bluuebunny/crossref_metadata_2025 huggingface dataset:
Sclerostin regulation: a promising therapy for periodontitis by modulating alveolar bone
Authors: Li Tian-Jiao , Wang Rui , Li Qin-Yang , Li Chun-Yu , Jiang Li
Published: June 2020

Periodontitis is one of the most prevalent epidemics affecting human health and life recently, and exploration of the pathogenesis and treatment of periodontitis has been valued by scholars. In recent years, sclerostin, a new factor on bone resorption and reconstruction caused by inflammation and mechanical stimulation, has been a research hotspot. This article summarizes the researches on sclerostin in periodontitis development in recent years. Among them, sclerostin has been shown to be a critical negative regulator of bone formation, thereby inhibiting bone remodeling in periodontitis development, and is closely associated with tooth movement. Besides, evidence indicates that the removal of sclerostin seems to reasonably protect the alveolar bone from resorption. Regulation of sclerostin expression is a novel, promising treatment for periodontitis and addresses several complications seen with traditional therapies; accordingly, many drugs with similar mechanisms have emerged. Moreover, the application prospect of sclerostin in periodontal therapy combined with orthodontic treatment is another promising approach. There are also a lot of drugs that regulate sclerostin. Anti-sclerostin antibody (Scl-Ab) is the most direct one that inhibits bone resorption caused by sclerostin. At present, drugs that inhibit the expression of sclerostin have been applied to the treatment of diseases such as multiple myeloma and osteoporosis. Therefore, the application of sclerostin in the oral field is just around the corner, which provides a new therapeutic bone regulation strategy in oral and general health.
Effect of ciRS-7 expression on clear cell renal cell carcinoma progression
Authors: Zhao Yan-Hui , Wang Zhi , Zhang Na , Cui Tao , Zhang Yan-Hui
Published: June 2020

Background

Circular RNA ciRS-7 has been reported to be involved in the progression of various cancers. However, ciRS-7 expression and its role in clear cell renal cell carcinoma (ccRCC) progression remains unclear. This study aimed to investigate the effect of ciRS-7 expression on ccRCC and the related signaling pathway.

Methods

ciRS-7 expression was analyzed using quantitative reverse transcription polymerase chain reaction in 87 pairs of ccRCC and matched adjacent normal tissues. The role of ciRS-7 in ccRCC cell proliferation and invasion was determined using the cell counting kit-8 and invasion assays, respectively. Potential mechanisms underlying the role of ciRS-7 in promoting ccRCC progression were explored by Western blotting. The relationship between the expression of ciRS-7 and features of ccRCC was analyzed by the Chi-square test and progression-free survival was determined using a Kaplan-Meier plot.

Results

ciRS-7 was overexpressed in ccRCC tissues compared with that in matched adjacent normal tissues. In addition, ciRS-7 up-regulation was closely associated with tumor diameter (P = 0.050), clinical stage (P = 0.009), and distant metastasis (P = 0.007). ciRS-7 knockdown in 786O and 769P cells markedly inhibited their proliferative and invasive abilities. In addition, ciRS-7 inhibition reduced phosphorylated epidermal growth factor receptor (p-EGFR) and phosphorylated serine/threonine kinase (p-Akt) levels.

Conclusions

ciRS-7 up-regulation could promote ccRCC cell proliferation and invasion, which may be related with the EGFR/Akt signaling pathway. ciRS-7 might be a potential ccRCC therapeutic target.
Cytomegalovirus seroprevalence, recurrence, and antibody levels
Authors: Bulka Catherine M. , Bommarito Paige A. , Aiello Allison E. , Fry Rebecca C.
Published: June 2020

Background:

The ubiquitous metals cadmium and lead are immunotoxic, but little is known about their relations to cytomegalovirus (CMV), a widespread herpesvirus. Although CMV infections are mostly asymptomatic, congenital infections are a leading cause of birth defects. In otherwise healthy individuals, there is also some evidence linking subclinical reactivations to accelerated age-related declines in immune function and chronic disease.

Methods:

Our objective was to evaluate associations of blood cadmium and lead biomarkers with CMV infection in a representative sample of the United States population. In seropositive individuals, we also examined associations with CMV-specific immunoglobulin G (IgG) antibody levels and suspected CMV recurrences. Using cross-sectional data from the 1999–2004 National Health and Nutrition Examination Surveys, we fit multivariable survey-weighted regression models accounting for potential confounding by sociodemographic and lifestyle factors and stratifying by age group to allow for heterogeneity. CMV recurrences were defined according to (1) the presence of either CMV-specific immunoglobulin M in sera or CMV viral DNA in urine, and (2) high CMV-specific IgG avidity.

Results:

We observed null associations for blood cadmium. Increasing blood lead quartiles were related to CMV seropositivity and higher CMV IgG levels (both P

trend
< 0.01), but not CMV recurrence, only among individuals who were 20–29 years of age.

