bluuebunny/crossref_metadata_2025 huggingface dataset:
Paucity of Clinical Practice Guidelines for the Rehabilitation of Burn Survivors
Authors: Gerber Lynn H. , Deshpande Rati , Prabhakar Shruthi , Cai Cindy , Garfinkel Steven , Pomeroy J. Mary Louise , Esselman Peter , Schneider Jeffrey
Published: April 2020

Clinical practice guidelines (CPGs) provide an efficient route from research to practice because they follow a prescribed, vetted process for evidence collection. CPGs offer underserved fields, such as burn rehabilitation, an accessible approach to reliable treatment. A literature search was performed using the terms “Burns AND CPGs AND Rehabilitation.” Three reviewers determined whether guideline development followed an established vetting process. “Rehabilitation” required evidence of treatment to improve, maintain, or restore human function and provide treatment to facilitate recovery. Only 160 articles were obtained and, after adding the term “functional outcome,” 62 remained for full-text review, of which 21 were eligible. When articles were scored for inclusion of both rehabilitation AND function or functional outcome AND guideline vetting, seven articles remained. One was community based. Nine articles had no recorded vetting process but addressed rehabilitation as an outcome. There is a paucity of CPGs relevant to clinical rehabilitation for burn survivors, likely a result of very few published intervention trials, rare randomized controlled trials addressing rehabilitation, absence of data to establish an evidence base for practice recommendations, an inadequate number of community-based intervention trials, and little patient input. It is likely that rehabilitation of burn survivors will improve if more people gain skills in meeting the needs of people with burn injury. An increase in trained professionals may lead to an increase in intervention trials and research to establish evidence for CPGs. People engaged in burn research have an opportunity to devise a systematic, generally agreed-upon approach toward evaluating burn patients and treatment outcomes that will permit data sharing across the world and assess patients throughout the acute and chronic phases of burn injury.
Incidental CT Findings Suspicious for COVID-19–Associated Pneumonia on Nuclear Medicine Examinations
Authors: Tulchinsky Mark , Fotos Joseph S. , Slonimsky Einat
Published: April 2020

Some patients undergoing routine SPECT/CT and PET/CT examinations during the COVID-19 pandemic may incidentally reveal findings of COVID-19–associated pneumonia (C-19AP) on localizing CT. It is critical for nuclear medicine physicians to develop diagnostic skills for timely recognition of typical findings of C-19AP on a localizing CT. Furthermore, it is our responsibility to know the optimal practices for safely isolating and managing such patients while protecting the staff, other patients at the facility, family and/or friend accompanying the patients, and the public in general from risky exposure to COVID-19 sources. We offer several steps following an encounter suspicious of C-19AP.
Open Reduction and Internal Fixation and Intraoperative Exploration of the Superior Retinacular Arterial System in Young Adults Garden III Femoral Neck Fracture: A 10 Case Report
Authors: Wang Zihua , Gu Luosha , Cheng Liangliang
Published: April 2020

At present, there is no uniform standard for the treatment of femoral neck fractures (FNFs) in young adults, and the current strategy is inclined to the native hip joint preservation. Femoral neck fractures in young adult are mostly caused by high-energy violence, and the blood supply of femoral head is severely damaged, which is prone to secondary femoral head avascular necrosis. In this article, we report 10 cases of young adult Garden III FNF treated with open reduction and internal fixation (ORIF) and microsurgical exploration of the superior retinacular vessels from 2015 to 2018, to more intuitively understand the involvement of superior retinacular vessels after displaced FNF in young adults. The results show that the SRA injury of Garden III FNF could be categorized into 3 types (type A–C), type A (6/10): the SRA vessels were kept intact, while they were pulled or compressed by displaced fracture fragment and could be revascularized by reduction; type B (3/10): the SRA vessels were avulsed with the superior retinaculum attachment avulsion fracture and could not be revascularized by reduction; and type C (1/10): the SRA vessels were ruptured, and the remnant of the vessel is present, which can be revascularized by vascular anastomosis. The previously mentioned results showed that the vascular damage of femoral head in Garden III FNF is quite complicated and might have the potential for being further classified into several subtypes.
Rotation Flaps in Series: Simple Innovation for Complex Scalp Defects
Authors: Sharma Ramesh K. , Sharma Raman
Published: April 2020

A 42-year-old man presented with 2 full thickness defects in left parieto-temporal and right temporo-occipital regions with normal intervening scalp tissue. These 2 adjacent but discontinuous defects were covered in one stage with an innovative rotation flap design that provided 1 flap each for these 2 defects. This innovative flap design permitted one stage reconstruction with primary closure of the donor sites.
Open Versus Closing Wedge Osteotomy and Application to Mandibular Reconstruction
Authors: Hu Shirley , Klimczak Jaclyn , Garner Weylon , Hart Hannah , Kadakia Sameep P. , Wood-Smith Donald , Abraham Manoj T.
Published: April 2020

Purpose:

To review the specific techniques of closing wedge osteotomy and open osteotomy, compare their clinical and radiographic outcomes, and apply these findings to mandibular reconstruction.

Methods:

A thorough review of the otolaryngology, facial plastic and reconstructive surgery, oral and maxillofacial surgery, and orthopedic surgery literature was conducted in the Ovid MEDLINE, EMBASE, and Google Scholar databases using the terms ‘osteotomy’ and ‘mandibular reconstruction.’

