bluuebunny/crossref_metadata_2025 huggingface dataset:
Recurrent/Intermittent Vaginal and Rectal Chlamydial Infection Following Treatment: A Prospective Cohort Study Among Female Sexually Transmitted Disease Clinic Patients
Authors: Khosropour Christine M , Soge Olusegun O , Suchland Robert , Leipertz Gina , Unutzer Anna , Pascual Rushlenne , Hybiske Kevin , Barbee Lindley A , Manhart Lisa E , Dombrowski Julia C , Golden Matthew R
Published: March 2019

Background

Rectal Chlamydia trachomatis (CT) is common among clinic-attending women, but little is known about clearance and health implications of rectal CT.

Methods

At the municipal sexually transmitted disease clinic in Seattle, Washington, in 2017–2018, we enrolled women at high risk for urogenital CT into an 8-week prospective study. Women received standard CT treatment at enrollment. Women self-collected daily rectal and vaginal specimens for nucleic acid amplification tests (NAATs) and completed weekly sexual exposure diaries. We performed CT culture on the enrollment rectal specimen.

Results

We enrolled 50 women; 13 (26%) tested positive for vaginal (n = 11) and/or rectal (n = 11) CT. Sixty percent of women with rectal CT per NAAT were also culture positive. Median time to CT clearance after azithromycin treatment was 8.0 days for vaginal CT and 7.0 days for rectal CT. Eight women with rectal CT at enrollment had at least 1 rectal CT-positive NAAT after clearance of the initial infection; none reported anal sex.

Conclusions

Most NAAT-positive rectal infections were culture positive, suggesting active infection. Time to NAAT clearance of rectal and genital tract CT was similar, and intermittent rectal CT positivity was common in the absence of anal sexual exposure. The cause of recurrent/intermittent rectal CT and the clinical implications of these infections require further study.
Data, capacity-building, and training needs to address rural health inequities in the Northwest United States: a qualitative study
Authors: Bekemeier Betty , Park Seungeun , Backonja Uba , Ornelas India , Turner Anne M
Published: March 2019

Objective

Rural public health system leaders struggle to access and use data for understanding local health inequities and to effectively allocate scarce resources to populations in need. This study sought to determine these rural public health system leaders’ data access, capacity, and training needs.

Materials and Methods

We conducted qualitative interviews across Alaska, Idaho, Oregon, and Washington with individuals expected to use population data for analysis or decision-making in rural communities. We used content analysis to identify themes.

Results

We identified 2 broad themes: (1) challenges in accessing or using data to monitor and address health disparities and (2) needs for training in data use to address health inequities. Participants faced challenges accessing or using data to address rural disparities due to (a) limited availability or access to data, (b) data quality issues, (c) limited staff with expertise and resources for analyzing data, and (d) the diversity within rural jurisdictions. Participants also expressed opportunities for filling capacity gaps through training—particularly for displaying and communicating data.

Discussion

Rural public health system leaders expressed data challenges, many of which can be aided by informatics solutions. These include interoperable, accessible, and usable tools that help capture, access, analyze, and display data to support health equity efforts in rural communities.

Conclusion

Informatics has the potential to address some of the daunting data-related challenges faced by rural public health system leaders working to enhance health equity. Future research should focus on developing informatics solutions to support data access and use in rural communities.
Ozone as a Potential Fumigant Alternative for the Management of Sitophilus oryzae (Coleoptera: Curculionidae) in Wheat
Authors: Amoah Barbara A , Mahroof Rizana M
Published: March 2019

Gaseous ozone, an oxidizing agent used as a disinfectant in food processing and preservation, has potential for the control of stored product insects. In this study, we investigated ozone for the management of the rice weevil, Sitophilus oryzae (L.) (Coleoptera: Curculionidae), a serious stored product insect pest. We exposed eggs, immature stages within wheat kernels, and adults of the rice weevil to 200-ppm ozone for 12, 24, 36, 48, and 60 h. Insects were placed at 5, 15, or 25 cm depth within a wheat mass in PVC pipes (10 cm in diameter, 30 cm in height) and exposed to ozone. Egg eclosion was recorded 10 d after treatment (DAT), and immature stages were observed for adult emergence 28 DAT. Adults were observed for survival immediately after ozone exposure and again at 1 and 2 DAT. Egg eclosion was significantly lower at 5 cm compared with 25 cm at all exposure times, but not the 12-h exposure time. For each exposure time tested, significantly lesser adults developed from kernels and none of the adults survived at the 5 cm depth compared with the 15 and 25 cm depths. Survival rate of adults was significantly higher at 25 cm depth than at 15 cm depth at the 24–60 h. The deeper the insect in the grain mass, the higher the survival rate. The work reported suggests that ozone is effective in killing all life stages of S. oryzae; however, the efficacy of the gas is dependent on the concentration, exposure time, depth, and gas loss.
Tritrophic Interactions of Cucumber Cultivar, Aphis gossypii (Hemiptera: Aphididae), and Its Predator Hippodamia variegata (Coleoptera: Coccinellidae)
Authors: Zahedi Abdossamad , Razmjou Jabraeil , Rafiee-Dastjerdi Hooshang , Leppla Norman C , Golizadeh Ali , Hassanpour Mahdi , Ebadollahi Asgar
Published: March 2019

