bluuebunny/crossref_metadata_2025 huggingface dataset:
Utility of the Hijdra Sum Score in Predicting Risk of Aneurysm in Patients With Subarachnoid Hemorrhage: A Single-Center Experience With 550 Patients
Authors: Kole Matthew J , Shea Phelan , Albrecht Jennifer S , Cannarsa Gregory J , Wessell Aaron P , Miller Timothy R , Jindal Gaurav , Gandhi Dheeraj , Aldrich E Francois , Simard J Marc
Published: August 2019

BACKGROUND

Subarachnoid hemorrhage (SAH) is most commonly caused by a ruptured vascular lesion. A significant number of patients presenting with SAH have no identifiable cause despite extensive cerebrovascular imaging at presentation. Significant neurological morbidity or mortality can result from misdiagnosis of aneurysm.

OBJECTIVE

To generate a model to assist in predicting the risk of aneurysm in this patient population.

METHODS

We conducted a retrospective study of all patients aged ≥18 yr admitted to a single center from March 2008 to March 2018 with nontraumatic SAH (n = 550). Patient information was compared between those with and without aneurysm to identify potential predictors. Odds ratios obtained from a logistic regression model were converted into scores which were summed and tested for predictive ability.

RESULTS

Female sex, higher modified Fisher or Hijdra score, nonperimesencephalic location, presence of intracerebral hemorrhage, World Federation of Neurosurgical Societies (WFNS) score ≥3, need for cerebrospinal fluid diversion on admission, and history of tobacco use were all entered into multivariable analysis. Greater modified Fisher, greater Hijdra score, WFNS ≥3, and hydrocephalus present on admission were significantly associated with the presence of an aneurysm. A model based on the Hijdra score and SAH location was generated and validated.

CONCLUSION

We show for the first time that the Hijdra score, in addition to other factors, may assist in identifying patients at risk for aneurysm on cerebrovascular imaging. A simple scoring tool based on patient sex, SAH location, and SAH burden can assist in predicting the presence of an aneurysm in patients with nontraumatic SAH.
Postoperative Stereotactic Body Radiotherapy for Spinal Metastases and the Impact of Epidural Disease Grade
Authors: Alghamdi Majed , Sahgal Arjun , Soliman Hany , Myrehaug Sten , Yang Victor X D , Das Sunit , Wilson Jefferson , Campbell Mikki , Lee Young K , Cawricz Monica , Da Costa Leo , Atenafu Eshetu G , Tseng Chia-Lin
Published: August 2019

BACKGROUND

Postoperative stereotactic body radiotherapy (pSBRT) is an emerging indication for spinal metastases (SM).

OBJECTIVE

To report our experience with pSBRT for SM.

METHODS

A retrospective chart review was performed for prospectively collected data of patients treated between September 2008 to December 2015 with pSBRT and followed with serial spinal MRIs every 2 to 3 mo until death or last follow-up. Univariate and multivariable analyses were performed to identify predictive factors.

RESULTS

A total of 83 spinal segments in 47 patients treated with a median dose of 24 Gy in 2 fractions were included, with mostly lung and breast primaries. A total of 59.3% had preoperative high-grade epidural disease (ED) and 39.7% were unstable. The 12-mo cumulative incidence of local failure was 17% for all segments, and 33.3%, 21.8%, and 0% in segments with postoperative high-grade, low-grade, and no ED, respectively. Downgrading preoperative ED was predictive of better local control (P = .03). The grade of postoperative ED was also predictive for local control (P < .0001), as was a longer interval between prior radiotherapy and pSBRT in those previously irradiated (P = .004). The 12-mo overall survival rate was 55%. One case of radiculopathy, 3 vertebral compression fractures, and no cases of myelopathy, hardware failure, or skin breakdown were observed.

CONCLUSION

pSBRT is an effective and safe treatment. The association between downgrading preoperative ED and better local control following pSBRT is confirmed and supports the concept of separation surgery.
Comparative study of obstetric antiphospholipid syndrome (OAPS) and non-criteria obstetric APS (NC-OAPS): report of 1640 cases from the EUROAPS registry
Authors: Alijotas-Reig Jaume , Esteve-Valverde Enrique , Ferrer-Oliveras Raquel , Sáez-Comet Luis , Lefkou Elmina , Mekinian Arsène , Belizna Cristina , Ruffatti Amelia , Hoxha Ariela , Tincani Angela , Nalli Cecilia , Marozio Luca , Maina Aldo , Espinosa Gerard , Ríos-Garcés Roberto , Cervera Ricard , Carolis Sara De , Monteleone Giuseppina , Latino Omar , Udry Sebastian , LLurba Elisa , Garrido-Gimenez Carmen , Trespidi Laura , Gerosa Maria , Chighizola Cecilia Beatrice , Rovere-Querini Patrizia , Canti Valentina , Mayer-Pickel Karoline , Tabacco Sara , Arnau Anna , Trapé Jaume , Ruiz-Hidalgo Domingo , Sos Laia , Farran-Codina Inmaculada ,   for the EUROAPS Study Group
Published: August 2019

Objectives

To compare clinical features, laboratory data and fetal-maternal outcomes between 1000 women with obstetric APS (OAPS) and 640 with aPL-related obstetric complications not fulfilling Sydney criteria (non-criteria OAPS, NC-OAPS).

Methods

This was a retrospective and prospective multicentre study from the European Registry on Obstetric Antiphospholipid Syndrome.

