A National Observational Study From 2010 to 2021 of the Trends in the Timing of Hip Surgery in Children With Cerebral Palsy: Is Surgery Being Performed Earlier?

Background Hip instability is a concern in pediatric cerebral palsy (CP) patients, with approximately one-third developing hip displacement. This may lead to pain, functional limitations, and decreased quality of life. Due to the progressive nature of hip displacement in CP, earlier surgical interventions may be beneficial. However, any shifts in practice to earlier surgical intervention, on a national scale, is not well described. The purpose of this study was to determine the recent trends in the surgical timing of hip interventions in children with CP. Methods A retrospective study was conducted using the PearlDiver Mariner all-payer claims database (PearlDiver Technologies, Colorado Springs, Colorado, United States). CP patients aged 10 years and younger were identified between 2010 and 2021. Hip surgeries including open reduction, adductor tenotomy, and pelvic osteotomy were identified. Patients were stratified by their age on the date of surgery and the year of the procedure. Linear regression analysis was conducted for temporal trends. Further, the compounded annual growth rate (CAGR) was calculated. Results A total of 309,677 CP patients were identified. For those aged one to four years old, the percentage undergoing hip surgery increased from 10.2% in 2010 to 19.4% in 2021. In the five- to 10-year-old age group, the surgery rate peaked at 14.9% in 2016 and steadily declined to 11.5% in 2021. The overall CAGR from 2010 to 2021 was +6.03% for the one- to four-year-old group and +0.88% for the five- to 10-year-old group. Linear regression demonstrated a significant association between year and the percentage of operations for patients ages one to four (R2=0.792, p<0.001), but not ages five-10 (R2=0.019, p=0.704). Conclusions Rates of surgical hip procedures in one- to four-year-old CP patients have been increasing since 2010, whereas the rate in five- to 10-year-old CP patients has been decreasing since 2016. Recently, CP patients may be undergoing hip surgery at younger ages.

Strengthening the Pipeline: Promoting Diversity into Orthopedic Surgery.

The United States is a nation of diverse racial and ethnic origins. Athletes represent the full spectrum of the nation's population. However, the orthopedic surgeons who serve as team physicians are Caucasian and male with staggeringly few exceptions. This manuscript provides an overview of the current status and barriers to diversity among orthopedic team physicians, along with strategies to address the issue. Specifically, pipeline initiatives implemented at one academic medical school and orthopedic surgery department are summarized as potential models that can be further developed by other institutions to enhance diversity in orthopedic surgery.

Opportunistic hand radiographs to screen for low forearm bone mineral density: a prospective and retrospective cohort study.

BACKGROUND: Low bone mineral density affects 53% of women over age 65 in the US, yet many are unaware and remain untreated. Underdiagnosis of forearm osteoporosis and related fragility fractures represent missed warning signs of more deadly, future fractures. This study aimed to determine if hand radiographs could serve as early, simple screening tools for predicting low forearm bone mineral density (BMD). METHODS: We evaluated posterior-anterior (PA) hand radiographs (x-rays) and Dual-energy X-ray absorptiometry (DXA) scans of 43 participants. The ratio of the intramedullary cavity to total cortical diameter of the second metacarpal (second metacarpal cortical percentage (2MCP)) was used as a potential diagnostic marker. Mixed-effects linear regression was performed to determine correlation of 2MCP with BMD from various anatomic regions. Repeated measures ANOVAs were used to compare BMD across sites. An optimal 2MCP cutoff for predicting forearm osteopenia and osteoporosis was found using Receiver Operating Curves. RESULTS: 2MCP is directly correlated with BMD in the forearm. The optimal 2MCP of 48.3% had 80% sensitivity for detecting osteoporosis of the 1/3 distal forearm. An 2MCP cutoff of 50.8% had 84% sensitivity to detect osteoporosis of the most distal forearm. Both 2MCP cutoffs were more sensitive at predicting forearm osteoporosis than femoral neck T-scores. CONCLUSIONS: These findings support the expansion of osteoporosis screening to include low-cost hand x-rays, aiming to increase diagnosis and treatment of low forearm BMD and fractures. Proposed next steps include confirming the optimal 2MCP cutoff at scale and integrating automatic 2MCP measurements into PAC systems.