Results:

Traditionally, open osteotomies were thought to result in greater rates of malunion. However, multiple meta-analyses within the orthopedic literature have refuted this. Closing wedge osteotomies, on the other hand, may increase the chance of damaging a perforator. Again, no studies have evaluated the relationship between type of osteotomy and flap survival or wound healing. The particular type of osteotomy performed often depends on the type of osseous flap being utilized.

Conclusions:

Open osteotomies are a viable and even preferred alternative, particularly in flaps without consistent perforators, such as scapular free flaps.
Illustrations in the Journal of Craniofacial Surgery
Authors: Choi Sang Chul , Wu XiaJing , Hwang Kun , Kim Hun , Han Seung Ho
Published: April 2020

The aim of this study is to analyze the medical illustrations that appeared in the Journal of Craniofacial Surgery (JCFS) during the last 3 years (2016–2018).

All illustrations in 2676 articles from 24 issues were analyzed.

In total, 363 articles (13.6%) contained illustrations (for total of 589 illustrations), and 38 articles (1.4%) cited illustrations from other articles. The number of illustrations increased over time (152 in 2016, 181 in 2017, and 256 in 2018; P = 0.007). The signature of the illustrator appeared in 16.5% of the illustrations, and the illustrator's name was acknowledged in 7.6%. The most frequent contents of the 589 illustrations were surgical procedures (55.4%), followed by anatomy (34.1%). Among the 555 illustrations showing regions of the body, the most frequently illustrated region was the oral cavity (41.6%), followed by the eye and periorbital region (18.4%), the nose (12.4%), and the head (11.4%). Of the 555 illustrations showing tissue, the tissue most frequently depicted was bone (52.8%), followed by soft tissue (42.5%). The mean score for clarity of the intended message was 3.5 ± 1.2. The mean score for artistic skill was 3.2 ± 1.0.

As the number of illustrations in JCFS increases, it is increasingly important that information on the illustrators be given. The journal editor should recommend that authors provide the illustrators’ information. From the author's perspective, the best illustration is one that tells the story the author wants to convey to readers. Therefore, the crucial point is the expression of the author's goal, rather than the esthetics of the illustration.
Traumatic Brain Injury in Trauma Patients With Isolated Facial Fractures
Authors: McCarty Justin C. , Kiwanuka Elizabeth , Gadkaree Shekhar , Siu Jennifer M. , Caterson Edward J.
Published: April 2020

Background:

Diagnosis of traumatic brain injury (TBI), and specifically mild TBI (mTBI), is a diagnostic challenge which can delay diagnosis preventing early intervention and follow-up care. Facial fractures represent an objective surrogate marker for potential force transmission to the neural cavity. The authors’ objective was to characterize the prevalence of TBI in trauma patients with isolated facial fractures stratified by injury severity.

Methods:

The authors performed a retrospective cross-sectional study of the National Trauma Databank (NTDB) from 2007 to 2014 assessing a total of 1,867,761 participants identified as having a TBI and 306,785(60.2%) had an isolated facial fracture using ICD-9 codes. TBI severity was subdivided using Glasgow Coma Scale into mTBI and moderate-to-severe TBI. Logistic regression assessed odds of mTBI and moderate-to-severe TBI with different isolated facial fractures adjusted for injury severity.

Results:

Trauma patients with isolated facial fractures of the nasal bone, mandible, malar region and maxilla, orbital floor, and alveolar and palate had a concomitant prevalence of mTBI ranging from 21.3% to 46.0% and moderate-to-severe TBI ranging from 7.3% to 18.4%. Mandibular fractures had the lowest odds of mTBI and moderate to severe TBI while alveolar and palate fractures had the highest odds of mTBI [OR3.20,95%CI (3.11–3.30)] and moderate to severe TBI [OR3.83,95%CI (3.65–4.01)].

Conclusions:

Isolated facial fractures have a high prevalence of mTBI at all injury severity levels. Clinicians can use the presence of facial fractures in trauma patients to serve as clinical markers for TBI, without distracting from already existing trauma protocols and their focus on treatment of immediate life-threatening injuries raising both awareness and potential for early intervention.
Volumetric Analysis of the Pterygopalatine Fossa by Semiautomatic Segmentation of Cone Beam Computed Tomography
Authors: Lentzen Max-Philipp , Safi Ali-Farid , Riekert Maximilian , Visser-Vandewalle Veerle , Grandoch Andrea , Zirk Matthias , Zöller Joachim E. , Kreppel Matthias
Published: April 2020

The aim of this study was to provide volumetric data of the pterygopalatine fossa by semiautomatic segmentation based upon cone beam computed tomography.

Cone beam computed tomography (CBCT) images of 100 patients were analyzed. By using the open source software “ITK-Snap,” the volumetric measurements of 200 pterygopalatine fossae were performed. For statistical investigations paired t test, and independent Student t test were performed. Also, the Pearsons chi-square test was applied. P values P < 0.05 were considered significant.

The mean volume was 578.376 mm3 for the right and 560.979 mm3 for the left side. The results indicated statistically significant differences according to the right and the left pterygopalatine fossa, regardless of gender (P < 0.05). The analysis of differences between males and females did not show any significant results (P > 0.05), although males present a slightly larger volume than females. According to the median age (59 years), younger patients presented smaller volumes, whereas older patients presented larger volumes. Nevertheless, no statistically significant differences according to age (χ2 = 3.520; P > 0.05) could be found.