Results

A total of 1650 women with 5251 episodes, 3601 of which were historical and 1650 latest episodes, were included. Altogether, 1000 cases (OAPS group) fulfilled the Sydney classification criteria and 650 (NC-OAPS group) did not. Ten NC-OAPS cases were excluded for presenting thrombosis during follow-up. All cases were classified as category I (triple positivity or double positivity for aPL) or category II (simple positivity). Overall, aPL laboratory categories showed significant differences: 29.20% in OAPS vs 17.96% in NC-OAPS (P < 0.0001) for category I, and 70.8% in OAPS vs 82% in NC-OAPS (P < 0.0001) for category II. Significant differences were observed when current obstetric complications were compared (P < 0.001). However, major differences between groups were not observed in treatment rates, livebirths and thrombotic complications. In the NC-OAPS group, 176/640 (27.5%) did not fulfil Sydney clinical criteria (subgroup A), 175/640 (27.34%) had a low titre and/or non-persistent aPL positivity but did meet the clinical criteria (subgroup B) and 289/640 (45.15%) had a high aPL titre but did not fulfil Sydney clinical criteria (subgroup C).

Conclusion

Significant clinical and laboratory differences were found between groups. Fetal-maternal outcomes were similar in both groups when treated. These results suggest that we could improve our clinical practice with better understanding of NC-OAPS patients.
The bulge sign – a simple physical examination for identifying progressive knee osteoarthritis: data from the Osteoarthritis Initiative
Authors: Wang Yuanyuan , Martel-Pelletier Johanne , Teichtahl Andrew J , Wluka Anita E , Hussain Sultana Monira , Pelletier Jean-Pierre , Cicuttini Flavia M
Published: August 2019

Objective

To examine whether the presence of bulge sign or patellar tap was associated with frequent knee pain, progression of radiographic OA (ROA) and total knee replacement (TKR).

Methods

This study included 4344 Osteoarthritis Initiative participants examined at baseline for bulge sign and/or patellar tap. The clinical signs were categorized as no (none at baseline and 2 years), resolved (present at baseline only), developed (present at 2 years only) and persistent (present at both time points). Frequent knee pain and progression of ROA over 4 years and TKR over 6 years were assessed. Binary logistic regression was used to examine the associations.

Results

A total of 12.7% of participants had bulge sign only, 2.0% had patellar tap only and 3.3% had both. A positive baseline bulge sign was associated with an increased risk of frequent knee pain [OR 1.31 (95% CI 1.04, 1.64), P = 0.02] and TKR [OR 1.47 (95% CI 1.06, 2.05), P = 0.02]. Developed bulge sign was associated with an increased risk of frequent knee pain [OR 1.75 (95% CI 1.34, 2.29), P < 0.001] and progressive ROA [OR 1.67 (95% CI 1.11, 2.51), P = 0.01]. Persistent bulge sign was associated with an increased risk of frequent knee pain [OR 1.60 (95% CI 1.09, 2.35), P = 0.02], progressive ROA [OR 1.84 (95% CI 1.01, 3.33), P = 0.045] and TKR [OR 2.13 (95% CI 1.23, 3.68), P = 0.007]. Patellar tap was not examined for its association with joint outcomes due to its low prevalence.

Conclusion

The presence of bulge sign identifies individuals at increased risk of frequent knee pain, progression of ROA and TKR. This provides clinicians with a quick, simple, inexpensive method for identifying those at higher risk of progressive knee OA who should be targeted for therapy.
Addressing food insecurity in the United States: the role of policy, systems changes, and environmental supports
Authors: Fleischhacker Sheila , Parks Courtney A , Yaroch Amy Lazarus
Published: August 2019

The growth of PSE changes across the food system helps illustrate the importance of translating multipronged approaches to address food insecurity in the U.S.
Combining MAP‐1:CD35 or MAP‐1:CD55 fusion proteins with pattern‐recognition molecules as novel targeted modulators of the complement cascade
Authors: Pérez‐Alós Laura , Bayarri‐Olmos Rafael , Skjoedt Mikkel‐Ole , Garred Peter
Published: August 2019

Dysregulation of the complement system is involved in the pathogenesis of several diseases, and its inhibition has been shown to be a feasible therapeutic option. Therefore, there is an interest in the development of complement modulators to treat complement activation–related inflammatory pathologies. Mannose‐binding lectin (MBL)/ficolin/collectin‐associated protein‐1 (MAP‐1) is a regulatory molecule of the lectin pathway (LP), whereas complement receptor 1 (CD35) and decay‐accelerating factor (CD55) are membrane‐anchored regulators with effects on the central effector molecule C3. In this study, we developed 2 novel soluble chimeric inhibitors by fusing MAP‐1 to the 3 first domains of CD35 (CD351–3) or the 4 domains of CD55 (CD551–4) to modulate the complement cascade at 2 different stages. The constructs showed biologic properties similar to those of the parent molecules. In functional complement activation assays, the constructs were very efficient in inhibiting LP activation at the level of C3 and in the formation of terminal complement complex. This activity was enhanced when coincubated with recombinant LP recognition molecules MBL and ficolin‐3. Recombinant MAP‐1 fusion proteins, combined with recombinant LP recognition molecules to target sites of inflammation, represent a novel and effective therapeutic approach involving the initiation and the central and terminal effector functions of the complement cascade.—Pérez‐Alós, L., Bayarri‐Olmos, R., Skjoedt, M.‐O., Garred, P. Combining MAP‐1:CD35 or MAP‐1:CD55 fusion proteins with pattern‐recognition molecules as novel targeted modulators of the complement cascade. FASEB J. 33, 12723–12734 (2019). www.fasebj.org
Reliable, Noncontact Imaging Tool for the Evaluation of Meibomian Gland Function: Sirius Meibography
Authors: Gulmez Sevim Duygu , Gumus Koray , Unlu Metin
Published: August 2019

Objectives:

To investigate the correlation between the clinical grading of the severity of meibomian gland dysfunction (MGD) and meibomian gland area (MGA) loss detected using Sirius meibography in the upper and lower eyelids and to correlate these parameters with dry eye signs and symptoms.

