Does a delay to surgery for preoperative echocardiogram affect outcomes in patients with hip fracture?

Introduction: Delay to surgery >24 hours has been shown to correlate with mortality rates in patients with hip fracture when left untreated. Many of these patients have multiple comorbidities, including aortic stenosis (AS), and undergo workup for operative clearance, which may delay time to surgery. The purpose of this study was to examine whether preoperative echocardiogram workup affects time to surgery, complications, and mortality after operative fixation for hip fracture. Methods: Our institutional hip fracture registry was retrospectively reviewed for inclusion over a 3-year period. Patients who had a preoperative echocardiogram (yECHO) for operative clearance were compared with those who did not (nECHO). Demographic data, time to surgery, overall complication rate, and mortality at 30 days, 90 days, and 1 year were collected. Results: Two cohorts consisted of 136 yECHO patients (45.8%) and 161 nECHO patients (54.2%). Thirty-two yECHO patients (23.5%) had AS. Patients in the yECHO cohort were more likely to have a complication for any cause compared with nECHO patients (25.7% vs. 10.6%, P = 0.01) and have a higher mortality rate at 1 year (38.9% vs. 17.4%, P = 0.001). There was no association found between AS and all-cause complication (P = 0.54) or 30-day (P = 0.13) or 90-day mortality rates (P = 0.79). However, patients with AS had a significantly higher mortality rate at 1 year (45.8% vs. 25.1%, P = 0.03). Conclusion: This study reinforces the benefits of ensuring less than a 24-hour time to surgery in the setting of a hip fracture and identifies an area of preoperative management that can be further optimized to prevent unnecessary prolongation in time to surgery. Patients with known aortic stenosis are not associated with increased 30-day or 90-day mortality or all-cause complications. Surgical delays in the yECHO cohort were attributed to preoperative medical assessments, including echocardiograms and the management of comorbidities. Therefore, the selective utilization of preoperative echocardiograms is needed and should be reserved to ensure they have a definitive role in guiding the perioperative care of patients with hip fracture. Level of Evidence: III.

Comparison of Outcomes After Reverse Total Shoulder Arthroplasty in Patients With Proximal Humerus Fractures Versus Rotator Cuff Arthropathy.

INTRODUCTION: Indications for reverse total shoulder arthroplasty (rTSA) has expanded to encompass complex proximal humerus fractures (PHFs) in recent years. The purpose of this study was to report and assess whether PHF patients treated with rTSA could achieve similar functional outcomes and short-term survivorship to patients who underwent rTSA for rotator cuff arthropathy (RTCA). METHODS: All consecutive patients with a preoperative diagnosis of PHF or RTCA, 18 years or older, treated with rTSA at a single academic institution between 2018 and 2020 with a minimum 2-year follow-up were retrospectively reviewed. Primary outcomes were survivorship defined as revision surgery or implant failure analyzed using the Kaplan-Meier survival curve, and functional outcomes, which included Quick Disabilities of the Arm, Shoulder, and Hand, and range of motion (ROM) were compared at multiple follow-up time points up to 2 years. Secondary outcomes were patient demographics, comorbidities, surgical data, length of hospital stay, and discharge disposition. RESULTS: A total of 48 patients were included: 21 patients (44%) were diagnosed with PHF and 27 patients (56%) had RTCA. The Kaplan-Meier survival rate estimates at 3 years were 90.5% in the PHF group and 85.2% in the RTCA group. No differences in revision surgery rates between the two groups (P = 0.68) or survivorship (P = 0.63) were found. ROM was significantly lower at subsequent follow-up time points in multiple planes (P < 0.05). A greater proportion of patients in the PHF group received cement for humeral implant fixation compared with the RTCA group (48% versus 7%, P = 0.002). The mean length of hospital stay was longer in PHF patients compared with RTCA patients (2.9 ± 3.8 days versus 1.6 ± 1.8 days, P = 0.13), and a significantly lower proportion of PHF patients were discharged home (67% versus 96%, P = 0.015). CONCLUSION: The rTSA implant survivorship at 3 years for both PHF and RTCA patients show comparable results. At the 2-year follow-up, RTCA patients treated with rTSA were found to have better ROM compared with PHF patients.

Direct versus indirect posterior malleolar fixation in the treatment of trimalleolar ankle fractures: Is there a difference in outcomes?