A Comprehensive Review of Bone Health in a Child: From Birth to Adulthood.

Bone health is critical for growth and development during childhood. Although fractures are common in children, fractures occurring in the absence of trauma should prompt physicians to consider underlying bone health disorders. This article provides an overview of the current definition of osteoporosis in children, highlighting its limitations and the potential for underdiagnosis. It also discusses the timing of screening initiation and various techniques used to assess bone health, along with their respective benefits and limitations. In addition, this article identifies several causes of primary and secondary osteoporosis in children, shedding light on previously overlooked disorders that can contribute to poor bone quality. The article emphasizes the importance of a multidisciplinary approach to therapeutic management and aims to optimize patient outcomes and improve the overall care of pediatric bone health disorders.

Postoperative sepsis and septic shock after hip fracture surgery.

INTRODUCTION: There is a paucity of research in the rates for sepsis and septic shock in the hip fracture population specifically, despite marked clinical and prognostic differences between these conditions. The purpose of this study was to determine the incidence, risk factors, and mortality rates for sepsis and septic shock as well as evaluate potential infectious causes in the surgical hip fracture population. METHODS: The ACS-NSQIP (2015-2019) was queried for patients who underwent hip fracture surgery. A backward elimination multivariate regression model was used to identify risk factors for sepsis and septic shock. Multivariate regression that controlled for preoperative variables and comorbidities was used to calculate the odds of 30-day mortality. RESULTS: Of 86,438 patients included, 871 (1.0%) developed sepsis and 490 (0.6%) developed septic shock. Risk factors for both postoperative sepsis and septic shock were male gender, DM, COPD, dependent functional status, ASA class ≥3, anemia, and hypoalbuminemia. Unique risk factors for septic shock were CHF and ventilator dependence. The 30-day mortality rate was 4.8% in aseptic patients, 16.2% in patients with sepsis, and 40.8% in patients who developed septic shock (p < 0.001). Patients with sepsis (OR 2.87 [95% CI 2.37-3.48], p < 0.001) and septic shock (OR 11.27 [95% CI 9.26-13.72], p < 0.001) had increased odds of 30-day mortality compared to patients without postoperative septicemia. Infections that preceded a diagnosis of sepsis or septic shock included urinary tract infections (24.7%, 16.5%), pneumonia (17.6%, 30.8%), and surgical site infections (8.5%, 4.1%). CONCLUSIONS: The incidence of sepsis and septic shock after hip fracture surgery was 1.0% and 0.6%, respectively. The 30-day mortality rate was 16.2% in patients with sepsis and 40.8% in patients with septic shock. Potentially modifiable risk factors for both sepsis and septic shock were anemia and hypoalbuminemia. Urinary tract infections, pneumonia, and surgical site infections preceded the majority of cases of sepsis and septic shock. Prevention, early identification, and successful treatment of sepsis and septic shock are paramount to lowering mortality after hip fracture surgery.

Sexual Dimorphisms in Adult Human Brown Adipose Tissue.

OBJECTIVE: This study aimed to quantify and compare the amount, activity, and anatomical distribution of cold-activated brown adipose tissue (BAT) in healthy, young, lean women and men. METHODS: BAT volume and 18 F-fluorodeoxyglucose uptake were measured by positron emission tomography and computerized tomography in 12 women and 12 men (BMI 18.5-25 kg/m2 , aged 18-35 years) after 5 hours of exposure to their coldest temperature before overt shivering. RESULTS: Women had a lower detectable BAT volume than men (P = 0.03), but there was no difference after normalizing to body size. The mean BAT glucose uptake and relative distribution of BAT did not differ by sex. 18 F-fluorodeoxyglucose uptake consistent with BAT was observed in superficial dorsocervical adipose tissue of 6 of 12 women but only 1 of 12 men (P = 0.02). This potential BAT depot would pose fewer biopsy risks than other depots. CONCLUSIONS: Despite differences in adiposity and total BAT volume, we found that healthy, lean, young women and men do not differ in the relative amount, glucose uptake, and distribution of BAT. Dorsocervical 18 F-fluorodeoxyglucose uptake was more prevalent in women and may be a remnant of interscapular BAT seen in human newborns. Future studies are needed to discern how BAT contributes to whole-body thermal physiology and body weight regulation in women and men.