Methods:

One hundred thirty eyes of 130 volunteer patients were enrolled. Meibomian gland dysfunction was defined as the presence of signs consistent with meibomian gland terminal duct obstruction and categorized between grades 1 and 4. Upper and lower MGA loss percentages were evaluated using Sirius meibography by two blinded examiners. Patients were categorized into two groups (positive and negative for MGD) based on their Ocular Surface Disease Index (OSDI) scores (≥15 and <14, respectively) and MGD grades (≥1 and 0, respectively).

Results:

The MGA loss percentage and ocular surface test results of the MGD group were greater than in the non-MGD group in both eyelids (P=0.001). Meibomian gland dysfunction grade and MGA loss for the lower eyelid was greater than that of the upper eyelids (P=0.002 and P<0.001, respectively). The OSDI score, tear film break-up time, and lissamine green staining were all significantly correlated with MGD grade and MGA loss in both eyelids (P<0.001). For the average measures of the MGA loss percentage in each scan, the intraclass correlation value was found as 0.994 (95% confidence interval [CI]: 0.992–0.995) for reader 1 and 0.988 (95% CI: 0.982–0.992) for reader 2.

Conclusions:

Our findings suggest that Sirius meibography, a noncontact imaging device, is a reliable tool for evaluating meibomian gland structure in patients with MGD and non-MGD of various ages and regardless of sex.
Mitomycin C-augmented Phacotrabeculectomy Versus Phacoemulsification in Primary Angle-closure Glaucoma: A Randomized Controlled Study
Authors: El Sayed Yasmine M. , Elhusseiny Abdelrahman M. , Albalkini Ahmed S. , El Sheikh Reem H. , Osman Mona A.
Published: August 2019

Precis:

Phacotrabeculectomy yielded similar results to phacoemulsification in primary angle-closure glaucoma (PACG) in terms of intraocular pressure (IOP) lowering, glaucoma medications and success rates. Although releasable sutures may have reduced the risk of hypotony; complications and interventions were more common with phacotrabeculectomy.

Purpose:

To compare the efficacy and safety of phacotrabeculectomy using releasable sutures and adjunctive mitomycin C versus phacoemulsification alone in the management of PACG.

Patients and Methods:

In total, 63 eyes of 63 PACG patients were randomized to undergo either mitomycin C-augmented phacotrabeculectomy with tight scleral flap closure using releasable sutures aiming at no flow or phacoemulsification alone. The primary outcomes were success rates and complications. Secondary outcomes were IOP and glaucoma medications.

Results:

The IOP and glaucoma medications were significantly reduced at 1, 3, 6, and 12 months postoperatively in both groups (P<0.001). There was no statistically significant difference in IOP, IOP reduction, success rates, or survival times between both groups. Glaucoma medications were only significantly lower in the phacotrabeculectomy group at 1 and 3 months. The rates of postoperative interventions and complications were higher in the phacotrabeculectomy group. Complete success, defined as an IOP of 6 to 21 mm Hg on no medications and with no signs of glaucoma progression, was achieved in 58% in the phacotrabeculectomy group, compared with 62% in the phacoemulsification group (P=0.9). Only 2 eyes (6%) in the phacoemulsification group required a subsequent trabeculectomy.

Conclusions:

Trabeculectomy did not seem to add an advantage when combined with phacoemulsification in PACG patients and was associated with more postoperative interventions. Despite the use of releasable sutures to allow titration of the IOP postoperatively, the rate of hypotony and other complications was higher in the phacotrabeculectomy group.
Flavobacteriaceae Bacteremia in Children
Authors: Cooper Shiri , Levy Itzhak , Ben-Zvi Haim , Ashkenazi-Hoffnung Liat , Ben-Shimol Shalom , Shachor-Meyouhas Yael , Grisaru-Soen Galia , Kriger Or , Yahav Dafna , Scheuerman Oded
Published: August 2019

Background:

The Flavobacteriaceae family includes rare pathogens in children; Chryseobacterium indologenes and Elizabethkingia meningosepticum are the most common pathogenic species, with a wide range of clinical presentations and high mortality rate. Although rare, diagnosis is important due to inherent resistance to multiple antibiotics, especially those typically prescribed for empiric treatment of aerobic Gram-negative bacterial infections.

Methods:

A multicenter retrospective study conducted in 5 Israeli hospitals, describing Flavobacteriaceae bacteremia confirmed by positive blood culture from 1998 to 2018.

Results:

Thirteen cases were included; 9 isolates were C. indologenes. Bacteremia was nosocomial or healthcare-associated in all cases. Bacteremia was associated with young age (median, 1 year, range 24 days–17 years), with only 2 (15.4%) cases in neonates, Central line-associated bloodstream infection as a source (5/13, 38%) and malignancy (7/13, 54.8%). Thirty-day all-cause mortality was 23% (3/13). Ninety-one percent of isolates were susceptible to trimethoprim-sulfamethoxazole, 82% to piperacillin-tazobactam and 92% to ciprofloxacin.

