bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Frailty Scale Score Before ICU Admission Is Associated With Mobility Disability in Septic Patients Receiving Early Rehabilitation
Authors: Nakajima Hiroki , Nishikimi Mitsuaki , Shimizu Miho , Hayashi Kazuhiro , Inoue Takayuki , Nishida Kazuki , Takahashi Kunihiko , Matsui Shigeyuki , Nishida Yoshihiro , Matsuda Naoyuki
Published: December 2019

Objectives:

To clarify the relationship between mobility disability at the time of discharge from the ICU and clinical factors evaluated at ICU admission in septic patients.

Design:

A single-center, retrospective, observational study.

Setting:

Ten-bed, the emergency and medical ICU.

Patients:

We analyzed the data of septic patients who were admitted to our ICU between September 2012 and September 2016 and received early rehabilitation.

Interventions:

None.

Measurements and Main Results:

The patients were categorized into two groups based on their scores on the ICU mobility scale at the time of discharge from the ICU: the mobility disability group (ICU mobility scale score < 9) and the no mobility disability group (ICU mobility scale score ≥ 9). Of the 110 eligible patients, 63 met the inclusion criteria; of these, 46 patients (73%) were classified into the mobility disability group, and 17 patients (27%) were classified into the no mobility disability group. The age (median, 72 vs 64 yr; p = 0.024), prevalence of patients with clinical frailty scale scores of greater than or equal to 5 (54% vs 12%; p = 0.003), Sequential Organ Failure Assessment score (median, 9.0 vs 6.0; p = 0.006) and rate of vasopressin use (26% vs 0%; p = 0.026) were significantly higher in the mobility disability group as compared with the no mobility disability group. Among the candidate variables for which values recorded before/at the time of ICU admission were available, the clinical frailty scale score was identified as the only independent, statistically significant predictor of mobility disability at ICU discharge (odds ratio, 7.77; 95% CI, 1.37–44.21; p = 0.021). The positive predictive value and negative predictive value of clinical frailty scale scores greater than or equal to 5 for mobility disability at ICU discharge were 92.6% and 41.7%, respectively.

Conclusions:

The clinical frailty scale score was associated with increased mobility disability at ICU discharge in septic patients receiving early rehabilitation.
Updates in Cervical Cancer Treatment
Authors: HILL EMILY K.
Published: December 2019

Although rates of cervical cancer in the United States have been declining due to vaccination and screening efforts, it remains the fourth most common cancer in women worldwide and is still far from being eradicated, even in developed nations. This review discusses recent developments in cervical cancer treatment and reviews the literature supporting recent practice changes encompassing staging, surgical management, radiation, chemotherapy, targeted agents including immunotherapy, and imaging.
GENETIC RISK FACTORS IN SEVERE, NONSEVERE AND ACUTE PHENOTYPES OF CENTRAL SEROUS CHORIORETINOPATHY
Authors: Mohabati Danial , Schellevis Rosa L. , van Dijk Elon H. C. , Fauser Sascha , den Hollander Anneke I. , Hoyng Carel B. , De Jong Eiko K. , Yzer Suzanne , Boon Camiel J. F.
Published: December 2019

Purpose:

To study genetic predispositions and differences between severe chronic central serous chorioretinopathy (cCSC), nonsevere cCSC, and acute central serous chorioretinopathy (aCSC).

Methods:

One hundred seventy-three severe cCSC patients, 272 nonsevere cCSC patients, 135 aCSC patients, and 1,385 control individuals were included. Eight single-nucleotide polymorphisms were genotyped in the ARMS2 (rs10490924), CFH (rs800292, rs1061170, rs1065489, rs1329428, rs2284664, rs3753394), and NR3C2 (rs2070951). Additionally, C4B gene copy numbers were analyzed.

Results:

A significant association in 5 single-nucleotide polymorphisms in the CFH gene could be reproduced among severe cCSC patients, including rs800292 (P = 0.0014; odds ratio [OR] = 1.93; 95% confidence interval [CI] = 1.51–2.47), rs1065489 (P = 2.22 × 10−4; OR = 0.49; 95% CI = 0.34–0.72), rs1329428 (P = 0.001; OR = 1.89; 95% CI = 1.49–2.40), rs2284664 (P = 1.21× 10−4; OR = 1.65; 95% CI = 1.28–2.13), and rs3753394 (P = 6.10× 10−4; OR = 0.61; 95% CI = 0.46–0.81). Carrying three C4B copies was protective for severe cCSC (P = 0.001; OR = 0.29; 95% CI = 0.14–0.61). No significant differences in allele frequencies could be found among the CSC phenotypes.

Conclusion:

Acute CSC, nonsevere cCSC, and severe cCSC all showed a similar association with the CFH and C4B genes, and the three phenotypes could not be distinguished based on the genetics. This shows that despite the differences in clinical presentation and severity, there is an overlap in the genetic predisposition of different CSC phenotypes. Nongenetic factors may play a more important role in determining the clinical course of CSC.
Changing Epidemiology and Predisposing Factors for Invasive Pneumococcal Disease at Two Australian Tertiary Hospitals
Authors: Hernstadt Hayley , Cheung Abigail , Hurem Daniel , Vasilunas Nan , Phuong Linny Kimly , Quinn Patrick , Agrawal Rishi , Daley Andrew J. , Cole Theresa , Gwee Amanda
Published: December 2019

Background:

Invasive pneumococcal disease (IPD) is associated with significant morbidity and mortality in children. Universal pneumococcal conjugate vaccination has changed the epidemiology of IPD. In vaccinated children, IPD can be a marker of an underlying immunodeficiency.

