bluuebunny/crossref_metadata_2025 huggingface dataset:
Early Impact of the State Innovation Models Initiative on Diagnosed Diabetes Prevalence Among Adults and Hospitalizations Among Diagnosed Adults
Authors: Fulton Brent D. , Hong Nianyi , Rodriguez Hector P.
Published: July 2019

Background:

The State Innovation Models (SIM) Initiative invested $254 million in 6 states in Round 1 to accelerate delivery system and payment reforms.

Objective:

The objective of this study was to examine the association of early SIM implementation and diagnosed diabetes prevalence among adults and hospitalization rates among diagnosed adults.

Research Design:

Quasi-experimental design compares diagnosed diabetes prevalence and hospitalization rates before SIM (2010–2013) and during early implementation (2014) in 6 SIM states versus 6 comparison states. County-level, difference-in-differences regression models were estimated.

Subjects:

The annual average of 4.5 million adults aged 20+ diagnosed with diabetes with 1.4 million hospitalizations in 583 counties across 12 states.

Measures:

Diagnosed diabetes prevalence among adults and hospitalization rates per 1000 diagnosed adults.

Results:

Compared with the pre-SIM period, diagnosed diabetes prevalence increased in SIM counties by 0.65 percentage points (from 10.22% to 10.87%) versus only 0.10 percentage points (from 9.64% to 9.74%) in comparison counties, a difference-in-differences of 0.55 percentage points. The difference-in-differences regression estimates ranged from 0.49 to 0.53 percentage points (P<0.01). Regression results for ambulatory care-sensitive condition and all-cause hospitalization rates were inconsistent across models with difference-in-differences estimates ranging from −5.34 to −0.37 and from −13.16 to 0.92, respectively.

Conclusions:

SIM Round 1 was associated with higher diagnosed diabetes prevalence among adults after a year of implementation, likely because of SIM’s emphasis on detection and care management. SIM was not associated with lower hospitalization rates among adults diagnosed with diabetes, but the SIM’s long-term impact on hospitalizations should be assessed.
Health Care Utilization After Paraprofessional-administered Substance Use Screening, Brief Intervention, and Referral to Treatment
Authors: Paltzer Jason , Moberg David Paul , Burns Marguerite , Brown Richard L.
Published: July 2019

Background:

Authorities recommend universal substance use screening, brief intervention, and referral to treatment (SBIRT) for all (ie, universal) adult primary care patients.

Objective:

The objective of this study was to examine long-term (24-mo) changes in health care utilization and costs associated with receipt of universal substance use SBIRT implemented by paraprofessionals in primary care settings.

Research Design:

This study used a difference-in-differences design and Medicaid administrative data to assess changes in health care use among Medicaid beneficiaries receiving SBIRT. The difference-in-differences estimates were used in a Monte Carlo simulation to estimate potential cost-offsets associated with SBIRT.

Subjects:

The treatment patients were Medicaid beneficiaries who completed a 4-question substance use screen as part of an SBIRT demonstration program between 2006 and 2011. Comparison Medicaid patients were randomly selected from matched clinics in Wisconsin.

Measures:

The study includes 4 health care utilization measures: outpatient days; inpatient length of stay; inpatient admissions; and emergency department admissions. Each outcome was assigned a unit cost based on mean Wisconsin Medicaid fee-for-service reimbursement amounts.

Results:

We found an annual increase of 1.68 outpatient days (P=0.027) and a nonsignificant annual decrease in inpatient days of 0.67 days (P=0.087) associated with SBIRT. The estimates indicate that the cost of a universal SBIRT program could be offset by reductions in inpatient utilization with an annual net cost savings of $782 per patient.

Conclusions:

Paraprofessional-delivered universal SBIRT is likely to yield health care cost savings and is a cost-effective mechanism for integrating behavioral health services in primary care settings.
Care coordination for children with medical complexity
Authors: de Banate Mary Ann , Maypole Jack , Sadof Matthew
Published: July 2019

Purpose of review

We review the literature to help the reader better understand the latest thinking on how best to identify, coordinate and fund care for children with medical complexity, a medically fragile high-cost subpopulation of children and youth with special healthcare needs.

Recent findings

Proprietary and public algorithms have been developed to identify children with medical complexity. Research on families and healthcare providers of children with medical complexity have identified essential components of effective care coordination. Calculation of the cost of care for this population is confounded by cost shifting to families and the variable course of illness in this heterogeneous high-cost population. Care coordination is a team sport that requires strong family partnerships, adequate time and resources to be done effectively. Multiple studies of different sizes have reported similar care coordination team structure, staffing ratios and cost ranges. Multiple options for funding this work now exist and can be tailored to individual environments.