Clinical intervention with the application of local anesthetics into the complex and vulnerable anatomy of the pterygopalatine fossa makes a thorough knowledge about the volumetric capacity indispensable. Therefore, the semiautomatic segmentation of CBCT images provides a useful, available and validated tool. Our results show that a final injected anesthetic volume larger than 1 ml exceeds the pterygopalatine fossa capacity considerably and could cause complications. To prevent this, volumetric analysis of this region can provide further information and enables an individualized patients‘ treatment.
Prevention of Autologous Costal Cartilage Graft Warping in Secondary Rhinoplasty
Authors: McGuire Connor , Samargandi Osama A. , Boudreau Colton , Whelan Ashley , Bezuhly Michael
Published: April 2020

Background:

Autogenous costal cartilage grafts (ACCG) are frequently used in secondary rhinoplasty; however, these grafts tend to warp. The objective of this study is to systematically evaluate current interventions to prevent warping of ACCGs and to assess long-term outcomes with their use.

Methods:

A systematic review was undertaken using a computerized search. Eligible articles assessed adult patients undergoing secondary rhinoplasty with ACCGs. Interventions to reduce warping were examined. Publication descriptors were extracted, heterogeneity was examined, and methodological quality of articles was assessed.

Results:

Eighteen studies were included. Most studies were published after 2010 (83.3%), assessed a single intervention (83.3%), and were of levels of evidence III and IV. Mean patient age was 30 (range 5–95 years) and studies included a mean of 64 cases (range 9–357). Nine of the 15 non-comparative studies were considered of high methodological quality, while all 3 comparative studies were considered high quality. Secondary rhinoplasties which did not describe a method to address warping showed increased rates of warping compared to counter balancing techniques, chimeric grafts, titanium microplating, Kirschner wire and suture usage, irradiation, and various carving techniques. Rates of warping remained low with no major complications with the use of a variety of approaches.

Conclusions:

ACCG warping during secondary rhinoplasty can be alleviated with a variety of techniques with no clear difference in outcomes between approaches. Plastic surgeons may consider adopting one of the various techniques described in order to reduce warping, maximize aesthetic outcomes and patient satisfaction.
Quantitative Evaluation of the Postoperative Changes in Nasal Septal Deviation by Diverse Movement of the Maxilla After Le Fort I Osteotomy
Authors: On Sung Woon , Baek Seung-Hak , Choi Jin-Young
Published: April 2020

The purposes of this study were to compare the postoperative changes in nasal septal (NS) deviation between total impaction (TI) and anterior elongation (AE) of the maxilla after Le Fort I osteotomy (LF-IO) and to investigate the correlation between the change in NS deviation and the amount of surgical maxillary movement. Twenty-eight patients, who underwent LF-IO and sagittal split osteotomy by a single surgeon, were divided into TI group (N = 13; mean = 1.5 mm) and AE group (N = 15; mean = 1.6 mm). NS deviation was measured using computed tomography and deviation indices before and after surgery at 3 coronal measurement planes (CMP) passing through the nasion, crista galli, and the most anterior point of the sphenoid sinus (MAPS). Then, statistical analysis was performed. The AE group did not have significant changes in any deviation indices after surgery. The TI group; however, exhibited significant increases in the MAPS-CMP and total deviation indices (0.67–1.16 mm, P < 0.01; 5.45–6.43 mm, P < 0.05). The TI group also exhibited a greater increase in the ΔMAPS-CMP deviation index than the AE group (0.49 mm versus 0.06 mm, P < 0.05). The amount of forward movement of the maxilla was positively correlated with the nasion-CMP and total deviation indices (r = 0.422, P < 0.05; r = 0.398, P < 0.05). LF-IO for TI and forward movement can worsen NS deviation posteriorly and anteriorly, respectively. It is necessary to manage the nasal septum and the nasal crest of the maxilla meticulously during LF-IO procedure.
Analysis of Clinical Significance of the Pterygospinous and Pterygoalar Bars
Authors: Harikrishnan Pandurangan
Published: April 2020

Presence of ossified structures at the skull base near the sphenoid bone in the infra temporal fossa are clinically significant. We studied the incidence of pterygospinous bar (PSB) and pterygoalar bar (PAB) in 140 dried human skulls. The incidence of pterygospinous bar was 22% and pterygoalar bar was 11%. An unusual large pterygspinous foramen was present in one of the skulls on the left side. Clinical significance of these bars are reviewed.
Technical Modifications Specific to the Cleft Le Fort I Osteotomy
Authors: Susarla Srinivas M. , Ettinger Russell , Preston Kathryn , Hitesh Kapadia  , Egbert Mark A.
Published: April 2020

Purpose:

To discuss technical modifications specific to the cleft Le Fort I osteotomy that improve mobilization and demonstrate the stability of the maxilla at the Le Fort I level in a cohort of patients with cleft palate (with or without cleft lip) who underwent traditional maxillary advancement.

Methods:

This was a retrospective evaluation of patients with cleft palate (+/− cleft lip) who underwent orthognathic surgery for management of skeletal malocclusions. All study subjects had a Le Fort I osteotomy +/− bilateral mandibular sagittal split osteotomies. The cleft Le Fort I osteotomy technique is modified to extensively release fibrous tissue and scar from the posterior maxilla, including around the tuberosity, along the posterior maxillary sinus wall, and circumferentially around the descending palatine canal. Maxillary position was assessed using angular and linear measurements pre-operatively (T0), immediately post-operatively (T1), and at 1-year post-operatively (T2). Descriptive and bivariate statistics were computed; a P 
< 0.05 was considered significant.

