bluuebunny/crossref_metadata_2025 huggingface dataset:
Perfluorooctanesulfonic Acid (PFOS) Thwarts the Beneficial Effects of Calorie Restriction and Metformin
Authors: Salter Deanna M , Wei Wei , Nahar Pragati P , Marques Emily , Slitt Angela L
Published: April 2021

A combination of calorie restriction (CR), dietary modification, and exercise is the recommended therapy to reverse obesity and nonalcoholic fatty liver disease. In the liver, CR shifts hepatic metabolism from lipid storage to lipid utilization pathways, such as AMP-activated protein kinase (AMPK). Perfluorooctanesulfonic acid (PFOS), a fluorosurfactant previously used in stain repellents and anti-stick materials, can increase hepatic lipids in mice following relatively low-dose exposures. To test the hypothesis that PFOS administration interferes with CR, adult male C57BL/6N mice were fed ad libitum or a 25% reduced calorie diet concomitant with either vehicle (water) or 100 μg PFOS/kg/day via oral gavage for 6 weeks. CR alone improved hepatic lipids and glucose tolerance. PFOS did not significantly alter CR-induced weight loss, white adipose tissue mass, or liver weight over 6 weeks. However, PFOS increased hepatic triglyceride accumulation, in both mice fed ad libitum and subjected to CR. This was associated with decreased phosphorylated AMPK expression in liver. Glucagon (100 nM) treatment induced glucose production in hepatocytes, which was further upregulated with PFOS (2.5 μM) co-treatment. Next, to explore whether the observed changes were related to AMPK signaling, HepG2 cells were treated with metformin or AICAR alone or in combination with PFOS (25 μM). PFOS interfered with glucose-lowering effects of metformin, and AICAR treatment partially impaired PFOS-induced increase in glucose production. In 3T3-L1 adipocytes, metformin was less effective with PFOS co-treatment. Overall, PFOS administration disrupted hepatic lipid and glucose homeostasis and interfered with beneficial glucose-lowering effects of CR and metformin.
A parsimonious mechanistic model of reproductive and vegetative growth in fruit trees predicts consequences of fruit thinning and branch pruning
Authors: Bevacqua Daniele , Melià Paco , Cividini Martina , Mattioli Francesca , Lescourret Françoise , Génard Michel , Casagrandi Renato
Published: April 2021

Productivity of fruit tree crops depends on the interaction between plant physiology, environmental conditions and agricultural practices. We develop a mechanistic model of fruit tree crops that reliable simulates the dynamics of variables of interest for growers and consequences of agricultural practices while relying on a minimal number of inputs and parameters. The temporal dynamics of carbon content in the different organs (i.e., shoots—S, roots—R and fruits—F) are the result of photosynthesis by S, nutrient supply by R, respiration by S, R and F, competition among different organs, photoperiod and initial system conditions partially controlled by cultural practices. We calibrate model parameters and evaluate model predictions using unpublished data from a peach (Prunus persica) experimental orchard with trees subjected to different levels of branch pruning and fruit thinning. Fiinally, we evaluate the consequences of different combinations of pruning and thinning intensities within a multi-criteria analysis. The predictions are in good agreement with the experimental measurements and for the different conditions (pruning and thinning). Our simulations indicate that thinning and pruning practices actually used by growers provide the best compromise between total shoot production, which impacts next year’s abundance of shoots and fruits, and current year’s fruit production in terms of quantity (yield) and quality (average fruit size). This suggests that growers are not only interested in maximizing current year’s yield but also in its quality and its durability. The present work provides for modelers a system of equations based on acknowledged principles of plant science easily modifiable for different purposes. For horticulturists, it gives insights on the potentialities of pruning and thinning. For ecologists, it provides a transparent quantitative framework that can be coupled with biotic and abiotic stressors.
Factors Affecting the Infection of Sweet Cherry (Prunus avium) Fruit by Podosphaera cerasi
Authors: Probst Claudia , Pandey Binod , Swamy Prashant , Grove Gary
Published: April 2021

