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BACKGROUND: Preeclampsia is associated with autonomic dysregulation during pregnancy; however, less is known about autonomic function in the first week postpartum after preeclampsia. METHODS: We retrospectively analyzed data from a prospective cohort of women with and without preeclampsia. Continuous blood pressure and heart rate were measured with finger plethysmography within 7 days postpartum. Frequency-domain blood pressure and heart rate variability (HRV) were calculated using spectral analysis. Time-domain HRV was calculated as the root mean square of successive R–R interval differences. We compared results between those with and without preeclampsia, as well as between those with new-onset preeclampsia, chronic hypertension with superimposed preeclampsia, and normotensive participants. RESULTS: A total of 70 postpartum women were enrolled: 20 normotensive, 29 new-onset preeclampsia, and 21 superimposed preeclampsia. Both low- and high-frequency blood pressure variabilities were higher in those with preeclampsia compared with controls (P =0.04 and P =0.02, respectively). This difference was driven by those with new-onset preeclampsia. The preeclampsia group had lower high-frequency HRV (P <0.005), a higher low-/high-frequency ratio of HRV (P <0.005), and lower time-domain HRV (P =0.01); this difference was seen in those with and without chronic hypertension. CONCLUSIONS: Postpartum patients with preeclampsia with and without chronic hypertension had lower HRV compared with normotensive postpartum controls. Higher blood pressure variability was observed only in those with nonsuperimposed preeclampsia, suggesting that the autonomic profile of preeclampsia may differ in patients with chronic hypertension. [ABSTRACT FROM AUTHOR]

The Causal Roadmap outlines a systematic approach to asking and answering questions of cause and effect: define the quantity of interest, evaluate needed assumptions, conduct statistical estimation, and carefully interpret results. To protect research integrity, it is essential that the algorithm for statistical estimation and inference be prespecified prior to conducting any effectiveness analyses. However, it is often unclear which algorithm will perform optimally for the real-data application. Instead, there is a temptation to simply implement one's favorite algorithm, recycling prior code or relying on the default settings of a computing package. Here, we call for the use of simulations that realistically reflect the application, including key characteristics such as strong confounding and dependent or missing outcomes, to objectively compare candidate estimators and facilitate full specification of the statistical analysis plan. Such simulations are informed by the Causal Roadmap and conducted after data collection but prior to effect estimation. We illustrate with two worked examples. First, in an observational longitudinal study, we use outcome-blind simulations to inform nuisance parameter estimation and variance estimation for longitudinal targeted minimum lossbased estimation. Second, in a cluster randomized trial with missing outcomes, we use treatment-blind simulations to examine type-I error control in two-stage targeted minimum loss-based estimation. In both examples, realistic simulations empower us to prespecify an estimation approach with strong expected finite sample performance, and also produce quality-controlled computing code for the actual analysis. Together, this process helps to improve the rigor and reproducibility of our research. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with refractory, symptomatic left ventricular (LV) mid-cavity obstructive (LVMCO) hypertrophic cardiomyopathy have few therapeutic options. Right ventricular pacing is associated with modest hemodynamic and symptomatic improvement, and LV pacing pilot data suggest therapeutic potential. We hypothesized that site-specific pacing would reduce LVMCO gradients and improve symptoms. METHODS: Patients with symptomatic-drug-refractory LVMCO were recruited for a randomized, blinded trial of personalized prescription of pacing (PPoP). Multiple LV and apical right ventricular pacing sites were assessed during an invasive hemodynamic study of multisite pacing. Patient-specific pacing-site and atrioventricular delays, defining PPoP, were selected on the basis of LVMCO gradient reduction and acceptable pacing parameters. Patients were randomized to 6 months of active PPoP or backup pacing in a crossover design. The primary outcome examined invasive gradient change with best-site pacing. Secondary outcomes assessed quality of life and exercise following randomization to PPoP. RESULTS: A total of 17 patients were recruited; 16 of whom met primary end points. Baseline New York Heart Association was 3±0.6, despite optimal medical therapy. Hemodynamic effects were assessed during pacing at the right ventricular apex and at a mean of 8 LV sites. The gradients in all 16 patients fell with pacing, with maximum gradient reduction achieved via LV pacing in 14 (88%) patients and right ventricular apex in 2. The mean baseline gradient of 80±29 mm Hg fell to 31±21 mm Hg with best-site pacing, a 60% reduction (P<0.0001). One cardiac vein perforation occurred in 1 case, and 15 subjects entered crossover; 2 withdrawals occurred during crossover. Of the 13 completing crossover, 9 (69%) chose active pacing in PPoP configuration as preferred setting. PPoP was associated with improved 6-minute walking test performance (328.5±99.9 versus 285.8±105.5 m; P=0.018); other outcome measures also indicated benefit with PPoP. CONCLUSIONS: In a randomized placebo-controlled trial, PPoP reduces obstruction and improves exercise performance in severely symptomatic patients with LVMCO. [ABSTRACT FROM AUTHOR]

