Citations

AbstractBackgroundVariations in care have been demonstrated both within and among institutions in many clinical settings. By standardizing perioperative practices, Enhanced Recovery After Surgery (ERAS) pathways reduce variation in perioperative care. We sought to characterize the variation in cytoreductive surgery (CRS)/heated intraperitoneal chemotherapy (HIPEC) perioperative practices among experienced US medical centers.MethodsData from the US HIPEC Collaborative represents a retrospective multi‐institutional cohort study of CRS and CRS/HIPEC procedures performed from 12 major academic institutions. Patient characteristics and perioperative practices were reported and compared. Institutional variation was analyzed using hierarchical mixed‐effects linear (continuous outcomes) or logistic (binary outcomes) regression models.ResultsA total of 2372 operations were included. CRS/HIPEC was performed most commonly for appendiceal histologies (64.2%). The rate of complications (overall 56.3%, range: 31.8‐70.9) and readmissions (overall 20.6%, range: 8.9‐33.3) varied by institution (P < .001). Institution‐level variation in perioperative practice patterns existed among measured ERAS pathway process/outcomes (P < .001). The percentages of variation with each process/outcome measure attributable solely to institutional practices ranged from 0.6% to 66.6%.ConclusionsSignificant variation exists in the perioperative care of patients undergoing CRS/HIPEC at major US academic institutions. These findings provide a strong rationale for the investigation of best practices in CRS/HIPEC patients.

AbstractImpedance has traditionally been employed in esophageal disease as a means to assess bolus flow and reflux episodes. Recent and ongoing research has provided new and novel applications for this technology. Measurement of esophageal mucosal impedance, via either multichannel intraluminal impedance catheters or specially designed endoscopically deployed impedance catheters, provides a marker of mucosal integrity. Mucosal impedance has been shown to segregate gastroesophageal reflux disease (GERD) and eosinophilic esophagitis from non‐GERD controls and may play a role in predicting response to reflux intervention. More data are needed with regard to other esophageal subgroups, outcome studies, and functional disease. Our paper reviews the history of impedance in esophageal disease, the means of assessing baseline and mucosal impedance, data with regard to the newly developed mucosal impedance probes, the clinical utility of mucosal impedance in specific clinical conditions, and limitations in our existing knowledge, along with suggestions for future studies.

ABSTRACT Osteoporosis is a chronic condition that reflects reduced bone strength and an associated increased risk for fracture. As a chronic condition, osteoporosis generally requires sustained medical intervention(s) to limit the risks for additional bone loss, compromise of skeletal integrity, and fracture occurrence. Further complicating this issue is the fact that the abrupt cessation of some therapies can be associated with an increased risk for harm. It is in this context that the COVID-19 pandemic has brought unprecedented disruption to the provision of health care globally, including near universal requirements for social distancing. In this Perspective, we provide evidence, where available, regarding the general care of patients with osteoporosis in the COVID-19 era and provide clinical recommendations based primarily on expert opinion when data are absent. Particular emphasis is placed on the transition from parenteral osteoporosis therapies. It is hoped that these recommendations can be used to safely guide care for patients with osteoporosis until a return to routine clinical care standards is available. © 2020 American Society for Bone and Mineral Research.