Powdery mildew caused by Podosphaera cerasi is the most important fungal disease of sweet cherries in the Pacific Northwest of the United States. In this study, several factors related to disease epidemiology were evaluated. The experiments were conducted to investigate flower susceptibility to P. cerasi infection by in planta and in vitro inoculation. The susceptibility of fruit at various developmental stages was investigated using defined concentrations of P. cerasi conidia. Furthermore, the threshold of conidial concentration required for fruit infection was determined. The pathogen activity during full bloom was limited and not related to fruit disease incidence and severity at harvest. Foliar infections always preceded fruit infections by an average of 42 days during the 3 years of the study. The onset of fruit infection followed, on average, 66 days after full bloom and appeared simultaneously on all susceptible cherry cultivars in the research orchard. Disease symptoms were only observed on fruit in Biologische Bundesanstalt, Bundessortenamt, and Chemical Industry scale 8 (maturity) in all cultivars examined. During this stage, a concentration of 500 conidia/ml was sufficient to cause fruit infection at harvest. Interaction between the inoculation dates and conidial concentration revealed a dependency of disease development on the host stage at the time of inoculation; the younger the fruit, the more conidia are needed to cause disease at harvest. Molecular studies showed a rapid increase in conidia viability at the transition from asymptomatic to the symptomatic disease of fruit. No evidence of ontogenic resistance of fruit to powdery mildew infection was observed.
THE RELATIONSHIP OF CORTISOL LEVELS WITH HIGH BLOOD PRESSURE IN RESIDENTS OF ST. PETERSBURG
Authors: Erin Anastasia , Rotar O. , Kolesova E. , Boyarinova M. , Alieva A. , Moguchaia E. , Baranova E. , Konradi A. , Shlyakhto E.
Published: April 2021

Objective:

Introduction. Cortisol is a hormone produced by the adrenal glands which can reflects stress and contributes to the development of elevated blood pressure. The aim of our work was to assess the association of increased morning cortisol with normal high blood pressure (BP) and hypertension (HT) in St. Petersburg residents.

Design and method:

Methods. A epidemiological survey of cardiovascular risk was performed in a multi-step stratified random sample of approximately 1600 participants of Saint = Petersburg in 2012–2013. 1600 participants aged 25–65 years were recruited. All subjects signed informed consent and filled validated questionnaires regarding lifestyle, concomitant disease and medication. Fasting blood sampling was performed according to standard procedures. Office BP was registered by OMRON (Japan) twice on right hand in sitting position with calculation of mean BP. Statistical analysis was performed using SPSS Statistics 20.

Results:

Results. Data analysis was possible in 1591 participants (566 (35,6%) males and 1025 (64,4%) females). The prevalence of different BP levels varies statistically significantly depending on gender, p less 0,0001. The average level of morning cortisol was significantly higher in males 526.65 [405.05;633.23] vs females 470.90 [362.55;597.25], p less 0,0001. Increased morning cortisol more than 536 nmol/l was significantly more often determined among males 263 (46.8%) comparing with females 371 (36.5%), p less 0,0001. The table 1 shows the prevalence of increased cortisol levels in groups different in BP.

According to the binary regression analysis adjusted for sex, age, abdominal obesity the association of cortisol level (morning) > 536 nmol/l with presence of normal high BP (OR 1.48 [1.04;2.11], p = 0.028) and HT (OR 1.59 [1.25;2.05], p less 0.0001) was revealed.

Conclusions:

Conclusions. Among the residents of St. Petersburg elevated cortisol levels was associated not only with hypertension but also with normal high blood pressure. Men had higher levels of the cortisol which was accompanied by higher prevalence of normal high blood pressure and hypertension compared to women.
Emerging Challenges in COVID-19 With Substance Use Disorders
Authors: Salahuddin Mohammed , Manzar Md Dilshad , Pandi-Perumal Seithikurippu R. , Bahammam Ahmed S.
Published: April 2021

Background and Objective:

People with substance use disorder (SUD) may be easily vulnerable to coronavirus disease-19 (COVID-19). Given the impaired lung function caused by COVID-19 may exacerbate the symptoms of patients already having preexisting opioids or central nervous system stimulants use disorder. This narrative review highlights the risks of interactions between COVID-19 and SUD.