The melon aphid, Aphis gossypii Glover, is a cosmopolitan pest that infests and damages a wide range of crop plants, especially cucurbits. It is a host of the coccinellid predator, Hippodamia variegata (Goeze), that has the potential to suppress the pest on leaves of cucumber plants grown in greenhouses. Melon aphids were reared on either Storm or Khasib cucumber cultivars to determine whether there would be a difference in their development and reproduction. The aphids from each cultivar were fed to H. variegata adults to assess their effects on the life history of the predator. The aphid population reared on Khasib leaves increased faster than the population on Storm leaves; however, the predators fed aphids from Storm leaves had a higher rate of population growth. Thus, the intrinsic rate of increase and net reproductive rate were greater for aphids reared on Khasib leaves but lower for H. variegata fed those aphids compared with aphids reared on the Storm cultivar. Additionally, clean and aphid-infested leaves from both cultivars were analyzed for total flavonoids, phenol, and chlorophyll, and the density of leaf trichomes was measured. The Storm leaves contained higher amounts of flavonoids and phenol, less chlorophyll, and a greater density of trichomes. Regardless of cucurbit cultivar, aphid feeding increased the flavonoids and phenol content and decreased the amount of chlorophyll.
Jayanta on Kumārila’s View of Liberation
Authors: Kataoka Kei
Published: March 2019

In his Nyāyamañjarī, the Nyāya scholar Bhaṭṭa Jayanta expounds on the issue of liberation when commenting on the Nyāyasūtra. In one of its subsections Jayanta discusses a sceptical view about the very possibility of liberation and the view of the Mīmāṁsāka scholar Kumārila. The present author focuses on this section of the Nyāyamañjarī and elucidates the theoretical criteria presupposed there in order to evaluate Jayanta’s attitude towards Kumārila. Jayanta regards Kumārila as one who internally denies liberation while externally admitting its possibility. The present author also sheds light on Jayanta’s view of the means of liberation in comparison to other Naiyāyika positions. Kumārila’s emphasis on the karmic law can be regarded as a trigger for Jayanta to reconsider the previous views of the Naiyāyikas. How to deal with the accumulated karmas while following the karmic law? The present article clarifies the merits of Jayanta’s solution in terms of theory and exegesis.
Effects of TACE and preventive antiviral therapy on HBV reactivation and subsequent hepatitis in hepatocellular carcinoma: a meta-analysis
Authors: Zhang Su-Su , Liu Jin-Xia , Zhu Jing , Xiao Ming-Bing , Lu Cui-Hua , Ni Run-Zhou , Qu Li-Shuai
Published: March 2019

Background and aim

The impact of transarterial chemoembolization (TACE) and preventive antiviral therapy on the occurrence of hepatitis B virus (HBV) reactivation and subsequent hepatitis remains controversial. This meta-analysis aimed to evaluate the effect of TACE and preventive antiviral therapy on the risk of HBV reactivation and subsequent hepatitis. Meanwhile, we explored the role of HBeAg status in HBV reactivation after TACE.

Methods

We performed this meta-analysis with 11 included studies to assess the effect of TACE and preventive antiviral therapy on predicting clinical outcomes in HBV-related hepatocellular carcinoma (HCC). The pooled odds ratios (OR) were calculated using a random or fixed effects model. PUBMED, MEDLINE, EMBASE and the Cochrane Central Register of Controlled were searched for the included articles (from 2000 to December 2017).

Results

Our results showed that TACE significantly increased the risk of HBV reactivation (OR: 3.70; 95% CI 1.45–9.42; P < 0.01) and subsequent hepatitis (OR: 4.30; 95% CI 2.28–8.13; P < 0.01) in HCC patients. There was no significant difference in HBV reactivation after TACE between HBeAg positive and negative patients (OR: 1.28; 95% CI 0.31–5.34; P = 0.73). Preventive antiviral therapy could statistically reduce the rate of HBV reactivation (OR: 0.08; 95% CI 0.02–0.32; P < 0.01) and hepatitis (OR: 0.22; 95% CI 0.06–0.80; P = 0.02) in those with TACE treatment.

Conclusions

The present study suggested that TACE was associated with a higher possibility of HBV reactivation and subsequent hepatitis. Preventive antiviral therapy is significantly in favor of a protective effect.
Proof of Concept for a Polyethylene Glycol/Gel Hybrid Testing Method
Authors: Delk Alexander A , Gammon Richard R
Published: March 2019

Objective

To test a hybrid polyethylene glycol (PEG)/gel method, specifically to attempt to increase reaction strength of accidentally overdiluted anti-Cob and broadly for proof of concept.

Methods

Methods were divided into 2 basic steps: sensitization and antiglobulin (AHG) testing. Sensitization was performed with PEG tubes, followed by AHG using the gel method. One wash was performed between the 2 steps. We tested 7 plasma antibody specimens.

Results

In addition to the first specimen, 6 additional antibodies were selected for detection by the PEG/gel hybrid method. Antibody reactivity was detected in all specimens tested with both methods. The PEG/gel method yielded enhanced reactivity in 3 of 7 antibodies (42.9%) and the equivalent of enhanced reactivity in 4 of 7 antibodies tested (57.1%).