Conclusions:

C. indologenes and E. meningosepticum are rare, nosocomial- or healthcare-associated pediatric bacteremia pathogens. Bacteremia was associated with young age, but in contrast to the literature, the majority of our cases were older than the neonatal age period. In addition, they were associated with central line-associated bloodstream infection and malignancy. The most adequate antibiotics according to resistance patterns were ciprofloxacin, trimethoprim-sulfamethoxazole and piperacillin-tazobactam.
Reconstruction of Large Anterior Palatal Fistulae Using Anteriorly Based Dorsal Tongue Flaps
Authors: Yang Zhao-hui , Zhong Jiang-long , Chen Wei-liang
Published: August 2019

Background:

An anterior palatal fistula in a bilateral cleft lip and palate is a challenging clinical dilemma. The authors evaluate the feasibility and outcomes of the reconstruction of large anterior palatal fistulae using anteriorly based dorsal tongue flaps.

Methods:

Eight patients with anterior palatal fistulae after repair of a bilateral cleft lip and palate using anteriorly based dorsal tongue flaps. The defect size varied from 1.0 × 1.0 cm to 1.5 × 2.0 cm, and the tongue flap size varied from 1.5 × 3.5 cm to 2.0 × 3.5 cm.

Results:

All patients underwent successful reconstruction of palatal defects using anteriorly based tongue flaps, and no case of spontaneous detachment of the tongue flap occurred. The patients with palatal fistulae were followed up for 10 to 30 months, and no recurrence was encountered.

Conclusion:

An anteriorly based dorsal tongue flap is a safe and feasible surgical technique for the closure of anterior palatal fistulae.
Modified Genioplasty Combined With Orthognathic Surgeries for the Treatment of Chin Defect Accompanying Micrognathia and Airway Stenosis
Authors: Chen Kai , Wang Lin , Xiao Yanju , Zhang Yaoyao , Wu Guomin
Published: August 2019

We reported a 16-year-old patient with chin defect accompanying micrognathia and airway stenosis owing to a traffic accident. The treatment of this patient involved a modified genioplasty associated with orthognathic surgeries. Through data analysis, we found that the patient's facial morphology and airway space are greatly improved compared with preoperation: y-axis(T4-T1) = −4.5 degree; FCA (T4-T1) = −18 degree; CSAmin(T4-T1) = 227 mm2. In conclusion, the modified genioplasty associated with orthognathic surgeries is an effective way to reshape the defected chin and treat micrognathia and airway stenosis in this case.
Nasal Surgery May Improve Upper Airway Collapse in Patients With Obstructive Sleep Apnea: A Drug-Induced Sleep Endoscopy Study
Authors: Bosco Gabriela , Pérez-Martín Nuria , Morato Marta , Racionero Miguel A. , Plaza Guillermo
Published: August 2019

Objective:

The aim of this study is to evaluate the effects of nasal surgery in the upper airway (UA) collapse using drug induced sleep endoscopy (DISE) in a group of patients with obstructive sleep apnea hypopnea syndrome (OSAHS).

Methods:

Prospective cohort of patients treated with nasal surgery between 2015 and 2016. All patients were diagnosed with mild to severe OSAHS. The inclusion criteria were age between 18 and 70 years, apnea–hypopnea index (AHI) higher than 15, and septal deviation. All patients had a DISE performed before surgery and 3 months after. The DISE findings were evaluated through the NOHL scale.

Results:

Thirty-four patients were included. Surgical success with subjective and objective improvement in nasal obstructions was achieved in all cases. The pattern of UA obstruction did change significantly following nasal surgery (P < 0.05). Before nasal surgery, 74% of the patients demonstrated multilevel obstruction. After nasal surgery, only 50% patients showed multilevel collapse (P < 0.05). Among patients with single-level collapse, the oropharynx was the most common location of obstruction. It became more frequent after nasal surgery was done (41% vs 21%,P < 0.05). Significant improvement was shown in hypopharyngeal collapse. Postoperative AHI decreased from a mean of 26.7 to 19 events/h, but this change was not significant.

Conclusion:

Nasal surgery may improve hypopharyngeal collapses observed during DISE in patients with OSAHS. Thus, an improvement in nasal obstruction may also modify the surgical plan based on UA functional findings in OSAHS patients.
Liver Resection Improves Survival in Colorectal Cancer Patients
Authors: Raoof Mustafa , Haye Sidra , Ituarte Philip H. G. , Fong Yuman
Published: August 2019

Objective:

The aim of this study was to estimate population-level causal effects of liver resection on survival of patients with colorectal cancer liver metastases (CRC-LM).

Background:

A randomized trial to prove that liver resection improves survival in patients with CRC-LM is neither feasible nor ethical. Here, we test this assertion using instrumental variable (IV) analysis that allows for causal-inference by controlling for observed and unobserved confounding effects.

Methods:

We abstracted data on patients with synchronous CRC-LM using the California Cancer Registry from 2000 to 2012 and linked the records to the Office of Statewide Health Planning and Development Inpatient Database. We used 2 instruments: resection rates in a patient's neighborhood (within 50-mile radius)—NALR rate; and Medical Service Study Area resection rates—MALR rate. IV analysis was performed using the 2SLS method.

Results:

A total of 24,828 patients were diagnosed with stage-IV colorectal cancer of which 16,382 (70%) had synchronous CRC-LM. Liver resection was performed in 1635 (9.8%) patients. NALR rates ranged from 8% (lowest-quintile) to 11% (highest-quintile), whereas MALR rates ranged from 3% (lowest quintile) to 19% (highest quintile). There was a strong association between instruments and probability of liver resection (F-statistic at median cut-off: NALR 24.8; MALR 266.8; P < 0.001). IV analysis using both instruments revealed a 23.6 month gain in survival (robust SE 4.4, P < 0.001) with liver resection for patients whose treatment choices were influenced by the rates of resection in their geographic area (marginal patients), after accounting for measured and unmeasured confounders.

