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Background Anatomical and experimental data indicate that onabotulinimtoxin A could be more efficient and cost-effective for treating chronic migraine with injections targeting the cranial sutures, where collaterals from the meninges penetrate the skull. Methods A new injection paradigm (FollowTheSutures) was tested for safety, tolerability and feasibility in a Phase II, open-label, non-controlled, single-center pilot study. Ninety units of onabotulinimtoxin A (Botox®), were injected in 18 sites over the area of the cranial sutures. Adverse events and potential beneficial effects were recorded in a headache diary at least 4 weeks before, and for 12 weeks after the injections. A higher dilution than normal of onabotulinimtoxin A was used to get better diffusion. Results Nineteen (of 20 included) women with chronic migraine received the injections and were evaluable. There was only one treatment-related adverse event (reduced power of chewing for some weeks). Otherwise, the procedure was overall well tolerated. Patients improved on most efficacy parameters after the injections. There was little or no effect on glabellar or forehead lines. Conclusions The protocol was safe and well tolerated. Lower risk of unblinding due to the absence of cosmetic effects should make the injection procedure well suited for a large, randomized, placebo-controlled study. If efficacy is confirmed, it will be markedly less costly than the standard procedure. Trial registration: EUDRACT (2017-002516-13), ClinicalTrials.gov (NCT03543254).

AbstractPurposeExternal validation of machine learning predictive models is achieved through evaluation of model performance on different groups of patients than were used for algorithm development. This important step is uncommonly performed, inhibiting clinical translation of newly developed models. Machine learning analysis of the Norwegian Knee Ligament Register (NKLR) recently led to the development of a tool capable of estimating the risk of anterior cruciate ligament (ACL) revision (https://swastvedt.shinyapps.io/calculator_rev/). The purpose of this study was to determine the external validity of the NKLR model by assessing algorithm performance when applied to patients from the Danish Knee Ligament Registry (DKLR).MethodsThe primary outcome measure of the NKLR model was probability of revision ACL reconstruction within 1, 2, and/or 5 years. For external validation, all DKLR patients with complete data for the five variables required for NKLR prediction were included. The five variables included graft choice, femur fixation device, KOOS QOL score at surgery, years from injury to surgery, and age at surgery. Predicted revision probabilities were calculated for all DKLR patients. The model performance was assessed using the same metrics as the NKLR study: concordance and calibration.ResultsIn total, 10,922 DKLR patients were included for analysis. Average follow‐up time or time‐to‐revision was 8.4 (± 4.3) years and overall revision rate was 6.9%. Surgical technique trends (i.e., graft choice and fixation devices) and injury characteristics (i.e., concomitant meniscus and cartilage pathology) were dissimilar between registries. The model produced similar concordance when applied to the DKLR population compared to the original NKLR test data (DKLR: 0.68; NKLR: 0.68–0.69). Calibration was poorer for the DKLR population at one and five years post primary surgery but similar to the NKLR at two years.ConclusionThe NKLR machine learning algorithm demonstrated similar performance when applied to patients from the DKLR, suggesting that it is valid for application outside of the initial patient population. This represents the first machine learning model for predicting revision ACL reconstruction that has been externally validated. Clinicians can use this in‐clinic calculator to estimate revision risk at a patient specific level when discussing outcome expectations pre‐operatively. While encouraging, it should be noted that the performance of the model on patients undergoing ACL reconstruction outside of Scandinavia remains unknown.Level of evidenceIII.

Aim There is an association between heart failure with preserved ejection fraction (HFpEF) and insulin resistance, but less is known about the diabetic continuum, and in particular about pre‐diabetes, in HFpEF. We examined characteristics and outcomes of participants with diabetes or pre‐diabetes in PARAGON‐HF. Methods and results Patients aged ≥50 years with left ventricular ejection fraction ≥45%, structural heart disease and elevated N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) were eligible. Patients were classified according to glycated haemoglobin (HbA1c): (i) normal HbA1c, <6.0%; (ii) pre‐diabetes, 6.0%–6.4%; (iii) diabetes, ≥6.5% or history of diabetes. The primary outcome was a composite of cardiovascular (CV) death and total heart failure hospitalizations (HFH). Of 4796 patients, 50% had diabetes and 18% had pre‐diabetes. Compared to patients with normal HbA1c, patients with pre‐diabetes and diabetes more often were obese, had a history of myocardial infarction and had lower Kansas City Cardiomyopathy Questionnaire scores, while patients with diabetes had more clinical evidence of congestion, but similar NT‐proBNP concentrations. The risks of the primary composite outcome (rate ratio [RR] 1.59, 95% confidence interval [CI] 1.35–1.88), total HFH (RR 1.67, 95% CI 1.39–2.02) and CV death (hazard ratio [HR] 1.35, 95% CI 1.07–1.71) were higher among patients with diabetes, compared to those with normal HbA1c. Patients with pre‐diabetes had a higher risk (which was intermediate between that of patients with diabetes and those with normal HbA1c) of the primary outcome (HR 1.27, 95% CI 1.00–1.60) and HFH (HR 1.35, 95% CI 1.03–1.77), but not of CV death (HR 1.02, 95% CI 0.75–1.40). Patients with diabetes treated with insulin had worse outcomes than those not, and those with ‘lean diabetes’ had similar mortality rates to those with a higher body mass index, but lower rates of HFH. Conclusion Pre‐diabetes is common in patients with HFpEF and is associated with worse clinical status and greater risk of HFH. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT01920711.