Conclusion

The reactivity of diluted anti-Cob (specimen 1) was increased; thus, our concept proved to be viable. The hybrid PEG/gel method showed the equivalent of enhanced or enhanced reactivity with all specimens tested and provided a stable medium.
Constant light element abundances suggest that the extended P1 in NGC 2808 is not a consequence of CNO-cycle nucleosynthesis
Authors: Cabrera-Ziri I , Lardo C , Mucciarelli A
Published: March 2019

Recent photometric results have identified a new population among globular cluster stars. This population, referred to as the ‘extended P1', has been suggested to be the manifestation of a new abundance pattern where the initial mass fraction of He changes among cluster stars that share the same CNO values. The current paradigm for the formation of the multiple stellar populations in globular clusters assumes that variations in He are the product of chemical ‘enrichment’ by the ashes of the CNO-cycle (which changes He and other elements like C, N and O simultaneously). We obtained MIKE@Magellan spectra of six giant stars in NGC 2808, a cluster with one of the strongest examples of the extended P1 population. We provide the first complete characterization of the light elements abundances for the stars along a significant range of the extended P1 photometric group. The stars from our sample appear to be homogeneous in C, N, O, Na, Mg and Al. The lack of a significant change in these products of the CNO-cycle suggests that unlike the rest of the populations identified to date, the photometric changes responsible for the extended P1 feature are a consequence of an alternative mechanism. Our measurements are consistent with the interpretations where the changes of the He mass fraction among these stars could be a consequence of p–p chain nucleosynthesis (which could increase the He in stars without affecting heavier elements). Having said that, direct measurements of He are necessary to conclude if variations of this element are present among extended P1 stars.
Fluorescence Video Angiography for Evaluation of Dynamic Perfusion Status in an Aneurysm Preclinical Experimental Setting
Authors: Grüter Basil Erwin , Täschler Dominik , Rey Jeannine , Strange Fabio , Nevzati Edin , Fandino Javier , Marbacher Serge , Coluccia Daniel
Published: March 2019

BACKGROUND

Experimental studies to assess aneurysm occlusion or perfusion typically rely on macroscopic examination or histological analysis but cannot assess dynamic perfusion.

OBJECTIVE

To describe an easy-to-implement and inexpensive fluorescence angiographic technique for the in vivo assessment and imaging of the dynamic perfusion status of aneurysms and their underlying blood vessels in a rat model.

METHODS

In a rat sidewall aneurysm model, the angiographic setup included 2 bandpass filters, a video camera, and a bicycle spotlight. After 48 rats underwent fluorescein angiography, dissections were performed to confirm the perfusion status by macroscopic and histologic examination of the aneurysm.

RESULTS

Direct injection of 0.2 mL fluorescein 10% Faure achieved strong, clear visibility in all 48 aneurysms. Macro-/microscopic examination identified residual perfusion in 25 and complete healing in 23 aneurysms. Fluorescein imaging identified 21 of these 25 aneurysms (84%) with residual perfusion and 22 of 23 aneurysms (96%) with no residual perfusion.

CONCLUSION

Our fluorescein imaging technique proved efficient for the evaluation of aneurysm patency and parent artery integrity in this experimental setting. Fluorescein is nontoxic, can be re-administered if needed, and, in this technique, can expand the armamentarium for the preclinical evaluation of dynamic perfusion status.
Multidisciplinary Approach to Malignant Peripheral Nerve Sheath Tumor of the Trigeminal Nerve: 2-Dimensional Operative Video
Authors: Abou-Al-Shaar Hussam , Gozal Yair M , Hunt Jason P , Couldwell William T
Published: March 2019

Malignant peripheral nerve sheath tumors (MPNSTs) of the trigeminal nerve are uncommon lesions that pose a surgical challenge to neurosurgeons. The case described in this video involved a 67-yr-old man who presented with a 2-yr history of left-sided facial numbness spreading from his chin along the left mandible to the preauricular area. He also reported left-sided tongue numbness and decreased taste on the left side of the tongue. On examination, he had left-sided facial numbness along the V3 distribution to pinprick and light touch. Magnetic resonance imaging (MRI) revealed an enhancing left V3 lesion extending from Meckel's cave to the angle of the mandible. The patient underwent a left temporal craniotomy for biopsy of the lesion, formalizing the diagnosis of a MPNST of the left trigeminal nerve. A multidisciplinary resection of his lesion was performed. Left infratemporal fossa approach with neck dissection, mandibulectomy, and frontotemporal craniotomy were performed. Additionally, a frontal external ventricular drain was placed for 3 d to aid in CSF diversion to avoid CSF leak, and free-flap reconstruction was undertaken. The patient tolerated the procedure well. Postoperatively, he retained his facial numbness, dysphagia, and dysarthria. The patient was discharged to inpatient rehabilitation on postoperative day 12. Postoperative computed tomography and MRI depicted complete resection of the left trigeminal nerve MPNST. At his last follow-up appointment, 3 mo after surgery, the patient reported significant improvement in his symptoms. Neuroimaging demonstrated no residual tumor and adjuvant radiotherapy was recommended. The patient provided consent for publication.
Deep Brain Stimulation in Patients With Concomitant Cardiac Pacemakers: A Case Series
Authors: Heard Tomas , Coyne Terry , Silburn Peter
Published: March 2019

BACKGROUND

Deep brain stimulation (DBS) is a treatment modality increasingly utilized in the management of neurological and psychiatric conditions. Neurosurgical technical considerations and contraindications have yet to be thoroughly characterized in the literature. The patient population for DBS includes many elderly patients with multiple comorbidities who require treatments and investigations that expose them to electromagnetic fields of varying strengths and durations, including other implanted electromodulatory devices.

OBJECTIVE

To determine if clinically significant interference arises between DBS and cardiac pacemaker systems.

METHODS

Here we audited 8 patients, mean age 72, with cardiac pacemakers and DBS implanted from 2007 to 2015. We investigated details of their neurological and electrocardiological treatment and progress and sought evidence for interference between the two systems.

RESULTS

We found no evidence of DBS dysfunction, and only one case of abnormal pacemaker interrogation 2 yr post-DBS implantation was found, which was thought to be secondary to a medication issue rather than neuromodulation interference.