Effective care coordination can positively impact the care of children with medical complexity. Recent work resulting in a better understanding of the needs of families and providers will guide the development of new technologies and measures.
A Phase 2, International, Multicenter, Open-label Clinical Trial of Subcutaneous Tbo-Filgrastim in Pediatric Patients With Solid Tumors Undergoing Myelosuppressive Chemotherapy
Authors: Federman Noah , Dragomir Monica D. , Kizyma Zoryana , Roganovic Jelena , Bias Peter , Lammerich Andreas , Ben Arie Zipi R. , Zou Linglong , Hoehn Gerald , Buchner Anton
Published: July 2019

This phase 2, multicenter, open-label trial investigated the safety and tolerability of tbo-filgrastim in pediatric patients receiving myelosuppressive chemotherapy. In total, 50 patients 1 month to below 16 years of age with solid tumors without bone marrow involvement were stratified into 3 age groups (2 infants, 30 children, 18 adolescents) and prophylactically administered tbo-filgrastim 5 µg/kg body weight once daily subcutaneously. The administration started after the last chemotherapy treatment in week 1 of the first cycle and continued until the expected neutrophil nadir had passed, and the neutrophil count had recovered to 2.0×109/L. The primary endpoint was safety and tolerability of tbo-filgrastim; secondary endpoints included efficacy. The mean (SD) number of doses administered was 9.2 (2.83) in children and 7.3 (1.88) in adolescents. Serious treatment-emergent adverse events were reported in 24% of patients; the most common were febrile neutropenia (FN) (12%), anemia (8%), and thrombocytopenia (8%). Nine patients (18%) experienced mild treatment-related treatment-emergent adverse events; the most common were musculoskeletal and connective tissue disorders (8%). No deaths or withdrawals occurred. The incidence of severe neutropenia (SN) was 52% and the mean (SD) duration of SN was 1.8 (2.21) days; FN incidence was 26%. A daily dose of tbo-filgrastim 5 μg/kg body weight administered to pediatric patients demonstrated a safety profile consistent with the safety profile in adult patients. The incidence of FN was on the lower end of the range reported in the literature and the SN results provide supportive data on the efficacy of tbo-filgrastim in pediatric patients.
Brentuximab Vedotin and High-dose Methotrexate Administrated Alternately for Refractory Anaplastic Large-cell Lymphoma With Central Nervous System Disease
Authors: Mitsunobu Takuro , Nishikawa Takuro , Kusuda Masaki , Nakagawa Shunsuke , Kodama Yuichi , Okamoto Yasuhiro , Kawano Yoshifumi
Published: July 2019

Pediatric anaplastic large-cell lymphoma (ALCL), which is characterized by strong expression of CD30, is usually responsive to multidrug chemotherapy. Brentuximab vedotin (BV) which is an anti-CD30 antibody-drug conjugate is a promising drug with effects on relapsing or refractory ALCL. However, its effects may not be sufficient for the central nervous system disease. The authors herein reported an 11-year-old boy with ALCL that progressed as central nervous system disease receiving intensive induction chemotherapy has achieved and maintained remission by BV and high-dose methotrexate administrated alternately. Alternate therapy with high-dose methotrexate may complement these shortcomings of BV to provide safe treatment without worsening adverse events.
Self-Reported Screening for Rectal Sexually Transmitted Infections Among Men Who Have Sex With Men
Authors: Menza Timothy William , Lipira Lauren , Bhattarai Amisha , Ramirez F. Joseph , Orellana E. Roberto
Published: July 2019

Background

Rectal gonorrhea and chlamydia are common and predict human immunodeficiency virus (HIV) acquisition among men who have sex with men (MSM); however, screening for rectal sexually transmitted infections (STIs) is not routine.

Methods

In 2017, we recruited sexually active MSM in the Portland, Oregon metropolitan area through venue-based sampling. Our outcome of interest was self-reported rectal STI screening in the prior 12 months among those who had a health care visit in the same time period. Stratified by HIV status and preexposure prophylaxis (PrEP) use, we assessed the prevalence and predictors of screening.

Results

Of 403 participants, 162 (40.2%) reported rectal STI screening. Sixty (25.7%) of 233 HIV-negative men who did not report PrEP use in the prior 12 months; 61 (69.3%) of the 88 HIV-negative men who reported PrEP use in the prior 12 months; and, 41 (59.4%) of 69 men living with HIV-reported screening, respectively. Among HIV-negative men who did not report PrEP use in the prior 12 months, having a health care provider who offered HIV testing (adjusted prevalence ratio [aPR], 2.21; 95% confidence interval [CI], 1.38–3.52) and condomless anal sex with casual partners in the prior 12 months (aPR, 1.63; 95% CI, 1.01–2.65) were independently associated with rectal STI screening. The HIV-negative men on PrEP who had a syphilis diagnosis in the prior 12 months were more likely to be screened than those without syphilis (aPR, 1.33; 95% CI, 1.11–1.59). Men living with HIV who reported having a provider who always or often initiates conversations about sex were more likely to report screening compared with men who did not have such a provider (aPR, 1.46; 95% CI, 1.06–2.03).

Conclusions

Rectal STI screening is not universal in a venue-based sample of sexually active MSM. Implementing innovative, acceptable, and accessible screening practices, enhancing health literacy around STI screening and improving provider comfort with talking about sex are paramount to increasing rectal STI screening.
Technical Report: Solar Ultraviolet Protection from Sunglasses
Authors: Rabbetts Ronald , Sliney David
Published: July 2019

SIGNIFICANCE

There is substantial scientific uncertainty about the necessary levels of protection in sunglasses to avoid delayed health effects from solar ultraviolet radiation in the ultraviolet A (UV-A) band. The longer-wavelength limit for UV-A and the inclusion of the spectral effectiveness function in the calculation of solar UV-A transmittance are questionable.

PURPOSE

There has been a wide range of informed opinion with regard to the level—or even need for—near-ultraviolet filtration (by absorption or reflection) in sunglasses. Many current sunglass filter lenses transmit very little near-ultraviolet radiant energy, whereas others transmit a significant fraction. There also are opposing commercial interests that argue either for strong filtration or for minimal protection. We review the evidence for potential risks and the challenge for the designer of any sunglass lens. It is shown that current standards are not at all cautious in their requirements for near-ultraviolet protection and do not meet a philosophical approach of minimizing needless exposure to optical energy that does not benefit vision.