Methods:

This is a retrospective audit of children younger than 18 years with IPD admitted to 2 tertiary pediatric hospitals in Australia between 2011 and 2017. Data on predisposing conditions, immunologic evaluation, pneumococcal serotype, antibiotic susceptibility and treatment were collected.

Results:

During the 7-year period, there were 131 presentations with IPD in 127 children; 3 children had recurrent IPD. Patients presented with sepsis (41%), empyema (29%), meningitis (18%), mastoiditis (12%), pneumonia (10%) and septic arthritis (4%). In 19 (15%) presentations, risk factors for IPD were present, including malignancy, hematologic disorder, chronic liver disease, chronic kidney disease and cochlear implant. Pneumococcal serotypes were determined in 78/131 (60%) of presentations: the most frequent serotypes were 19A (19%), 3 (13%), 7F (10%) and 19F (8%) and non-vaccine serotypes 22F (8%), 35B (6%), 15A (4%) and 38 (4%). Overall, 11% of isolates were non-susceptible to ceftriaxone. Only 36 patients (32%) had an immunologic evaluation, and 4 patients had proven or probable immunodeficiency.

Conclusion:

Although pneumococcal conjugate vaccine serotypes 19A, 3, 19F and 7F remain frequent causes of IPD, non-vaccine serotypes are emerging. Our data support vancomycin treatment for children with pneumococcal meningitis given 11% of our isolates were not susceptible to ceftriaxone. It is important to consider underlying conditions predisposing to IPD in a population with high rates of pneumococcal vaccination.
Concurrent Bacteremia Due to Non-vaccine Serotype 24F Pneumococcus in Twins: A Rapid Increase in Serotype 24F-invasive Pneumococcal Disease and its High Invasive Potential
Authors: Kawabata Toshiaki , Tenokuchi Yoichi , Yamakuchi Hiroki , Sameshima Hirotsugu , Katayama Hirosuke , Ota Takeshi , Tokunaga Masatomo , Takezaki Tomoko , Tamae Suehiro , Nakamura Toru , Chang Bin , Kodama Yuichi , Imuta Naoko , Ooka Tadasuke , Okamoto Yasuhiro , Suga Shigeru , Nishi Junichiro
Published: December 2019

Although concurrent bacteremia in siblings is rare, serotype 24F Streptococcus pneumoniae was isolated from the blood of twin 1-year-old girls within a 3-day interval, supporting the high invasive potential of this serotype. As the prevalence of childhood serotype 24F-invasive pneumococcal diseases increases in Europe and the Western Pacific Region, investigation and surveillance of this serotype are necessary.
Clinical Profile, Liver Dysfunction and Outcome of Dengue Infection in Children
Authors: Prasad Durga , Bhriguvanshi Arpita
Published: December 2019

Background:

Liver involvement in dengue illness is common and can lead to acute liver failure (ALF). No single method can effectively identify patients at risk for disease progression and bad outcome. We aimed to determine the relationship between liver dysfunction, kinetics of liver function tests (LFTs) and severity of hepatitis on the outcome in pediatric dengue illness.

Methods:

We conducted a prospective observational study of hospitalized children (1–12 years) with dengue infection (July 2014–July 2015). Serial monitoring of LFTs was done in confirmed dengue cases. Patients were classified into non-severe (NSD) and severe dengue (SD). Severity of hepatitis was graded: mild, moderate and severe hepatitis. Events were noted during hospitalization.

Results:

One hundred two children (66, boys), median age 72 (48–96) months, were analyzed (NSD, n = 41; SD, n = 61). Elevated transaminases (92%) was the most common abnormality; aspartate transaminase (AST) and alanine transaminase (ALT) in 87% and 82%, respectively. Maximum abnormalities in LFTs peaked at day 5 (AST, ALT) and day 7 (Alkaline Phosphatase [ALP], gamma-glutamyl transferase) of illness. Elevated transaminases was found to be higher in SD than NSD (100% vs. 80%, P = 0.006). Severe hepatitis developed organ dysfunction such as altered sensorium (P < 0.001), ALF (P < 0.001), acute kidney injury (P < 0.001) and shock (P < 0.001), more commonly than those with mild to moderate hepatitis. Fourteen patients died, two-thirds of whom had severe hepatitis (P < 0.001). Using binary logistic regression, presence of severe hepatitis and shock at presentation was an independent predictor for ALF (odds ratio: 77; 95% confidence interval : 13–457, P < 0.001) and mortality (odds ratio: 55; 95% confidence interval: 4.6–66, P < 0.001), respectively.