CONCLUSION

Our research reassures the clinician that pacemakers and DBS systems do not appear to affect one another and provides guidance on minimizing possibility of this.
Surgical Resection of a Recurrent Intramedullary Spinal Epidermoid Cyst: 2-Dimensional Operative Video
Authors: Nichols Noah , Yerneni Ketan , Osorio Joseph A , McDermott Michael , Tan Lee A
Published: March 2019

Intramedullary spinal epidermoid cysts are rare tumors and only account for 1% of all spinal tumors in adults. Epidermoid cysts can develop from ectodermal tissue that was inappropriately positioned in the primitive neural tube during closure; acquired forms exist for epidermoid cysts as they can emerge in an iatrogenic manner following repeated lumbar punctures. Malignant progression of epidermoid cysts is extremely rare, and symptoms typically depend on tumor location. Surgical resection is the preferred treatment. Gross total resection is ideal; however, partial resections have demonstrated satisfactory long-term outcomes.

 We present a 54-yr-old man with symptomatic recurrence of thoracic intramedullary epidermoid cyst after two prior resections (25 yr and 11 yr ago, respectively). The patient noted worsening back pain, leg spasticity and weakness. Magnetic resonance imaging (MRI) of the thoracic spine demonstrated interval expansion of the upper thoracic intramedullary epidermoid cyst compared to surveillance MRI from 3 yr prior.

 Given the progressive nature of symptoms, the patient elected to have surgical resection of the tumor. This operative video highlights the technique and surgical nuances of gross-total resection of a recurrent thoracic intramedullary spinal epidermoid cyst. This patient was noted to have a stable neurological exam at the 6-mo follow-up visit with planned adjuvant radiation treatment.

 There is no identifying information in this video. Patient consent was obtained for publishing of the material included in the video.
Intraoperative Management of an Enlarged Suprameatal Tubercle During Microvascular Decompression of the Trigeminal Nerve, Surgical and Anatomical Description: 2-Dimensional Operative Video
Authors: Peris-Celda Maria , Perry Avital , Carlstrom Lucas P , Graffeo Christopher S , Link Michael J
Published: March 2019

The suprameatal tubercle is a variable prominence of the posterior aspect of the petrous part of the temporal bone located above the internal acoustic meatus. An enlarged suprameatal tubercle (EST) may present an obstacle during posterior fossa operations, including microvascular decompression (MVD).

 In this video we present the case of a 55-yr-old woman with 2 yr of medically refractory left V2-3 typical trigeminal neuralgia. Magnetic resonance imaging (MRI) was suspicious for a compressive superior cerebellar artery (SCA) loop, and negative for any other pathological findings. A left retrosigmoid craniotomy was performed, and upon initial exploration, only the most proximal, superior aspect of the trigeminal nerve was unobscured by an EST. The EST was subsequently removed using the ultrasonic aspirator with bone cutting attachment, allowing full visualization of the nerve from root entry zone (REZ) to Meckel's cave. Inferiorly, a small EST remnant was left to protect the VII-VIII complex. An MVD was performed using Teflon felt to elevate the SCA loop off the REZ and nerve, which was then fully explored, to ensure complete decompression. The patient recovered well with resolved trigeminal neuralgia and no new deficit.

 EST is a rare anatomic variant, with potentially significant implications for visualization of structures superior and deep to the internal acoustic canal, including the trigeminal REZ and nerve. Resection of the tubercle is safe, and recommended where it markedly obstructs the operative corridor. Care should be taken to wax the drilled surface of the petrous temporal bone and minimize incumbent risk of cerebrospinal fluid leak.

 Informed consent was appropriately documented and verified as outlined by our institutional guidelines.
Embolization of a Complex Facial Arteriovenous Malformation, Balloon-Assisted Flow Arrest, and Controlled n-BCA Injection with Dextrose Push Technique: 2-Dimensional Operative Video
Authors: Brunozzi Denise , Alaraj Ali
Published: March 2019

N-butyl cyanoacrylate glue (n-BCA, Cerenovus, Irvine, California) is commonly used to treat arteriovenous malformation (AVM). Even though Onyx (ethylene vinyl alcohol, Medtronic, Dublin, Ireland) presents more controlled injection, n-BCA is colorless, thus preferable for treatment of superficial facial malformations. N-BCA injection into AVM can result in premature distal migration or early precipitation and reflux into the feeder vessels. Here we describe a trans-arterial balloon assisted technique embolization of a complex facial AVM with n-BCA. A 22-yr-old female with chronic oral/gum bleeding presented with a complex facial AVM. She underwent selective transarterial n-BCA balloon assisted treatment with dextrose push. Informed written consent was obtained. A Scepter dual lumen balloon (MicroVention, Aliso Viejo, California) and a Prowler microcatheter (Cerenovus) were introduced via a 6-French Envoy guide catheter (Cerenovus) selectively into the AVM feeder. The balloon was positioned 3 cm proximal to the Prowler microcatheter tip and fully inflated to create flow arrest. Diluted 25% concentration of n-BCA in Ethiodol Oil was injected through the Prowler microcatheter. The distal migration of the n-BCA was modulated with simultaneous injection of Dextrose 5% in water via the Scepter balloon. This resulted in a controlled glue injection without early distal glue migration (because of the flow arrest) nor early proximal glue precipitation or reflux (because of the dextrose infusion), obtaining complete cure of the complex facial AVM. Glue embolization with flow arrest and dextrose push allows well controlled injection, and it represents a valid option also for high flow vascular lesions.
ERK2 phosphorylates the epigenetic regulator CXXC-finger protein 1 (CFP1)
Authors: Karra Aroon S. , Klein Aileen M. , Earnest Svetlana , Stippec Steve , Wichaidit Chonlarat , McGlynn Kathleen , Trudgian David C. , Mirzaei Hamid , Cobb Melanie H.
Published: March 2019

Background

The Ras-Raf-MEK-ERK signaling pathway is essential for proper development and homeostatic regulation in eukaryotic cells and underlies progression of several types of cancer. Many pathway functions are performed by extracellular signal-regulated kinase (ERK)1 and 2 (ERK1/2), serine/threonine protein kinases of the mitogen-activated protein kinase (MAPK) family that interact with a large number of substrates and are highly active in the nucleus.