METHODS

The arguments for and against various factors in eye protection from ultraviolet radiation are discussed. The solar UV-A transmittance of some sunglass and clear spectacle lens materials has been calculated using the formulae and methods used in the International Standards Organization sunglass standard. The Annex gives results of the calculations both with and without the S(λ) erythemal weighting function and up to 380 or 400 nm.

RESULTS

The solar UV-A transmittance calculated with the S(λ) function and only up to 380 nm gives numerical results that are lower than taking either the upper limit for UV-A as 400 nm or without the S(λ) function.

CONCLUSIONS

Most sunglass lenses will still pass the requirements with the more stringent requirements, but some spectacle lens materials will need extra treatment.
Prodromal Phase of Hemolytic Uremic Syndrome Related to Shiga Toxin–Producing Escherichia coli
Authors: Balestracci Alejandro , Meni Battaglia Luciana , Toledo Ismael , Martin Sandra Mariel , Alvarado Caupolican
Published: July 2019

Objectives

This study aimed to evaluate practice patterns during prodromal phase of hemolytic uremic syndrome related to Shiga toxin–producing Escherichia coli (STEC-HUS).

Methods

Trajectories of children from first symptoms until STEC-HUS admitted consecutively at our center (period 2000–2017) were retrospectively reviewed. Early recommended practices include identification of STEC infections, antibiotics and antiperistaltic avoidance, and administration of anticipatory intravenous fluids; therefore, implementation and changes over time (before and after 2011) of such interventions were assessed. In addition, early management was correlated with acute disease outcomes.

Results

Of 172 patients, 98 (57%) had early consults, 75 of them visit the pediatric emergency department. Those seen with watery diarrhea (n = 74) were managed as outpatients, whereas 27 of the 45 assisted with bloody diarrhea were hospitalized for diagnosis other than STEC-HUS. Stool cultures were performed in 13.4% (23/172), 18% (31/172) received antibiotics, and 12.8% (22/172) received endovenous fluids; none received antiperistaltic agents. Shiga toxin–producing E. coli infection was proven in 4% (7/172) before HUS. Rate of cultured patients and treated with intravenous fluids remained unchanged over time (P = 0.13 and P = 0.48, respectively), whereas antibiotic prescription decreased from 42.8% to 16.6% (P = 0.005). Main acute outcomes (need for dialysis, pancreatic compromise, central nervous system involvement, and death) were similar (P > 0.05) regardless of whether they received antibiotics or intravenous fluids.

Conclusions

During the diarrheal phase, 57% of patients consulted; three-quarters of them consulted to the pediatric emergency department. Shiga toxin–producing E. coli detection was poor, antibiotic use remained high, and anticipatory volume expansion was underused. These findings outline the critical need to improve the early management of STEC-HUS.
PD-L1 Expression Correlates With Young Age and CD8+ TIL Density in Poorly Differentiated Cervical Squamous Cell Carcinoma
Authors: Saglam Ozlen , Zhou Junmin , Wang Xuefeng , Conejo-Garcia Jose R.
Published: July 2019

Management options are limited in advanced or recurrent cervical carcinoma. The Food and Drug Administration has recently approved programed cell death-1 (PD-1)/PD-ligand-1 (PD-L1) inhibitors for the treatment of advanced PD-L1 positive cervical cancer. We studied PD-L1 expression in cervical squamous cell carcinoma (CSCC) samples initially on a The tissue microarray and then in full-tissue sections from poorly differentiated (grade 3) cancers. Tissue microarray was composed of 45 grade 3 and 2 (moderately differentiated) tumors. PD-L1 expression was evaluated as categorical data and by obtaining combined positive score of neoplastic and mononuclear inflammatory cells. In tissue microarray samples PD-L1 expression was higher in poorly differentiated cancers compared with grade 2 tumors by immunohistochemistry. Full-tissue sections from grade 3 CSCC (n=22) were stained with PD-L1, CD8, and VEGF antibodies. Poorly differentiated CSCC samples had diffuse (≥50%) and focal/patchy staining patterns. The latter pattern showed localized tumor-stroma interface staining in 5 samples with low combined positive score. Importantly, younger patients (median=36) had tumors with higher expression. PD-L1 expression was associated with larger tumor size and absent lymphovascular invasion. In addition, CD8+ tumor-infiltrating lymphocyte density within the neoplastic tissue matched with PD-L1 levels. The overall survival rates did not correlate with PD-L1 expression. However, in early-stage disease high CD8+ tumor-infiltrating lymphocyte density within the peritumoral stroma was associated with better survival outcomes in multivariate analysis. PD-L1 expression and CD8+ tumor-infiltrating lymphocyte density may be useful to define a subgroup of patients with relatively better prognosis in poorly differentiated CSCC. It is warranted to validate our results in a larger sample size.
Mapping the Affective Dimension of Embodiment With the Sensation Manikin: Validation Among Chronic Pain Patients and Modification by Mindfulness-Oriented Recovery Enhancement
Authors: Hanley Adam W. , Garland Eric L.
Published: July 2019

Objective

Mindfulness-based interventions target novel pain relief mechanisms not captured by legacy pain scales, including 1) cultivating awareness of pleasant and neutral sensations proximal to unpleasant sensations and 2) interoceptively mapping sensation location and spatial distribution.