Methods:

This article has systematically reviewed and collated relevant papers and articles identified through PubMed focusing on SUD and COVID-19.

Results:

SUD is characterized by an array of combined mental, physical, and behavioral symptoms, which is undoubtedly of great public health concern especially in the context of the recent advent of the COVID-19 pandemic. The myriad of physiological changes caused by COVID-19 and SUD may be additive or synergistic on various organ functions, hence this review has highlighted potential challenges and possible outcomes because of these interactions. Systematic delineation to parse out the combined COVID-19 and SUD pathology on a given organ function is crucial. Moreover, the primary measures to tackle the COVID-19 pandemic like home confinement and lack of social support may be a significant predictor of relapse in already sober individuals, thus alternate methodologies may be needed to confine this problem.

Conclusion:

This review highlights the importance of the intertwined epidemics interactions and proposes early measures to recognize the scope of problem at the individual level to prevent future challenges.
Outcomes of Women Undergoing Excision of the Retained Cervix After Supracervical Hysterectomy
Authors: McHale Melissa P. , Smith Anna Jo B. , Fader Amanda N. , Wethington Stephanie L.
Published: April 2021

OBJECTIVE:

To characterize the indications for and complication rates of excision of the retained cervix after supracervical hysterectomy.

METHODS:

We performed a retrospective cohort study of women undergoing excision of the retained cervix after supracervical hysterectomy in the 2010–2014 National Inpatient Sample. International Classification of Diseases, Ninth Revision codes were used to identify indication for the procedure and surgical complications. We weighted the hospital-level data to obtain nationwide estimates of patient characteristics, surgical complications, and length of stay.

RESULTS:

Nationwide, 1,140 women underwent excision of the retained cervix after hysterectomy. Their mean age was 49 years, and the majority were White and privately insured. Leiomyomas were the most commonly coded indication (35%, 95% CI 29–42), followed by prolapse (14%, 95% CI 9–18). Eighteen percent (95% CI 13.0–23.1) were performed for malignancy, including 5.3% (95% CI 2.3–8.2) for cervical cancer. Only 11.5% (95% CI 7.3–15.6) of cases were performed laparoscopically. The overall complication rate was high (38%, 95% CI 32–45), particularly for bleeding complications (26%, 95% CI 20–31) and transfusion (15%, 95% CI 11–20). Gastrointestinal complication rates were second highest (8%, 95% CI 5–12); ileus was the most common gastrointestinal complication (7.0%, 95% CI 3.7–10.4). The median length of stay was 2 days (range 0–34).

CONCLUSION:

Women who undergo excision of the retained cervix after supracervical hysterectomy experience high rates of complications, the most common of which was bleeding. Patient counseling regarding removal of the cervix at the time of hysterectomy should include this information.
Surgical Outcome of Spinal Fusion for Osteogenesis Imperfecta With Scoliosis: Is the Hybrid System With Pedicle Screws Applicable to Weak, Tiny, and Fragile Vertebrae?
Authors: Ito Masaaki , Kakutani Kenichiro , Miyamoto Hiroshi , Suzuki Teppei , Yurube Takashi , Uno Koki
Published: April 2021

Introduction:

Corrective surgery for spinal deformity associated with osteogenesis imperfecta (OI) is challenging due to the severe and rigid deformity combined with extreme bone fragility. However, surgical outcomes still remain unclear. In addition, the applicability of pedicle screws (PSs) to the tiny and fragile vertebrae in patients with OI is poorly understood. This study evaluated the surgical outcome, and the accuracy and safety of PS placement in patients with OI.

Methods:

Twenty-five patients with OI were included in this study. Mean age was 21.0±9.3 (10 to 49) years. Mean follow-up was 5.8±2.0 years. The Sillence classification showed 16 patients had the mildest type I, 1 patient had moderate type IV, and 8 patients had the most severe type III. Fifteen patients underwent anterior release followed by posterior fusion, and 10 patients underwent only posterior fusion. The accuracy of PS placement was evaluated with postoperative computed tomography.