Results

We identified the epigenetic regulator CXXC-finger protein 1 (CFP1) as a protein that interacts with ERK2 on chromatin. CFP1 is involved in multiple aspects of chromatin regulation, including histone methylation and DNA methylation. Here, we demonstrate the overlapping roles for ERK1/2 and CFP1 in regulation of immediate early gene (IEG) induction. Our work suggests multiple modes of co-regulation and demonstrates that CFP1 is required for an optimal signal-dependent response. We also show that CFP1 is an ERK2 substratein vitroand identify several phosphorylation sites. Furthermore, we provide evidence that Su(var)3-9, Enhancer-of-zeste and Trithorax (Set)1b, a CFP1-interacting histone methylase, is phosphorylated by ERK2 and is regulated by CFP1.

Conclusion

Our work highlights ERK1/2 interactions with chromatin regulators that contribute to MAPK signaling diversity in the nucleus.
Circulating Lysophosphatidylcholines, Phosphatidylcholines, Ceramides, and Sphingomyelins and Ovarian Cancer Risk: a 23-year Prospective Study
Authors: Zeleznik Oana A. , Clish Clary B. , Kraft Peter , Avila-Pancheco Julian , Eliassen A. Heather , Tworoger Shelley S.
Published: March 2019

Background

Experimental evidence supports a role of lipid dysregulation in ovarian cancer progression and metastasis. We estimated associations with ovarian cancer risk for circulating levels of four lipid groups measured 3-23 years before diagnosis.

Methods

Analyses were conducted among cases (N = 252) and matched controls (N = 252) from the Nurses’ Health Studies. We used logistic regression adjusting for risk factors to investigate associations of lysophosphatidylcholines (LPC), phosphatidylcholines (PC), ceramides (CER), and sphingomyelins (SM) with ovarian cancer risk overall and by histotype. A Bonferroni adjusted p-value threshold of 0.0125 (0.05/4; 4 measured lipid groups) was used to evaluate statistical significance. Odds ratios (OR; 10thto the 90thpercentile) and 95% confidence intervals of ovarian cancer risk were estimated.

Results

C16:0 SM, C18:0 SM, C16:0 CER and SM sum were significantly positively associated with ovarian cancer risk, with ORs ranging from 1.95-2.10, with stronger ORs for postmenopausal women (2.02-3.22). ORs were generally similar for serous/poorly differentiated and endometrioid/clear cell tumors, although most did not meet the Bonferroni-adjusted p-value for significance. C18:1 LPC and the ratio of LPC to PC were significantly inversely, while C18:0 SM was significantly positively, associated with risk of endometrioid/clear cell tumors.

Conclusion

Elevated levels of circulating SMs 3-23 years before diagnosis were associated with increased risk of ovarian cancer, regardless of histotype, with stronger associations among postmenopausal women. Prospective and experimental studies are required to validate our findings and understand the role of lipid dysregulation, SMs in particular, in ovarian carcinogenesis.
Older age at Initiation of Antiretroviral Therapy Predicts Low Bone Mineral Density in Children with perinatally-infected HIV in Zimbabwe
Authors: Gregson Celia L , Hartley April , Majonga Edith , Mchugh Grace , Crabtree Nicola , Rukuni Ruramayi , Bandason Tsitsi , Mukwasi-Kahari Cynthia , Ward Kate A , Mujuru Hilda , Ferrand Rashida A
Published: March 2019

Background

Perinatally-acquired HIV infection commonly causes stunting in children, but how this affects bone and muscle development is unclear. We investigated differences in bone and muscle mass and muscle function between children with HIV (CWH) and uninfected children.

Setting

Cross-sectional study of CWH (6–16 years) receiving antiretroviral therapy (ART) for >6 months and children in the same age-group testing HIV-negative at primary health clinics in Zimbabwe.

Methods

From Dual-energy X-ray Absorptiometry (DXA) we calculated total-body less-head (TBLH) Bone Mineral Content (BMC) for lean mass adjusted-for-height (TBLH-BMCLBM) Z-scores, and lumbar spine (LS) Bone Mineral Apparent Density (BMAD) Z-scores.

Results

The 97 CWH were older (mean age 12.7vs. 10.0 years) and therefore taller (mean height 142cmvs. 134cm) than those 77 uninfected. However, stunting (height-for-age Z-score≤-2) was more prevalent in CWH (35%vs. 5%,p<0.001). Amongst CWH, 15% had low LS-BMAD (Z-score ≤-2) and 13% had low TBLH-BMCLBM, vs. 1% and 3% respectively in those uninfected (bothp≤0.02). After age, sex, height and puberty adjustment, LS-BMAD was 0.33 SDs (95%CI −0.01, 0.67;p=0.06) lower in CWH, with no differences in TBLH-BMCLBM, lean mass or grip strength by HIV status. However, there was a strong relationship between age at ART initiation and both LS-BMAD Z-score (r=-0.33,p=0.001) and TBLH-BMCLBMZ-score (r=-0.23,p=0.027); for each year ART initiation was delayed a 0.13 SD reduction in LS-BMAD was seen.