Background: Parents’ participation in the neonatal intensive care unit (NICU) reduces length of stay and positively affects infants’ psychological, cognitive, and behavioural outcomes. Healthcare professionals in the NICU focus on both parents, but tend to have the main focus on the mother and the infant. Therefore, fathers may experience a lack of support and feel that they are being disregarded in the NICU. Purpose: To study fathers’ experiences with father groups during NICU admission with their preterm infant. The father group is a 90-minute intervention based on dialogue between fathers and a male healthcare professional. Methods: A qualitative content analysis was conducted using 10 online semistructured interviews with fathers participating in a father group. The study was reported according to the Standards for Reporting Qualitative Research. Results: The overall theme emerging from our analysis was “Emotional support, encouragement, and an enhanced capacity to deal with the situation and with life in the NICU.” This theme emerged from the categories “Meeting with peers and sharing reflections” and “Fathers’ territory” based on 5 subcategories. Implications for Practice: Participation in father groups gives fathers recognition for being important as parents in the NICU, improves fathers’ mental well-being, and enhances their coping capacity. Father groups support fathers in the NICU and can be integrated into NICU practices and policies to enhance a family-centered approach. Implications for Research: This study revealed a need for further research to determine whether participation in a father group has a measurable effect on clinical outcomes [ABSTRACT FROM AUTHOR]

BACKGROUND: One-fifth of the patients with peripheral artery disease (PAD) experience depression and stress. Depression and stress may impact patients' abilities to be physically active, a key recommendation for supporting overall PAD management to improve symptoms and reduce the risk of cardiovascular events. We aimed to study interrelationships between 1-year longitudinal trajectories of depression, stress, and physical activity following a PAD diagnosis. METHODS: Patients with new or worsening PAD symptoms enrolled at 10 US PORTRAIT study (Patient-Centered Outcomes Related to Treatment Practices in Peripheral Arterial Disease: Investigating Trajectories) vascular specialty clinics (CT, LA, MI, MO, NC, OH, and RI) were assessed at baseline, 3, 6, and 12 months between June 2, 2011 and December 3, 2015. Depressive symptoms were measured with the 8-item Patient Health Questionnaire, perceived stress with the 4-item Perceived Stress Scale and physical activity with items from the INTERHEART study. Path analysis was used to examine the longitudinal relationship between depression and physical activity and perceived stress and physical activity. RESULTS: A total of 766 patients were included (mean age of 68.2 [±9.4] years; 57.7% male). Overall, 17.8% reported significant depressive symptoms, 36.0% experienced increased perceived stress, and 44.1% were sedentary upon PAD diagnosis. A decrease in physical activity preceded a rise in subsequent depressive symptoms (β ranges -0.45 [95% CI, -0.80 to -0.09]; -0.81 [95% CI, -1.19 to 0.42]) over the course of 1 year. Low physical activity scores at the initial presentation were followed by high perceived stress at 3 months (β=-0.44 [95% CI, -0.80 to -0.07]). CONCLUSIONS: In symptomatic PAD, a decrease in physical activity was followed by an increased risk of depressive symptoms and perceived stress at subsequent intervals over the course of 1 year following PAD diagnosis and treatment. Integrated behavioral health approaches for PAD, addressing physical activity and managing depression or distress, are indicated as collective PAD treatment goals. [ABSTRACT FROM AUTHOR]