Results:

Scoliosis was corrected from 95.6 to 65.8 degrees after surgery (correction rate 32.5%) and 68.1 degrees at final follow-up (both, P<0.01). Space available for the lung was improved from 76.3% to 84.9% (P<0.05). No implant dislodgement occurred after surgery. A total of 290 screws were placed, of which 213 screws (73.4%) were placed completely. However, 30 screws (10.3%) penetrated >2 mm. In particular, rates of >2 mm penetration was much higher in type III than type I and IV (27.8% vs. 3.0%; P<0.01). Complications related to spinal surgery included 2 transient neurological disturbances.

Conclusions:

PSs were applicable to spinal fusion surgery in patients with OI. However special care should be taken in placing PSs because of the weakness of the pedicle cortex, which was easily penetrated especially in Sillence type III.

Level of Evidence:

Level IV.
Long-term survival in an acute promyelocytic leukemia patient with recurrent granulocytic sarcomas
Authors: Zhou Xuehui , Li Chengwen
Published: April 2021

Rationale:

Granulocytic sarcoma (GS) is an extramedullary myeloid tumor composed of immature cells of the granulocytic series. It rarely occurs in acute promyelocytic leukemia (APL). No case of long-term survival in an APL patient with recurrent GS has been reported.

Patient concerns:

A 54-year-old female patient was diagnosed with APL in 1995 and has been in complete remission (CR) of bone marrow morphology for 24 years; however, recurrent GS occurred successively in ovary, breast, spine, body of sternum, lymph nodes, soft tissues from 2004 to 2019.

Diagnoses:

The immunohistochemistry confirmed the diagnosis of GS, and fluorescence in situ hybridization (FISH) revealed its origin from APL.

Interventions:

She received surgery, and had an excellent response to all-trans retinoic acid (ATRA), DA (daunorubicin combined with cytarabine) regimens, and arsenic trioxide (ATO).

Outcomes:

The patient achieved CR in March 2020 after radiotherapy followed by ATO and ATRA. So far, she is still in follow-up.

Lessons:

It is rare that recurrent GS at multiple sites is involved in APL patient with bone marrow morphology in CR. It is interesting to observe a long-term excellent response to ATRA, chemotherapy and ATO. Although multiple recurrence of GS in patients with APL is rare, the data in this case highlight the need for individualized treatment when such conditions occur.
Assessment of lesion-associated myocardial ischemia based on fusion coronary CT imaging – the FUSE-HEART study
Authors: Stanescu Alexandra Gorea , Benedek Imre , Opincariu Diana , Hodas Roxana , Ratiu Mihaela , Benedek Theodora
Published: April 2021

Introduction:

Multimodality assessment of coronary artery lesions has demonstrated superior effectiveness compared to the conventional approach, for assessing both anatomical and functional significance of a coronary stenosis. Multiple imaging modalities can be integrated into a fusion imaging tool to better assess myocardial ischemia.

Material and methods:

The FUSE-HEART trial is a single center, prospective, cohort study that will assess the impact of a coronary artery stenosis on myocardial function and viability, based on advanced fusion imaging technics derived from Cardiac Computed Tomography Angiography (CCTA). Moreover, the study will investigate the correlation between morphology and composition of the coronary plaques and myocardial ischemia in the territory irrigated by the same coronary artery. At the same time, imaging parameters will be correlated with inflammatory status of the subjects. The trial will include 100 subjects with coronary lesions found on CCTA examination. The study population will be divided into 2 groups: first group will consist of subjects with anatomically significant coronary lesions on native coronary arteries and the second one will include subjects surviving an acute myocardial infarction. The vulnerability score of the subjects will be calculated based on presence of CCTA vulnerability markers of the coronary plaques: napkin ring sign, positive remodeling, spotty calcifications, necrotic core, and low-density plaques. 3D fusion images of the coronary tree will be generated, integrating the images reflecting wall motion with the ones of coronary circulation. The fusion models will establish the correspondence between plaque composition and wall motion in the subtended myocardium of the coronary artery. The study primary outcome will be represented by the rate of major adverse cardiac events related to myocardial ischemia at 1-year post assessment, in correlation with the degree of coronary artery stenosis and myocardial ischemia or viability.