AbstractIntroductionHarboring two copies of the apolipoprotein E (APOE) ε2 allele strongly protects against Alzheimer's disease (AD). However, the effect of this genotype on gray matter (GM) volume in cognitively unimpaired individuals has not yet been described.MethodsMulticenter brain magnetic resonance images (MRIs) from cognitively unimpaired ε2 homozygotes were matched (1:1) against all other APOE genotypes for relevant confounders (n = 223). GM volumes of ε2 genotypic groups were compared to each other and to the reference group (APOE ε3/ε3).ResultsCarrying at least one ε2 allele was associated with larger GM volumes in brain areas typically affected by AD and also in areas associated with cognitive resilience. APOE ε2 homozygotes, but not APOE ε2 heterozygotes, showed larger GM volumes in areas related to successful aging.DiscussionIn addition to the known resistance against amyloid‐β deposition, the larger GM volumes in key brain regions may confer APOE ε2 homozygotes additional protection against AD‐related cognitive decline.

Background: Transbronchial lung forceps biopsy (TBLF) is of limited value for the diagnosis of interstitial lung disease (ILD). However, in cases with predominantly peribronchial pathology, such as sarcoidosis, TBLF is considered to be diagnostic in most cases. The present study examines whether transbronchial lung cryobiopsy (TBLC) is superior to TBLF in terms of diagnostic yield in cases of sarcoidosis. Methods: In this post hoc analysis of a prospective, randomized, controlled, multicentre study, 359 patients with ILD requiring diagnostic bronchoscopic tissue sampling were included. TBLF and TBLC were both used for each patient in a randomized order. Histological assessment was undertaken on each biopsy and determined whether sarcoid was a consideration. Results: A histological diagnosis of sarcoidosis was established in 17 of 272 cases for which histopathology was available. In 6 out of 17 patients, compatible findings were seen with both TBLC and TBLF. In 10 patients, where the diagnosis of sarcoidosis was confirmed by TBLC, TBLF did not provide a diagnosis. In one patient, TBLF but not TBLC confirmed the diagnosis of sarcoidosis. Conclusions: In this post hoc analysis, the histological diagnosis of sarcoidosis was made significantly more often by TBLC than by TBLF. As in other idiopathic interstitial pneumonias (IIPs), the use of TBLC should be considered when sarcoidosis is suspected.

Background: Stressed blood volume (SBV) is a major determinant of systemic and pulmonary venous pressures which, in turn, determine left and right ventricular fillings and regulates cardiac output via the Frank-Starling mechanism. It is not known whether inhibition of the SGLT2 (sodium–glucose cotransporter-2) favorably affects SBV. We investigated the effect of empagliflozin on estimated SBV in patients with heart failure and reduced ejection fraction compared with placebo. Methods: This was a post hoc analysis of an investigator-initiated, double-blinded, placebo-controlled, randomized trial. Seventy patients were assigned to empagliflozin 10 mg or matching placebo once daily for 12 weeks. Patients underwent right heart catheterization at rest and during exercise at baseline and follow-up. The outcome was change in estimated SBV after 12 weeks of empagliflozin treatment over the full range of exercise, determined using a recently introduced analytical approach based on invasive hemodynamic assessment. Results: Patients with heart failure and reduced ejection fraction, mean age, 57 years and mean ejection fraction 27%, with 47 patients (71%) receiving diuretics were randomized. The effect of empagliflozin on estimated SBV over the full range of exercise loads showed a statistically significant reduction compared with placebo (−198.4 mL [95% CI, −317.4 to −79.3] P =0.001), a 9% decrease. The decrease in estimated SBV by empagliflozin was significantly correlated with the decrease in PCWP ( R =−0.33, P <0.0001). The effect of empagliflozin was consistent across subgroup analysis. Conclusions: Empagliflozin treatment significantly reduced SBV compared with placebo after 12 weeks of treatment in patients with stable chronic heart failure and reduced ejection fraction during sub maximal exercise. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03198585.