Abstract PARADIGHM is an actively recruiting, prospective, observational registry (NCT01922440/EUPAS16927). The primary objective is to evaluate the safety and effectiveness of recombinant human parathyroid hormone, rhPTH(1-84), treatment in patients with chronic hypoparathyroidism (HypoPT) under routine clinical care. The secondary objective is to characterize the clinical course of chronic HypoPT under conditions of routine clinical practice. At enrollment, registry inclusion criteria are patients having a HypoPT diagnosis &gt;6 months and receiving conventional therapy (CT; eg, calcium supplements and active vitamin D), rhPTH(1-84) plus CT, or rhPTH(1-84). We present baseline characteristics of patients as of a June 30 2019 data cut. Baseline was defined as the value entered at the time of enrollment (Visit 1). Baseline symptom data exclude patients who initiated rhPTH(1-84) prior to enrollment (n=68) and are herein presented as two groups: those subsequently prescribed with rhPTH(1-84) after enrollment or those treated with CT. All data are summarized descriptively. Patient data from 64 centers in Europe and North America were analyzed. In the analysis population (n=737), 587 patients (79.6%) were female, 620 (84.1%) were white, and the mean (SD) age was 49.1 (16.45) years. The mean (SD) BMI was 19.3 (5.73) kg/m2 and 30.0 (7.72) kg/m2 in patients aged &lt;18 (n=25) and ≥18 (n=587) years, respectively. The primary cause of HypoPT was thyroid surgery (n=547 [74.2%]; of these, 281 [60.0%] underwent surgery for thyroid cancer). Endocrinologists were the prescribing specialists for most patients (n=660 [89.6%]). Vitamin D and analogs were prescribed for 90.1% of patients (calcitriol, 74.2%, native vitamin D, 47.4%, alfacalcidol, 7.9%,), calcium for 81.0% (calcium carbonate, 57.9%, calcium citrate, 27.1%), and thyroid hormones for 71.2% (levothyroxine, 73.4%; liothyronine, 5.8%). Symptoms reported at enrollment for the rhPTH(1-84) (n=66) and the CT groups (n=603), respectively, included fatigue (53.0%, 39.3%), paresthesia (48.5%, 29.2%), muscle twitching (48.5%, 21.1%), muscle cramping (40.9%, 33.0%), headaches (33.3%, 17.6%), anxiety (28.8%, 20.1%), muscle pain (28.8%, 19.2%), tetany (28.8%, 12.1%), and brain fog (27.3%, 16.3%). The baseline data for the overall population appear to be representative of patients with chronic HypoPT. Baseline data suggest that at enrollment patients prescribed rhPTH(1-84) after enrollment appear to have an increased burden of disease than patients receiving CT based on symptoms. PARADIGHM will be a valuable resource of real-world longitudinal data for patients with chronic HypoPT.

Abstract Background: Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders characterized by end-organ resistance to PTH. Most subtypes are caused by pathogenic variants or epigenetic alterations in GNAS, which encodes the alpha subunit of the G protein regulating end-organ response to PTH. PHP type 1B (PHP1B) is caused by methylation defects in GNAS and presents with isolated renal PTH resistance. Clinical Case: A 29-year-old gentleman presented with intermittent muscle spasms, perioral and digital paresthesias, fatigue, and anxiety. Family history was notable for similar symptoms in his sister and nephew. Physical examination revealed normal stature, non-dysmorphic facies, and no soft tissue ossifications or skeletal anomalies. Chvostek sign was positive. Laboratory studies showed total calcium 6.0 mg/dL (n 8.6–10.0 mg/dL), phosphorus 6.8 mg/dL (n 2.5–3.5 mg/dL), creatinine 0.8 mg/dL (n 0.8–1.3 mg/dL), albumin 5.0 (n 3.5–5.0 mg/dL), PTH 231 pg/mL (n 15–65 pg/mL), total 25-hydroxyvitamin D 19 mg/mL (n 20–50 ng/mL), and 1,25-dihydroxyvitamin D 45 pg/mL (n 18–64 pg/mL). Additional endocrine testing showed TSH 6.4 mIU/L (n 0.3–4.2 mIU/L), free T4 1.1 ng/dL (n 0.9–1.7 ng/dL), and TPO antibody &lt;0.3 IU/mL (n &lt;9.0 IU/mL). Renal ultrasound was normal. CT head showed diffuse intracranial calcifications. He was diagnosed with PHP1B and started on calcitriol, cholecalciferol, and calcium carbonate. He declined genetic testing. Repeat laboratory studies were improved with total calcium 8.5 mg/dL, phosphorus 3.9 mg/dL, total 25-hydroxyvitamin D 49 mg/mL, PTH 124 pg/mL, and 24-hour urinary calcium 269 mg (n &lt;250 mg). Conclusion: International consensus guidelines for the diagnosis and management of PHP and related disorders were recently published by Mantovani et al. in 2018. Proposed clinical and biochemical major criteria include PTH resistance, ectopic ossifications, early-onset obesity, TSH resistance, and Albright hereditary osteodystrophy (AHO; round facies, short stature, brachydactyly, developmental delay). Unlike PHP type 1A, PHP1B often presents later in life and features of AHO are usually absent, so diagnosis requires a high degree of clinical suspicion. It is recommended that patients with suspected PHP have molecular confirmation with sequencing, methylation, and/or copy number variant analysis of GNAS. Routine monitoring of calcium, phosphorus, and PTH levels and treatment with active vitamin D analogues with or without calcium supplements are advised to maintain normal calcium and phosphorus and PTH &lt;2 times the upper limit of normal. Other recommendations include renal imaging for nephrocalcinosis, eye exam for cataracts, CT head imaging (in patients with neurological findings) for calcifications, regular dental care, and management of comorbid endocrinopathies. A multidisciplinary approach is needed in this complex, heterogeneous group of disorders.