Conclusion

Size-adjusted low bone density is common in CWH. Delay in initiating ART adversely affects bone density. Findings support immediate ART initiation at HIV diagnosis.
Comparative analysis, applications, and interpretation of electronic health record-based stroke phenotyping methods
Authors: Thangaraj Phyllis M. , Kummer Benjamin R. , Lorberbaum Tal , Elkind Mitchell V. S. , Tatonetti Nicholas P.
Published: March 2019

Background and Purpose

Accurate identification of acute ischemic stroke (AIS) patient cohorts is essential for a wide range of clinical investigations. Automated phenotyping methods that leverage electronic health records (EHRs) represent a fundamentally new approach cohort identification. Unfortunately, the current generation of these algorithms is laborious to develop, poorly generalize between institutions, and rely on incomplete information. We systematically compared and evaluated the ability of several machine learning algorithms and case-control combinations to phenotype acute ischemic stroke patients using data from an EHR.

Methods

Using structured patient data from the EHR at a tertiary-care hospital system, we built machine learning models to identify patients with AIS based on 75 different case-control and classifier combinations. We then determined the models’ classification ability for AIS on an internal validation set, and estimated the prevalence of AIS patients across the EHR. Finally, we externally validated the ability of the models to detect self-reported AIS patients without AIS diagnosis codes using the UK Biobank.

Results

Across all models, we found that the mean area under the receiver operating curve for detecting AIS was 0.963±0.0520 and average precision score 0.790±0.196 with minimal feature processing. Logistic regression classifiers with L1 penalty gave the best performance. Classifiers trained with cases with AIS diagnosis codes and controls with no cerebrovascular disease diagnosis codes had the best average F1 score (0.832±0.0383). In the external validation, we found that the top probabilities from a model-predicted AIS cohort were significantly enriched for self-reported AIS patients without AIS diagnosis codes (65-250 fold over expected).

Conclusions

Our findings support machine learning algorithms as a way to accurately identify AIS patients without relying on diagnosis codes or using process-intensive manual feature curation. When a set of AIS patients is unavailable, diagnosis codes may be used to train classifier models. Our approach is potentially generalizable to other academic institutions and further external validation is needed.
Estimating the effect of the 2005 change in BCG policy in England: A retrospective cohort study
Authors: Abbott Sam , Christensen Hannah , Welton Nicky , Brooks-Pollock Ellen
Published: March 2019

Background

In 2005, England changed from universal Bacillus Calmette–Guérin (BCG) vaccination of school-age children to targeted BCG vaccination of high-risk children at birth.

Methods

We combined notification data from the Enhanced Tuberculosis Surveillance system, with demographic data from the Labour Force Survey to construct retrospective cohorts of individuals in England relevant to both the universal, and targeted vaccination programmes between Jan 1, 2000 and Dec 31, 2010. For each cohort, we estimated incidence rates over a 5 year follow-up period and used Poisson and Negative Binomial regression models in order to estimate the impact of the change in policy on TB.

Results

In the non-UK born, we found evidence for an association between a reduction in incidence rates and the change in BCG policy (school-age IRR: 0.74 (95%CI 0.61, 0.88), neonatal IRR: 0.62 (95%CI 0.44, 0.88)). We found some evidence that the change in BCG policy was associated with a increase in incidence rates in the UK born school-age population (IRR: 1.08 (95%CI 0.97, 1.19)) and weaker evidence of an association with a reduction in incidence rates in UK born neonates (IRR: 0.96 (95%CI 0.82, 1.14)). Overall, we found that the change in BCG policy was associated with directly preventing 385 (95% CI −105, 881) TB cases.

Conclusions

Withdrawing universal vaccination at school-age and targeting BCG vaccination towards high-risk neonates was associated with reduced incidence of TB in England. This was largely driven by reductions in the non-UK born. There was a slight increase in UK born school-age cases.

Key Messages

There is little existing literature on the impact of withdrawing universal school-age BCG vaccination and introducing high-risk neonatal BCG vaccination on TB incidence rates in the populations directly affected by the vaccination programmes.

There was strong evidence that the change in policy was associated with a decrease in TB incidence rates in non-UK born neonates and school-age children. In the UK born individuals, there was some evidence that the change in policy was associated with an increase in TB incidence rates in those relevant to the universal school-age scheme, with little evidence of a decrease in incidence rates in those relevant to the high-risk neonatal vaccination scheme.

Overall the change in vaccination policy was associated with preventing TB cases, mainly in the non-UK born.

These results provide an important evaluation of the direct effects of both withdrawing and implementing a BCG vaccination programme in a low incidence, high income, country and are relevant to several other countries that have made similar changes to their vaccination programmes.
Reducing RSV hospitalisation in a lower-income country by vaccinating mothers-to-be and their households
Authors: Brand Samuel P. C. , Munywoki Patrick , Walumbe David , Keeling Matt J. , Nokes D. James
Published: March 2019