Methods

We created a digital sensation manikin (SM) by overlaying a human figure silhouette with a grid of 469 “sensation” pixels. A series of five research questions examined the SM’s discriminant validity, construct validity, incremental validity, convergence with an objective measure of pain attentional bias, and sensitivity to a mindfulness-based psychological treatment, Mindfulness-Oriented Recovery Enhancement (MORE). A sample of opioid treated chronic pain patients (n = 108; age, 53.79 (12.94) years; female, 65%) was recruited to answer research questions 1 to 5, and a sample of healthy controls (n = 91; age, 36.47 (13.50) years; female, 55%) was recruited as the comparison group for research question 1.

Results

Chronic pain patients reported significantly more unpleasant sensations than did healthy controls (p < .001, d = 1.23) and significantly fewer pleasant sensations (p = .001, d = 0.50). The SM also evidenced expected relationships with multiple measures of pain (r = 0.26–0.29) and well-being (r = −0.21 to 0.28), uniquely predicted pain interference (β = −0.18), and exhibited a significant association with pain attentional bias (r = 0.25). Finally, mindfulness-based intervention via MORE significantly increased the ratio of pleasant to unpleasant sensations reported by chronic pain patients relative to an active control condition (p = .036, d = 0.51).

Conclusions

This study supports the SM’s validity and indicates that assessing both pleasant and unpleasant sensations broadens the scope of pain measurement. Although the SM would benefit from further optimization, its continued use is likely to contribute to improved assessment and treatment options for chronic pain patients.
Liver Stiffness Detected by Shear Wave Elastography Predicts Esophageal Varices in Cirrhotic Patients
Authors: Yu Jian-Bin , Xiong Hui , Yuan Xin-Chun , Zhou Ai-Yun
Published: July 2019

Ultrasound elastography has become a promising noninvasive approach for assessing liver fibrosis. The purpose of this study was to evaluate the diagnosis ability of liver stiffness detected by shear wave elastography (SWE) for predicting the presence of esophageal varices (EVs) in cirrhotic patients. Four hundred sixty-eight cirrhotic patients were enrolled consecutively. Liver stiffness and EVs were detected by SWE and endoscopy, respectively. The baseline characteristics were recorded, and areas under the receiver operating characteristic curves (AUROCs) were used to compare the diagnosis accuracy. Multivariate analysis was used to identify the risk factors for EVs in cirrhosis. The mean liver stiffness was 18.4 kPa with a range of 6.8 to 52.5 kPa. Two hundred seventy-one patients had no EVs (57.9%), 139 patients had F1 EVs (29.7%), and 58 patients had high-risk EVs (12.4%). The optimal cutoff values of SWE for predicting EVs and high-risk varices were 18.5 and 20.4 kPa, respectively. The AUROCs for predicting the incidence of EVs were 0.792 (95% confidence interval [CI], 0.884–0.842), 0.814 (95% CI, 0.658–0.875), and 0.895 (95% CI, 0.813–0.918) for platelet, platelet count–to–spleen diameter ratio, and liver stiffness, respectively. For predicting the presence of high-risk varices, liver stiffness again had the highest AUROC. Multivariate analysis identified liver stiffness and platelet count–to–spleen diameter ratio as independent predictive factors for EVs in cirrhosis. Liver stiffness measured by SWE is an effective diagnostic tool for predicting EVs with greater accuracy, and SWE value is an independent factor for predicting high-risk EVs.
Tailored Posterior Pharyngeal Fat Grafting Outcomes in Velopharyngeal Insufficiency Managed According to a Simplified Algorithm
Authors: Denadai Rafael , Raposo-Amaral Cesar Augusto , Sabbag Anelise , Vieira Pedro Ribeiro , Buzzo Celso Luiz , Raposo-Amaral Cassio Eduardo
Published: July 2019

Background

This study aimed to evaluate the outcomes of posterior pharyngeal fat grafting for the management of velopharyngeal insufficiency using a simplified therapeutic algorithm and a tailored surgical technique.

Methods

This was a prospective study of consecutive nonsyndromic patients with repaired cleft palate and velopharyngeal insufficiency who were stratified according to a simplified algorithm (minimally scarred palate, transverse orientation of levator veli palatini, and pinhole-to-small velopharyngeal gaps) and who underwent tailored posterior pharyngeal fat grafting. The patients were screened for obstructive sleep apnea before and after surgery. Three blinded evaluators randomly rated perceptual speech (hypernasality, audible nasal emission, and intraoral pressure) and nasoendoscopic (velopharyngeal active gap size) characteristics using audio and video recordings. Successful speech outcome was defined as normal or borderline sufficient velopharyngeal function at 15 months after surgery.

Results

All included patients (n = 96) presented with a preoperative and postoperative low risk of obstructive sleep apnea. At 15 months after surgery, hypernasality (0.26 ± 0.53), audible nasal emissions (0.29 ± 0.48), intraoral pressure (0.1 ± 0.31), and velopharyngeal closure size (1.86 ± 0.34) were significantly decreased (all, P < 0.05) compared with the corresponding preoperative measurements (hypernasality, 2.17 ± 0.75; audible nasal emissions, 1.89 ± 0.82; intraoral pressure, 0.85 ± 0.35; and velopharyngeal closure size, 0.2 ± 0.49). In total, 84 (87.5%) patients showed successful speech outcomes.