Results:

Twenty-eight patients with cleft palate (with or without cleft lip) were included. The sample's mean age was 18.9 ± 1.4 years and included 11 females. The majority of subjects (64.3%) underwent bimaxillary surgery; eight subjects (28.6%) had segmental maxillary surgery and 14 subjects (50%) had simultaneous maxillary interpositional bone grafting. The mean maxillary sagittal advancement was 6.1 mm (range: 0–10 mm). At 1-year post-operatively, the absolute change in SNA was 0.7 ± 0.9 degrees; the absolute change in maxillary sagittal position was 0.8 ± 0.6 mm. There was no association between the magnitude of advancement and the magnitude of position change (P = 0.86). Stability was not influenced by segmental surgery, bone grafting, or bimaxillary surgery (P 
> 0.33).

Conclusion:

Using a modified technique with extensive release of posterior scar and graduated intra-operative traction, maxillary advancement of up to 10 mm can be performed in patients with cleft palate (± cleft lip) with sagittal relapse of < 1 mm at 1-year post-operatively.
Early outcomes following trauma related to sex: A matched analysis of military service members in the department of defense trauma registry
Authors: Morte Kaitlin , Kuckelman John , Marenco Christopher , Lammers Daniel , Bingham Jason , Eckert Matthew
Published: April 2020

BACKGROUND

Several studies have identified sex as a factor influencing early outcomes after trauma. With the increased representation of women in combat roles, there is a need for improved understanding of the pathophysiology of traumatic injury in women. The purpose of this study was to define sex-based differences in early combat trauma outcomes amongst military service members.

METHODS

A retrospective review of the Department of Defense Trauma Registry between 2008 and 2016 was performed. A 2:1 case control match was performed to match for Injury Severity Score, mechanism of injury, and age. The primary outcome of the study was mortality.

RESULTS

A total of 4,625 patients were included in the study, 2.2% of whom were women. Women were less significantly injured than men (Injury Severity Score, 7.7 vs. 11, p = 0.003) and more likely to sustain blunt trauma (81% vs. 62.5%, p = 0.01). After case-control matching, 202 men and 101 women were evaluated. There was no statistical difference in the primary outcome of mortality. There was no statistical difference in Glasgow Coma Scale score, crystalloid or colloid administration, Packed Red Blood Cells (PRBC), platelet, cryoprecipitate, or plasma usage between men and women.

CONCLUSION

Contrary to the civilian trauma literature, our study demonstrated no significant difference in early mortality between male and female combat casualties in a matched cohort. This finding may represent a difference in injury patterns, resuscitation practices, or lifesaving interventions in a deployed setting as compared with civilian setting. As the proportion of women involved in combat operations continues to increase, prospective studies should be performed to better define injury patterns, as well as early and late outcomes related to military trauma in the female population.

LEVEL OF EVIDENCE

Retrospective, Level IV.
Relationship of body mass index, serum creatine kinase, and acute kidney injury after severe trauma
Authors: Vasquez Charles R. , DiSanto Thomas , Reilly John P. , Forker Caitlin M. , Holena Daniel N. , Wu Qufei , Lanken Paul N. , Christie Jason D. , Shashaty Michael G.S.
Published: April 2020

OBJECTIVES

Body mass index (BMI) is associated with acute kidney injury (AKI) after trauma, but underlying mechanisms are unclear. Body mass index correlates with both excess adiposity and increased muscle mass. Since the latter could predispose to severe rhabdomyolysis after trauma, we hypothesized that the BMI-AKI association may be partially explained by a direct relationship of BMI with serum creatine kinase (CK).

METHODS

Prospective cohort study of 463 critically ill patients admitted to a level I trauma center from 2005 to 2015 with Injury Severity Score of >15 and serum CK measured in the first 7 days. We defined AKI by AKI Network creatinine criteria. We used simple linear regression to determine the association of BMI with peak CK and multivariable logistic regression to adjust the BMI-AKI association for peak CK and confounders.

RESULTS

Median age was 43 years, 350 (76%) were male, 366 (79%) had blunt mechanism, and median Injury Severity Score was 24. Body mass index was associated with peak CK (R
2 = 0.05, p < 0.001). Acute kidney injury developed in 148 patients (32%), and median time to peak CK was 29 hours (interquartile range, 15–56 hours) after presentation. Body mass index was significantly associated with AKI in multivariable models adjusted for age, race, sex, diabetes, injury mechanism and severity, and red blood cell transfusions (odds ratio [OR], 1.31 per 5 kg/m2; 95% confidence interval [CI], 1.09–1.58; p = 0.004). Adding peak CK to the model partially attenuated the association of BMI with AKI (OR, 1.26 per 5 kg/m2; 95% CI, 1.04–1.52; p = 0.018), and peak CK was also associated with AKI (OR, 1.19 per natural log; 95% CI, 1.00–1.41; p = 0.049). Peak CK remained associated with AKI when restricted to patients with values of <5,000 U/L (OR, 1.31 per natural log; 95% CI, 1.01–1.69; p = 0.043).

CONCLUSION

Serum CK correlated with BMI and partially attenuated the association of BMI with AKI after major trauma, suggesting that excess muscle injury may contribute to the BMI-AKI association.

LEVEL OF EVIDENCE

Epidemiologic study, level III.
Risk assessment for intra-abdominal injury following blunt trauma in children: Derivation and validation of a machine learning model
Authors: Pennell Christopher , Polet Conner , Arthur L. Grier , Grewal Harsh , Aronoff Stephen
Published: April 2020

BACKGROUND

Computed tomography is the criterion standard for diagnosing intra-abdominal injury (IAI) but is expensive and risks radiation exposure. The Pediatric Emergency Care Applied Research Network (PECARN) model identifies children at low risk of IAI requiring intervention (IAI-I) in whom computed tomography may be omitted but does not provide an individualized risk assessment to positively predict IAI-I. We sought to apply machine learning algorithms to the PECARN blunt abdominal trauma (BAT) data set experimentally to create models for predicting both the presence and absence of IAI-I for pediatric BAT victims.