Conclusion:

Less than 10% of patients with CRC-LM had liver resection. Significant geographic variation in resection rates is attributable to community biases. Liver resection leads to extensive survival benefit, accounting for measured and unmeasured confounders.
Effect of Postoperative Permissive Anemia and Cardiovascular Risk Status on Outcomes After Major General and Vascular Surgery Operative Interventions
Authors: Kougias Panos , Sharath Sherene , Mi Zhibao , Biswas Kousick , Mills Joseph L.
Published: August 2019

Objectives:

To determine the effect of postoperative permissive anemia and high cardiovascular risk on postoperative outcomes.

Methods:

The Veterans Affairs Surgical Quality Improvement Program and Corporate Data Warehouse databases were queried for patients who underwent major vascular or general surgery operations. The status of cardiovascular risk was assessed by calculating the Revised Cardiac Risk Index. Primary endpoint was a composite of mortality, myocardial infarction, acute renal failure, coronary revascularization, or stroke within 90 days postoperatively.

Results:

We analyzed 142,510 procedures performed from 2000 to 2015. Postoperative anemia was the strongest independent predictor of the primary endpoint whose odds increased by 43% for every g/dL drop in postoperative nadir Hb [95% confidence interval (95% CI): 41–45]. Cardiac risk status as described by the RCRI also independently predicted the primary endpoint, with an additive effect particularly evident at postoperative nadir Hb values below 10 gm/dL. Postoperative anemia, after age, was the second strongest independent predictor of long-term (12 years) mortality (hazard ratio: 1.18, 95% CI: 1.17–1.19).

Conclusion:

Postoperative anemia is strongly associated with postoperative ischemic events, 90-day mortality, and long-term mortality. Restrictive transfusion should be used cautiously after major general and vascular operations, particularly in patients at a high cardiovascular risk.
Fractional Ablative Laser Therapy is an Effective Treatment for Hypertrophic Burn Scars
Authors: Miletta Nathanial , Siwy Katherine , Hivnor Chad , Clark Jason , Shofner Joshua , Zurakowski David , Anderson R. Rox , Lee Kachiu , Donelan Matthias
Published: August 2019

Objective:

The aim of this study is to determine objective and subjective changes in mature hypertrophic burn scars treated with a fractional ablative carbon dioxide (CO2) laser.

Background:

Fractional CO2 laser treatment has been reported to improve burn scars, with increasing clinical use despite a paucity of controlled, prospective clinical studies using objective measures of improvement.

Methods:

A multicenter, site-controlled, prospective open-label study was conducted from 2013 to 2016. Objective and patient-reported outcome measures were documented at baseline, at each monthly laser treatment, and 6 months after treatment. Objective measurements employed were: mechanical skin torque to measure viscoelastic properties; ultrasonic imaging to measure scar thickness; and reflectometry to measure erythema and pigmentation. Subjective measures included health-related quality of life, patient and investigator scar assessment scales, and blinded scoring of before and after photographs. Subjects aged 11 years or older with hypertrophic burn scars were recruited. Each subject received 3 monthly treatment sessions with an ablative fractionated CO2 laser.

Results:

Twenty-nine subjects were enrolled, of whom 26 received at least 1 fractional CO2 laser treatment and 22 received 3 treatments. Mean age of those completing all 3 treatments was 28 years. Statistically significant objective improvements in elastic stretch (P < 0.01), elastic recovery (P < 0.01), extensibility (P < 0.01), and thickness (P < 0.01) were noted. Patient- and physician-reported scar appearance and pain/pruritus were significantly improved (P < 0.01). There was no regression of improvement for at least 6 months after treatment.

Conclusions:

Fractional ablative laser treatment provides significant, sustained improvement of elasticity, thickness, appearance, and symptoms of mature hypertrophic burn scars.
A systematic review and meta-analysis on the effectiveness of an invasive strategy compared to a conservative approach in elderly patients with non-ST elevation acute coronary syndrome
Authors: P. Reaño Joan Dymphna , C. Dimalala Maria Grethel , B. Shiu Louie Alfred , Miralles Karen V. , Pestaño Noemi S. , R. Punzalan Felix Eduardo , Tumanan-Mendoza Bernadette , T. Reyes Michael Joseph , Castillo Rafael R.
Published: August 2019

Background

Elderly patients, 65 years old and older, largely represent (>50 %) of hospital- admitted patients with acute coronary syndrome (ACS). Data are conflicting comparing efficacy of early routine invasive (within 48-72 hours of initial evaluation) versus conservative management of ACS in this population.

Objective

We aimed to determine the effectiveness of routine early invasive strategy compared to conservative treatment in reducing major adverse cardiovascular events in elderly patients with non-ST elevation (NSTE) ACS.

Data Sources

We conducted a systematic review of randomized controlled trials through PubMed, Cochrane, and Google Scholar database.

Study Selection

The studies included were randomized controlled trials that evaluated the effectiveness of invasive strategy compared to conservative treatment among elderly patients ≥ 65 years old diagnosed with NSTEACS. Studies were included if they assessed any of the following outcomes of death, cardiovascular mortality, myocardial infarction (MI), stroke, recurrent angina, and need for revascularization. Five articles were subsequently included in the meta-analysis.

Data Extraction

Three independent reviewers extracted the data of interest from the articles using a standardized data collection form that included study quality indicators. Disparity in assessment was settled by an independent adjudicator.

Data Synthesis

All pooled analyses were based on fixed effects model. A total of 2,495 patients were included, 1337 in the invasive strategy group, and 1158 in the conservative treatment group.