The secondary outcomes are represented by the rate of re-hospitalization, rate of survival and rate of major adverse cardiovascular events (including cardiovascular death or stroke), in correlation with the morphology and composition of atheromatous plaques located in a coronary artery, and myocardial ischemia in the territory irrigated by the same coronary artery.

Conclusion:

In conclusion, FUSE-HEART will be a study based on modern imaging tools that will investigate the impact of a coronary artery stenosis on myocardial function and viability, using advanced fusion imaging technics derived from CCTA, sighting to validate plaque composition and morphology, together with inflammatory biomarkers, as predictors to myocardial viability.
Association between MMP-2 gene polymorphism and cataract susceptibility
Authors: Jiang Huaiyan , Gao Yang , Chen Zhen , Xu Hongxia
Published: April 2021

Background:

Matrix metalloproteinase-2 (MMP-2) polymorphisms have been considered as risk factors of cataracts, but the results still remain controversial. In this study, we have performed a systematic meta-analysis to evaluate the association between MMP-2 polymorphisms and cataract risks.

Methods:

Published literature was retrieved from Wanfang, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, Chongqing VIP Chinese Science and Technology Periodical Database, PubMed, Embase, and Web of Science databases. The case–control studies that explored the association between MMP-2 polymorphisms and cataract risks were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random- or fixed-effects model.

Results:

This study could provide high-quality and evidence-based medical evidence for the correlation between MMP-2 polymorphisms and cataract risks

Conclusion:

The study could provide updated evidence for the evaluation of the relationship between MMP-2 polymorphism and cataract risk.

Ethics and dissemination:

The private information from individuals will not be published. This systematic review also will not involve endangering participant rights. Ethical approval is not available. The results may be published in a peer-reviewed journal or disseminated in relevant conferences.

OSF Registration Number:

DOI 10.17605/OSF.IO/KU9NE.
Associations of Common Depression Treatment Metrics With Patient-centered Outcomes
Authors: Carlo Andrew D. , Basu Anirban , Unützer Jürgen
Published: April 2021

Background:

Various metrics predicated on Patient Health Questionnaire-9 (PHQ-9) scores denote depression “response” or “remission” over time, but few have been empirically validated. We compare the associations of depression response and remission metrics with concomitant clinical improvement in patient-centered outcomes (PCOs).

Subjects:

Secondary analysis of PHQ-9 and PCO data from the treatment arm (n=906) of the Improving Mood—Promoting Access to Collaborative Treatment (IMPACT) trial.

Research Design:

We conducted univariate correlations between 9 depression treatment metrics and 4 PCOs. For each PCO, we specified a multivariate linear fixed-effects regression model with penalized LASSO (least absolute shrinkage and selection operator) variable selection that included parameters for each incremental absolute PHQ-9 decrease between 0 and 16 points. Model predictive properties were assessed using a split sample analysis.

Results:

There was a notable variation in depression improvement rates across metrics. Each metric was significantly associated with PCOs in univariate analyses. In the multivariate models, the cumulative likelihood of PCO improvement was most improved by absolute PHQ-9 score decreases of 7–9 and 14–16 points. The multivariate models showed greater area under the curve (0.671–0.804) in out-of-sample predictions of PCO changes than the univariate models (0.529–0.649).