Summary: The use of chlordiazepoxide in the treatment of alcohol withdrawal symptoms poses a risk of prolonged sedation with the need of weeks lasting antidote treatment, and extended hospitalization due to active metabolites with very long half-lives. We present four case stories to elucidate this issue. One patient received 800 mg chlordiazepoxide and was treated with flumazenil for 42 days. Another patient was treated with 100 mg chlordiazepoxide. 5 days after administration of chlordiazepoxide, concentrations of chlordiazepoxide and its active metabolite demoxepam, were within therapeutic range, the patient was treated with flumazenil for 6 days. He died after palliative care. The great individual variation in the clinical effect of chlordiazepoxide depends on the activity of the CYP P450 system, especially CYP3A4/A5 and CYPS2C19, which can be impaired in cirrhotic and elderly patients. [ABSTRACT FROM AUTHOR]

Objective: We evaluated a protocolized endoscopic necrosectomy approach with a lumen-apposing metal stent (LAMS) in patients with large symptomatic walled-off pancreatic necrosis (WON) comprising significant necrotic content, with or without infection. Summary Background Data: Randomized trials have shown similar efficacy of endoscopic treatment compared with surgery for infected WON. Design: We conducted a regulatory, prospective, multicenter single-arm clinical trial examining the efficacy and safety of endoscopic ultrasound -guided LAMS with protocolized necrosectomy to treat symptomatic WON ≥6 cm in diameter with >30% solid necrosis. After LAMS placement, protocolized WON assessment was conducted and endoscopic necrosectomy was performed for insufficient WON size reduction and persistent symptoms. Patients with radiographic WON resolution to ≤ 3 cm and/or 60-day LAMS indwell had LAMS removal, then 6-month follow-up. Primary endpoints were probability of radiographic resolution by 60 days and procedure-related serious adverse events. Results: Forty consecutive patients were enrolled September 2018 to March 2020, of whom 27 (67.5%) were inpatients and 19 (47.5%) had clinical evidence of infection at their index procedure. Mean WON size was 15.0 ± 5.6 cm with mean 53.2% ± 16.7% solid necrosis. Radiographic WON resolution was seen in 97.5% (95% CI, 86.8%, 99.9%) by 60 days, without recurrence in 34 patients with 6-month follow-up data. Mean time to radiographic WON resolution was 34.1 ± 16.8 days. Serious adverse events occurred in 3 patients (7.5%), including sepsis, vancomycin-resistant enterococcal bacteremia and shock, and upper gastrointestinal bleeding. There were no procedure-related deaths. Conclusions: Endoscopic ultrasound-guided drainage with protocolized endoscopic necrosectomy to treat large symptomatic or infected walled-off necrotic pancreatic collections was highly effective and safe. Clinicaltrials.-gov no: NCT03525808. [ABSTRACT FROM AUTHOR]

Background: Frozen embryo transfer (frozen-ET) is increasingly common because of improved cryopreservation methods and elective freezing of all embryos. Frozen-ET is associated with higher risk of hypertensive disorders in pregnancy than both natural conception and fresh embryo transfer (fresh-ET), but whether this is attributable to parental factors or treatment is unknown. Methods: Using the Medical Birth Registries of Denmark (1994–2014), Norway, and Sweden (1988–2015), linked to data from national quality registries and databases on assisted reproduction, we designed a population-based cohort study with within-sibship comparison. We included 4 426 691 naturally conceived, 78 300 fresh-ET, and 18 037 frozen-ET singleton pregnancies, of which 33 209 sibships were conceived using different conception methods. Adjusted odds ratios (aOR) of hypertensive disorders in pregnancy for fresh-ET and frozen-ET versus natural conception with 95% CI were estimated using multilevel logistic regression, where random effects provided conventional population-level estimates and fixed effects gave within-sibship estimates. Main models included adjustment for birth year, maternal age, parity, and country. Results: Risk of hypertensive disorders in pregnancy was higher after frozen-ET compared to natural conception, both at population-level (7.4% versus 4.3%, aOR, 1.74 [95% CI, 1.61–1.89]) and within sibships (aOR, 2.02 [95% CI, 1.72–2.39]). For fresh-ET, risk was similar to natural conception, both at population-level (aOR, 1.02 [95% CI, 0.98–1.07]) and within sibships (aOR, 0.99 [95% CI, 0.89–1.09]). Conclusions: Frozen-ET was associated with substantially higher risk of hypertensive disorders in pregnancy, even after accounting for shared parental factors within sibships. [ABSTRACT FROM AUTHOR]