Results

Meta-analysis showed less incidence of revascularization in the invasive (2%) over conservative treatment groups (8%), with overall risk ratio of 0.31 (95% CI 0.16-0.61, I2 =0%). There was also less incidence of stroke in the invasive (2%) versus conservative group (3%) but this was not statistically significant. A significant benefit was noted in the reduction of all-cause mortality (RR 0.63, 95% CI 0.55-0.72, I2=84%) and myocardial infarction (RR 0.62, 95% CI 0.49- 0.79, I2=63%) but with significant heterogeneity.

Conclusion

There was a significantly lower rate of revascularization in the invasive strategy group compared to the conservative treatment group. In the reduction of all-cause mortality and MI, there was benefit favoring invasive strategy but with significant heterogeneity. These findings do not support the bias against early routine invasive intervention in the elderly group with NSTEACS. However, further studies focusing on the elderly with larger population sizes are still needed.
Apolipoprotein B underlies the causal relationship of circulating blood lipids with coronary heart disease
Authors: Richardson Tom G , Sanderson Eleanor , Palmer Tom M. , Ala-Korpela Mika , Ference Brian A , Smith George Davey , Holmes Michael V
Published: August 2019

Background

Circulating blood lipids cause coronary heart disease (CHD). However, the precise way in which one or more lipoprotein lipid-related entities account for this relationship remains unclear. We sought to explore the causal relationships of blood lipid traits with risk of CHD using multivariable Mendelian randomization.

Methods

We conducted GWAS of circulating blood lipid traits in UK Biobank (up to n=440,546) for LDL cholesterol, triglycerides and apolipoprotein B to identify lipid-associated SNPs. Using data from CARDIoGRAMplusC4D for CHD (consisting of 60,801 cases and 123,504 controls), we performed univariable and multivariable Mendelian randomization (MR) analyses. Similar analyses were conducted for HDL cholesterol and apolipoprotein A-I.

Findings

GWAS identified multiple independent SNPs associated at P<5×10−8 for LDL cholesterol (220), apolipoprotein B (n=255), triglycerides (440), HDL cholesterol (534) and apolipoprotein AI (440). Between 56-93% of SNPs identified for each lipid trait had not been previously reported in large-scale GWAS. Almost half (46%) of these SNPs were associated at P<5×10−8 with more than one lipid related trait. Assessed individually using MR, each of LDL cholesterol (OR 1.66 per 1 standard deviation higher trait; 95%CI: 1.49; 1.86; P=2.4×10−19), triglycerides (OR 1.34; 95%CI: 1.25, 1.44; P=9.1×10−16) and apolipoprotein B (OR 1.73; 95%CI: 1.56, 1.91; P=1.5×10−25) had effect estimates consistent with a higher risk of CHD. In multivariable MR, only apolipoprotein B (OR 1.92; 95%CI: 1.31, 2.81; P=7.5×10−4) retained a robust effect with the estimate for LDL cholesterol (OR 0.85; 95%CI: 0.57; 1.27; P=0.44) reversing and that of triglycerides (OR 1.12; 95%CI: 1.02, 1.23; P=0.01) becoming markedly weaker.

Individual MR analyses showed a 1-SD higher HDL-C (OR 0.80; 95%CI: 0.75, 0.86; P=1.7×10−10) and apolipoprotein A-I (OR 0.83; 95%CI: 0.77, 0.89; P=1.0×10−6) to lower the risk of CHD but these effect estimates weakened to include the null on accounting for apolipoprotein B.

Conclusions

Apolipoprotein B is of fundamental causal relevance in the aetiology of CHD, and underlies the relationship of LDL cholesterol and triglycerides with CHD.
Identifying subtypes of a stigmatized medical condition
Authors: Gabashvili Irene S.
Published: August 2019

Background

Some conditions - such as obesity, depression and functional odor disorders - come with a social stigma. Understanding the etiology of these conditions helps to avoid stereotypes and find remedies. One of the major obstacles facing researchers, especially for those studying socially distressing metabolic malodor, is the difficulty in assembling biologically homogenous study cohorts.

Objective

The aim of this study was to examine phenotypic variance, self-reported data and laboratory tests for the purpose of identifying clinically relevant and etiologically meaningful subtypes of idiopathic body odor and the “People are Allergic To Me” (PATM) syndrome.

Methods

Participants with undiagnosed body odor conditions enrolled to participate in this research study initiated by a healthcare charity MEBO Research and sponsored by Wishart Research group at the Metabolomics Innovation Centre, University of Alberta, Canada. Primary outcomes were differences in metabolite concentrations measured in urine, blood and breath of test and control groups. Principal component analyses and other statistical tests were carried out for these measurements.

Results

While neither of existing laboratory tests could reliably predict chronic malodor symptoms, several measurements distinguished phenotypes at a significance level less than 5%. Types of malodor can be differentiated by self-reported consumption of (or sensitivity to) added sugars (p<0.01), blood alcohols after glucose challenge (especially ethanol: p<0.0005), urinary excretion of phenylalanine, putrescine, and combinations of blood or urine metabolites.

Conclusions

Our preliminary results suggest that malodor heterogeneity can be addressed by analyses of phenotypes based on patients’ dietary and olfactory observations. Our studies highlight the need for more trials. Future research focused on comprehensive metabolomics and microbiome sequencing will play an important role in the diagnosis and treatment of malodor.