Conclusion:

Blood cadmium levels do not appear to be related to immunological markers of CMV infections. The possibility that lead exposures increase the risk of CMV infection and impair immune control of the virus in young adults was suggested. Prospective studies are needed to confirm.
Potential Mechanisms of Cardiac Injury and Common Pathways of Inflammation in Patients With COVID-19
Authors: Centurión Osmar Antonio , Scavenius Karina E. , García Laura B. , Torales Judith M. , Miño Luís M.
Published: June 2020

Due to the lack of prospective, randomized, controlled clinical studies on inflammation and cardiovascular involvement, the exact mechanism of cardiac injury among patients with Coronavirus Disease 2019 (COVID-19) still remains uncertain. It was demonstrated that there is a high and significantly positive linear correlation between troponin T and plasma high-sensitivity C-reactive protein levels, biomarkers of cardiac injury and systemic inflammation, respectively. Cardiac injury and inflammation is a relatively common association among patients hospitalized with COVID-19, and it is related to higher risk of in-hospital mortality. In our literature search, we identified several potential mechanisms of myocardial tissue damage, namely, coronavirus-associated acute myocarditis, angiotensin-converting enzyme 2 receptor binding affinity to the virus Spike protein, increased cytokine secretion, and hypoxia-induced cardiac myocyte apoptosis. Elucidation of the disease pathogenesis and prospective histopathological studies are crucial for future proper treatment in case of renewed outbreaks. Of interest is that with hundred of thousands of bodies available for autopsy studies, no prospective investigation has been reported so far. Strong efforts and continued research of the cardiovascular complications and identification of risk factors for poor prognosis in COVID-19 are steadily needed. The high morbidity and mortality of COVID-19, its monumental economic burden and social impact, the despair of a new pandemic outbreak, and the thread of potential utilization of novel severe acute respiratory syndrome coronavirus 2 as biologic weapons make it a preponderant necessity to better comprehend the therapeutic management of this lethal disease. Emerging as an acute infectious disease, COVID-19 may become a chronic epidemic because of genetic recombination. Therefore, we should be ready for the reemergence of COVID-19 or other coronaviruses.
OCRIPLASMIN FOR VITREOMACULAR TRACTION IN CLINICAL PRACTICE
Authors: Steel David H. W. , Patton Niall , Stappler Theodor , Karia Niral , Hoerauf Hans , Patel Nishal , Wachtlin Joachim , Raber Thomas , Kozma-Wiebe Petra ,   on behalf of the INJECT study investigators
Published: June 2020

Purpose:

Randomized clinical trials have demonstrated the safety and efficacy of ocriplasmin in patients with vitreomacular traction (VMT), including those with macular hole (MH). The INJECT study prospectively evaluated ocriplasmin in the setting of clinical practice.

Methods:

INJECT was a Phase 4, multicenter, prospective observational study. Patients were followed up for 12 months. Assessments included nonsurgical VMT resolution, nonsurgical MH closure, best-corrected visual acuity, occurrence of vitrectomy, and adverse events.

Results:

The efficacy population (N = 395) received an ocriplasmin injection and had optical coherence tomography–confirmed VMT at baseline. At Day 28, the rate of nonsurgical VMT resolution was 40.7% in the overall group, and the rate of nonsurgical MH closure was 36.0% in the VMT with MH group. At Month 12, the rate of ≥2-line best-corrected visual acuity gain (irrespective of vitrectomy) was 36.8% in the overall group and 59.6% in the VMT with MH group. The percentage of patients who underwent vitrectomy in the study eye was 29.1% in the overall group and 55.6% in the VMT with MH group. Photopsia (9.8%) and vitreous floaters (6.8%) were the most frequent adverse events.

Conclusion:

The INJECT study showed that ocriplasmin is effective in a clinical setting in patients with VMT, with or without MH. No new safety signals were identified from this large and surgeon-selected patient group, although the significant limitations of the study design without an image reading center and scheduled study visit timings should be noted.
Deployment of a computerized ward visitor registration system in coronavirus disease 2019 epidemic: Experiences of a large academic medical center in Taiwan
Authors: Hsu Chia-An , Yuan Eunice J. , Fen Jun-Jeng , Lee Chung-Yuan , Ming Jin-Lain , Chen Tzeng-Ji , Lee Wui-Chiang , Chen Shih-Ann
Published: June 2020

Background:

Visitors to hospitalized patients during an epidemic might themselves be carriers and are therefore likely to spread the disease in wards. Although measures were taken to restrict hospital visits, traditional paper-based registration is insufficient to screen and monitor the numbers of visitors to a large hospital.

Methods:

Throughout March 2020, during the coronavirus disease 2019 crisis, a computer system was deployed in the 2800-bed Taipei Veterans General Hospital (Taipei, Taiwan) to register, screen, and monitor inpatient visitors. This system comprised three parts: online registration form, entrance check-in interface, and registration database. The early utilization of this newly deployed system was then analyzed.

Results:

A total of 22,336 visits were recorded between March 11, 2020, and March 31, 2020, with 1064 a day on average. Out of these visits, 18.1% (n = 4049) had made online reservations within 48 hours. On the other hand, of all 4941 online reservations, 18.1% (n = 892) were no-shows. In the last 12 days of the study period, eight prospective visitors were identified as ineligible by the computer system, and so their visits were denied.

Conclusion:

Using a computer system, the hospital was able to enforce restrictions on hospital visits. Although the online registration system had not been fully used yet in the early phase of adoption, its superiority from the standpoint of disease control should enable hospital managers to consider abolishing on-site visitor registration.
The Influence of Preoperative Anxiety, Optimism, and Pain Catastrophizing on Acute Postoperative Pain in Patients Undergoing Cardiac Surgery
Authors: Tai Ai-Lin , Hsieh Hsiu-Fen , Chou Pi-Ling , Chen Hsing-Mei , Liu Yi
Published: June 2020

Background

Acute postoperative pain (APOP) may cause complications and delay healing. Analgesics alone cannot completely relieve APOP. Preoperative anxiety, optimism, and pain catastrophizing are predictors of APOP. No study author has examined the mediating effect of pain catastrophizing on APOP in patients undergoing cardiac surgery.