Conclusions:

Many children with dengue have liver involvement. Severe hepatitis in dengue is associated with significant organ dysfunction and poor outcome.
Low catechol-O-methyltransferase and stress potentiate functional pain and depressive behavior, especially in female mice
Authors: Zhang Xin , Kanter Katie , Chen Jiegen , Kim Seungtae , Wang Yaomin , Adeyemi Clementine , O'Buckley Sandra C. , Nackley Andrea G.
Published: December 2019

Low levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, and stress, which potentiates catecholamine release from sympathetic nerves, are fundamental to chronic functional pain syndromes and comorbid depression, which predominantly affect females. Here, we sought to examine the independent and joint contributions of low COMT and stress to chronic functional pain and depression at the behavioral and molecular level. Male and female C57BL/6 mice received sustained systemic delivery of the COMT inhibitor OR486 over 14 days and underwent a swim stress paradigm on days 8 to 10. Pain and depressive-like behavior were measured over 14 days, and brain-derived neurotrophic factor (BDNF; a factor involved in nociception and depression) and glucocorticoid receptor (GR; a stress-related receptor) expression were measured on day 14. We found that stress potentiates the effect of low COMT on functional pain and low COMT potentiates the effect of stress on depressive-like behavior. The joint effects of low COMT and stress on functional pain and depressive-like behavior were significantly greater in females vs males. Consistent with behavioral data, we found that stress potentiates COMT-dependent increases in spinal BDNF and low COMT potentiates stress-dependent decreases in hippocampal BDNF in females, but not males. Although low COMT increases spinal GR and stress increases hippocampal GR expression, these increases are not potentiated in the OR486 + stress group and are not sex-specific. These results suggest that genetic and environmental factors that enhance catecholamine bioavailability cause abnormalities in BDNF signaling and increase risk of comorbid functional pain and depression, especially among females.
Dexpramipexole blocks Nav1.8 sodium channels and provides analgesia in multiple nociceptive and neuropathic pain models
Authors: Urru Matteo , Muzzi Mirko , Coppi Elisabetta , Ranieri Giuseppe , Buonvicino Daniela , Camaioni Emidio , Coppini Raffaele , Pugliese Anna Maria , Tanaka Brian , Estacion Mark , Waxman Stephen G. , Dib-Hajj Sulayman D. , Chiarugi Alberto
Published: December 2019

Selective targeting of sodium channel subtypes Nav1.7, Nav1.8, and Nav1.9, preferentially expressed by peripheral nociceptors, represents a unique opportunity to develop analgesics devoid of central side effects. Several compounds that target Nav1.7 and Nav1.8 with different degrees of selectivity have been developed and are currently being tested in clinical trials for multiple pain indications. Among these chemicals, benzothiazole-like compounds emerged as potent sodium channel blockers. We evaluated the effects of dexpramipexole, a benzothiazole-bearing drug with pleiotypic neuroactive properties and a good safety profile in humans, on sodium conductances of dorsal root ganglia neurons, as well as in multiple nociceptive and neuropathic pain models. Dexpramipexole blocks TTX-resistant sodium conductances in cultured rat dorsal root ganglion neurons with an IC50 of 294.4 nM, suggesting selectivity towards Nav1.8. In keeping with this, dexpramipexole does not affect sodium currents in dorsal root ganglion neurons from Nav1.8 null mice and acquires binding pose predicted to overlap that of the Nav1.8 channel-selective blocker A-8034637. The drug provides analgesia when parenterally, orally, or topically applied in inflammatory and visceral mouse pain models, as well as in mice affected by neuropathic pain induced by oxaliplatin, nerve constriction, or diabetes. Pain reduction in mice occurs at doses consistent with those adopted in clinical trials. The present findings confirm the relevance of selective targeting of peripheral Nav1.8 channels to pain therapy. In light of the excellent tolerability of dexpramipexole in humans, our results support its translational potential for treatment of pain.
Correlates and motivations of prescription opioid use among adolescents 12 to 17 years of age in the United States
Authors: Groenewald Cornelius B. , Patel Kushang V. , Rabbitts Jennifer A. , Palermo Tonya M.
Published: December 2019

Despite significant efforts, the opioid crisis remains a pressing health concern affecting adolescents. The primary aim of this study was to describe recent sociodemographic shifts in the opioid epidemic. We examined whether rates of opioid use, including opioid misuse and opioid use disorder among 12 to 17 year olds in the United States, differ according to sociodemographic factors, physical and mental health, and substance use characteristics using data from the 2015 and 2016 National Survey on Drug Use and Health. We also examined motivations for opioid misuse. The study included 27,857 participants. Black, non-Hispanic adolescents were more likely to both use and misuse opioids as compared to white, non-Hispanic adolescents, a clear difference from previous studies. The main motivation for misuse by adolescents was relief of physical pain (50%, 95% confidence interval 46%-54%). Adolescents who reported pain relief as the major reason for misuse had increased odds of substance use as compared to adolescents who did not report any opioid misuse. However, odds for substance use was greatest among adolescents who reported reasons other than pain relief for opioid misuse. National Survey on Drug Use and Health self-report data suggest recent shifts in opioid misuse with minority adolescents appearing to be at increased risk of opioid misuse compared with white adolescents. Relief of physical pain is the most common motivation for opioid misuse.
Patient self-inflicted lung injury and positive end-expiratory pressure for safe spontaneous breathing
Authors: Yoshida Takeshi , Grieco Domenico L. , Brochard Laurent , Fujino Yuji
Published: December 2019

Purpose of review

The potential risks of spontaneous effort and their prevention during mechanical ventilation is an important concept for clinicians and patients. The effort-dependent lung injury has been termed ‘patient self-inflicted lung injury (P-SILI)’ in 2017. As one of the potential strategies to render spontaneous effort less injurious in severe acute respiratory distress syndrome (ARDS), the role of positive end-expiratory pressure (PEEP) is now discussed.