Abstract Background Patient-worn accelerometer is increasingly used in patients with heart failure and reduced ejection fraction (HFrEF) to assess daily activity and and as surrogate endpoint. We examined the association between cardiac physiology and daily activity by patient-worn accelerometer recordings in stable HFrEF patients. Methods In this descriptive study, physical average daily accelerometer units (PADA) and total average daily accelerometer unit (TADA) were assessed by a accelerometer recordings. Sixty three stable ambulatory patients with HFrEF, mainly men (92%), mean age 58±10 years, and ejection-fraction 26±4% underwent hemodynamic exercise testing, and accelerometry (Table 1). Patients were divided by PADA in a low and high activity level groups based on counts per minute physical activity. Results Patients in the low activity group were older and more frequently treated with diuretics. At rest, the low activity group was characterized by a lower cardiac index (CI) (2.2±0.4 vs. 2.4±0.4 l/min/m2, p=0.01), Stroke volume (SV) (70±19 vs. 81±17 ml, p=0.02) but not pulmonary capillary wedge pressure (PCWP) (12±5 vs. 11±5 mmHg, p=0.3) (Figure 1). Low activity group reached a lower CI (4.8±1.7 vs. 6.6±1.7 l/min/m2, p&lt;0.001) and SV (94±32 vs. 121±29 ml, p&lt;0.001), but not in PCWP (31±12 vs. 27±8 mmHg, p=0.2) or arterial-venous O2 content difference (A-VO2 diff) (13.00±2.32 vs. 12.96±1.65 ml O2/dl, p=0.9) at peak exercise. The attenuated increase was associated with attenuated increase in SV rther than increase in heart rate (42±23 vs. 52±21 bpm, p=0.07). Finally, CI at peak exercise was the only independent variable associated with PADA after adjusting for age, gender, and BMI (p&lt;0.0001). The PADA and TADA were associated to functional assessments using Kansas City Cardiomyopathy Questionnaire, but not with New York Heart Association class or N-terminal pro brain natriuretic peptide (NT-proBNP) (Table 1). Conclusion Accelerometer-assessed activity in patients with HFrEF are associated with impairments in LV performance, SV reserve and cardiac output during exercise, to a greater extent than changes in arterial-venous O2 content difference or pulmonary vascular pressures. Accelerometer data may provide information about the functional status that we do not nessecary find in the widely used tools in both research and daily clinical practice. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): This work was supported by the Danish Heart Foundation [grant numbers 17-R116-A7714-22076, 18-R124-A8573-22107]; Steno Diabetes Center Odense, Denmark [grant number 3363] and A.P. Møller Foundation for the Advancement of Medical Science [grant number 17-L-0339]. Table 1. Baseline and regression analysisFigure 1. Change in PCWP and CI by exercise

Background: Several factors are associated with an increased risk of anterior cruciate ligament (ACL) reconstruction revision. However, the ability to accurately translate these factors into a quantifiable risk of revision at a patient-specific level has remained elusive. We sought to determine if machine learning analysis of the Norwegian Knee Ligament Register (NKLR) can identify the most important risk factors associated with subsequent revision of primary ACL reconstruction and develop a clinically meaningful calculator for predicting revision of primary ACL reconstruction. Methods: Machine learning analysis was performed on the NKLR data set. The primary outcome was the probability of revision ACL reconstruction within 1, 2, and/or 5 years. Data were split randomly into training sets (75%) and test sets (25%). Four machine learning models were tested: Cox Lasso, survival random forest, generalized additive model, and gradient boosted regression. Concordance and calibration were calculated for all 4 models. Results: The data set included 24,935 patients, and 4.9% underwent a revision surgical procedure during a mean follow-up (and standard deviation) of 8.1 ± 4.1 years. All 4 models were well-calibrated, with moderate concordance (0.67 to 0.69). The Cox Lasso model required only 5 variables for outcome prediction. The other models either used more variables without an appreciable improvement in accuracy or had slightly lower accuracy overall. An in-clinic calculator was developed that can estimate the risk of ACL revision (Revision Risk Calculator). This calculator can quantify risk at a patient-specific level, with a plausible range from near 0% for low-risk patients to 20% for high-risk patients at 5 years. Conclusions: Machine learning analysis of a national knee ligament registry can predict the risk of ACL reconstruction revision with moderate accuracy. This algorithm supports the creation of an in-clinic calculator for point-of-care risk stratification based on the input of only 5 variables. Similar analysis using a larger or more comprehensive data set may improve the accuracy of risk prediction, and future studies incorporating patients who have experienced failure of ACL reconstruction but have not undergone subsequent revision may better predict the true risk of ACL reconstruction failure. Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.