Objective

The aims of this study were to investigate the relationship between preoperative anxiety, optimism, pain catastrophizing, confounding factors (age, sex, type of surgery, and preoperative pain), and APOP and to examine the mediating effect of pain catastrophizing.

Methods

The authors of this cross-sectional study used a convenience sampling method and included 100 adults undergoing cardiac surgery in a southern Taiwanese medical center. The patients were asked to complete the State-Trait Anxiety Inventory-State subscale, Pain Catastrophizing Scale, and Life Orientation Test-Revised questionnaires before surgery. Postoperatively, the patients were asked to report their pain intensity on a numerical rating scale. Results were analyzed using SPSS version 22.

Results

Patients had a mild level of anxiety, a moderate level of optimism, and pain catastrophizing before surgery, as well as a moderate level of APOP. Men reported lower levels of APOP than women (z = −2.0, P < .05). APOP was significantly associated with preoperative anxiety (r = 0.48, P < .01), optimism (r = −0.45, P < .01), and pain catastrophizing (r = 0.65, P < .01). Only pain catastrophizing was a significant predictor of APOP (β = 0.60, P < .001) and fully mediated the relationship between anxiety and APOP (z = 4.92, P < .001). The final model explained 42% of the variance in APOP.

Conclusions

Pain catastrophizing should be assessed before surgery. Reducing pain catastrophizing would decrease APOP and improve the quality of pain management.
Implementation of the Clinical Nurse Leader Role in the Veterans Health Administration
Authors: Miltner Rebecca S. , Haddock Kathlyn Sue , Patrician Patricia A. , Williams Marjory
Published: June 2020

The Veterans Health Administration (VHA) led implementation of the Clinical Nurse Leader (CNL) role nationally with the goal to meet system needs for strong clinical leadership across all settings. After a decade of CNL role implementation, the VHA supported this evaluation to determine the current state, the successes, the challenges, and the fidelity to the original intent of the role. The team used mixed methods to evaluate the state of the CNL initiative. Ten evaluation activities were undertaken including a facility survey directed toward chief nurse executives at all VHA facilities, and a second survey directed at registered nurses who completed a CNL graduate program, were certified as a CNL, or were currently enrolled in a CNL graduate program. The evaluation results suggest the CNL initiative had not yet accomplished the stated goals to improve cost and financial outcomes, increase patient satisfaction, increase staff satisfaction and retention, improve quality and internal processes, and facilitate practice model transformation including evidence-based practice and collaborative, interdisciplinary practice across the system. Observed CNL practices within the VHA could serve as exemplars for developing a care delivery model that could achieve these goals and offer potential paths to move this role forward.
Missed Nursing Care in Pediatric and Neonatal Care Settings
Authors: Ogboenyiya Anisa A. , Tubbs-Cooley Heather L. , Miller Elaine , Johnson Kimberly , Bakas Tamilyn
Published: June 2020

Introduction:

Missed nursing care is required care that is delayed, incomplete, or left undone during a nurse's working shift. Missed nursing care is most often studied in adult populations; however, it may have significant consequences in pediatric and neonatal care settings. The purpose of this integrative review is to describe missed nursing care in pediatric and neonatal nursing care settings.

Methods:

SCOPUS and PubMed were used in the literature search. Multiple combinations of the keywords and phrases “missed nursing care,” “pediatric,” “neonatal,” “care left undone,” or “nursing care rationing” were used for the literature search. Missed nursing care is a relatively new topic as the first article on the subject was published in 2006; therefore, inclusion criteria were set to English articles published between January 1, 2006 and October 11, 2019 that reported on missed nursing care in pediatric and neonatal inpatient care settings.

Results:

Fourteen articles met inclusion criteria. Missed nursing care in pediatric and neonatal nursing care settings is associated with workload, patient acuity, work environment, and nurse characteristics, and is related to prolonged hospitalization of preterm infants.

Clinical Implications:

Providing nurses with an adequate amount of resources and tools to avoid missed nursing care will continue to improve care delivery. Missed nursing care and related patient and nurse outcomes in diverse pediatric and neonatal samples remains an area for future research.
Fatigue and Sleep Quality Predict Eating Behavior Among People With Type 2 Diabetes
Authors: Zhu Bingqian , Chen Xiangfang , Park Chang G. , Zhu Daqiao , Izci-Balserak Bilgay
Published: June 2020

Background

People with Type 2 diabetes frequently report increased fatigue and sleep disturbance. These symptoms might put them at a higher risk for unhealthy eating behavior—detrimental to diabetes control.

Objectives

The aim of the study was to examine the effect of fatigue and sleep on eating behavior in people with Type 2 diabetes by using a daily diary approach.

Methods

Data from 56 patients were collected during a baseline interview and an 8-day ambulatory assessment period in the free-living setting. Each day, participants completed one diary upon awakening to assess their sleep duration and sleep quality during the previous night and morning fatigue. They also completed one diary before going to bed to assess their eating behavior during the day (e.g., uncontrolled eating, cognitive restraint, emotional eating, and snacking). Data from 7 days were analyzed using generalized estimating equations.