Background: Lactation and breastfeeding present an extraordinary challenge for mothers of prematurely born infants.Purpose: To explore the significance of and the circumstances that affect lactation for mothers of premature infants.Methods: A qualitative exploratory study based on single, in-depth, semistructured interviews with 16 purposefully sampled mothers of premature infants admitted to the neonatal intensive care unit (NICU). Data were analyzed using content analysis. The study was reported according to Standards for Reporting Qualitative Research.Findings: The overall theme was "From expressing human milk to breastfeeding-an essential element in the journey to motherhood." The theme emerged from 3 categories: the birth preparation time has been interrupted; expressing human milk is essential for lactation; and the motherhood journey encompasses breastfeeding. The analysis also revealed that the categories were impacted by initiating, performing, and maintaining lactation and further influenced by inhibitors and promoters.Implications For Practice: The promoters for performing milk expression and breastfeeding should be stimulated and the inhibitors should be eliminated. The achievement of "zero separation" and mother-infant couplet care in the NICU would be beneficial. In order for mothers to maintain successful lactation, it is essential that they receive supportive around-the-clock access to health professionals with expertise in lactation and breastfeeding until exclusive breastfeeding is well established.Implications For Research: The study highlights the need to investigate mother-infant as one entity rather than separately as mother and infant. [ABSTRACT FROM AUTHOR]

Objective: The goal of this study was to assess the long-term effectiveness of combination therapy for intermittent claudication, compared with supervised exercise only. Background: Supervised exercise therapy is recommended as first-line treatment for intermittent claudication by recent guidelines. Combining endovascular revascularization plus supervised exercise shows promising results; however, there is a lack of long-term follow-up. Methods: The ERASE study is a multicenter randomized clinical trial, including patients between May 2010 and February 2013 with intermittent claudication. Interventions were combination of endovascular revascularization plus supervised exercise (n = 106) or supervised exercise only (n = 106). Primary endpoint was the difference in maximum walking distance at long-term follow-up. Secondary endpoints included differences in pain-free walking distance, ankle-brachial index, quality of life, progression to critical limb ischemia, and revascularization procedures during follow-up. This randomized trial report is based on a post hoc analysis of extended follow-up beyond that of the initial trial. Patients were followed up until 31 July 2017. Data were analyzed according to the intention-to-treat principle. Results: Median long-term follow-up was 5.4 years (IQR 4.9–5.7). Treadmill test was completed for 128/212 (60%) patients. Whereas the difference in maximum walking distance significantly favored combination therapy at 1-year follow-up, the difference at 5-year follow-up was no longer significant (53 m; 99% CI–225 to 331; P = 0.62). No difference in pain-free walking distance, ankle-brachial index, and quality of life was found during long-term follow-up. We found that supervised exercise was associated with an increased hazard of a revascularization procedure during follow-up (HR 2.50; 99% CI 1.27–4.90; P < 0.001). The total number of revascularization procedures (including randomized treatment) was lower in the exercise only group compared to that in the combination therapy group (65 vs 149). Conclusions: Long-term follow up after combination therapy versus supervised exercise only, demonstrated no significant difference in walking distance or quality of life between the treatment groups. Combination therapy resulted in a lower number of revascularization procedures during follow-up but a higher total number of revascularizations including the randomized treatment. Trial Registration: Netherlands Trial Registry Identifier: NTR2249 [ABSTRACT FROM AUTHOR]

