last decade with improving trends in live birth rates being consistent with a multi-center Italian cohort of 122 pregnancies (76% vs 75.4% live birth rates respectively).3, 6 Salient findings include the protective effect of aspirin on fetal loss and concordance of first and second pregnancy losses, which have been partially endorsed by a recent contemporary series from Harvard on 130 pregnancies. The study showed adverse impact of prior fetal loss (OR 8.82, P = .023) with a trend toward improved outcomes with aspirin use (OR 0.33, P = .12).7 Our discrepant observations regarding the lack of impact of JAK2, CALR mutations, or interferon use on outcomes warrant further collaborative investigations.3, 4 Lastly, the current series serves as a valuable resource for reproductive counseling of young women with MPN. CONFLICT OF INTEREST The authors declare no potential conflict of interest. REFERENCES 1Szuber N, Vallapureddy RR, Penna D, et al. Myeloproliferative neoplasms in the young: Mayo Clinic experience with 361 patients age 40 years or younger. Am J Hematol. 2018; 93: 1474- 1484. 2Alimam S, Bewley S, Chappell LC, et al. Pregnancy outcomes in myeloproliferative neoplasms: UK prospective cohort study. Br J Haematol. 2016; 175: 31- 36. 3Rumi E, Bertozzi I, Casetti IC, et al. Impact of mutational status on pregnancy outcome in patients with essential thrombocytemia. Haematologica. 2015; 100: e443- e445. 4Passamonti F, Randi ML, Rumi E, et al. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation. Blood. 2007; 110: 485- 489. 5Gangat N, Wolanskyj AP, Schwager S, Tefferi A. Predictors of pregnancy outcome in essential thrombocythemia: a single institution study of 63 pregnancies. Eur J Haematol. 2009; 82: 350- 353. 6Melillo L, Tieghi A, Candoni A, et al. Outcome of 122 pregnancies in essential thrombocythemia patients: a report from the Italian registry. Am J Hematol. 2009; 84: 636- 640. 7How C, Leiva O, Bogue T, et al. Pregnancy outcomes, risk factors, and gestational cell count trends in pregnant women with essential thrombocythemia and polycythemia vera. Blood. 2019; 134:4172. Citing Literature Volume95, Issue5May 2020Pages E114-E117 ReferencesRelatedInformation