Results

During the 7 days, controlling for age, gender, and body mass index, between-person fatigue was a significant predictor of uncontrolled eating, emotional eating, and snacking. Similarly, controlling for the covariates, between-person sleep quality was a significant predictor of uncontrolled eating and emotional eating. No associations were found between sleep duration and eating behavior.

Discussions

At the between-person level, reporting higher fatigue or poorer sleep quality was associated with higher levels of unhealthy eating behavior. Patients with Type 2 diabetes with high fatigue or poor sleep quality may require additional attention to support their healthy eating.
Latent Profile Analysis of a Syndemic of Vulnerability Factors on Incident Sexually Transmitted Infection in a Cohort of Black Men Who Have Sex With Men Only and Black Men Who Have Sex With Men and Women in the HIV Prevention Trials Network 061 Study
Authors: Dyer Typhanye V. , Turpin Rodman E. , Stall Ron , Khan Maria R. , Nelson LaRon E. , Brewer Russell , Friedman M. Reuel , Mimiaga Matther J. , Cook Robert L. , O'Cleirigh Conall , Mayer Kenneth H.
Published: June 2020

Background

Sexually transmitted infections (STIs) are important public health concerns among black men who have sex with men only (BMSMO), as well as those who have sex with both men and women (BMSMW). Sexually transmitted infections also increase risk of acquiring and HIV, which is also a critical concern. Compared with BMSMO, research shows that BMSMW experience elevated levels of HIV/STI vulnerability factors occurring at the intrapersonal, interpersonal, and social/structural levels. These factors may work independently, increasing one's risk of engaging in high-risk sexual behaviors, but often work in a synergistic and reinforcing manner. The synergism and reinforcement of any combination of these factors are known as a syndemic, which increases HIV/STI risk.

Methods

Data from the HIV Prevention Trials Network (HPTN) 061 study (n = 799) was used to conduct a latent profile analysis to identify unique combinations of risk factors that may form a syndemic and that may vary between BMSMO and BMSMW. We hypothesized that the convergence of syndemic factors would differ between groups and predict sexual risk and subsequent incident STI.

Results

For BMSMO who had a high sexual risk profile, the syndemic factors characterizing this group included perceived racism, incarceration, intimate partner violence, depression, and binge drinking. For BMSMW with a high sexual risk profile, the syndemic factors that characterized this group were incarceration, depression, and binge drinking.

Conclusions

The current analysis highlights syndemic profiles that differentiated BMSMO and BMSMW from one another and supports the need for tailored interventions that address specific syndemic factors for both subpopulations of black men who have sex with men.
Primary Syphilis of the Neck Mimicking Pyodermatitis
Authors: Ramoni Stefano , Genovese Giovanni , Pastena Andrea , Cusini Marco
Published: June 2020

The authors describe an atypical case of primary syphilis of the neck. The unusual clinical presentation and localization led to an initial diagnostic mistake. This case confirms the polymorphic character of syphilis. Considering the increased incidence of sexually transmitted infections worldwide, a high index of suspicion should be maintained by physicians.
Local Policy and Programmatic Activity to Address the US Opioid Crisis: A Cross-Sectional Survey of County Governments
Authors: Swann William L. , Schreiber Terri L. , Wright Steven L. , Davis Mark W. , Kim Sojeong , Kim Serena Y. , Osei-Kojo Alex , Lamiotte Megan
Published: June 2020

Context:

Despite attention to federal and state governments' response to the US opioid crisis, few studies have systematically examined local governments' role in tackling this problem.

Objectives:

To determine what opioid policy and programmatic activities local governments are implementing, which activities are more challenging and require a greater latent ability to implement, and what community, environmental, and institutional factors shape such ability.

Design:

A cross-sectional survey and multistage sampling procedure.

Setting/Participants:

Of all 358 county governments in 5 purposively selected states (Colorado, North Carolina, Ohio, Pennsylvania, and Washington) surveyed, 171 counties (response rate = 47.8%) with complete data on self-reported policy and programmatic activities and predictor variables were eligible for analysis.

Main Outcome Measures:

Nineteen opioid policy and programmatic activities were analyzed individually and combined into a latent implementation ability index using empirical Bayes means estimates.

Results:

Item response theory and bivariate analysis were applied. Item response theory estimates suggested that having police officers carry naloxone and establishing a task force of community leaders were easier to implement than more challenging activities such as establishing needle exchanges and allowing arrest alternatives for opioid offenses. Covering individuals' treatment costs was predicted to involve the highest ability. County population size (r = 0.34; 95% confidence interval [CI], 0.20-0.47), population density (r = 0.35; 95% CI, 0.21-0.47), and being a Pennsylvania county (r = 0.45; 95% CI, 0.32-0.56) showed the strongest associations with latent implementation ability.

Conclusions:

Counties appear engaged in opioid policy and programmatic activity, although some activities are likely more difficult and may require greater ability to implement than others. More sparsely populated counties appear more disadvantaged in implementing activities for tackling the opioid crisis and may need additional assistance to leverage their ability to build a comprehensive policy and programmatic infrastructure.
Breast Augmentation in the Transfemale Patient: Comprehensive Principles for Planning and Obtaining Ideal Results
Authors: Coon Devin , Lee Erica , Fischer Beverly , Darrach Halley , Landford Wilmina N.
Published: June 2020

Background:

A growing number of transgender women present to plastic surgeons seeking breast augmentation. Despite some advocating their technical similarity, the authors have found substantially different planning and techniques are needed to obtain aesthetic results in transgender patients versus cosmetic breast augmentation. The authors sought to develop an approach for operative planning and technique to elucidate these differences and obtain consistent results.