METHODS

Using the PECARN data set, we derived and validated predictive models for IAI-I. The data set was divided into derivation (n = 7,940) and validation (n = 4,089) subsets. Six algorithms were tested to create 2 models using 19 clinical variables including emesis, dyspnea, Glasgow Coma Scale score of <15, visible thoracic or abdominal trauma, seatbelt sign, abdominal distension, tenderness or rectal bleeding, peritoneal signs, absent bowel sounds, flank pain, pelvic pain or instability, sex, age, heart rate, and respiratory rate (RR). Five algorithms were fitted to predict the absence (low-risk model) or presence (high-risk model) of IAI-I. Models were validated using the test subset.

RESULTS

For the low-risk model, four algorithms were significantly better than the baseline rate (2.28%) when validated using the test set. The random forest model identified 73% of children as low risk, having a predicted IAI-I rate of 0.54%. For the high-risk model, all six algorithms had added predictive power compared with the baseline rate with the highest reportable risk being 39.0%. By incorporating both models into a web application, child-specific risks of IAI-I can be estimated ranging from 0.28% to 39.0%

CONCLUSION

We developed a tool that provides a child-specific risk estimate for IAI-I after BAT. This publically available model provides a powerful tool for clinicians triaging pediatric victims of blunt abdominal trauma.

LEVEL OF EVIDENCE

Prognostic, Level II.
Retrobulbar Spot Sign in Metachronous Bilateral Central Retinal Artery Occlusion of Cardioembolic Origin
Authors: Lottspeich Christian , Mackert Marc J. , Köhler Anton , Bauer Axel , Hoffmann Ulrich , Czihal Michael
Published: April 2020

A 78-year-old man suffered sudden visual loss of his right eye. Five years earlier, he had experienced vision loss of his left eye due to central retinal artery occlusion (CRAO); back then, the etiology for the CRAO was not established. Current ocular ultrasound depicted a hyperechoic spot within the optic nerve in both eyes. Echocardiography identified a calcified mass adherent to the mitral valve as the embolic source of the CRAO. This case shows the value of ocular B-mode ultrasound in demonstration and proof of the etiology for CRAO.
GABAB receptor-mediated tonic inhibition of locus coeruleus neurons plays a role in deep anesthesia induced by isoflurane
Authors: Hung Wei-Chen , Chu Yun-Lin , Tsai Meng-Li , Wong Shi-Bing , Min Ming-Yuan , Chen Ruei-Feng , Yang Hsui-Wen
Published: April 2020

Noradrenergic neurons in the locus coeruleus referred to as locus coeruleus neurons, provide the major supply of norepinephrine to the forebrain and play important roles in behavior through regulation of wakefulness and arousal. In a previous study using brain slice preparations, we reported that locus coeruleus neurons are subject to tonic inhibition mediated by γ-aminobutyric acid B receptors (GABABRs) and that the extent of tonic inhibition varies with ambient GABA levels. Since ambient GABA in the locus coeruleus was reported to fluctuate during the sleep-wakefulness cycle, here we tested whether GABABR-mediated tonic inhibition of locus coeruleus neurons could be a mechanism underlying changes in brain arousal. We first demonstrated that GABABR-mediated tonic inhibition of locus coeruleus neurons also exists in vivo by showing that local infusion of CGP35348, a GABABR antagonist, into the locus coeruleus increased the firing rate of locus coeruleus neurons in anesthetized rats. We then showed that this manipulation accelerated the behavioral emergence of rats from deep anesthesia induced by isoflurane. Together, these observations show that GABABR-mediated tonic inhibition of locus coeruleus neurons occurs in vivo and support the idea that this effect may be important in regulating the functional state of the brain.
Room-temperature-storable PCR Mixes for SARS-CoV-2 Detection
Authors: Xu Jiasu , Wang Jin , Zhong Zecheng , Su Xiaosong , Yang Kunyu , Chen Zhongfu , Zhang Dongxu , Li Tingdong , Wang Yingbin , Zhang Shiyin , Ge Shengxiang , Zhang Jun , Xia Ningshao
Published: April 2020

A novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) emerged in late 2019, causing an outbreak of pneumonia [coronavirus disease 2019 (COVID-19)] in Wuhan, China, which then rapidly spread globally. Although the use of ready-made reaction mixes can enable more rapid PCR-based diagnosis of COVID-19, the need to transport and store these mixes at low temperatures presents challenges to already overburdened logistics networks. Here, we present an optimized freeze-drying procedure that allows SARS-CoV-2 PCR mixes to be transported and stored at ambient temperatures, without loss of activity. Additive-supplemented PCR mixes were freeze-dried. The residual moisture of the freeze-dried PCR mixes was measured by Karl-Fischer titration. We found that freeze-dried PCR mixes with ∼1.2% residual moisture are optimal for storage, transport, and reconstitution. The sensitivity, specificity, and repeatability of the freeze-dried reagents were similar to those of freshly prepared, wet reagents. The freeze-dried mixes retained activity at room temperature (18∼25°C) for 28 days, and for 14 and 10 days when stored at 37°C and 56°C, respectively. The uptake of this approach will ease logistical challenges faced by transport networks and make more cold storage space available at diagnosis and hospital laboratories. This method can also be applied to the generation of freeze-dried PCR mixes for the detection of other pathogens.
Dual mechanisms of ictal high frequency oscillations in human rhythmic onset seizures
Authors: Smith Elliot H. , Merricks Edward M. , Liou Jyun-You , Casadei Camilla , Melloni Lucia , Thesen Thomas , Friedman Daniel , Doyle Werner , Emerson Ronald G. , Goodman Robert R. , McKhann Guy M. , Sheth Sameer A. , Rolston John D. , Schevon Catherine A.
Published: April 2020