Conclusions

Tailored posterior pharyngeal fat grafting is an effective and safe surgical strategy for the management of velopharyngeal insufficiency in a selected cohort of patients with repaired cleft palate.
Partial Adenoidectomy in Patients With Palatal Abnormalities
Authors: Salna Ingrid , Jervis-Bardy Joshua , Wabnitz David , Rees Guy , Psaltis Alkis , Johnson Adam
Published: July 2019

Background:

Velopharyngeal insufficiency is a feared complication of adenoidectomies in patients with palatal abnormalities. Thus, the benefits of adenoidectomy in this population are less understood. The techniques of partial adenoidectomy aim to preserve velopharyngeal closure while sufficiently debulking the nasal airway to ameliorate obstruction and snoring.

Methodology:

Systematic review of online databases using a combination of search terms including “cleft palate,” “submucosal cleft palate,” “short palate,” “adenoidectomy,” “partial adenoidectomy,” “subtotal adenoidectomy,” and “powered adenoidectomy.” Two independent reviewers assessed the eligibility of each study based on predefined inclusion criteria.

Results:

From 323 studies identified, 8 were included. All were retrospective case series, except 1 prospective study. Study period ranged from 1.1 to 14 years (median 7.5 years). There were 172 patients with a cleft palate (n = 80), submucous cleft palate (n = 67) or another defined palatal abnormality [short soft palate (n = 14), bifid uvula (n = 4), questionable palatal mobility (n = 4) or incomplete CP (n = 3)] identified. Mean age was 5.5 years and just over half were male (58%). Nearly all patients showed improvement in nasal airway obstruction and snoring. The pooled risk for velopharyngeal insufficiency across all studies was 2 out of 122, which approximates to 1.6% of patients. There were very few complications.

Conclusion:

This is the first systematic review of partial adenoidectomy in patients with palatal abnormalities. Sub-total adenoidectomy in patients with submucosal cleft palate or repaired cleft palate appears to be a safe and efficacious procedure. There is; however, a need for prospective data collection using a standardized technique in large patient series required to properly assess outcomes.
Does a Recent Urinary Tract Infection Increase the Risk of Postprocedure Urinary Tract Infection After Onabotulinum Toxin A?
Authors: Bickhaus Jennifer A. , Bradley Megan S. , Amundsen Cindy L. , Visco Anthony G. , Truong Tracy , Li Yi-Ju , Siddiqui Nazema Y.
Published: July 2019

Objectives

The objective of this study was to evaluate the risk of postprocedure urinary tract infection (UTI) after injection of onabotulinum toxin A (BTX-A) in women who had a UTI within 30 days before procedure.

Methods

This was a retrospective cohort study of women who underwent their first injection of BTX-A from 2010 to 2016. Two cohorts were identified: (1) recent UTI (within 30 days before injection) and (2) no recent UTI. Our primary outcome was UTI within 90 days after BTX-A. Continuous variables were analyzed using the Wilcoxon rank sum test, and categorical variables were analyzed using Fisher exact or χ2 tests.

Results

One hundred sixty-six women underwent their first BTX-A injection. Twenty-five (15%) had a recent UTI and 141 (85%) did not. Women with a recent UTI were more likely to have a subsequent infection (52% vs 26%, P < 0.01). However, in a logistic regression model, controlling for history of recurrent UTI, age, history of diabetes mellitus, periprocedural antibiotics, and urinary retention requiring catheterization, the association between having a recent UTI, and a subsequent UTI was no longer significant (adjusted odds ratio, 1.98; 95% confidence interval, 0.60–6.50; P = 0.26).

Conclusions

Performing a first injection of BTX-A within 30 days of a UTI does not increase the odds of postprocedure UTI. Therefore, BTX-A therapy does not need to be delayed after a recent UTI.
Osteochondroma of the Pubic Symphysis Involved With Aberrantly Placed Minisling: A Case Report
Authors: Lee Wai , Amin Katherine , Kieras David M. , Coy David L. , Ruhoy Steven M. , Lee Una J.
Published: July 2019

Osteochondromas are benign bone tumors that rarely involve the pubic symphysis. This case report describes a 41-year-old woman with a pubic symphyseal osteochondroma associated with an aberrantly placed single incision sling. After an outside surgeon placed a single incision midurethral sling for stress urinary incontinence, she developed pelvic pain, dyspareunia and vaginal mesh sling exposure. Imaging demonstrated a 2.6 centimeter calcified mass posterior to the pubic symphysis. The patient underwent excision of the mass and the eroded mesh sling via vaginal and abdominal approaches. Pathology demonstrated osteochondroma aggregated around mesh. This is a rare case of a single incision sling placed aberrantly into a pubic symphyseal osteochondroma that required excision.
Normal Awake, Drowsy, and Sleep EEG Patterns That Might Be Overinterpreted as Abnormal
Authors: Asadi-Pooya Ali A. , Sperling Michael R.
Published: July 2019

Knowledge of normal patterns is essential for correct EEG interpretation. The overinterpretation of EEG (i.e., ascribing abnormality to EEG patterns that are not associated with disease) is a common problem and can contribute to misdiagnosis and mismanagement. Here, the authors concisely review normal patterns that might be improperly interpreted as abnormal. These include posterior slow waves of youth, central theta, K complexes, asymmetric sleep spindles, hypnagogic and hypnopompic hypersynchrony, arousal patterns, rhythmic midtemporal theta of drowsiness, and the wicket rhythm. Recognition of these patterns will lead to greater accuracy in EEG interpretation and help avoid incorrect management.
Higher energy requirement during weight-loss maintenance on a low- versus high-carbohydrate diet: secondary analyses from a randomized controlled feeding study
Authors: Ebbeling Cara B , Bielak Lisa , Lakin Paul R , Klein Gloria L , Wong Julia MW , Luoto Patricia K , Wong William W , Ludwig David S
Published: July 2019

Background

Longer-term feeding studies suggest that a low-carbohydrate diet increases energy expenditure, consistent with the carbohydrate-insulin model of obesity. However, the validity of methodology utilized in these studies, involving doubly-labeled water, has been questioned.