Trial Registration

The study discussed in the manuscript was registered as NCT02692495 at clinicaltrials.gov. The results were compared with our earlier study registered as NCT02683876.
ScalaFlux: a scalable approach to quantify fluxes in metabolic subnetworks
Authors: Millard Pierre , Schmitt Uwe , Kiefer Patrick , Vorholt Julia A. , Heux Stéphanie , Portais Jean-Charles
Published: August 2019

13C-metabolic flux analysis (13C-MFA) allows metabolic fluxes to be quantified in living organisms and is a major tool in biotechnology and systems biology. Current13C-MFA approaches model label propagation starting from the extracellular13C-labeled nutrient(s), which limits their applicability to the analysis of pathways close to this metabolic entry point. Here, we propose a new approach to quantify fluxes through any metabolic subnetwork of interest by modeling label propagation directly from the metabolic precursor(s) of this subnetwork. The flux calculations are thus purely based on information from within the subnetwork of interest, and no additional knowledge about the surrounding network (such as atom transitions in upstream reactions or the labeling of the extracellular nutrient) is required. This approach, termed ScalaFlux for SCALAble metabolic FLUX analysis, can be scaled up from individual reactions to pathways to sets of pathways. ScalaFlux has several benefits compared with current13C-MFA approaches: greater network coverage, lower data requirements, independence from cell physiology, robustness to gaps in data and network information, better computational efficiency, applicability to rich media, and enhanced flux identifiability. We validated ScalaFlux using a theoretical network and simulated data. We also used the approach to quantify fluxes through the prenyl pyrophosphate pathway ofSaccharomyces cerevisiaemutants engineered to produce phytoene, using a dataset for which fluxes could not be calculated using existing approaches. A broad range of metabolic systems can be targeted with minimal cost and effort, making ScalaFlux a valuable tool for the analysis of metabolic fluxes.

Author Summary

Metabolism is a fundamental biochemical process that enables all organisms to operate and grow by converting nutrients into energy and ‘building blocks’. Metabolic flux analysis allows the quantification of metabolic fluxesin vivo, i.e. the actual rates of biochemical conversions in biological systems, and is increasingly used to probe metabolic activity in biology, biotechnology and medicine. Isotope labeling experiments coupled with mathematical models of large metabolic networks are the most commonly used approaches to quantify fluxes within cells. However, many biological questions only require flux information from a subset of reactions, not the full network. Here, we propose a new approach with three main advantages over existing methods: better scalability (fluxes can be measured through a single reaction, a metabolic pathway or a set of pathways of interest), better robustness to missing data and information gaps, and lower requirements in terms of measurements and computational resources. We validate our method both theoretically and experimentally. ScalaFlux can be used for high-throughput flux measurements in virtually any metabolic system and paves the way to the analysis of dynamic fluxome rearrangements.
A novel human monoclonal antibody specific to the A33 glycoprotein recognizes colorectal cancer and inhibits metastasis
Authors: Murer Patrizia , Plüss Louis , Neri Dario
Published: August 2019

Colorectal cancer represents the second most common cause of cancer-related death. The human A33 transmembrane glycoprotein is a validated tumor-associated antigen, expressed in 95% of primary and metastatic colorectal cancers. Using phage display technology, we generated a human monoclonal antibody (termed A2) specific to A33 and we compared its epitope and performance to those of previously described clinical-stage anti-human A33 antibodies. All antibodies recognized a similar immunodominant epitope, located in the V-domain of A33, as revealed by SPOT-analysis. The A2 antibody homogenously stained samples of poorly, moderately and well-differentiated colon adenocarcinomas. All antibodies also exhibited an intense staining of healthy human colon sections. The A2 antibody, reformatted in murine IgG2a format, preferentially localized to A33-transfected CT26 murine colon adenocarcinomas in immunocompetent mice with a homogenous distribution within the tumor mass, while other antibodies exhibited a patchy uptake in neoplastic lesions. A2 efficiently induced killing of A33-expressing cells through antibody-dependent cell-mediated cytotoxicity in vitro and was able to inhibit the growth of A33-positive murine CT26 and C51 lung metastases in vivo. Anti-A33 antibodies may thus represent useful vehicles for the selective delivery of bioactive payloads to colorectal cancer, or may be used in IgG format in settings of minimal residual disease.
Prototypical pacemaker neurons are immunocompetent cells
Authors: Klimovich Alexander , Giacomello Stefania , Björklund Åsa , Faure Louis , Kaucka Marketa , Giez Christoph , Murillo-Rincon Andrea P. , Matt Ann-Sophie , Crupi Gabriele , de Anda Jaime , Wong Gerard C.L. , D’Amato Mauro , Adameyko Igor , Bosch Thomas C.G.
Published: August 2019

Pacemaker neurons exert control over neuronal circuit function by their intrinsic ability to generate rhythmic bursts of action potential. Recent work has identified rhythmic gut contractions in human, mice and hydra to be dependent on both neurons and the resident microbiota. However, little is known about the evolutionary origin of these neurons and their interaction with microbes. In this study, we identified and functionally characterized prototypical ANO/SCN/TRPM ion channel expressing pacemaker cells in the basal metazoanHydraby using a combination of single-cell transcriptomics, immunochemistry, and functional experiments. Unexpectedly, these prototypical pacemaker neurons express a rich set of immune-related genes mediating their interaction with the microbial environment. Functional experiments validated a model of the evolutionary emergence of pacemaker cells as neurons using components of innate immunity to interact with the microbial environment and ion channels to generate rhythmic contractions.
Expression and Purification of a Mammalian Protein: Cytosolic Domain of IRE1α from Insect Sf21 Cells
Authors: Oak Amrita , Jansen Grace , Chan Christina
Published: August 2019