Purpose: The purpose of this study was to examine the differences in functional outcomes between direct and indirect surgical fixation methods of the posterior malleolus in the setting of trimalleolar fractures and identify any variables affecting patient outcomes. Methods: Primary outcomes were evaluated by PROMIS scores for short-term outcomes regarding total pain (TP) and total function (TF) comparing 40 patients with direct fixation with 77 with indirect fixation. Continuous variables were analyzed using t tests for parametric variables and the Mann-Whitney U test for nonparametric variables. Categorical variables were analyzed using a χ2 test. Univariate and multivariate linear regression models were performed to analyze factors that affect outcomes of TP and TF. Results: There was no difference in TP or TF between groups (P = 0.65 vs. P = 0.19). On univariate linear regression for TP, BMI, incidence of complication, tobacco use, and open injury showed significance in increasing pain levels with open injuries providing the greatest effect (coef = 11.8). On multivariate analysis, BMI, incidence of complication, open injury, and tourniquet time all significantly increased pain. For TF, univariate analysis showed age, BMI, incidence of complication, and diabetes to decrease function, and use of external fixator and tourniquet time increased function. In the multivariate model, increased BMI, open injuries, and increasing tourniquet time all decreased TF while use of an external fixator increased TF. Conclusion: This study showed no difference in TP and TF using the PROMIS outcome scores when comparing direct fixation versus indirect fixation under univariate and multivariate models. Level of Evidence: Therapeutic III.

Dual regulation of miR-375 and CREM genes in pancreatic beta cells.

MicroRNA-375 (miR-375) is upregulated in the islets of some diabetics and is correlated with poor outcome. Previous work in our laboratory showed that cyclic adenosine monophosphate (cAMP) reduces miR-375 expression and could provide a way to restore normal miR-375 levels, however the transcription repression mechanism is unknown. Using a chromatin immunoprecipitation assay we show that cAMP response element modulator (CREM) binds to the miR-375 promoter 3-fold above background and we find that CREM represses transcription from the miR-375 promoter 1.8-fold. While investigating miR-375 target genes we discovered that several microRNA:mRNA target prediction algorithms listed human CREM as a target gene of miR-375. The predicted binding site is conserved in primates but not in other species. We found that indeed miR-375 binds to the predicted site on human CREM and represses translation of a green fluorescent protein reporter gene by 30%. These findings suggest a primate-specific double-negative feedback loop, a mechanism that would keep these important ß-cell regulators in check.

Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label treatment.

Pancreatic cancer (PDAC) is a highly aggressive malignancy for which the identification of novel therapies is urgently needed. Here, we establish a human PDAC organoid biobank from 31 genetically distinct lines, covering a representative range of tumor subtypes, and demonstrate that these reflect the molecular and phenotypic heterogeneity of primary PDAC tissue. We use CRISPR-Cas9 genome editing and drug screening to characterize drug-gene interactions with ARID1A and BRCA2. We find that missense- but not frameshift mutations in the PDAC driver gene ARID1A are associated with increased sensitivity to the kinase inhibitors dasatinib (p < 0.0001) and VE-821 (p < 0.0001). We conduct an automated drug-repurposing screen with 1,172 FDA-approved compounds, identifying 26 compounds that effectively kill PDAC organoids, including 19 chemotherapy drugs currently approved for other cancer types. We validate the activity of these compounds in vitro and in vivo. The in vivo validated hits include emetine and ouabain, compounds which are approved for non-cancer indications and which perturb the ability of PDAC organoids to respond to hypoxia. Our study provides proof-of-concept for advancing precision oncology and identifying candidates for drug repurposing via genome editing and drug screening in tumor organoid biobanks.

Patient-derived xenografts and organoids model therapy response in prostate cancer.

Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.

Secretion and Function of Pituitary Prolactin in Evolutionary Perspective.