Objective

The aim of this study was to determine whether dietary energy requirement for weight-loss maintenance is higher on a low-versus high-carbohydrate diet.

Methods

The study reports secondary outcomes and exploratory analyses from a feeding study in which the primary outcome was total energy expenditure. After attaining a mean Run-in weight loss of 10.5%, 164 adults with pre-weight-loss BMI of ≥25 were randomly assigned to Test diets containing Low (20%), Moderate (40%) or High (60%) carbohydrate for 20 weeks. Calorie content of Test diets was adjusted to maintain individual body weight within 2 kg of the post-weight-loss value. In analyses by Intention-to-Treat (ITT, study completers, n=148) and Per Protocol (PP, those achieving the weight-loss maintenance target, n=110), we compared estimated energy requirement from 10 to 20 weeks on the Test diets using ANCOVA. Insulin secretion was assessed pre-weight-loss as insulin concentration 30 minutes following 75 grams oral glucose (Insulin-30).

Results

Estimated energy requirement was higher in the LowvsHigh group by models involving ITT (ranging from 181 [CI 8–353] to 223 [40–406] kcal/d;P≤0.04) and PP (ranging from 245 [43–446] to 295 [91–499] kcal/d;P≤0.02). This difference remained significant in sensitivity analyses accounting for change in adiposity and possible non-adherence. In observational analyses, pre-weight loss Insulin-30 predicted adverse change in body composition following weight loss.

Conclusions

Energy requirement was higher on a low-versus high-carbohydrate diet during weight-loss maintenance, commensurate with total energy expenditure. These data are consistent with the carbohydrate-insulin model and lend qualified support for the validity of the doubly-labeled water method with diets varying in macronutrient composition.
Pair housing makes calves more optimistic
Authors: Bučková Katarína , Špinka Marek , Hintze Sara
Published: July 2019

Individual housing of dairy calves is common farm practice, but has negative effects on calf welfare. A compromise between practice and welfare may be housing calves in pairs. We compared learning performances and affective states as assessed in a judgement bias task of individually housed and pair-housed calves. Twenty-two calves from each housing treatment were trained on a spatial Go/No-go task with active trial initiation to discriminate between the location of a teat-bucket signalling either reward (positive location) or non-reward (negative location). We compared the number of trials to learn the operant task (OT) for the trial initiation and to finish the subsequent discrimination task (DT). Ten pair-housed and ten individually housed calves were then tested for their responses to ambiguous stimuli positioned in-between the positive and negative locations. Housing did not affect learning speed (OT: F1,34 = 0.42, P = 0.52; DT: F1,34 = 0.25, P = 0.62), but pair-housed calves responded more positively to ambiguous cues than individually housed calves (χ21 = 6.76, P = 0.009), indicating more positive affective states. This is the first study to demonstrate that pair housing improves the affective aspect of calf welfare when compared to individual housing.
Genetic paths to evolutionary rescue and the distribution of fitness effects along them
Authors: Osmond Matthew M , Otto Sarah P , Martin Guillaume
Published: July 2019

The past century has seen substantial theoretical and empirical progress on the genetic basis of adaptation. Over this same period a pressing need to prevent the evolution of drug resistance has uncovered much about the potential genetic basis of persistence in declining populations. However, we have little theory to predict and generalize how persistence – by sufficiently rapid adaptation – might be realized in this explicitly demographic scenario. Here we use Fisher’s geometric model with absolute fitness to begin a line of theoretical inquiry into the genetic basis of evolutionary rescue, focusing here on asexual populations that adapt throughde novomutations. We show how the dominant genetic path to rescue switches from a single mutation to multiple as mutation rates and the severity of the environmental change increase. In multi-step rescue, intermediate genotypes that themselves go extinct provide a ‘springboard’ to rescue genotypes. Comparing to a scenario where persistence is assured, our approach allows us to quantify how a race between evolution and extinction leads to a genetic basis of adaptation that is composed of fewer loci of larger effect. We hope this work brings awareness to the impact of demography on the genetic basis of adaptation.
Integrative proteomic and phosphoproteomic profiling of prostate cell lines
Authors: Katsogiannou Maria , Boyer Jean-Baptiste , Valdeolivas Alberto , Remy Elisabeth , Calzone Laurence , Audebert Stéphane , Rocchi Palma , Camoin Luc , Baudot Anaïs
Published: July 2019

Background

Prostate cancer is a major public health issue, mainly because patients relapse after androgen deprivation therapy. Proteomic strategies, aiming to reflect the functional activity of cells, are nowadays among the leading approaches to tackle the challenges not only of better diagnosis, but also of unraveling mechanistic details related to disease etiology and progression.

Methods

We conducted here a large SILAC-based Mass Spectrometry experiment to map the proteomes and phosphoproteomes of four widely used prostate cell lines, namely PNT1A, LNCaP, DU145 and PC3, representative of different cancerous and hormonal status.