The aim of this study was to assess if an evidence-based educational program focused on vocation and calling could improve undergraduate nursing students' sense of meaning in life and sense of calling/vocation. Using a mixed-methods, quasi-experimental design, a statistically significant increase occurred in sense of meaning in life and calling/vocation. Qualitative responses revealed growth in self-knowledge, importance of individual pathways, and recognition of nursing as one's calling. Courses on calling may encourage nursing students to commit to nursing as a calling. [ABSTRACT FROM AUTHOR]

Background: To determine risk factors for postradiation optic atrophy (PROA) after plaque radiotherapy for uveal melanoma. Methods: A single center, retrospective cohort study of patients diagnosed with uveal melanoma involving choroid and/or ciliary body treated with plaque between January 1, 2008, and December 31, 2016. Outcomes included development of PROA with pallor alone or with concomitant neuroretinal rim thinning (NRT). Cox regression analysis was performed to identify risk factors for PROA. Results: Of 78 plaque-irradiated patients, PROA developed in 41 (53%), with concomitant NRT in 15 (19%). Risk factors for PROA of any type included presentation with worse visual acuity (odds ratio [95% confidence interval] 5.6 [2.3-14.1], P < 0.001), higher baseline intraocular pressure (IOP; 14 vs 16 mm Hg) (1.1 [1.0-1.2], P = 0.03), shorter tumor distance to optic disc (1.3 [1.2-1.5], P < 0.001) and foveola (1.2 [1.1-1.3], P < 0.001), subfoveal subretinal fluid (3.8 [2.0-7.1], P < 0.001), greater radiation prescription depth (1.3 [1.1-1.6], P = 0.002), dose to fovea (point dose) (1.01 [1.01-1.02], P < 0.001), and mean (1.02 [1.02-1.03], P < 0.001) and maximum dose to optic disc per 1 Gy increase (1.02 [1.01-1.03], P < 0.001). On multivariate modeling, dose to disc, baseline IOP, and subfoveal fluid remained significant. Subanalysis revealed risk factors for pallor with NRT of greater mean radiation dose to disc (1.03 [1.01-1.05], P = 0.003), higher maximum IOP (17 vs 20 mm Hg) (1.4 [1.2-1.7], P < 0.001), and subfoveal fluid (12 [2-63], P = 0.004). Conclusion: PROA may result in NRT in addition to optic disc pallor. Risk factors for PROA included higher radiation dose to optic disc, higher baseline IOP, and subfoveal fluid. Higher maximum IOP contributed to concomitant NRT. [ABSTRACT FROM AUTHOR]

BACKGROUND: Despite recent guideline recommendations, quantitative perfusion (QP) estimates of myocardial blood flow from cardiac magnetic resonance (CMR) have only been sparsely validated. Furthermore, the additional diagnostic value of utilizing QP in addition to the traditional visual expert interpretation of stress-perfusion CMR remains unknown. The aim was to investigate the correlation between myocardial blood flow measurements estimated by CMR, positron emission tomography, and invasive coronary thermodilution. The second aim is to investigate the diagnostic performance of CMR-QP to identify obstructive coronary artery disease (CAD). METHODS: Prospectively enrolled symptomatic patients with >50% diameter stenosis on computed tomography angiography underwent dual-bolus CMR and positron emission tomography with rest and adenosine-stress myocardial blood flow measurements. Subsequently, an invasive coronary angiography (ICA) with fractional flow reserve and thermodilution-based coronary flow reserve was performed. Obstructive CAD was defined as both anatomically severe (>70% diameter stenosis on quantitative coronary angiography) or hemodynamically obstructive (ICA with fractional flow reserve ≤0.80). RESULTS: About 359 patients completed all investigations. Myocardial blood flow and reserve measurements correlated weakly between estimates from CMR-QP, positron emission tomography, and ICA-coronary flow reserve (r<0.40 for all comparisons). In the diagnosis of anatomically severe CAD, the interpretation of CMR-QP by an expert reader improved the sensitivity in comparison to visual analysis alone (82% versus 88% [ P =0.03]) without compromising specificity (77% versus 74% [ P =0.28]). In the diagnosis of hemodynamically obstructive CAD, the accuracy was only moderate for a visual expert read and remained unchanged when additional CMR-QP measurements were interpreted. CONCLUSIONS: CMR-QP correlates weakly to myocardial blood flow measurements by other modalities but improves diagnosis of anatomically severe CAD. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481712. [ABSTRACT FROM AUTHOR]