Recent findings

Experimental and clinical data indicate that vigorous spontaneous effort may worsen lung injury, whereas, at the same time, the intensity of spontaneous effort seems difficult to control when lung injury is severe. Experimental studies found that higher PEEP strategy can be effective to reduce lung injury from spontaneous effort while maintaining some muscle activity. The recent clinical trial to reevaluate systemic early neuromuscular blockade in moderate–severe ARDS (i.e., reevaluation of systemic early neuromuscular blockade (ROSE) trial) support that a higher PEEP strategy can facilitate ‘safe’ spontaneous breathing under the light sedation targets (i.e., no increase in barotrauma nor 90 days mortality versus early muscle paralysis).

To prevent P-SILI in ARDS, it seems feasible to facilitate ‘safe’ spontaneous breathing in patients using a higher PEEP strategy in severe ARDS.
Prader Willi syndrome: endocrine updates and new medical therapies
Authors: Harris Rebecca M. , Stafford Diane E.J.
Published: December 2019

Purpose of review

Prader Willi syndrome is characterized not only by hyperphagia frequently resulting in obesity, but also by endocrine dysfunction across a variety of axes. This article reviews the most recent literature regarding possible causes of hyperphagia and the nature of endocrinopathies seen in Prader Willi syndrome, as well as current research into possible therapies.

Recent findings

Investigation into neurologic, metabolic and hormonal drivers of hyperphagia and obesity has revealed new insights and clarified underlying pathophysiology. Additional studies continue to elucidate the hormonal deficiencies seen in the syndrome, allowing for improvements in clinical care.

The underlying causes of the hyperphagia and progressive obesity frequently seen in Prader Willi Syndrome are largely unknown and likely multifactorial. Understanding the hormonal and metabolic drivers at work in PWS, as well as the nature of other hormonal dysfunction seen in the syndrome is necessary to guide current management and future research directions.
Novel insights into the pathobiology of humoral alloimmune memory in kidney transplantation
Authors: Torija Alba , Favà Alex , Meneghini Maria , Crespo Elena , Bestard Oriol
Published: December 2019

Purpose of review

Humoral alloimmunity against human leukocyte antigen (HLA) antigens is the main barrier for successful transplantation. Recent researches have shown that this complex effector immune mechanism is driven by a number of B-cell subsets, which can orchestrate in a perfect and synergistic multistep manner the rejection of the organ transplant. Herein, our purpose is to review the immunobiology of humoral response and discuss novel therapeutic strategies derived from this evidence.

Recent findings

Among the distinct cellular components of the humoral alloimmune system, memory B cells (mBC) have been shown to play a key role initiating and maintaining the antidonor humoral alloimmune response, thus its assessment apart from monitoring donor (HLA)-specific antibodies (DSA) in the sera may improve the understanding of the alloimmune status of transplant patients at different time points. Furthermore, targeting alloreactive mBC as well as other B and T-cell counterparts have highlighted for the first time, that novel therapeutic strategies with a more mechanistic rationale are highly warranted for achieving an effective anti-HLA humoral alloimmune control, also in human kidney transplantation.

The complex mechanisms of humoral allorecognitition in transplantation seem to be progressively better understood with the implementation of novel immune technologies. This new insight should serve for the development of novel immunosuppressive strategies to achieve an optimal humoral alloimmune regulation.
Genetic background and transplantation outcomes: insights from genome-wide association studies
Authors: Zanoni Francesca , Kiryluk Krzysztof
Published: December 2019

Purpose of review

The current review summarizes recent advances in the genetic studies of transplantation outcomes, including new genome-wide association studies for acute rejection, allograft survival, pharmacogenomics, and common transplant comorbidities.

Recent findings

Genetic studies of kidney transplantation outcomes have begun to address the question of genetic compatibility beyond human leukocyte antigens, including the role of genome-wide mismatches in missense variants, and the ‘genomic collision’ hypothesis under which the risk of rejection may be increased in recipients homozygous for loss-of-function variants with grafts from nonhomozygous donors. In recent pilot studies, missense mismatch scores for transmembrane and secreted proteins were associated with antibodies against the mismatched peptides and reduced allograft survival. A ‘genomic collision’ at the LIMS1 locus involving a common deletion near LIMS1 gene was associated with anti-LIMS1 antibody response and increased risk of rejection. Additional genetic factors under active investigation include genome-wide polygenic risk scores for renal function and apolipoprotein L1 risk genotypes in African-American kidney donors. Due to the heterogeneity and complexity of clinical outcomes, new genome-wide association studies for rejection, allograft survival, and specific transplant comorbidities will require larger multicenter meta-analyses.

Genetic compatibilities between donor and recipient represent an important determinant of rejection and long-term allograft survival. Genetic background of transplant donors may be additionally predictive of allograft function, while recipient's genomes are likely determinant of a wide range of transplantation outcomes, from rejection susceptibility to pharmacogenetics and various comorbidities related to prolonged immunosuppression.
Deceased donor kidney allocation schemes and international exchange
Authors: Heemann Uwe , Oberbauer Rainer , Sprangers Ben , Gökalp Cenk , Bemelman Frederike
Published: December 2019

Purpose of review

In this review, we summarize different allocation schemes around the world and identify ways to exchange organs between countries.

Recent findings

The primary goal of transplantation is prolongation of patient survival and an improved quality of life. Most allocation systems try to match the potential survival of the organ with the life expectancy of its recipient. Kidney transplantation enables cost reductions by the avoidance of dialysis for the healthcare system, which is sometimes the driving force for state interventions to enhance donor recruitment

The major benefit from international exchange is the possibility to transplant highly sensitized patients or patients with rare HLA allele.