Methods:

All patients who underwent breast augmentation at the Johns Hopkins Center for Transgender Health were included in this study. Anthropometric assessments were obtained and comparative statistics between operative and nonoperative cohorts were calculated. Outcomes were analyzed and a patient-reported survey was performed to evaluate patient satisfaction.

Results:

Fifty-nine consecutive transfemale patients presented for evaluation. Anthropometric measurements included base width (median, 15.0 ± 2.1 cm), notch–to-nipple distance (median, 22.0 cm), nipple-to-midline distance (median, 12.0 cm), areolar diameter (median, 3.5 ± 1.5 cm), and upper pole pinch (mean, 1.8 ± 1.1 cm). Thirty-six patients underwent augmentation mammaplasty. Postoperative complications (8.3 percent) included a minor hematoma and grade III capsular contracture in two patients. Patients were asked to complete a brief outcomes survey and reported an improvement in psychosocial well-being and high satisfaction rate (100 percent) with the overall cosmetic result.

Conclusions:

Transgender female patients represent a unique patient population requiring special consideration of anatomical differences in key planning decisions. The authors delineate the first systematic algorithm that addresses these differences, emphasizing maneuvers such as routine inframammary fold lowering. This can allow experienced augmentation surgeons to obtain excellent aesthetic and patient-reported outcomes in this population. As with cosmetic breast augmentation, patient satisfaction rates are high.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Comparison of Treatment Outcomes after Collagenase Injection and Percutaneous Needle Fasciotomy for Dupuytren’s Contracture: Objective and Subjective Comparisons with a 3-Year Follow-Up
Authors: Abe Yoshihiro
Published: June 2020

Background:

This study compared the effectiveness of injectable collagenase clostridium histolyticum and percutaneous needle fasciotomy in the treatment of Dupuytren’s contracture.

Methods:

Patients with a total passive extension deficit of 30 degrees or more in a single digital ray were enrolled and assigned randomly to receive either collagenase clostridium histolyticum injections or percutaneous needle fasciotomy. Preoperative severity of proximal interphalangeal joint contracture for Dupuytren’s disease was classified according to the British Society for Surgery of the Hand as less than 30 degrees (stage I) or 30 degrees or more (stage II).

Results:

Of the 70 patients enrolled, 36 patients with 46 joints received collagenase clostridium histolyticum injections and 34 patients with 48 joints received percutaneous needle fasciotomy. At day 30, successful corrections were obtained in only 50 percent of the injection group and 67 percent of the fasciotomy group for stage II proximal interphalangeal joints. Recurrences were frequent among patients with stage II joint contractures. The mean Quick Disabilities of the Arm, Shoulder and Hand questionnaire score at day 30 was significantly higher in the injection group compared with the fasciotomy group (7.5 versus 4.2, respectively). In the injection group, adverse events were reported for all patients. In the fasciotomy group, complications were reported for 15 percent of patients.

Conclusions:

The collagenase clostridium histolyticum and percutaneous needle fasciotomy groups had similar outcomes for Dupuytren’s contracture with 3 years’ follow-up. Recurrences were frequent among patients with stage II proximal interphalangeal joint contractures. The Unité Rhumatologique des Affections de la Main scale and Quick Disabilities of the Arm, Shoulder and Hand questionnaire score decreased significantly for both groups at final follow-up.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, II.
Volumetric Differences in the Suprafascial and Subfascial Compartments of Patients with Secondary Unilateral Lower Limb Lymphedema
Authors: Chu Sung-Yu , Wang Stewart C. , Chan Wen-Hui , Wang Nicholas , Huang Yen-Ling , Cheng Ming-Huei , Cederna Paul Stephen
Published: June 2020

Background:

The subfascial compartment (deep to the deep fascia) in extremity lymphedema has not been evaluated. This study investigated the volumetric differences between the suprafascial and subfascial compartments of patients with unilateral lower extremity lymphedema.

Methods:

Thirty-two female patients with unilateral lower extremity lymphedema were enrolled, with eight patients in each of Cheng lymphedema grades I to IV. The volumes of the suprafascial and subfascial compartments were calculated after manually drawing the region of interest on computed tomographic images. The volumetric differences and their ratios in the suprafascial and subfascial compartments between each patient’s bilateral limbs were compared.

Results:

The volume of the lymphedematous limbs (9647 ml) was significantly greater than the volume of unaffected limbs (6906 ml), with a median volumetric difference of 2097 ml (30.6 percent) (p < 0.01). The median suprafascial compartment volumetric difference was 1887 ml (56.6 percent) and the subfascial compartment volumetric difference was 208 ml (4.7 percent) (p < 0.01). The median volumetric difference ratio of the thigh and lower leg was 24.6 percent and 40.6 percent, respectively. The median volumetric differences in Cheng lymphedema grades I to IV were 1012, 1787, 2434, and 4107 ml, respectively, which were statistically significant among the four Cheng lymphedema grades using the Kruskal-Wallis test (p < 0.01).