High frequency oscillations (HFOs) recorded from intracranial electrodes during epileptiform discharges are a proposed biomarker of epileptic brain tissue and may also be useful for seizure forecasting, with mixed results. Despite such potential for HFOs, there is limited investigation into the spatial context of HFOs and their relationship to simultaneously recorded neuronal activity. We sought to further understand the biophysical underpinnings of ictal HFOs using unit recordings in the human neocortex and mesial temporal lobe during rhythmic onset seizures. We compare features of ictal discharges in both the seizure core and penumbra (spatial seizure domains defined by multiunit activity patterns). We report differences in spectral features, unit-local field potential coupling, and information theoretic characteristics of HFOs before and after local seizure invasion. Furthermore, we tie these timing-related differences to spatial domains of seizures, showing that penumbral discharges are widely distributed and less useful for seizure localization.
Analysis of Infected Host Gene Expression Reveals Repurposed Drug Candidates and Time-Dependent Host Response Dynamics for COVID-19
Authors: Xing Jing , Shankar Rama , Drelich Aleksandra , Paithankar Shreya , Chekalin Evgenii , Dexheimer Thomas , Chua Mei-Sze , Rajasekaran Surender , Tseng Chien-Te Kent , Chen Bin
Published: April 2020

The repurposing of existing drugs offers the potential to expedite therapeutic discovery against the current COVID-19 pandemic caused by the SARS-CoV-2 virus. We have developed an integrative approach to predict repurposed drug candidates that can reverse SARS-CoV-2-induced gene expression in host cells, and evaluate their efficacy against SARS-CoV-2 infectionin vitro. We found that 13 virus-induced gene expression signatures computed from various viral preclinical models could be reversed by compounds previously identified to be effective against SARS- or MERS-CoV, as well as drug candidates recently reported to be efficacious against SARS-CoV-2. Based on the ability of candidate drugs to reverse these 13 infection signatures, as well as other clinical criteria, we identified 10 novel candidates. The four drugs bortezomib, dactolisib, alvocidib, and methotrexate inhibited SARS-CoV-2 infection-induced cytopathic effect in Vero E6 cells at < 1 µM, but only methotrexate did not exhibit unfavorable cytotoxicity. Although further improvement of cytotoxicity prediction and bench testing is required, our computational approach has the potential to rapidly and rationally identify repurposed drug candidates against SARS-CoV-2. The analysis of signature genes induced by SARS-CoV-2 also revealed interesting time-dependent host response dynamics and critical pathways for therapeutic interventions (e.g. Rho GTPase activation and cytokine signaling suppression).
Is the impact of social distancing on coronavirus growth rates effective across different settings? A non-parametric and local regression approach to test and compare the growth rate
Authors: Lancastle Neil
Published: April 2020

Epidemiologists use mathematical models to predict epidemic trends, and these results are inherently uncertain when parameters are unknown or changing. In other contexts, such as climate, modellers use multi-model ensembles to inform their decision-making: when forecasts align, modellers can be more certain. This paper looks at a sub-set of alternative epidemiological models that focus on the growth rate, and it cautions against relying on the method proposed in (Pike & Saini, 2020): relying on the data for China to calculate future trajectories is likely to be subject to overfitting, a common problem in financial and economic modelling. This paper finds, surprisingly, that the data for China are double-exponential, not exponential; and that different countries are showing a range of different trajectories. The paper proposes using non-parametric and local regression methods to support epidemiologists and policymakers in assessing the relative effectiveness of social distancing policies. All works contained herein are provided free to use worldwide by the author underCC BY 2.0.
Further Evidence of a Possible Correlation Between the Severity of Covid-19 and BCG Immunization
Authors: Dolgikh Serge
Published: April 2020

In this work we observe a number of cases supporting the possible correlation between the administration of BCG tuberculosis vaccine and the severity of Covid-19 effects in the population proposed in the earlier works [1]. Based on the early preliminary analysis of the publicly available data we propose a number of arguments and observations providing further support for the correlation hypothesis and make an observation that the effectiveness of the protection effect of BCG immunization, if confirmed, may depend to a significant extent on the age of administration, with the early age inoculation more effective for the lasting protection.
Global access to handwashing: implications for COVID-19 control in low-income countries
Authors: Brauer Michael , Zhao Jeff T , Bennitt Fiona B , Stanaway Jeffrey D
Published: April 2020

Background

Low-income countries have reduced health care system capacity and are therefore at risk of substantially higher COVID-19 case fatality rates than those currently seen in high-income countries. Handwashing is a key component of guidance to reduce transmission of the SARS-CoV-2 virus, responsible for the COVID-19 pandemic. Prior systematic reviews have indicated the effectiveness of handwashing to reduce transmission of respiratory viruses. In low-income countries, reduction of transmission is of paramount importance but social distancing is challenged by high population densities and access to handwashing facilities with soap and water is limited.

Objectives

To estimate global access to handwashing with soap and water to inform use of handwashing in the prevention of COVID-19 transmission.