Background: Social isolation among HIV-positive persons might be an important barrier to care. Using data from the SEARCH Study in rural Kenya and Uganda, we constructed 32 community-wide, sociocentric networks and evaluated whether less socially connected HIV-positive persons were less likely to know their status, have initiated treatment, and be virally suppressed.Methods: Between 2013 and 2014, 168,720 adult residents in the SEARCH Study were census-enumerated, offered HIV testing, and asked to name social contacts. Social networks were constructed by matching named contacts to other residents. We characterized the resulting networks and estimated risk ratios (aRR) associated with poor HIV care outcomes, adjusting for sociodemographic factors and clustering by community with generalized estimating equations.Results: The sociocentric networks contained 170,028 residents (nodes) and 362,965 social connections (edges). Among 11,239 HIV-positive persons who named ≥1 contact, 30.9% were previously undiagnosed, 43.7% had not initiated treatment, and 49.4% had viral nonsuppression. Lower social connectedness, measured by the number of persons naming an HIV-positive individual as a contact (in-degree), was associated with poorer outcomes in Uganda, but not Kenya. Specifically, HIV-positive persons in the lowest connectedness tercile were less likely to be previously diagnosed (Uganda-West aRR: 0.89 [95% confidence interval (CI): 0.83, 0.96]; Uganda-East aRR: 0.85 [95% CI: 0.76, 0.96]); on treatment (Uganda-West aRR: 0.88 [95% CI: 0.80, 0.98]; Uganda-East aRR: 0.81 [0.72, 0.92]), and suppressed (Uganda-West aRR: 0.84 [95% CI: 0.73, 0.96]; Uganda-East aRR: 0.74 [95% CI: 0.58, 0.94]) than those in the highest connectedness tercile.Conclusions: HIV-positive persons named as a contact by fewer people may be at higher risk for poor HIV care outcomes, suggesting opportunities for targeted interventions. [ABSTRACT FROM AUTHOR]

BACKGROUND: The ERASE (Endovascular Revascularization and Supervised Exercise) study showed that a combination therapy of endovascular revascularization followed by supervised exercise resulted in greater improvement in walking ability and quality of life as compared with supervised exercise only (standard care) in patients with intermittent claudication. The cost-effectiveness of the combination therapy as compared with supervised exercise is not well defined. In this report, the cost-effectiveness analysis of the ERASE study is presented. METHODS: Two hundred twelve patients were randomly assigned to the combination therapy (n=106) or supervised exercise only (n=106) and were followed for 12 months. Cumulative costs per patient were collected using the in-hospital resource utilization data and cost-questionnaires. Quality-adjusted life years were estimated using the EuroQol-5D questionnaire. Incremental cost-effectiveness ratios were calculated from both the health care and societal perspective. The associated uncertainty was determined using bootstrap techniques and acceptability curves. RESULTS: As compared with supervised exercise only, the combination therapy cost an additional €1.462 (99% CI, 388 to 3862) from the health care perspective and €161 (99% CI, -2286 to 3106) from the societal perspective. Accumulated quality-adjusted life- years during 1 year follow-up were 0.042 (99% CI, -0.009 to 0.118) higher in the combination therapy group. The incremental cost-effectiveness ratio was €34.810 from the health care perspective and €3.833 from the societal perspective. Compared with supervised exercise, at a willingness-to-pay threshold of €80.000 per quality-adjusted lifeyear, the combination therapy had a probability of 87% and 95% of being cost-effective from the health care and societal perspective, respectively. CONCLUSIONS: Combination therapy of endovascular revascularization followed by supervised exercise is clinically and economically a more attractive approach than supervised exercise only for intermittent claudication up to 12-month followup. Yet, the long-term cost- and clinical effectiveness of both strategies for specific patient groups remains to be defined. [ABSTRACT FROM AUTHOR]