The hypothalamo-pituitary system developed in early vertebrates. Prolactin is an ancient vertebrate hormone released from the pituitary that exerts particularly diverse functions. The purpose of the review is to take a comparative approach in the description of prolactin, its secretion from pituitary lactotrophs, and hormonal functions. Since the reproductive and osmoregulatory roles of prolactin are best established in a variety of species, these functions are the primary subjects of discussion. Different types of prolactin and prolactin receptors developed during vertebrate evolution, which will be described in this review. The signal transduction of prolactin receptors is well conserved among vertebrates enabling us to describe the whole subphylum. Then, the review focuses on the regulation of prolactin release in mammals as we have the most knowledge on this class of vertebrates. Prolactin secretion in response to different reproductive stimuli, such as estrogen-induced release, mating, pregnancy and suckling is detailed. Reproduction in birds is different from that in mammals in several aspects. Prolactin is released during incubation in avian species whose regulation and functional significance are discussed. Little information is available on prolactin in reptiles and amphibians; therefore, they are mentioned only in specific cases to explain certain evolutionary aspects. In turn, the osmoregulatory function of prolactin is well established in fish. The different types of pituitary prolactin in fish play particularly important roles in the adaptation of eutherian species to fresh water environments. To achieve this function, prolactin is released from lactotrophs in hyposmolarity, as they are directly osmosensitive in fish. In turn, the released prolactin acts on branchial epithelia, especially ionocytes of the gill to retain salt and excrete water. This review will highlight the points where comparative data give new ideas or suggest new approaches for investigation in other taxa.

Risk factors for liposomal bupivacaine resistance after total hip or knee arthroplasties: a retrospective observational cohort in 237 patients.

PURPOSE: Liposomal bupivacaine demonstrated promise decreasing postoperative pain in total hip and total knee arthroplasty (THA/TKA). Some randomized trials have shown non-superior results; however, confounding variables were not accounted for in such analyses. This study attempts to determine risk factors associated with failure of pain management in patients receiving liposomal bupivacaine. METHODS: Postoperative pain scores were collected following primary or revision arthroplasties between January 2016 and December 2017. Retrospective analysis of institutional total joint quality and outcomes registry was screened and patients undergoing primary or revision arthroplasties who completed a multi-modal pain management including liposomal bupivacaine were included in the study. Patients with a history of infection/deviated from the institutional pain management protocol were excluded. RESULTS: A total of 237 patients were included for analysis. Younger patients less than 64 years old had significantly higher pain scores between 0 and 12 h and > 24 h. Active smokers had significantly higher pain scores between 0 and 6 h and > 24 h. Patients with a history of opioid use/pain management had significantly higher pain scores at 6-12 h and 24-48 h. Regression analysis indicated risk factors for resistance to liposomal bupivacaine are younger patients less than 64 years old, those undergoing primary THA, and patients with a history of smoking/pain management/opioid use. CONCLUSION: We identify risk factors for resistance to liposomal bupivacaine, which include younger age less than 64 years old, history of smoking/pain management/opioid use. Future studies should use these risk factors as exclusion criteria when using liposomal bupivacaine or initiating any randomized trials regarding efficacy.

Linking otolith microchemistry and surface water contamination from natural gas mining.

Unconventional natural gas drilling and the use of hydraulic fracturing technology have expanded rapidly in North America. This expansion has raised concerns of surface water contamination by way of spills and leaks, which may be sporadic, small, and therefore difficult to detect. Here we explore the use of otolith microchemistry as a tool for monitoring surface water contamination from generated waters (GW) of unconventional natural gas drilling. We exposed Brook Trout in the laboratory to three volumetric concentrations of surrogate generated water (SGW) representing GW on day five of drilling. Transects across otolith cross-sections were analyzed for a suite of elements by LA-ICP-MS. Brook Trout exposed to a 0.01-1.0% concentration of SGW for 2, 15, and 30 days showed a significant (p < 0.05) relationship of increasing Sr and Ba concentrations in all but one treatment. Analyses indicate lesser concentrations than used in this experiment could be detectable in surface waters and provide support for the use of this technique in natural habitats. To our knowledge, this is the first demonstration of how trace elements in fish otoliths may be used to monitor for surface water contamination from GW.

Prolactin-induced and neuronal activation in the brain of mother mice.