In a broad international exchange system, there are three possibilities: exchange of surplus organs, exchange of organs to support patients with a potentially excessive waiting time because of HLA antibodies or rare alleles, and exchange of organs to make the best possible match between donor and recipient.

It is possible to shape a hierarchical allocation scheme, which could be applicable in the majority of populations despite different geographical and socioeconomic conditions: allocation to recipients with special requirements (high-urgency, highly sensitized); identification of a within the region/country; in case no suitable recipient can be identified, offer countrywide or between countries; for every organ transferred to another country, there must be an obligation to give one back.
Relationship of School-Based Physical Therapy Services to Student Goal Achievement
Authors: Chiarello Lisa A. , Effgen Susan K. , Jeffries Lynn M. , McCoy Sarah Westcott , Tezanos Alejandro G. Villasante
Published: December 2019

Purpose:

To explore the relationships of school-based physical therapy services to student goal achievement.

Methods:

One hundred nine physical therapists and 296 students participated in a practice-based study. Therapists formatted goals using goal attainment scaling and evaluated goal achievement. Using the School-Physical Therapy Interventions for Pediatrics system, therapists documented services weekly for 20 weeks. Group comparisons and logistic regressions were conducted.

Results:

For primary goals, no documented physical therapy services were associated with exceeding goal expectation. For posture/mobility goals, more minutes in self-care activities and services on behalf of the students were associated with exceeding goal expectation; use of cognitive and behavioral training interventions was associated with not exceeding goal expectation (P < .05). For recreation/fitness goals, greater use of functional strength and mobility for playground access and cognitive/behavioral interventions were associated with exceeding goal expectation (P < .05).

Conclusion:

A limited number of physical therapy services was associated with exceeding goal expectation.
Validity of General Movement Assessment Based on Clinical and Home Videos
Authors: Yeh Kuo-Kuang , Liu Wen-Yu , Wong Alice May-Kuen , Lein Reyin
Published: December 2019

Introduction:

The purposes of this study were to develop an instructional leaflet on home video recording for the General Movement Assessment (GMA) and to examine the concurrent and predictive validity of the GMA completed by physical therapists (PTs) and completed by parents.

Methods:

The GMA and the Alberta Infant Motor Scale (AIMS) were completed by PTs in the clinic. Parents completed the GMA following the instructional leaflet.

Results:

The content validity of the leaflet was 0.83. The consistency of the GMA results between sources was κ = 0.869. The concurrent validity of the GMA at a corrected age of 3 months was κ = 0.266 (PT) versus 0.525 (parent) using the 10th-percentile cutoffs of the AIMS. The positive likelihood ratio was 26 (PT) versus 25 (parents) at a corrected age of 12 months based on 5th-percentile cutoffs of the AIMS.

Conclusions:

Home GMA videos are valid for clinical assessment following the instructional leaflet.
An Institutional Approach to the Management of Asymptomatic Chorioamnionitis-Exposed Infants Born ≥35 Weeks Gestation
Authors: Chiruvolu Arpitha , Petrey Barbara , Stanzo Karen C. , Daoud Yahya
Published: December 2019

Introduction:

Our newborn practice routinely treated asymptomatic chorioamnionitis-exposed infants born at 35 weeks gestation or greater with empiric antibiotics. Starting April 1, 2017, we implemented an algorithm of not treating, unless there was an abnormal clinical and/or laboratory evaluation. The goal of this quality improvement initiative was to reduce the percentage of chorioamnionitis-exposed infants treated with antibiotics (primary outcome measure) to <50%.

Methods:

We compared 123 chorioamnionitis-exposed infants born 1 year before implementation (pre-algorithm group, April 1, 2016, to March 31, 2017) with 111 born 1 year following implementation (post-algorithm group, April 1, 2017, to March 31, 2018). The primary outcome measure was analyzed monthly using a run chart.

Results:

The maternal and neonatal characteristics were similar between both groups. Significantly fewer infants in the post-algorithm group received antibiotics compared with the pre-algorithm group (4.5% versus 96.8%; P < 0.01). There were no differences in median hospital length of stay or incidence of neonatal intensive care unit admissions between both groups. There were no positive blood cultures or readmissions within 7 days for early-onset sepsis in either group.

Conclusion:

An institutional approach of monitoring chorioamnionitis-exposed infants with a clinical and laboratory evaluation decreased antibiotic utilization in the mother-baby unit by 95% without an increase in hospital length of stay, neonatal intensive care unit admissions, or readmissions for early-onset sepsis.
Carbapenem use in critically ill patients
Authors: Patrier Juliette , Timsit Jean-François
Published: December 2019

Purpose of review

To review available data on carbapenem use in ICU. Carbapenem is a broad spectrum well tolerated antibiotic family that keep an excellent activity to extended spectrum β-lactamases and AmpC hyperproducer and in susceptible Pseudomonas aeruginosa and Acinetobacter baumannii. It becomes a drug of choice for empirical therapy of suspected sepsis in known or presumably known ESBLE carriers.