Results

We identified more than 3000 proteins and phosphosites, from which we quantified more than 1000 proteins and 500 phosphosites after stringent filtering. Extensive exploration of this proteomics and phosphoproteomics dataset allowed characterizing housekeeping as well as cell-line specific proteins, phosphosites and functional features of each cell line. In addition, by comparing the sensitive and resistant cell lines, we identified protein and phosphosites differentially expressed in the resistance context. Further data integration in a molecular network highlighted the differentially expressed pathways, in particular migration and invasion, RNA splicing, DNA damage repair response and transcription regulation.

Conclusions

Overall, this study proposes a valuable resource toward the characterization of proteome and phosphoproteome of four widely used prostate cell lines and reveals candidates to be involved in prostate cancer progression for further experimental validation.
The costs of close contacts: Visualizing the energy landscape of cell contacts at the nanoscale
Authors: Kulenkampff K. , Lippert A. H. , McColl J. , Santos A. M. , Ponjavic A. , Lee S. F. , Davis S. J. , Klenerman D.
Published: July 2019

Cell-cell contact often underpins signalling between cells. Contact is mediated by proteins on both cells creating interfaces with gap sizes typically around 14 nm. Protein binding and accumulation leads to the contact becoming crowded, reducing the rate of protein diffusion, even for unbound proteins. Here we show that, by tracking quantum dots of different dimensions for extended periods of time, it is possible to obtain the probability of a molecule entering the contact, the change in its diffusion upon entry and the impact of spatial heterogeneity of adhesion protein density in the contact. By analysing the contacts formed by a T cell interacting with adhesion proteins anchored to a supported lipid bilayer, we find that probes are excluded from contact entry in a size-dependent manner for gap-to-probe differences of 4.1 nm. We also observe probes being trapped inside the contact and a decrease in diffusion of up to 85% in dense adhesion protein contacts. This approach provides new insights into the nature of cell-cell contacts, revealing that cell contacts are highly heterogeneous, due to topography- and protein density-related processes. These effects are likely to profoundly influence signalling between cells.

Statement of Significance

The spatial distribution and diffusion of proteins has been shown to be important for various signalling machineries. As such size-dependent reorganisation of proteins in the immune cell-contact has been shown to affect activation of immune cells. While these studies relied on bulk measurements to investigate protein exclusion, small scale topographical changes and protein dynamics could not be evaluated. However, recent studies show that T cell activation is mediated by nanoscale structures. In our study the use molecular probes of various sizes to investigate the energy landscape of single molecules in a cell contact. This provides additional information and insights which cannot be determined by performing bulk experiments alone indicates.
Gestational pertussis vaccination and the infant’s cellular immune response against whole-cell pertussis vaccine in the first year of life
Authors: Argondizo-Correia Carolina , Rehder de Andrade Vaz-de-Lima Lourdes , Uchima Uehara Elaine , Gatti Fernandes Eder , Keico Sato Helena , Sayuri Sato Ana Paula , José de Albuquerque Luna Expedito , Ayres de Castilho Euclides , Alves de Brito Cyro
Published: July 2019

Pertussis resurgence worldwide calls for new prevention strategies, as the recently incorporated vaccine booster dose during pregnancy, whose aim is to protect newborns from infection. In Brazil, maternal Tdap vaccination is recommended since 2014, and we reported that this strategy promotes high transplacental transfer of anti-PT IgG and it is effective in protecting infants early in life. Young children are the most susceptible group and with higher mortality rates, however, it is not well known whether the elicited anti-pertussis maternal antibodies could influence in the children’s immune responses further in life, especially after their own vaccination against pertussis. Considering this scenario, we conducted a study with children born to mothers who either received or not the booster dose during pregnancy, after their primary pertussis vaccination, in order to investigate the first impact of maternal immunisation on the response to infant immunisation regarding the cellular immune response, while comparing with data from the literature. As transfer of maternal antibodies could result in attenuation of the immune response to vaccination in infants, this study performed to determine whether higher levels of maternal antibodies could influence in the immune response of infants to the whole-pertussis vaccination series. Results showed no difference in cytokine production between groups, a first suggestion that maternal vaccination may not interfere with recognition and cellular response generation to vaccination. This data, together with humoral immunity and epidemiological studies, is important for the implementation of maternal immunisation strategies nationwide and will contribute to assure public policies regarding vaccination schemes.

Importance

Pertussis, or whopping cough, is a respiratory infectious disease caused by a bacterial agent, resulting in violent coughs and possibly death in vulnerable groups, such as young children and neonates. It is known that pregnant mothers transfer antibodies to their developing foetuses for protection in early life, however anti-pertussis antibodies are not highly detected in young children. Thus, a pertussis maternal vaccination was implemented to increase maternal anti-pertussis antibodies levels in pregnant women and therefore the transference to the foetus. However, maternal antibodies can also interfere in the child immune response in the first months of life. The significance of our research is in analysing the cellular immune response of children born from pertussis-vaccinated mothers, which will give a first glimpse on how maternal antibodies could modulate the child’s response to pertussis in early life.
Model Plasma Membrane exhibits a Microemulsion in both Leaves providing a Foundation for “Rafts”
Authors: Allender D. W. , Giang H. , Schick M.
Published: July 2019

We consider a model plasma membrane, one that describes the outer leaf as consisting of sphingomyelin, phosphatidylcholine, and cholesterol, and the inner leaf of phosphatidylethanolamine, phosphatidylserine, phosphatidyl-choline, and cholesterol. Their relative compositions are taken from experiment, and the cholesterol freely interchanges between leaves. Fluctuations in composition are coupled to fluctuations in the membrane height as in the Leibler-Andelman mechanism. Provided that the membrane is of relatively constant thickness, this coupling of fluctuations also provides a coupling between the composition fluctuations of the two leaves. Structure functions display, for components in both leaves, a peak at non-zero wavevector. This indicates that the disordered fluid membrane is characterized by structure on a scale given by membrane properties. From measurements on the plasma membrane, this scale is on the order of 100 nm. The theory provides a tenable basis for the origin of “rafts”.