Nursing has important consequences on mothers. To separate the prolactin-mediated and the neuronally-mediated actions of nursing, neurons directly affected by prolactin were visualized using pSTAT5 immunohistochemistry in relation to Fos-expressing neurons in suckled mother mice. In response to pup exposure following 22-h pup deprivation, we found a markedly elevated number of pSTAT5-containing neurons in several brain regions, including the lateral septum, medial amygdaloid nucleus, subparafascicular area, caudal periaqueductal gray, dorsal raphe, lateral parabrachial nucleus, nucleus of the solitary tract, and the periventricular, medial preoptic, paraventricular, arcuate and ventromedial nuclei of the hypothalamus. Pup exposure also induced Fos expression in all of these brain regions except the arcuate and ventromedial hypothalamic nuclei. Bromocriptine treatment known to reduce prolactin levels eliminated pSTAT5 from most brain regions while it did not affect Fos activation following suckling. The degree of colocalization for pSTAT5 and Fos ranged from 8 to 80% in the different brain regions suggesting that most neurons responding to pup exposure in mother mice are driven either by prolactin or direct neuronal input from the pups, while the number of neurons affected by both types of inputs depends on the examined brain area. In addition, both pSTAT5 and Fos were also double-labeled with estrogen receptor alpha (ERα) in mother mice, which revealed a very high degree of colocalization between pSTAT5 and ERα with much less potential interaction between Fos- and ERα-containing neurons suggesting that estrogen-sensitive neurons are more likely to be affected by prolactin than by direct neuronal activation.

Process-Function Data Mining for the Discovery of Solid-State Iron-Oxide PV.

Data mining tools have been known to be useful for analyzing large material data sets generated by high-throughput methods. Typically, the descriptors used for the analysis are structural descriptors, which can be difficult to obtain and to tune according to the results of the analysis. In this Research Article, we show the use of deposition process parameters as descriptors for analysis of a photovoltaics data set. To create a data set, solar cell libraries were fabricated using iron oxide as the absorber layer deposited using different deposition parameters, and the photovoltaic performance was measured. The data was then used to build models using genetic programing and stepwise regression. These models showed which deposition parameters should be used to get photovoltaic cells with higher performance. The iron oxide library fabricated based on the model predictions showed a higher performance than any of the previous libraries, which demonstrates that deposition process parameters can be used to model photovoltaic performance and lead to higher performing cells. This is a promising technique toward using data mining tools for discovery and fabrication of high performance photovoltaic materials.

A Thalamo-Hypothalamic Pathway That Activates Oxytocin Neurons in Social Contexts in Female Rats.

Oxytocin is released from neurons in the paraventricular hypothalamic nucleus (PVN) in mothers upon suckling and during adult social interactions. However, neuronal pathways that activate oxytocin neurons in social contexts are not yet established. Neurons in the posterior intralaminar complex of the thalamus (PIL), which contain tuberoinfundibular peptide 39 (TIP39) and are activated by pup exposure in lactating mothers, provide a candidate projection. Innervation of oxytocin neurons by TIP39 neurons was examined by double labeling in combination with electron microscopy and retrograde tract-tracing. Potential classic neurotransmitters in TIP39 neurons were investigated by in situ hybridization histochemistry. Neurons activated after encounter with a familiar conspecific female in a familiar environment were mapped with the c-Fos technique. PVN and the supraoptic nucleus oxytocin neurons were closely apposed by an average of 2.0 and 0.4 TIP39 terminals, respectively. Asymmetric (presumed excitatory) synapses were found between TIP39 terminals and cell bodies of oxytocin neurons. In lactating rats, PIL TIP39 neurons were retrogradely labeled from the PVN. TIP39 neurons expressed vesicular glutamate transporter 2 but not glutamic acid decarboxylase 67. PIL contained a markedly increased number of c-Fos-positive neurons in response to social encounter with a familiar conspecific female. Furthermore, the PIL received ascending input from the spinal cord and the inferior colliculus. Thus, TIP39 neurons in the PIL may receive sensory input in response to social interactions and project to the PVN to innervate and excite oxytocin neurons, suggesting that the PIL-PVN projection contributes to the activation of oxytocin neurons in social contexts.

Behavioral Health Screening among Massachusetts Children Receiving Medicaid.

OBJECTIVE: To assess the impact of a Massachusetts Medicaid policy change (the Children's Behavioral Health Initiative; CBHI, which required and reimbursed behavioral health [BH] screening with standardized tools at well child visits and developed intensive home- and community-based BH services) on primary care practice examining the relationship of BH screening to subsequent BH service utilization. STUDY DESIGN: Using a repeated cross-sectional design, our 2010 and 2012 Medicaid study populations each included 2000 children/adolescents under the age of 21 years. For each year, the population was randomly selected and stratified into 4 age groups, with 500 members selected per group. Two data sources were used: medical records and Medicaid claims. RESULTS: The CBHI had a large impact on formal BH screening and treatment utilization among children/adolescents enrolled in Medicaid. Screening increased substantially (73%: 2010; 74%: 2012) since the baseline/premandate period (2007) when only 4% of well child visits included a formal screen. BH utilization increased among those formally screened but decreased among those with informal assessments. CONCLUSIONS: CBHI implementation transformed the relationship between primary care and BH services. Changes in regulation and payment resulted in widespread BH screening in Massachusetts primary care practices caring for children/adolescents on Medicaid.