Recent findings

Carbapenems remained the drug of choice for severe ESBLE infections. In severe critically ill patients, high off-label dose is necessary especially in patients with sepsis and glomerular hyperfiltration. Nevertheless, large spectrum of carbapenems leads to initial overuse. The increase in the overall consumption in the past years with lack of systematic re-evaluation observed is responsible of and carbapenem-selection pressure that contribute to the increase of carbapenem-resistant enterobacteriaceae, A. Baumannii and P. Aeruginosa in ICUs.

Carbapenems remained a cornerstone of antibiotic therapy of severe infections. Emerging carbapenem resistance is related to the increase of carbapenem consumption. High doses are recommended for early therapy followed by systematic reevaluation on a daily basis with shift to narrow spectrum antimicrobials if possible and early stopping rules.
Poor Outcomes in Kidney Transplant Candidates and Recipients With History of Falls
Authors: Chu Nadia M. , Shi Zhan , Berkowitz Rachel , Haugen Christine E. , Garonzik-Wang Jacqueline , Norman Silas P. , Humbyrd Casey , Segev Dorry L. , McAdams-DeMarco Mara A.
Published: December 2019

Background.

Falls occur in 28% of hemodialysis patients and increase the risk of physical impairment, morbidity, and mortality. Therefore, it is likely that kidney transplantation (KT) candidates with recurrent falls are less likely to access KT and more likely to experience adverse post-KT outcomes.

Methods.

We used a 2-center cohort study of KT candidates (n = 3666) and recipients (n = 770) (January 2009 to January 2018). Among candidates, we estimated time to listing, waitlist mortality, and transplant rate by recurrent falls (≥2 falls) before evaluation using adjusted regression. Among KT recipients, we estimated risk of mortality, graft loss, and length of stay by recurrent falls before KT using adjusted regression.

Results.

Candidates with recurrent falls (6.5%) had a lower chance of listing (adjusted hazard ratio [aHR] = 0.68, 95% confidence interval [CI], 0.56-0.83) but not transplant rate; waitlist mortality was 31-fold (95% CI, 11.33-85.93) higher in the first year and gradually decreased over time. Recipients with recurrent falls (5.1%) were at increased risk of mortality (aHR = 51.43, 95% CI, 16.00-165.43) and graft loss (aHR = 33.57, 95% CI, 11.25-100.21) in the first year, which declined over time, and a longer length of stay (adjusted relative ratio [aRR] = 1.13, 95% CI, 1.03-1.25). In summary, 6.5% of KT candidates and 5.1% of recipients experienced recurrent falls which were associated with adverse pre- and post-KT outcomes.

Conclusions.

While recurrent falls were relatively rare in KT candidates and recipients, they were associated with adverse outcomes. Transplant centers should consider employing fall prevention strategies for high-risk candidates as part of comprehensive prehabilitation.
Outcomes After Declining a Steatotic Donor Liver for Liver Transplant Candidates in the United States
Authors: Jackson Kyle R. , Bowring Mary G. , Holscher Courtenay , Haugen Christine E. , Long Jane J. , Liyanage Luckmini , Massie Allan B. , Ottmann Shane , Philosophe Benjamin , Cameron Andrew M. , Segev Dorry L. , Garonzik-Wang Jacqueline
Published: December 2019

Background.

Steatotic donor livers (SDLs, ≥30% macrosteatosis on biopsy) are often declined, as they are associated with a higher risk of graft loss, even though candidates may wait an indefinite time for a subsequent organ offer. We sought to quantify outcomes for transplant candidates who declined or accepted an SDL offer.

Methods.

We used Scientific Registry of Transplant Recipients offer data from 2009 to 2015 to compare outcomes of 759 candidates who accepted an SDL to 13 362 matched controls who declined and followed candidates from the date of decision (decline or accept) until death or end of study period. We used a competing risk framework to understand the natural history of candidates who declined and Cox regression to compare postdecision survival after declining versus accepting (ie, what could have happened if candidates who declined had instead accepted).

Results.

Among those who declined an SDL, only 53.1% of candidates were subsequently transplanted, 23.8% died, and 19.4% were removed from the waitlist. Candidates who accepted had a brief perioperative risk period within the first month posttransplant (adjusted hazard ratio [aHR]:2.493.494.89,P< 0.001), but a 62% lower mortality risk (aHR:0.310.380.46,P< 0.001) beyond this. Although the long-term survival benefit of acceptance did not vary by candidate model for end-stage liver disease (MELD), the short-term risk period did. MELD 6–21 candidates who accepted an SDL had a 7.88-fold higher mortality risk (aHR:4.807.8812.93,P< 0.001) in the first month posttransplant, whereas MELD 35–40 candidates had a 68% lower mortality risk (aHR:0.110.320.90,P= 0.03).

Conclusions.

Appropriately selected SDLs can decrease wait time and provide substantial long-term survival benefit for liver transplant candidates.
A Practical Guide to the Clinical Implementation of Biomarkers for Subclinical Rejection Following Kidney Transplantation
Authors: Naesens Maarten , Friedewald John , Mas Valeria , Kaplan Bruce , Abecassis Michael M.
Published: December 2019