Conclusions:

The volumetric differences in the lymphedematous limb were statistically significantly greater than in the unaffected limb, including both suprafascial and subfascial compartments. The volumetric differences are consistent with the Cheng lymphedema grading system as a reliable indicator of unilateral extremity lymphedema.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Diagnostic, IV.
The Economic Burden of Out-of-Pocket Expenses for Plastic Surgery Procedures
Authors: Billig Jessica I. , Chen Jung-Sheng , Lu Yu-Ting , Chung Kevin C. , Sears Erika D.
Published: June 2020

Background:

Health insurance reimbursement structure has evolved, with patients becoming increasingly responsible for their health care costs through rising out-of-pocket expenses. High levels of cost sharing can lead to delays in access to care, influence treatment decisions, and cause financial distress for patients.

Methods:

Patients undergoing the most common outpatient reconstructive plastic surgery operations were identified using Truven MarketScan databases from 2009 to 2017. Total cost of the surgery paid to the insurer and out-of-pocket expenses, including deductible, copayment, and coinsurance, were calculated. Multivariable generalized linear modeling with log link and gamma distribution was used to predict adjusted total and out-of-pocket expenses. All costs were inflation-adjusted to 2017 dollars.

Results:

The authors evaluated 3,165,913 outpatient plastic and reconstructive surgical procedures between 2009 and 2017. From 2009 to 2017, total costs had a significant increase of 25 percent, and out-of-pocket expenses had a significant increase of 54 percent. Using generalized linear modeling, procedures performed in outpatient hospitals conferred an additional $1999 in total costs (95 percent CI, $1978 to $2020) and $259 in out-of-pocket expenses (95 percent CI, $254 to $264) compared with office procedures. Ambulatory surgical center procedures conferred an additional $1698 in total costs (95 percent CI, $1677 to $1718) and $279 in out-of-pocket expenses (95 percent CI, $273 to $285) compared with office procedures.

Conclusions:

For outpatient plastic surgery procedures, out-of-pocket expenses are increasing at a faster rate than total costs, which may have implications for access to care and timing of surgery. Providers should realize the increasing burden of out-of-pocket expenses and the effect of surgical location on patients’ costs when possible.
Photoaged Skin Therapy with Adipose-Derived Stem Cells
Authors: Charles-de-Sá Luiz , Gontijo-de-Amorim Natale Ferreira , Rigotti Gino , Sbarbati Andrea , Bernardi Paolo , Benati Donatella , Bizon Vieira Carias Rosana , Maeda Takiya Christina , Borojevic Radovan
Published: June 2020

Background:

The major intrinsic cause of facial skin degeneration is age, associated with extrinsic factors such as exposure to sun. Its major pathologic causes are degeneration of the elastin matrix, with loss of oxytalan and elaunin fibers in the subepidermal region, and actinic degeneration of elastin fibers that lose their functional properties in the deep dermis. Therapy using autologous adipose mesenchymal stem cells for regeneration of extracellular matrix in patients with solar elastosis was addressed in qualitative and quantitative analyses of the dermal elastic fiber system and the associated cells.

Methods:

Mesenchymal stem cells were obtained from lipoaspirates, expanded in vitro, and introduced into the facial skin of patients submitted after 3 to 4 months to a face-lift operation. In the retrieved skin, immunocytochemical analyses quantified elastic matrix components; cathepsin K; matrix metalloproteinase 12 (macrophage metalloelastase); and the macrophage M2 markers CD68, CD206, and hemeoxygenase-1.

Results:

A full de novo formation of oxytalan and elaunin fibers was observed in the subepidermal region, with reconstitution of the papillary structure of the dermal-epidermal junction. Elastotic deposits in the deep dermis were substituted by a normal elastin fiber network. The coordinated removal of the pathologic deposits and their substitution by the normal ones was concomitant with activation of cathepsin K and matrix metalloproteinase 12, and with expansion of the M2 macrophage infiltration.

Conclusion:

The full regeneration of solar elastosis was obtained by injection of in vitro expanded autologous adipose mesenchymal stem cells, which are appropriate, competent, and sufficient to elicit the full structural regeneration of the sun-aged skin.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Estimating life years lost to diabetes: outcomes from analysis of National Diabetes Audit and Office of National Statistics data
Authors: Heald Adrian H. , Stedman Mike , Davies Mark , Livingston Mark , Alshames Ramadan , Lunt Mark , Rayman Gerry , Gadsby Roger
Published: June 2020

With sustained growth of diabetes numbers, sustained patient engagement is essential. Using nationally available data, we have shown that the higher mortality associated with a diagnosis of T1DM/T2DM could produces loss of 6.4 million future life years in the current UK population. In the model, the ‘average’ person with T1DM (age 42.8 years) has a life expectancy from now of 32.6 years, compared to 40.2 years in the equivalent age non diabetes mellitus population, corresponding to lost life years (LLYs) of 7.6 years/average person. The ‘average’ person with T2DM (age 65.4 years) has a life expectancy from now of 18.6 years compared to the 20.3 years for the equivalent non diabetes mellitus population, corresponding to LLY of 1.7 years/average person. We estimate that for both T1DM and T2DM, one year with HbA1c >58 mmol/mol loses around 100 life days. Linking glycaemic control to mortality has the potential to focus minds on effective engagement with therapy and lifestyle recommendation adherence.
Microevolution in the major outer membrane protein OmpA of Acinetobacter baumannii
Authors: Viale Alejandro M. , Evans Benjamin A.
Published: June 2020

Acinetobacter baumannii

is nowadays a relevant nosocomial pathogen characterized by multidrug resistance (MDR) and concomitant difficulties to treat infections. OmpA is the most abundant