Methods

We utilized observational surveys and spatiotemporal Gaussian process regression modeling in the context of the Global Burden of Diseases, Injuries, and Risk Factors Study, to estimate access to a handwashing station with available soap and water for 1062 locations from 1990 to 2019.

Results

Despite overall improvements from 1990 (33.6% [95% uncertainty interval 31.5–35.6] without access) to 2019, globally in 2019, 2.02 (1.91–2.14) billion people—26.1% (24.7–27.7) of the global population lacked access to handwashing with available soap and water. More than 50% of the population in sub-Saharan Africa and Oceania were without access to handwashing in 2019, while in eight countries, more 50 million or more persons lacked access.

Discussion

For populations without handwashing access, immediate improvements in access or alternative strategies are urgently needed, while disparities in handwashing access should be incorporated into COVID-19 forecasting models when applied to low-income countries.

Funding

Bill & Melinda Gates Foundation. MB was supported in part by the Pathways to Equitable Healthy Cities grant from the Wellcome Trust.
The Risk of Secondary Malignancies in Patients with Ovarian Cancer: A Systematic Review and Meta-Analysis
Authors: Heydari Keyvan , Rismantab Sahar , Alizadeh-Navaei Reza , Shamshirian Amir , Shadmehri Nima , Lotfi Parisa , Zamani-Kiasari Alieh , Shamshirian Danial
Published: April 2020

This study was performed to systematically asses the risk of secondary malignancies in patients with ovarian cancer. We conducted a systematic search in PubMed, Web of Science, and Scopus databases up to September 2019 to find target studies. In this study, the overall SIR has been calculated with fixed/random-effects models. Sixteen cohort studies including 122715 ovarian cancer patients with 4458 secondary malignancies have been included in this meta-analysis. Combined SIRs showed an increased risk of secondary malignancies prevalence (SIR: 1.81, 95%CI 1.58-2.03). The most prevalence diagnosed malignancies were as follows: breast cancer (1.34, 95%CI 1.5-1.18), intestine (2.36, 95%CI 1.11-3.61), colorectal (1.73, 95%CI 1.44-2.02), pancreatic (1.42, 95%CI 1.13-1.71), cervical cancer (11.57, 95%CI 6.94-16.21), renal (1.43, 95%CI 1.11-1.74), bladder (2.13, 95%CI 1.77-2.50), leukemia (3.33, 95%CI 2.23-4.43), connective tissue (2.61, 95%CI 1.56-3.66), and thyroid (1.59, 95%CI 1.13-2.04). In regards to the results, various malignancies have a greater prevalence in patients with ovarian cancer in comparison to the general public. Corpus cancer, leukemia cancer, endometrium cancer, connective tissue malignancy, and bladder cancer are among the high risks in these patients and need to be considered for them. Hence, the survival rate of the patients can be increased through prevention and early diagnosis.
An amino-terminal point mutation increases EAAT2 anion currents without affecting glutamate transport rates
Authors: Mertens Bettina M I , Kortzak Daniel , Franzen Arne , Fahlke Christoph
Published: April 2020

Excitatory amino acid transporters (EAATs) are prototypic dual function proteins that function as coupled glutamate/Na+/H+/K+transporters and as anion-selective channels. Both transport functions are intimately intertwined at the structural level: secondary active glutamate transport is based on elevator-like movements of the mobile transport domain across the membrane, and the lateral movement of this domain results in anion channel opening. This particular anion channel gating mechanism predicts the existence of mutant transporters with changed anion channel properties, but without alteration in glutamate transport. We here report that the L46P mutation in the human EAAT2 transporter fulfils this prediction. L46 is a pore-forming residue of the EAAT2 anion channels at the cytoplasmic entrance into the ion conduction pathway. In whole-cell patch clamp recordings, we observed larger macroscopic anion current amplitudes for L46P than for WT EAAT2. Moreover, changes in selectivity made gluconate permeant in L46P EAAT2. Non-stationary noise analysis revealed unchanged unitary current amplitudes in mutant EAAT2 anion channels. Rapid L-glutamate application under forward transport conditions demonstrated that L46P does not reduce the transport rate of individual transporters. Since individual transport rates and unitary anion current amplitudes are unaffected, absolute open probabilities of EAAT2 anion channels were quantified as ratio of anion currents by glutamate uptake currents. We found up to sevenfold increased absolute open probability of L46P EAAT2 anion channels. Our results reveal an important determinant of the diameter of EAAT2 anion pore and demonstrate the existence of anion channel gating processes outside the EAAT uptake cycle.
Sonication of the Anterior Thalamus with MRI-Guided Low Intensity Focused Ultrasound Pulsation (LIFUP) Changes Pain Thresholds in Healthy Adults: A Double-Blind, Concurrent LIFUP/MRI Study
Authors: Badran Bashar W. , Caulfield Kevin , Stomberg-Firestein Sasha , Summers Philip , Dowdle Logan T. , Savoca Matt , Li Xingbao , Austelle Christopher W. , Short E. Baron , Borckardt Jeffrey J. , Spivak Norman , Bystritsky Alexander , George Mark S.
Published: April 2020

Background

Low Intensity Focused Ultrasound Pulsation (LIFUP) is a noninvasive brain stimulation method that may modulate deep brain structures using ultrasonic waves. Presently there are limited studies in humans rigorously assessing behavioral effects following LIFUP sonication of deep brain nuclei. As an initial test, we investigated whether sonication of the anterior thalamus, a central relay structure of nociception, would modulate thermal pain thresholds in healthy individuals.