Noninvasive biomarkers are needed to monitor stable patients following kidney transplantation (KT), as subclinical rejection, currently detectable only with invasive surveillance biopsies, can lead to chronic rejection and graft loss. Several biomarkers have recently been developed to detect rejection in KT recipients, using different technologies as well as varying clinical monitoring strategies defined as “context of use (COU).” The various metrics utilized to evaluate the performance of each biomarker can also vary, depending on their intended COU. As the use of molecular biomarkers in transplantation represents a new era in patient management, it is important for clinicians to better understand the process by which the incremental value of each biomarkers is evaluated to determine its potential role in clinical practice. This process includes but is not limited to an assessment of clinical validity and utility, but to define these, the clinician must first appreciate the trajectory of a biomarker from bench to bedside as well as the regulatory and other requirements needed to navigate this course successfully. This overview summarizes this process, providing a framework that can be used by clinicians as a practical guide in general, and more specifically in the context of subclinical rejection following KT. In addition, we have reviewed available as well as promising biomarkers for this purpose in terms of the clinical need, COU, assessment of biomarker performance relevant to both the need and COU, assessment of biomarker benefits and risks relevant to the COU, and the evidentiary criteria of the biomarker relevant to the COU compared with the current standard of care. We also provide an insight into the path required to make biomarkers commercially available once they have been developed and validated so that they used by clinicians outside the research context in every day clinical practice.
Reverse-Engineering the Cortical Architecture for Controlled Semantic Cognition
Authors: Jackson Rebecca L. , Rogers Timothy T. , Lambon Ralph Matthew A.
Published: December 2019

We present a ‘reverse engineering’ approach to deconstruct cognition into neurocomputational mechanisms and their underlying cortical architecture, using controlled semantic cognition as a test case. By systematically varying the structure of a computational model and assessing the functional consequences, we identified architectural properties necessary for generating the core functions of the semantic system. Semantic cognition presents a challenging test case as the brain must achieve two seemingly contradictory functions: abstracting context-invariant conceptual representations across time and modalities, whilst producing specific context-sensitive behaviours appropriate for the immediate task. These functions were best achieved in models possessing a single, deep multimodal hub with sparse connections from modality-specific inputs, and control systems acting on peripheral rather than deep network layers. These architectural features correspond well with those suggested by neural data, strongly supporting the efficacy of the reverse engineering approach, and further generating novel hypotheses about the neuroanatomy of controlled semantic cognition.
Prostate Specific Membrane Antigen expression in the vasculature of primary lung carcinomas associates with faster metastatic dissemination to brain
Authors: Ramanathan Jayendrakishore Tanjore , Lehtipuro Suvi , Sihto Harri , Tóvári József , Reiniger Lilla , Téglási Vanda , Moldvay Judit , Nykter Matti , Haapasalo Hannu , Joncour Vadim Le , Laakkonen Pirjo
Published: December 2019

Glioblastomas and brain metastases (BM) of solid tumors are the most common central nervous system neoplasms associated with very unfavorable prognosis. In this study, we report the association of Prostate Specific Membrane Antigen with various clinical parameters in a large cohort of primary and secondary brain tumors. A tissue micro array containing 371 cases of ascending grade gliomas pertaining to astrocytic origin, samples of 52 cases of primary lung carcinomas with matching brain metastases with follow-up time accounting to 10.4 years was evaluated for PSMA expression using immunohistochemistry. In addition, PSMA expression was studied in brain metastases arising from melanomas and breast carcinomas. Neovascular expression of PSMA was evident alongside with high expression in the proliferating microvasculature of glioblastomas when compared to the tumor cell expression. This result corroborated with the results obtained from thein silico(cancer genome databases) analyses. In the matched primary lung cancers and their brain metastases (n = 52), vascular PSMA expression in primary tumors led to significantly accelerated metastatic dissemination to the brain with a tendency towards poor overall survival. Taken together, we report the vascular expression of PSMA in the primary and secondary brain tumors that globally associates with the malignant progression and poor outcome of the patients.
Elucidation of the determinant for orchestration of solo unisexual cycle in an important human fungal pathogen
Authors: Hu Pengjie , Liu Huimin , Chen Lei , He Guang-Jun , Tian Xiuyun , Yao Xiaoxia , Zhao Tong , Li Chunli , Tao Changyu , Yang Ence , Wang Linqi
Published: December 2019

In fungi, the sex-determination program universally directs sexual development and syngamy (the fusion of gametes) that underlies pre-meiotic diploidization. However, the contribution of sex-determination to syngamy-independent sexual cycle, which requires autopolyploidization as an alternative approach to elevate ploidy before meiosis, remains unclear in fungi and other eukaryotes. The human fungal pathogenCryptococcus neoformans, as a model organism for studying fungal sexual reproduction, can undergo syngamy-dependent bisexual and syngamy-independent solo unisexual reproduction, in which endoreplication is considered to enable pre-meiotic self-diploidization. Here, by characterizing a mutant lacking all the core sex-determination factors, we show that sex-determination plays a central role in bisexual syngamy but is not strictly required for unisexual development and self-diploidization. This implies an unknown circuit, rather than the sex-determination program, for specifically coordinatingCryptococcusunisexual cycle. We reveal that syngamy and self-diploidization are both governed by the Qsp1-directed paracrine system via two regulatory branches, Vea2 and Cqs2. Vea2 directs bisexual syngamy through the sex-determination program; conversely, Cqs2 is dispensable for bisexual syngamy but activates unisexual endoreplication. Through functional profiling of 41 transcription factors documented to regulateCryptococcussexual development, we reveal that only Cqs2 can drive and integrate all unisexual phases and ensure the production of meiospore progenies. Furthermore, ChIP-seq analysis together with genetic evaluation indicate that Cqs2 induces unisexual self-diploidization through its direct control ofPUM1, whose expression is sufficient to drive autopolyploidization. Therefore, Cqs2 serves as the critical determinant that orchestratesCryptococcusmultistage unisexual cycle that does not strictly require the sexual-determination program.
Chances and challenges of machine learning based disease classification in genetic association studies illustrated on age-related macular degeneration
Authors: Günther Felix , Brandl Caroline , Winkler Thomas W. , Wanner Veronika , Stark Klaus , Küchenhoff Helmut , Heid Iris M.
Published: December 2019