Statement of Significance

The hypothesis that the plasma membrane is not homogeneous, but rather is heterogeneous, with rafts” of one composition floating in a sea of another, has overturned conventional views of this membrane and how it functions. Proteins prefer either the raft or the sea, and so are not uniformly distributed. Hence they perform more efficiently. From experiment, rafts are thought to be about 100 nm. However there is no realistic model that provides: a length scale for the rafts; a raft in both leaves of the membrane; the composition of the raft. We provide such a model. In contrast to other theories, the raft and sea are distinguished not only by composition, but also by a difference in curvature.
Physiological basis of noise-induced hearing loss in a tympanal ear
Authors: Warren Ben , Fenton Georgina E , Klenschi Elizabeth , Windmill James FC , French Andrew S
Published: July 2019

Acoustic overexposure, such as listening to music too loud and too often, results in noise-induced hearing loss. The pathologies of this prevalent sensory disorder begin in the synapses of the primary auditory receptors, their postsynaptic partners and supporting cells. The extent of noise-induced damage, however, is determined by over-stimulation of primary auditory receptors. When over-stimulated, an excessive amount of positive ions flood into the primary auditory receptors, triggering the activation of ion channels and possibly disrupting their ability to encode sound. A systematic characterisation of the electrophysiological function of primary auditory receptors is warranted to understand how noise-exposure impacts on downstream targets, where the pathologies of hearing loss begin. Here, we used the experimentally-accessible locust ear to characterise noise-induced changes in the auditory receptors. Although, we found a decrease in ability of the primary auditory neurons to encode sound, this is probably due to pathologies of their supporting cells.
Establishment and validation of an endoplasmic reticulum stress reporter to monitor zebrafish ATF6 activity in development and disease
Authors: Clark Eric M. , Nonarath Hannah J.T. , Bostrom Jonathan R. , Link Brian A.
Published: July 2019

Induction of endoplasmic reticulum (ER) stress is associated with diverse developmental and degenerative diseases. Modified ER homeostasis causes activation of conserved stress pathways at the ER called the unfolded protein response (UPR). ATF6 is a transcription factor activated during ER stress as part of a coordinated UPR. ATF6 resides at the ER, and upon activation is transported to the Golgi apparatus where it is cleaved by proteases to create an amino-terminal cytoplasmic fragment (ATF6f). ATF6f translocates to the nucleus to activate transcriptional targets. Here, we describe establishment and validation of zebrafish reporter lines forATF6activity. These transgenic lines are based on a defined and multimerizedATF6consensus site which drives either eGFP or destabilized eGFP (d2GFP), enabling dynamic study ofATF6activity during development and disease. The results show that the reporter is specific for the ATF6 pathway, active during development, and induced in disease models known to engage UPR. Specifically, during development,ATF6activity is highest in the lens, skeletal muscle, fins, and gills. The reporter is also activated by common chemical inducers of ER stress including tunicamycin, thapsigargin, and brefeldin A, as well as by heat shock. In both an ALS and a cone dystrophy model,ATF6reporter expression is induced in spinal cord interneurons or photoreceptors, respectively, suggesting a role for ATF6 response in multiple neurodegenerative diseases. Collectively our results show theseATF6reporters can be used to monitorATF6activity changes throughout development and in zebrafish models of disease.

Summary Statement

We have established and validated transgenic zebrafish reporter lines to quantitatively measure the ATF6 branch of the endoplasmic reticulum stress pathway in development and disease.
Molecular Architecture of the Bardet-Biedl Syndrome Protein 2-7-9 Subcomplex
Authors: Ludlam W. Grant , Aoba Takuma , Cuéllar Jorge , Bueno-Carrasco M. Teresa , Makaju Aman , Moody James D. , Franklin Sarah , Valpuesta José M. , Willardson Barry M.
Published: July 2019

Bardet-Biedl syndrome (BBS) is a genetic disease caused by mutations that disrupt the function of the BBSome, an eight-subunit complex that plays an important role in transport of proteins in primary cilia. To better understand the molecular basis of the disease, we analyzed the structure of a BBSome subcomplex consisting of three homologous BBS proteins (BBS2, BBS7, and BBS9) by an integrative structural modeling approach using electron microscopy and chemical crosslinking coupled with mass spectrometry. The resulting molecular model revealed an overall structure that resembles a flattened triangle. Within the structure, BBS2 and BBS7 form a tight dimer based on a coiled-coil interaction, and BBS9 associates with the dimer via an interaction with the α-helical domain of BBS2. Interestingly, a BBS-linked mutation of BBS2 (R632P) is located in the α-helical domain at the interface between BBS2 and BBS9, and binding experiments showed that this mutation disrupted the interaction of BBS2 with BBS9. This finding suggests that BBSome assembly is disrupted by the R632P substitution, providing a molecular explanation for BBS in patients harboring this mutation.