Pheochromocytoma and Paraganglioma Patients With Poor Survival Often Show Brown Adipose Tissue Activation.

CONTEXT: Pheochromocytomas/paragangliomas (PPGLs) are neuroendocrine tumors that can secrete norepinephrine (NE). Brown adipose tissue (BAT) activation is mediated through the action of NE on ß-adrenoceptors (ß-ARs). In some malignancies, BAT activation is associated with higher cancer activity. OBJECTIVE: To study the relationship between BAT activation and PPGL clinical outcomes. DESIGN: A retrospective case-control study that included 342 patients with PPGLs who underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (18F-FDG PET/CT) imaging at the National Institutes of Health (NIH). We excluded all patients with parasympathetic tumors and those who underwent 18F-FDG PET/CT after PPGL resection. Scans of 205 patients were reviewed by 2 blinded nuclear medicine physicians; 16 patients had BAT activation on 18F-FDG PET/CT [7.80%; age 27.50 (15.00-45.50) years; 10 female/6 male; body mass index [BMI] 24.90 [19.60-25.35] kg/m2). From the remaining 189 patients, we selected 36 matched controls (age 34.4 [25.4-45.5] years; 21 female/15 male; BMI 25.0 [22.0-26.0] kg/m2). PRIMARY OUTCOME MEASURE: Overall survival. RESULTS: The presence of active BAT on 18F-FDG PET/CT was associated with decreased overall survival when compared with the control group (HRz 5.80; 95% CI, 1.05-32.05; P = 0.02). This association remained significant after adjusting for the SDHB mutation. Median plasma NE in the BAT group was higher than the control group [4.65 vs 0.55 times above the upper limit of normal; P < 0.01]. There was a significant association between higher plasma NE levels and mortality in PPGLs in both groups. CONCLUSIONS: Our findings suggest that the detection of BAT activity in PPGL patients is associated with higher mortality. We suggest that BAT activation could either be reflecting or contributing to a state of increased host stress that may predict poor outcome in metastatic PPGL.

Opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity.

The current obesity pandemic results from a physiological imbalance in which energy intake chronically exceeds energy expenditure (EE), and prevention and treatment strategies remain generally ineffective. Approaches designed to increase EE have been informed by decades of experiments in rodent models designed to stimulate adaptive thermogenesis, a long-term increase in metabolism, primarily induced by chronic cold exposure. At the cellular level, thermogenesis is achieved through increased rates of futile cycling, which are observed in several systems, most notably the regulated uncoupling of oxidative phosphorylation from ATP generation by uncoupling protein 1, a tissue-specific protein present in mitochondria of brown adipose tissue (BAT). Physiological activation of BAT and other organ thermogenesis occurs through ß-adrenergic receptors (AR), and considerable effort over the past 5 decades has been directed toward developing AR agonists capable of safely achieving a net negative energy balance while avoiding unwanted cardiovascular side effects. Recent discoveries of other BAT futile cycles based on creatine and succinate have provided additional targets. Complicating the current and developing pharmacological-, cold-, and exercise-based methods to increase EE is the emerging evidence for strong physiological drives toward restoring lost weight over the long term. Future studies will need to address technical challenges such as how to accurately measure individual tissue thermogenesis in humans; how to safely activate BAT and other organ thermogenesis; and how to sustain a negative energy balance over many years of treatment.

Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity.

BACKGROUNDMirabegron is a ß3-adrenergic receptor (ß3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that ß3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODSWe treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by [18F]-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTSChronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSIONThese findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of ß3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).

Whole Body and Regional Quantification of Active Human Brown Adipose Tissue Using 18F-FDG PET/CT.