Respiratory syncytial virus is the leading cause of lower respiratory tract infection among infants. RSV is a priority for vaccine development. In this study, we investigate the potential effectiveness of a two-vaccine strategy aimed at mothers-to-be, thereby boosting maternally acquired antibodies of infants, and their household cohabitants, further cocooning infants against infection. We use a dynamic RSV transmission model which captures transmission both within households and communities, adapted to the changing demographics and RSV seasonality of a low-income country. Model parameters were inferred from past RSV hospitalisations, and forecasts made over a 10-year horizon. We find that a 50% reduction in RSV hospitalisations is possible if the maternal vaccine effectiveness can achieve 75 days of additional protection for newborns combined with a 75% coverage of their birth household co-inhabitants (∼7.5% population coverage).
Expression patterns of PD-L1 and PD-1 provide rationales for immune checkpoint inhibition in soft tissue sarcomas
Authors: Orth Martin F. , Buecklein Veit L. , Kampmann Eric , Subklewe Marion , Noessner Elfriede , Cidre-Aranaz Florencia , Romero-Pérez Laura , Wehweck Fabienne S. , Lindner Lars , Issels Rolf , Kirchner Thomas , Altendorf-Hofmann Annelore , Grünewald Thomas G. P. , Knösel Thomas
Published: March 2019

Soft tissue sarcomas (STS) are highly malignant cancers with mesenchymal origin. In many instances, clinical outcome is poor due to high rates of local recurrence and metastasis.

The programmed death receptor ligand 1 (PD-L1) is expressed in several cancers. PD-L1 interacts with its receptor, PD-1, on the surface of tumor infiltrating lymphocytes (TILs), thereby attenuating anti-cancer immune response. Immune checkpoint inhibitors targeting this interaction are promising new anti-cancer drugs. However, present studies on the PD-L1 and PD-1 expression status in STS are limited either by small sample size, analysis of single STS subtypes, or lack of combinatorial assessment of PD-L1, PD-1 and TILs.

To overcome these limitations, we evaluated the expression patterns of intratumoral PD-L1, the amount of TILs and their PD-1 expression status, as well as associations with clinicopathological parameters in a large and comprehensive cohort of 274 samples comprising more than six STS subtypes.

We found that nearly all STS subtypes showed partial PD-L1 expression, albeit with a broad range of PD-L1 positivity across subtypes (50% angiosarcomas, 23% UPS, 13% leiomyosarcomas, 12% dedifferentiated liposarcomas, 3% synovial sarcomas, 0 MPNST, and 18% mixed sarcomas). Co-expression and correlation analyses uncovered that expression of PD-L1 was associated with more PD-1 positive TILs (P< 0.001), higher tumor grading (P= 0.022) and worse patients’ 5-year overall survival (P= 0.016).

In sum, the substantial portion of STS showing PD-L1 expression, the simultaneous presence of PD-1 positive TILs, and the association of PD-L1 with unfavorable clinical outcome provide a rationale for immune checkpoint inhibition in patients with PD-L1-positive STS.
The Anaerobic Efflux Pump MdtEF-TolC Confers Resistance to Cationic Biocides
Authors: Novoa Diego , Conroy-Ben Otakuye
Published: March 2019

TheE. coliRND transporter MdtEF-TolC is a tri-partite efflux pump that exports toxic substances. Little is known of the full range of substrate specificity of the anaerobic efflux pump, but MdtF shares similar homology and substrate specificity to the major RND efflux protein AcrB. To determine the substrate range of the anaerobic efflux pump MdtEF-TolC,E. colimutants were exposed to 210 different biocides, and growth was monitored. This approach was used to validate AcrAB-TolC substrates and discover new chemicals transported by the major antibiotic efflux protein. Results showed that overexpression of MdtEF conferred resistance to the same substrates as AcrAB-TolC, but were limited to cationic amino-based biocides. Alignment of the amino acids lining the distal pocket of MdtF and AcrB revealed a more acidic isoelectric point (pI) of an order of magnitude in MdtF, whereas the proximal pocket and external cleft were homologous and displayed identical pIs. This analysis suggests that pH, which determines acid-base speciation, and the distal pocket surface proteins play a role in MdtF substrate specificity.

Importance

High-throughput screening ofE. colimutants revealed that the substrates of the anaerobic efflux pump MdtEF-TolC are the same cationic biocides exported by AcrAB-TolC. Comparison of the protein sequences of the distal pocket, proximal pocket, and external cleft of the two RND proteins showed homology in amino acid surface charge and isoelectric point. Residue differences within the distal pocket are responsible for a more acidic pI and greater negative charge of the inner membrane protein MdtF surface, and support the findings of transport of cationic substances.
Resistance Rate Distribution of MDR-TB Among Pulmonary Tuberculosis Patients Attending Nnamdi Azikiwe University Teaching Hospital Nnewi and ST Patrick’S Hospital Mile 4 Abakiliki in Southeast Nigeria
Authors: Okoro Chinenye Esther , Akujobi Confort Nnenna , Udoh Iniekong Philip , Ibhawaegbele Stellamaris Ojiuzor , Ezema Charles Ikechukwu , Ezeugwu Uchechukwu Anthonia , Dozie-Nwakile Ogechukwu Calista , Okpe Aaron Chukwuemeka
Published: March 2019