A. baumannii

outer membrane (OM) protein, and is involved in virulence, host-cell recognition, biofilm formation, regulation of OM stability, permeability and antibiotic resistance. OmpA members are two‐domain proteins with an N‐terminal eight‐stranded β‐barrel domain with four external loops (ELs) interacting with the environment, and a C‐terminal periplasmic domain binding non‐covalently to the peptidoglycan. Here, we combined data from genome sequencing, phylogenetic and multilocus sequence analyses from 975 strains/isolates of the

Acinetobacter calcoaceticus

/

Acinetobacter baumannii

complex (ACB), 946 from

A. baumannii

, to explore ompA microevolutionary divergence. Five major ompA variant groups were identified (V1 to V5) in

A. baumannii

, encompassing 52 different alleles coding for 23 different proteins. Polymorphisms were concentrated in five regions corresponding to the four ELs and the C‐terminal end, and provided evidence for intra‐genic recombination. ompA variants were not randomly distributed across the

A

.

baumannii

phylogeny, with the most frequent V1(lct)a1 allele found in most clonal complex 2 (CC2) strains and the second most frequent V2(lct)a1 allele in the majority of CC1 strains. Evidence was found for assortative exchanges of ompA alleles not only between separate

A

.

baumannii

lineages, but also different ACB species. The overall results have implications for

A. baumannii

evolution, epidemiology, virulence and vaccine design.
Evaluation ofin vitroactivity of manogepix against multidrug-resistant and pan-resistantCandida aurisfrom the New York Outbreak
Authors: Zhu YanChun , Kilburn Shannon , Kapoor Mili , Chaturvedi Sudha , Shaw Karen Joy , Chaturvedi Vishnu
Published: June 2020

An ongoingCandida aurisoutbreak in the New York metropolitan area is the largest recorded to date in North America. Laboratory surveillance revealed NYC. aurisisolates are resistant to fluconazole, with variable resistance to other currently used broad-spectrum antifungal drugs, and that several isolates are pan-resistant. Thus, there is an urgent need for new drugs with a novel mechanism of action to combat the resistance challenge. Manogepix (MGX) is a first-in-class agent that targets the fungal Gwt1 enzyme. The prodrug, fosmanogepix, is currently in Phase 2 clinical development for the treatment of fungal infections. We evaluated the susceptibility of 200 New YorkC. aurisisolates to MGX and 10 comparator drugs using CLSI methodology. MGX demonstrated lower MICs than comparators (MIC50and MIC900.03 mg/L; range 0.004-0.06 mg/L). The MGX epidemiological cutoff value (ECV, 99% cutoff) for the testedC. aurisisolates was 0.06 mg/L. MGX was 8-32-fold more active than the echinocandins, 16-64-fold more active than the azoles, and 64-fold more active than amphotericin B. No differences were found in the MGX or comparators’ MIC50, MIC90, or GEOMEAN values when subsets of clinical, surveillance, and environmental isolates were evaluated. The range of MGX MIC values for sixC. aurispan-resistant isolates was 0.008-0.015 mg/L, and the median and mode MIC values were 0.015 mg/L, demonstrating that MGX retains activity against these isolates. These data support further clinical evaluation of fosmanogepix for the treatment ofC. aurisinfections, including highly resistant isolates.
Development and Characterization of Patient-Derived Xenografts from Non-Small Cell Lung Cancer Brain Metastases
Authors: Baschnagel Andrew M. , Kaushik Saakshi , Durmaz Arda , Goldstein Steve , Ong Irene M. , Abel Lindsey , Clark Paul A. , Leal Ticiana , Buehler Darya , Iyer Gopal , Scott Jacob G. , Kimple Randall J.
Published: June 2020

Introduction

The purpose of this study was to establish and characterize a direct-from patient-derived xenograft (PDX) model of non-small cell lung cancer (NSCLC) brain metastases.

Methods

Surgically obtained tissue was implanted subcutaneously and as orthotopic intracranial implants into immunodeficient mice. Histology and DNA loci were compared between original tumor and subsequent PDX passages. Tumors underwent RNA and DNA sequencing and relevant therapeutic targets were identified. Tumor growth rates were assessed following treatment with radiation, MEK inhibitor selumetinib, or MET inhibitor savolitinib. Cell lines were established.

Results

Nine NSCLC brain metastases PDXs were established. Morphologically, strong retention of cytoarchitectural features was observed between original patient tumor and subcutaneous and intracranial tumors. Short tandem repeat analysis demonstrated strong concordance between patient tumors and subsequent PDX passages. Transcriptome and mutation analysis revealed high correlation between matched patient and PDX samples. Significant growth inhibition occurred with radiation, with selumetinib in tumors harboring KRAS G12C mutations and with savolitinib in a tumor with MET exon 14 skipping mutation. The combination of radiation and savolitinib resulted in significant tumor growth delay compared to radiation or savolitinib alone our MET exon 14 skipping mutation PDX. Early passage cell strains showed high consistency between patient and PDX tumors.