Methods

We enrolled 19 healthy individuals in this three-visit, double-blind, randomized, sham-controlled, crossover trial. Participants attended a first MRI screening visit to acquire anatomical scans for LIFUP targeting. They then attended two identical experimental LIFUP/MRI visits (counterbalanced by condition) at least one-week apart. Within the MRI scanner, participants received two, 10-minute sessions of either active or sham LIFUP spread 10 minutes apart to the right anterior thalamus [Fundamental frequency:650khz, pulse repetition frequency: 10 HZ, Pulse Width: 5ms, Duty Cycle: 5%, Sonication Duration: 30s, Inter-Sonication Interval: 30 s, Number of Sonications: 10, ISPTA.3 719 mW/cm2]. Each 10-minute session was delivered in a block design (30s ON, 30s OFF). The primary outcome measure was quantitative sensory thresholding (QST), measuring sensory, pain, and tolerance thresholds to a thermal stimulus applied to the left forearm before and after LIFUP. Thermal stimuli were also applied in the scanner during certain blocks, either alone, or during LIFUP.

Results

Two 10-minute sessions of thalamic LIFUP produced a significant antinociceptive effect on pain thresholds. Temperature sensitivity increases were significantly attenuated (timeXcondition p=0.046) after active LIFUP (0.51 degree change) relative to sham stimulation (1.08 degrees). LIFUP also changed sensory and tolerance thresholds mathematically but this was not statistically significant with this sample. LIFUP delivered concurrently with thermal pain had no immediate behavioral effect.

Conclusions

Two, 10-minute sessions of anterior thalamic LIFUP has antinociceptive effects in healthy individuals. Future studies should optimize the parameter space and dose and perhaps investigate multi-session LIFUP interventions for pain disorders.
Zoledronate extends healthspan and survival via the mevalonate pathway in a FOXO-dependent manner
Authors: Chen Zhengqi. , Cordero Julia , Slack Cathy , Zeidler Martin , Bellantuono Ilaria
Published: April 2020

Increased longevity has not been paralleled by extended healthspan, resulting in more years spent with multiple diseases in older age. As such, interventions to improve healthspan are urgently required. Zoledronate is a nitrogen containing bisphosphonate, which inhibits the farnesyl pyrophosphate synthase (FPPS) enzyme, central to the mevalonate pathway. It is already used clinically to prevent fractures in osteoporotic patients, who have been reported to derive unexpected and unexplained survival benefits. In this study we show that zoledronate has beneficial effects on both lifespan and healthspan usingDrosophilaas a model. We found that zoledronate extended lifespan, improved climbing activity and reduced intestinal epithelial dysplasia and permeability in aged flies. Mechanistic studies showed that zoledronate conferred resistance to oxidative stress and reduced accumulation of X-ray-induced DNA damage via inhibition of FPPS. Moreover, zoledronate inhibited pAKT in the mTOR pathway and functioned via dFOXO, a molecule associated with increased longevity, downstream of the mevalonate pathway. Taken together, our work indicates that zoledronate, a drug already widely used and dosed only once a year to prevent osteoporosis, modulates important mechanisms of ageing. Its repurposing holds great promise as a treatment to improve healthspan.
Human Transcription Factor and Protein Kinase Gene Fusions in Human Cancer
Authors: Salokas Kari , Weldatsadik Rigbe G. , Markku Varjosalo
Published: April 2020

Oncogenic gene fusions are estimated to account for up-to 20 % of cancer morbidity. Originally, oncofusions were identified in blood cancer, but recently multiple sequence-level studies of cancer genomes have established oncofusions throughout all tissue types. However, the functional implications of the identified oncofusions have often not been investigated. In this study, the identified oncofusions from a fusion detection approach (DEEPEST) were analyzed in more detail. In total, DEEPEST contains 28863 unique fusions. From sequence analysis, we found that almost 30% of them (8225) are expected to produce functional fusion proteins with features from both parent genes. Kinases and transcription factors were found to be the main gene families of the protein producing fusions. Considering their role as initiators, actors, and termination points of cellular signaling pathways, we focused our in-depth analyses on them. The domain architecture of the fusions, as well as of their expected interactors, suggests that abnormal molecular context of intact protein domains brought about by fusion events may unlock the oncogenic potential of the wild type counterparts of the fusion proteins. To understand overall effects of oncofusions on cellular signaling, we performed differential expression analysis using TCGA cancer project samples. Results indicated oncofusion-specific alterations in expression levels of individual genes, and overall lowering of the expression levels of key cellular pathways, such as signal transduction, proteolysis, microtubule cytoskeleton organization, and in particular regulation of transcription. The sum of our results suggests that kinase and transcription factor oncofusions globally deregulate cellular signaling, possibly via acquiring novel functions.
High contribution of canopy to oleoresin accumulation in loblolly pine trees
Authors: Parrish Amber N. , Turner Glenn W. , Lange B. Markus
Published: April 2020

The shoot system of all loblolly pine (Pinus taedaL.) contains abundant resin ducts, and the oleoresins contained within them have demonstrated roles in constitutive defenses. This study is providing a quantitative assessment of oleoresin biosynthesis and accumulation in resin ducts. Morphometric analyses of representative tissue sections indicate that the fractional volume of resin ducts is particularly high in the cortex of young stems and their needles, representing a major portion of total pine resins from primary growth of the canopy. We demonstrate that it is possible to extrapolate oleoresin formation from the microscopic scale (tissues sections) to the macroscale (entire trees), which has implications for assessing resins as renewable feedstocks for bioproducts.