Eukaryotic proteins can be expressed in different heterologous systems. However, mammalian proteins in general have specific post-translational processing requirements that may not be fulfilled by a regular bacterial expression system. In this study, we use an insect cell system to express a mammalian protein of interest. Spodoptera frugiperda (Sf21) cells were used in conjunction with a baculoviral expression system to produce the cytosolic domain (CD) of IRE1, an endoplasmic reticulum (ER) stress sensor protein. Inositol Requiring Enzyme 1 (IRE1) is a dual function kinase and endoribonuclease protein that cleaves X-box binding protein (XBP1) mRNA. We used the pFastBac plasmid to insert the coding sequence into a recombinant bacmid shuttle vector which was then used to infect Sf21 cells. The expressed protein was then purified with an MBPTrap column to obtain >85% pure protein.
HMGB1 mediates the development of tendinopathy due to mechanical overloading
Authors: Zhao Guangyi , Zhang Jianying , Nie Daibang , Zhou Yiqin , Li Feng , Onishi Kentaro , Wang James H-C.
Published: August 2019

Mechanical overloading is a major cause of tendinopathy, but the underlying pathogenesis of tendinopathy is unclear. Here we report that high mobility group box1 (HMGB1) is released to the tendon extracellular matrix and initiates an inflammatory cascade in response to mechanical overloading in a mouse model. Moreover, administration of glycyrrhizin (GL), a naturally occurring triterpene and a specific inhibitor of HMGB1, the tendon’s inflammatory reactions. Also, while prolonged mechanical overloading in the form of long-term intensive treadmill running induces Achilles tendinopathy in mice, administration of GL completely blocks the tendinopathy development. Additionally, mechanical overloading of tendon cells in vitro induces HMGB1 release to the extracellular milieu, thereby eliciting inflammatory and catabolic responses as marked by increased production of prostaglandin E2 (PGE2) and matrix metalloproteinase-3 (MMP-3) in tendon cells. Application of GL abolishes the cellular inflammatory/catabolic responses. Collectively, these findings point to HMGB1 as a key molecule that is responsible for the induction of tendinopathy due to mechanical overloading placed on the tendon.
Solution structure and assembly of β-amylase2 fromArabidopsis thaliana
Authors: Chandrasekharan Nithesh P. , Ravenburg Claire M. , Roy Ian R. , Monroe Jonathan D. , Berndsen Christopher E.
Published: August 2019

Starch is a key energy storage molecule in plants that requires controlled synthesis and breakdown for effective plant growth. β-amylases (BAMs) hydrolyze starch into maltose to help meet the metabolic needs of the plant. In the model plant,Arabidopsis thaliana, there are nine BAMs which have apparently distinct functional and domain structures, although the functions of only a few of the BAMs are known and there are no 3-D structures of BAMs from this organism. Recently, AtBAM2 was proposed to form a tetramer based on chromatography and activity assays of mutants, however there was no direct observation of this tetramer. We collected small-angle X-ray scattering data on AtBAM2 and N-terminal mutants to describe the structure and assembly of the tetramer. Comparison of the scattering of the AtBAM2 tetramer to data collected using the sweet potato (Ipomoea batatas) BAM5, which is also reported to form a tetramer, showed there were differences in the overall assembly. Analysis of N-terminal truncations of AtBAM2 identified a loop sequence found only in BAM2 orthologs that appears to be critical for AtBAM2 tetramer assembly as well as activity.
The hunger games: sensing host arginine is essential for Leishmania parasite virulence
Authors: Goldman-Pinkovich Adele , Kannan Sriram , Nitzan-Koren Roni , Puri Madhu , Bar-Avraham Yael , McDonald Jacqueline A. , Sur Aakash , Zhang Wen-Wei , Matlashewski Greg , Madhubala Rentala , Michaeli Shulamit , Myler Peter J. , Zilberstein Dan
Published: August 2019

Arginine homeostasis in lysosomes is critical for growth and metabolism of mammalian cells. They employ a specific sensor (SLC38A9) that monitors intra-lysosome arginine sufficiency and subsequently up-regulates cellular mTORC1 activity. Lysosomes of macrophages (phagolysosomes) are the niche where the parasitic protozoan Leishmania resides and causes important human disease. Several years ago, we discovered that upon arginine starvation, cultured Leishmania parasites promptly activate a MAPK2-mediated Arginine Deprivation Response (ADR) pathway, resulting in up-regulation of the Leishmania arginine transporter (AAP3), as well as a small group of other transporters. Significantly, ADR is also activated during macrophage infection, implying that the intracellular parasite actively depletes arginine within the host phagolysosome, likely to prevent mTORC1 activation and enhance intracellular development. We hypothesize that ADR-mediated up-regulation of AAP3 activity is necessary to withstand the resultant arginine starvation. Both copies of the AAP3 genes are located (in tandem) on a tetrasomic chromosome (chr31), but only one (AAP3.2) is responsive to arginine deprivation. CRISPR/Cas9-mediated disruption of the AAP3 locus yielded mutants that retain a basal level of arginine transport (mediated by AAP3.1), but lack a functional copy of AAP3.2 and are therefore not responsive to arginine starvation. While these mutants grow normally in culture as promastigotes, they were impaired in their ability to develop inside THP1 macrophages grown under physiological concentrations of arginine (0.1 mM). However, flooding the macrophage growth medium with arginine (1.5 mM) restored parasite infectivity and intracellular growth to that of wild type. The results indicate that inside the host macrophage, Leishmania must overcome the arginine “Hunger Games” by up-regulating transport of arginine via the ADR. Furthermore, the AAP3.2 mutants were ~70-80% less virulent in Balb/C mice, showing, for the first time, that the ability to monitor and respond to changes in host metabolite levels is essential for pathogenesis.