Abstract Background: Hypoparathyroidism (HP) is caused by a deficiency in parathyroid hormone (PTH), which leads to hypocalcemia and hyperphosphatemia. Standard of care (SoC), i.e. large doses of calcium (Ca) and active vitamin D, worsens hypercalciuria and increases the serum Ca (sCa) x serum phosphate (sP) product. Studies have shown that continuous subcutaneous infusion of PTH(1-34) normalizes sCa, sP, serum magnesium, urine Ca (uCa) and bone turnover better than SoC or once- or twice-daily injections of PTH in HP patients. TransCon PTH, an investigational long-acting prodrug of PTH (1-34) transiently bound to an inert carrier via a linker, is under development as a potential once-daily replacement therapy for HP. Under physiological conditions, linker auto-cleavage occurs, releasing active PTH at a controlled rate with ~60 hour half-life. Phase 1 trial results demonstrated that once-daily TransCon PTH provided a flat, infusion like profile within the normal range of PTH 24 hours per day, increasing sCa while controlling uCa and decreasing sP, with no evidence of bone anabolic activity. Phase 2 Design: PaTH Forward is a global phase 2 trial evaluating the safety, tolerability, and efficacy of TransCon PTH in adult subjects with HP. Patients with HP treated with SoC were randomized at sites worldwide to daily TransCon PTH 15, 18 or 21 µg PTH(1-34) or daily blinded placebo via pen-injector for 4 weeks. The primary composite endpoint requires 1) normal albumin-adjusted sCa, and 2) normal Fractional Excretion of Ca (or ≥50% decrease from baseline), and 3) not taking active D, and 4) taking ≤1000 mg/d of Ca. After four weeks, all subjects enter an open-label extension period with the opportunity to receive TransCon PTH individually optimized to doses of 6 to 30 µg daily to evaluate long-term safety and efficacy. Other endpoints include the impact of treatment on patient experience, CaxP product, bone turnover markers, and bone mass by DXA and TBS to confirm the lack of anabolic effect. Preliminary Results: Approximately 55 subjects are expected to be randomized and dosed. Preliminary diary data on the initial 8 subjects completing 4 weeks of follow-up in the extension trial shows that all have discontinued SoC. Additional information will be presented at ENDO 2020. The Phase 2 trial is designed to inform the starting dose for a global pivotal phase 3 trial and evaluate TransCon PTH as a “true” PTH replacement therapy.

Abstract Context: The majority of patients with hypoparathyroidism (HypoPT) are women. It is not known whether the presence of hypoparathyroidism influences the pregnancy outcomes. Sweden has excellent conditions for research in this area, with high-quality population-based registers covering essentially all inpatient care and birth records. In this study, data were linked from the Swedish National Patient Register and Swedish Medical Birth Register to examine the potential influence of maternal hypoPT on the number of childbirths and various pregnancy outcomes. Design and Setting: Population-based cohort study in Sweden. Patients: Through the Swedish National Patient Register and the Total Population Register, we identified 1267 women with HypoPT and 12 670 age-matched controls who gave birth between 1997 and 2016. Results: There was no significant difference in mean age at delivery for women with HypoPT (32 (SD, 5.2)) years and controls (32.5 (5.0)). There were significantly more women with HypoPT who smoked at baseline (p= 0.007) and within 3 months of pregnancy (p=0.022) compared to controls. Significantly more women with HypoPT had part time work or were not working during pregnancy compared to controls (p = 0.002). The mean number of infants per woman was 0.30 (SD, 0.62) in the HypoPT group and 0.33 (SD, 0.60) in the control group (p=0.644). Compared with the control group, the risk of elective cesarean section was higher in the HypoPT group (p=0.002). However, there was no difference in the proportion of women undergoing an acute cesarean section between cases and controls (p=0.754). The mean pregnancy duration in women with HypoPT was 38.87 (2.11) weeks compared to 39.23 (2.04) weeks for the controls (p= 0.001). Infants born to mothers with HypoPT were significantly shorter (p=0.016), but no difference was seen in weight or head circumference compared to infants born to controls. No difference was observed in prevalence of small- or large-for gestational age compared to controls. There were no differences between groups with respect to infant sex or Apgar scores at 1, 5 and 10 min, congenital malformations or stillbirth. There was furthermore no difference in pain medication use by mothers during delivery between the groups (p=0,733). Conclusion: The majority of women with HypoPT had normal pregnancy outcomes, and the overall risks must be considered to be low. Still, our findings are of importance for antenatal counseling in women with HypoPT as their risk for elective cesarean section was significantly higher compared with controls. Their children were shorter and the higher rate of smoking among HypoPT women may be an additional risk factor.