In endothermic animals, brown adipose tissue (BAT) is activated to produce heat for defending body temperature in response to cold. BAT's ability to expend energy has made it a potential target for novel therapies to ameliorate obesity and associated metabolic disorders in humans. Though this tissue has been well studied in small animals, BAT's thermogenic capacity in humans remains largely unknown due to the difficulties of measuring its volume, activity, and distribution. Identifying and quantifying active human BAT is commonly performed using 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography and computed tomography (PET/CT) scans following cold-exposure or pharmacological activation. Here we describe a detailed image-analysis approach to quantify total-body human BAT from 18F-FDG PET/CT scans using an open-source software. We demonstrate the drawing of user-specified regions of interest to identify metabolically active adipose tissue while avoiding common non-BAT tissues, to measure BAT volume and activity, and to further characterize its anatomical distribution. Although this rigorous approach is time-consuming, we believe it will ultimately provide a foundation to develop future automated BAT quantification algorithms.

Regulation of Human Adipose Tissue Activation, Gallbladder Size, and Bile Acid Metabolism by a ß3-Adrenergic Receptor Agonist.

ß3-adrenergic receptor (AR) agonists are approved to treat only overactive bladder. However, rodent studies suggest that these drugs could have other beneficial effects on human metabolism. We performed tissue receptor profiling and showed that the human ß3-AR mRNA is also highly expressed in gallbladder and brown adipose tissue (BAT). We next studied the clinical implications of this distribution in 12 healthy men given one-time randomized doses of placebo, the approved dose of 50 mg, and 200 mg of the ß3-AR agonist mirabegron. There was a more-than-dose-proportional increase in BAT metabolic activity as measured by [18F]-2-fluoro-D-2-deoxy-d-glucose positron emission tomography/computed tomography (medians 0.0 vs. 18.2 vs. 305.6 mL ⋅ mean standardized uptake value [SUVmean] ⋅ g/mL). Only the 200-mg dose elevated both nonesterified fatty acids (68%) and resting energy expenditure (5.8%). Previously undescribed increases in gallbladder size (35%) and reductions in conjugated bile acids were also discovered. Therefore, besides urinary bladder relaxation, the human ß3-AR contributes to white adipose tissue lipolysis, BAT thermogenesis, gallbladder relaxation, and bile acid metabolism. This physiology should be considered in the development of more selective ß3-AR agonists to treat obesity-related complications.

Induction of alpha-synuclein pathology in the enteric nervous system of the rat and non-human primate results in gastrointestinal dysmotility and transient CNS pathology.

Alpha-Synuclein (α-syn) is by far the most highly vetted pathogenic and therapeutic target in Parkinson's disease. Aggregated α-syn is present in sporadic Parkinson's disease, both in the central nervous system (CNS) and peripheral nervous system (PNS). The enteric division of the PNS is of particular interest because 1) gastric dysfunction is a key clinical manifestation of Parkinson's disease, and 2) Lewy pathology in myenteric and submucosal neurons of the enteric nervous system (ENS) has been referred to as stage zero in the Braak pathological staging of Parkinson's disease. The presence of Lewy pathology in the ENS and the fact that patients often experience enteric dysfunction before the onset of motor symptoms has led to the hypothesis that α-syn pathology starts in the periphery, after which it spreads to the CNS via interconnected neural pathways. Here we sought to directly test this hypothesis in rodents and non-human primates (NHP) using two distinct models of α-syn pathology: the α-syn viral overexpression model and the preformed fibril (PFF) model. Subjects (rat and NHP) received targeted enteric injections of PFFs or adeno-associated virus overexpressing the Parkinson's disease associated A53T α-syn mutant. Rats were evaluated for colonic motility monthly and sacrificed at 1, 6, or 12 months, whereas NHPs were sacrificed 12 months following inoculation, after which the time course and spread of pathology was examined in all animals. Rats exhibited a transient GI phenotype that resolved after four months. Minor α-syn pathology was observed in the brainstem (dorsal motor nucleus of the vagus and locus coeruleus) 1 month after PFF injections; however, no pathology was observed at later time points (nor in saline or monomer treated animals). Similarly, a histopathological analysis of the NHP brains revealed no pathology despite the presence of robust α-syn pathology throughout the ENS which persisted for the entirety of the study (12 months). Our study shows that induction of α-syn pathology in the ENS is sufficient to induce GI dysfunction. Moreover, our data suggest that sustained spread of α-syn pathology from the periphery to the CNS and subsequent propagation is a rare event, and that the presence of enteric α-syn pathology and dysfunction may represent an epiphenomenon.