Conclusion

We have established a robust human xenograft model system for investigating NSCLC brain metastases. These PDXs and cell lines show strong phenotypic and molecular correlation with the original patient tumors and provide a valuable resource for testing preclinical therapeutics.
Macrophage-associated lipin-1 transcriptional co-regulatory activity is involved in atherosclerosis
Authors: Blackburn Cassidy M.R. , Schilke Robert M. , Vozenilek Aimee E. , Finck Brian N. , Woolard Matthew D.
Published: June 2020

During atherosclerosis, macrophages engulf and break down deposited modified low-density lipoproteins (modLDLs) into lipids and free fatty acids. The lipids and free fatty acids from these modLDLs either need to be stored during a process called glycerolipid synthesis or broken down during β-oxidation. In addition, free fatty acids can activate transcription factors to promote a pro-resolving macrophage phenotype. The protein lipin-1 is involved in both glycerolipid synthesis and β-oxidation. Lipin-1 enzymatic activity is a key step in the glycerolipid synthesis pathway; lipin-1 transcriptional co-regulatory activity either augments or represses various transcription factors that are activated via free fatty acids that promote β-oxidation and inhibit inflammation. Lipin-1 enzymatic activity increases pro-inflammatory macrophage phenotypes and is atherogenic. In contrast, we have also demonstrated that lipin-1 transcriptional co-regulatory activity promotes pro-resolving macrophage phenotypes leading us to the hypothesis that lipin-1 transcriptional co-regulatory activity is atheroprotective. Using a mouse model to delete lipin-1 in myeloid cells, we have demonstrated that loss of lipin-1 increases plaque size and pro-inflammatory gene expression. We have also shown mice lacking lipin-1 in myeloid cells have increased plaque collagen deposition and larger necrotic core formation. Combined, these data suggest that though lipin-1 enzymatic activity is atherogenic, lipin-1 transcriptional co-regulatory activity is atheroprotective. Overall, the results suggest that the dual activities of lipin-1 contribute to atherosclerosis progression in opposite ways.
Microfluidics-enabled 96-well perfusion system for high-throughput tissue engineering and long-term all-optical electrophysiology
Authors: Wei Lai , Li Weizhen , Entcheva Emilia , Li Zhenyu
Published: June 2020

This work demonstrates a novel high-throughput (HT) microfluidics-enabled uninterrupted perfusion system (HT-μUPS) and validates its use with chronic all-optical electrophysiology in human excitable cells. HT-μUPS consists of a soft multichannel microfluidic plate cover which could button on a commercial HT 96-well plate. Herein, we demonstrate the manufacturing process of the system and its usages in acute and chronic all-optical electrophysiological studies of human induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CM) and engineered excitable (Spiking HEK) cells. HT-μUPS perfusion maintained functional voltage and calcium responses in iPSC-CM and Spiking HEK cells under spontaneous conditions and under optogenetic pacing. Long-term culture with HT-μUPS improved cell viability and optogenetically-tracked calcium responses in Spiking HEK cells. The scalability and simplicity of this design and its compatibility with HT all-optical electrophysiology can empower cell-based assays for personalized medicine using patient-derived cells.
CaaX-like protease of cyanobacterial origin is required for complex plastid biogenesis in malaria parasites
Authors: Meister Thomas R. , Tang Yong , Pulkoski-Gross Michael J. , Yeh Ellen
Published: June 2020

Plasmodiumparasites and related apicomplexans contain an essential “complex plastid” organelle of secondary endosymbiotic origin, the apicoplast. Biogenesis of this complex plastid poses a unique challenge requiring evolution of new cellular machinery. We previously conducted a mutagenesis screen for essential apicoplast biogenesis genes to discover organellar pathways with evolutionary and biomedical significance. Here we validate and characterize a gene candidate from our screen, Pf3D7_0913500. Using a conditional knockdown strain, we show that Pf3D7_0913500 depletion causes growth inhibition that is rescued by the sole essential product of the apicoplast, isopentenyl pyrophosphate (IPP), and results in apicoplast loss. Because Pf3D7_0913500 had no previous functional annotation, we name itapicoplast-minus IPP-rescued 4 (AMR4). AMR4 has an annotated CaaX Protease and Bacteriocin Processing (CPBP) domain, which in eukaryotes typically indicates a role in CaaX post-prenylation processing. Indeed, AMR4 is the only CaaX-like protease inPlasmodiumparasites which are known to require protein prenylation, and we confirm that the conserved catalytic residue of AMR4 is required for its apicoplast function. However, we unexpectedly find that AMR4 does not act in a CaaX post-prenylation processing pathway inP. falciparum. Instead, we find that AMR4 is imported into the apicoplast and is derived from a cyanobacterial CPBP gene which was retained through both primary and secondary endosymbiosis. Our findings suggest that AMR4 is not a true CaaX protease, but instead acts in a conserved, uncharacterized chloroplast pathway that has been retained for complex plastid biogenesis.

Importance

Plasmodiumparasites, which cause malaria, and related apicomplexans are important human and veterinary pathogens. These parasites represent a highly divergent and understudied branch of eukaryotes, and as such often defy the expectations set by model organisms. One striking example of unique apicomplexan biology is the apicoplast, an essential but non-photosynthetic plastid derived from an unusual secondary (eukaryote-eukaryote) endosymbiosis. Endosymbioses are a major driver of cellular innovation, and apicoplast biogenesis pathways represent a hotspot for molecular evolution. We previously conducted an unbiased screen for apicoplast biogenesis genes inP. falciparumto uncover these essential and innovative pathways. Here, we validate a novel gene candidate from our screen and show that its role in apicoplast biogenesis does not match its functional annotation predicted by model eukaryotes. Our findings suggest that an uncharacterized chloroplast maintenance pathway has been reused for complex plastid biogenesis in this divergent branch of pathogens.