Imaging technology and machine learning algorithms for disease classification set the stage for high-throughput phenotyping and promising new avenues for genome-wide association studies (GWAS). Despite emerging algorithms, there has been no successful application in GWAS so far. We established machine learning based disease classification in genetic association analysis as a misclassification problem. To evaluate chances and challenges, we performed a GWAS based on automated classification of age-related macular degeneration (AMD) in UK Biobank (images from 135,500 eyes; 68,400 persons). We quantified misclassification of automatically derived AMD in internal validation data (images from 4,001 eyes; 2,013 persons) and developed a maximum likelihood approach (MLA) to account for it when estimating genetic association. We demonstrate that our MLA guards against bias and artefacts in simulation studies. By combining a GWAS on automatically derived AMD classification and our MLA in UK Biobank data, we were able to dissect true association (ARMS2/HTRA1, CFH) from artefacts (nearHERC2) and to identify eye color as relevant source of misclassification. On this example of AMD, we are able to provide a proof-of-concept that a GWAS using machine learning derived disease classification yields relevant results and that misclassification needs to be considered in the analysis. These findings generalize to other phenotypes and also emphasize the utility of genetic data for understanding misclassification structure of machine learning algorithms.
Worldwide recombination in emergent white-nose syndrome pathogenPseudogymnoascus destructans
Authors: Sharma Lav , Sousa Márcia , Faria Ana S. , Nunes-Pereira Margarida , Cabral João A. , Phillips Alan J. L. , Marques Guilhermina , Paiva-Cardoso Maria das Neves
Published: December 2019

Pseudogymnoascus destructans(Pd), the emergent fungus causing bat “White-Nose Syndrome”, responsible for ∼6 million mortalities in the United States (US), is thought to expand clonally in North America and Europe. Presence of distinct mating-types in Europe led to numerous research attempts searching for population sexuality worldwide. This study not only presents the first evidence of genetic recombination in Pd but also detects recombination in Pd genotype data generated by previous studies in Europe and North America, through clone-corrected linkage disequilibrium analysis. Portuguese and other European populations are apparently reproducing through sex between two mating-types. Seeming parasexual recombination in the invasive single mating-type US population rings alarms for the North American bat populations and deserves urgent attention. This study emphasizes on clone-correction in linkage disequilibrium analysis.

One Sentence Summary

Clone-correction yielded signs of elusive recombination in the global “clonal” populations of white-nose syndrome pathogen.
An implicit memory of errors limits human sensorimotor adaptation
Authors: Albert Scott T. , Jang Jihoon , Sheahan Hannah , Teunissen Lonneke , Vandevoorde Koenraad , Shadmehr Reza
Published: December 2019

After extended practice, motor adaptation reaches a limit in which learning appears to stop, despite the fact that residual errors persist. What prevents the brain from eliminating the residual errors? Here we found that the adaptation limit was causally dependent on the second order statistics of the perturbation; when variance was high, learning was impaired and large residual errors persisted. However, when learning relied solely on explicit strategy, both the adaptation limit and its dependence on perturbation variability disappeared. In contrast, when learning depended entirely, or in part on implicit learning, residual errors developed. Residual errors in implicit performance were caused by variance-dependent modifications to error sensitivity, not forgetting. These observations are consisted with a model of learning in which the implicit system becomes more sensitive to error when errors are consistent, but forgets this memory of errors over time. Thus, residual errors in motor adaptation are a signature of the implicit learning system, caused by an error sensitivity that depends on the history of past errors.
The connectome of theCaenorhabditis eleganspharynx
Authors: Cook Steven J. , Crouse Charles M. , Yemini Eviatar , Hall David H. , Emmons Scott W. , Hobert Oliver
Published: December 2019

Detailed anatomical maps of individual organs and entire animals have served as invaluable entry points for ensuing dissection of their evolution, development, and function. The pharynx of the nematodeCaenorhabditis elegansis a simple neuromuscular organ with a self-contained, autonomously acting nervous system, composed of 20 neurons that fall into 14 anatomically distinct types. Using serial EM reconstruction, we re-evaluate here the connectome of the pharyngeal nervous system, providing a novel and more detailed view of its structure and predicted function. Contrasting the previous classification of pharyngeal neurons into distinct inter- and motorneuron classes, we provide evidence that most pharyngeal neurons are also likely sensory neurons and most, if not all, pharyngeal neurons also classify as motorneurons. Together with the extensive cross-connectivity among pharyngeal neurons, which is more widespread than previously realized, the sensory-motor characteristics of most neurons define a shallow network architecture of the pharyngeal connectome. Network analysis reveals that the patterns of neuronal connections are organized into putative computational modules that reflect the known functional domains of the pharynx. Compared to the somatic nervous system, pharyngeal neurons both physically associate with a larger fraction of their neighbors and create synapses with a greater proportion of their neighbors. We speculate that the overall architecture of the pharyngeal nervous system may be reminiscent of the architecture of ancestral, primitive nervous systems.