Tuberculosis, one of the oldest recorded human afflictions, is still one of the biggest killers among the infectious diseases, despite the worldwide use of a live attenuated vaccine and several antibiotics. This study was designed to assess the resistance rate distribution of MDR-TB among pulmonary tuberculosis patients attending Nnamdi Azikiewe University Teaching Hospital (NAUTH) Nnewi and St Patrick’s Hospital Mile 4 Abakaliki in the Southeast Nigeria. Patients with persistent cough for over two weeks were screened by Ziehl-Neelsen (ZN) technique for the presence of acid fast bacilli (AFB) in their sputum and a total of 103 patients with AFB positive sputum samples were recruited. The positive sputum samples were subjected to Xpert MTB/RIF assay (GeneXpert®, Cepheid USA) and culture on Lowestein Jensen medium for 42days at 37°C. Drug susceptibility testing was done on the isolates using the nitrate reduction assay (NRA). Xpert MTB/RIF assay detected MTB in 83(80.6%) samples out of which 45(67.2%) were rifampicin resistant. Sixty-seven (80.7%) of the isolates were resistant to at least one of the first-line drugs. Primary resistance was 91% while 19.4%, 35.8%, 22.4% and 22.4% of the isolates were resistant to one, two, three and four drugs respectively. Isoniazid had the highest rate of resistance (57.8%) while Ethambutol had the least (34.9%) and 30(44.8%) of the resistant isolates were MDR. Smoking (P=.002), gender (P=.002) and history of TB treatment (P=.012) were significantly associated with drug resistance. Educational status was significantly associated with MDR-TB (P=.020). NAUTH and St Patrick’s hospital had MDR-TB rates of 38.9% and 46.9% respectively. The findings of this study indicate high prevalence of MDR-TB among patients with pulmonary TB in the study sites and this portrays a menace to adequate TB control. Prompt diagnosis of TB, adequate patient compliance to therapy and increased awareness and mass education is recommended
Development, characterization and standardization of a nose-only inhalation exposure system for exposure of rabbits to small particle aerosols containingFrancisella tularensis
Authors: O’ Malley Katherine J. , Bowling Jennifer D. , Barry Eileen M. , Hazlett Karsten R. O. , Reed Douglas S.
Published: March 2019

Inhalation ofFrancisella tularensis(Ft) causes pneumonic tularemia in humans, a severe disease with a 30-60% mortality rate. Reproducible delivery of aerosolized virulent bacteria in relevant animal models is essential for evaluating medical countermeasures. Here we developed optimized protocols for infecting New Zealand White (NZW) rabbits with aerosols containingFt. We evaluated relative humidity, aerosol exposure technique, and bacterial culture conditions to optimize spray factor (SF), a central metric of aerosolization. This optimization reduced both inter-and intra-daily variability and were applicable to multiple isolates ofFt. Further improvements in the accuracy and precision of the inhaled pathogen dose were achieved through enhanced correlation of bacterial culture OD and CFU. Plethysmograph data collected during exposures found that respiratory function varied considerably between rabbits, was not a function of weight, and did not improve with acclimation to the system. Vaccine Strain (LVS)-vaccinated rabbits were challenged via aerosol with human-virulentFtSCHU S4 that had been cultivated in either Mueller Hinton Broth (MHB) or Brain Heart Infusion (BHI) broth. LVS-vaccinated animals challenged with MHB-SCHU S4 experienced short febrile periods (median: 3.2 days), limited weight loss (< 5%), and longer median survival times (~18 d) that were significantly different than unvaccinated controls. In contrast, LVS-vaccinated rabbits challenged with BHI SCHU S4 experienced longer febrile periods (median: 5.5 days), greater weight loss (> 10%), and median survival times that were not significantly different than unvaccinated controls. These studies highlight the importance of careful characterization and optimization of protocols for aerosol challenge with pathogenic agents.
Bioelectrical signaling via domain wall migration
Authors: McNamara Harold M. , Salegame Rajath , Tanoury Ziad Al , Xu Haitan , Begum Shahinoor , Ortiz Gloria , Pourquie Olivier , Cohen Adam E.
Published: March 2019

Abstract

Electrical signaling in biology is typically associated with action potentials, transient spikes in membrane voltage that return to baseline. The Hodgkin-Huxley equations of electrophysiology belong to a more general class of reaction-diffusion equations which could, in principle, support patterns of membrane voltage which are stable in time but structured in space. Here we show theoretically and experimentally that homogeneous or nearly homogeneous tissues can undergo spontaneous spatial symmetry breaking into domains with different resting potentials, separated by stable bioelectrical domain walls. Transitions from one resting potential to another can occur through long-range migration of these domain walls. We map bioelectrical domain wall motion using all-optical electrophysiology in an engineered stable cell line and in human iPSC-derived myoblasts. Bioelectrical domain wall migration may occur during embryonic development and during physiological signaling processes in polarized tissues. These results demonstrate a novel form of bioelectrical pattern formation and long-range signaling.
Modeling decision-making under uncertainty: a direct comparison study between human and mouse gambling data
Authors: Cabeza Lidia , Giustiniani Julie , Chabin Thibault , Ramadan Bahrie , Joucla Coralie , Nicolier Magali , Pazart Lionel , Haffen Emmanuel , Fellmann Dominique , Gabriel Damien , Peterschmitt Yvan
Published: March 2019

Decision-making is a conserved evolutionary process enabling to choose one option among several alternatives, and relying on reward and cognitive control systems. The Iowa Gambling Task allows to assess human decision-making under uncertainty by presenting four cards decks with various cost-benefit probabilities. Participants seek to maximize their monetary gains by developing long-term optimal choice strategies. Animal versions have been adapted with nutritional rewards but interspecies data comparisons are still scarce. Our study directly compared physiological decision-making performances between humans and wild-type C57BL/6 mice. Human subjects fulfilled an electronic Iowa Gambling Task version while mice performed a maze-based adaptation with four arms baited in a probabilistic way. Our data show closely matching performances among species with similar patterns of choice behaviors. Moreover, both populations clustered into good, intermediate, and poor decision-making categories with similar proportions. Remarkably, mice good decision-makers behaved as humans of the same category, but slight differences among species have been evidenced for the other two subpopulations. Overall, our direct comparative study confirms the good face validity of the rodent gambling task. Extended behavioral characterization and pathological animal models should help strengthen its construct validity and disentangle determinants of decision-making in animals and humans.