Abstract We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

Abstract Background The pediatric resuscitation and trauma outcome (PRESTO) model was developed to aid comparisons of risk‐adjusted mortality after injury in low‐ and middle‐income countries (LMICs). We sought to validate PRESTO using data from a middle‐income country (MIC) trauma registry and compare its performance to the Pediatric Trauma Score (PTS), Revised Trauma Score, and pediatric age‐adjusted shock index (SIPA). Methods We included children (age < 15 years) admitted to a single trauma center in South Africa from December 2012 to January 2019. We excluded patients missing variables necessary for the PRESTO model—age, systolic blood pressure, pulse, oxygen saturation, neurologic status, and airway support. Trauma scores were assigned retrospectively. PRESTO's previously high‐income country (HIC)‐validated optimal threshold was compared to MIC‐validated threshold using area under the receiver operating characteristic curves (AUROC). Prediction of in‐hospital death using trauma scoring systems was compared using ROC analysis. Results Of 1160 injured children, 988 (85%) had complete data for calculation of PRESTO. Median age was 7 (IQR: 4, 11), and 67% were male. Mortality was 2% ( n = 23). Mean predicted mortality was 0.5% (range 0–25.7%, AUROC 0.93). Using the HIC‐validated threshold, PRESTO had a sensitivity of 26.1% and a specificity of 99.7%. The MIC threshold showed a sensitivity of 82.6% and specificity of 89.4%. The MIC threshold yielded superior discrimination (AUROC 0.86 [CI 0.78, 0.94]) compared to the previously established HIC threshold (0.63 [CI 0.54, 0.72], p < 0.0001). PRESTO showed superior prediction of in‐hospital death compared to PTS and SIPA (all p < 0.01). Conclusion PRESTO can be applied in MIC settings and discriminates between children at risk for in‐hospital death following trauma. Further research should clarify optimal decision thresholds for quality improvement and benchmarking in LMIC settings.

Abstract Background: Erythropoiesis stimulating agents (ESAs) consistently have been shown to decrease transfusions in anemic oncology patients. However, whether they increase mortality in cancer patients is under debate. Results from individual studies conflict, and results from literature based meta-analyses are inconclusive. We conducted a meta-analysis based on individual patient data (IPD) from all available randomized controlled trials (RCTs). Meta-analyses with individual patient data offer several advantages over study-level analysis, including the ability to gain statistical power and increase validity using time-to-event analyses, to adjust for prognostic variables that may have confounded the original treatment comparisons and to investigate subgroups in which treatment may be either more or less effective or harmful. Methods: An international collaboration conducted an individual patent data meta-analysis of ESA effects on mortality in cancer patients. With guidance from an independent steering committee of international experts in hematology, oncology, radiotherapy, epidemiology, medical statistics and a consumer representative, we developed a detailed protocol and statistical analysis plan. Independent RCT investigators and representatives from pharmaceutical companies who submitted data provided additional input through the project’s advisory board. IPD from RCTs of ESA plus red blood cell transfusion (RBCT) (as needed) versus placebo or no ESA plus RBCT (as needed), for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy, were included. Hazard ratios and 95% confidence intervals (CIs) were calculated per study and meta-analyzed with fixed-effects and random-effects models. Primary endpoints were overall survival (during active study phase and for the longest follow-up available) for patients receiving chemotherapy, and for all cancer patients regardless of anticancer treatment. Stratified multivariable Cox-regression analyses were conducted to assess the impact of baseline imbalances and to identify potential effect modifiers. Duplicate main statistical analyses were conducted independently at two academic statistical departments. Results: Data on 13933 patients enrolled in 53 studies were included in the analysis. Data were provided by the companies Amgen Inc., Johnson & Johnson Pharmaceutical Research & Development, L.L.C., and F. Hoffmann-La Roche Ltd.; and by five independent investigators. Results are currently undergoing internal verification and final evaluation and will be presented at the meeting. Conclusion: Final conclusions will be presented at the meeting. Future analyses using IPD will be conducted to estimate the risks (clots, tumor progression) and potential benefits (transfusion needs and quality of life/fatigue) from other outcomes.