Associations between the patient-centered medical home and preventive care and healthcare quality for non-elderly adults with mental illness: A surveillance study analysis.

BACKGROUND: Patient-centered medical homes (PCMHs) may improve outcomes for non-elderly adults with mental illness, but the extent to which PCMHs are associated with preventive care and healthcare quality for this population is largely unknown. Our study addresses this gap by assessing the associations between receipt of care consistent with the PCMH and preventive care and healthcare quality for non-elderly adults with mental illness. METHODS: This surveillance study used self-reported data for 6,908 non-elderly adults with mental illness participating in the 2007-2012 Medical Expenditure Panel Survey. Preventive care and healthcare quality measures included: participant rating of all healthcare; cervical, breast, and colorectal cancer screening; current smoking; smoking cessation advice; flu shot; foot exam and eye exam for people with diabetes; and follow-up after emergency room visit for mental illness. Multiple logistic regression models were developed to compare the odds of meeting preventive care and healthcare quality measures for participants without a usual source of care, participants with a non-PCMH usual source of care, and participants who received care consistent with the PCMH. RESULTS: Compared to participants without a usual source of care, those with a non-PCMH usual source of care had better odds of meeting almost all measures examined, while those who received care consistent with the PCMH had better odds of meeting most measures. Participants who received care consistent with the PCMH had better odds of meeting only one measure compared to participants with a non-PCMH usual source of care. CONCLUSIONS: Compared with having a non-PCMH usual source of care, receipt of care consistent with the PCMH does not appear to be associated with most preventive care or healthcare quality measures. These findings raise concerns about the potential value of the PCMH for non-elderly adults with mental illness and suggest that alternative models of primary care are needed to improve outcomes and address disparities for this population.

Bacillus coagulans GBI-30, 6086 Modulates Faecalibacterium prausnitzii in Older Men and Women.

BACKGROUND: Advancing age is linked to a decrease in beneficial bacteria such as Bifidobacterium spp. and reduced aspects of innate immune function. OBJECTIVES: We investigated whether daily consumption of a probiotic [Bacillus coagulans GBI-30, 6086 (BC30); GanedenBC(30)] could improve immune function and gut function in men and women aged 65-80 y, using a double-blind, placebo-controlled crossover design. METHOD: Thirty-six volunteers were recruited and randomly assigned to receive either a placebo (microcrystalline cellulose) or the probiotic BC30 (1 × 10(9) colony-forming units/capsule). Volunteers consumed 1 treatment capsule per day for 28 d, followed by a 21-d washout period before switching to the other treatment. Blood and fecal samples were collected at the beginning and end of each treatment period. Fecal samples were used to enumerate bacterial groups and concentrations of calprotectin. Peripheral blood mononuclear cells (PBMCs) were extracted from whole blood to assess natural killer cell activity and lipopolysaccharide (LPS)-stimulated cytokine production. C-reactive protein concentrations were measured in plasma. RESULTS: Consumption of BC30 significantly increased populations of Faecalibacterium prausnitzii by 0.1 log10 cells/mL more than during consumption of the placebo (P = 0.03), whereas populations of Bacillus spp. increased significantly by 0.5 log10 cells/mL from baseline in volunteers who consumed BC30 (P = 0.007). LPS-stimulated PBMCs showed a 0.2 ng/mL increase in the anti-inflammatory cytokine IL-10 28 d after consumption of BC30 (P < 0.05), whereas the placebo did not affect IL-10, and no overall difference was found in the effect of the treatments. CONCLUSIONS: Daily consumption of BC30 by adults aged 65-80 y can increase beneficial groups of bacteria in the human gut and potentially increase production of anti-inflammatory cytokines. This study shows the potential benefits of a probiotic to improve dysbiosis via modulation of the microbiota in older persons.