Conclusions:

Choice of depression response metric impacts observed response and remission rates, though PCOs tend to improve with depression improvement regardless of metric choice. Absolute incremental PHQ-9 score decreases are broadly associated with an increased likelihood of favorable PCO scores. Our findings support a novel PHQ-9 metric defined by an absolute score change of 8 points or greater.
The CERTAIN Study Results
Authors: Wright Thomas C. , Stoler Mark H. , Ferenczy Alex , Ranger-Moore James , Fang Qijun , Kapadia Monesh , Singh Shalini , Ridder Ruediger
Published: April 2021

The Lower Anogenital Squamous Terminology (LAST) Project recommends the use of p16 immunohistochemistry as an adjunct to morphologic assessment of cervical biopsies according to a specific set of criteria. We analyzed the effect of adjunctive p16 according to LAST criteria in a US-based diagnostic utility study involving 70 surgical pathologists providing a total of 38,500 reads on cervical biopsies. Compared with the results obtained using hematoxylin and eosin-stained slides only, including p16-stained slides per LAST criteria increased sensitivity and specificity for diagnosing histologic high-grade squamous intraepithelial lesions across all cases by 8.1% (95% confidence interval [95% CI], 6.5-9.7; P<0.0001) and 3.5% (95% CI, 2.8-4.2; P<0.0001), respectively, using expert consensus diagnoses on hematoxylin and eosin+p16 as reference. Within the subset of cases classified by the pathologists as fulfilling the LAST criteria, adding p16 significantly increased both sensitivity (+11.8%; 95% CI, 9.5-14.0; P<0.0001) and specificity (+9.7%; 95% CI, 7.8-11.5; P<0.0001). However, a comparable improvement in sensitivity (+11.0%; 95% CI, 7.8-14.1; P<0.0001) was found when p16 was used in cases for which p16 staining was not ordered per LAST by the pathologists, whereas specificity decreased by −0.8% (95% CI, −1.1 to −0.5; P<0.0001). The study demonstrates a clinically and statistically significant increase in sensitivity and specificity for high-grade squamous intraepithelial lesion when p16 is used according to LAST criteria. Expanding the use of p16 into non-LAST cases would lead to a comparable improvement in sensitivity within this subgroup of biopsies, at the cost of a minimal, but statistically significant difference in specificity.
Morphologic and Molecular Findings in Myxoid Hepatic Adenomas
Authors: Rowan Daniel J. , Yasir Saba , Chen Zongming E. , Mounajjed Taofic , Erdogan Damgard Sibel , Cummins Lisa , Zhang Lizhi , Whitcomb Emma , Falck Vince , Simon Sanford M. , Singhi Aatur D. , Torbenson Michael S.
Published: April 2021

Myxoid hepatic adenomas are a rare subtype of hepatic adenomas with distinctive deposition of extracellular myxoid material between the hepatic plates. A total of 9 cases were identified in 6 women and 3 men with an average of 59±12 years. The myxoid adenomas were single tumors in 5 cases and multiple in 4 cases. In 1 case with multiple adenomas, the myxoid adenoma arose in the background of GNAS-mutated hepatic adenomatosis. Myxoid hepatic adenomas had a high frequency of malignant transformation (N=5 cases). They were characterized at the molecular level by HNF1A inactivating mutations, leading to loss of LFABP protein expression. In addition, myxoid adenomas had recurrent mutations in genes within the protein kinase A (PKA) pathway or in genes that regulate the PKA pathway: GNAS, CDKN1B (encodes p27), and RNF123. In sum, myxoid adenomas are rare, occur in older-aged persons, have a high risk of malignant transformation, and are characterized by the combined inactivation of HNF1A and additional mutations that appear to cluster in the PKA pathway.
Higher colorectal tissue HIV infectivity in cisgender women compared with MSM before and during oral preexposure prophylaxis
Authors: Sekabira Rogers , McGowan Ian , Yuhas Krista , Brand Rhonda M. , Marzinke Mark A. , Manabe Yukari C. , Frank Ian , Eron Joseph , Landovitz Raphael J. , Anton Peter , Cranston Ross D. , Anderson Peter , Mayer Kenneth H. , Amico K. Rivet , Wilkin Timothy J. , Chege Wairimu , Kekitiinwa Adeodata R. , McCauley Marybeth , Gulick Roy M. , Hendrix Craig W.
Published: April 2021

Objective:

The objective of this study was to compare HIV-negative cisgender women (CGW) with MSM for mucosal tissue differences in pharmacokinetics, HIV infectivity and cell phenotype.

Design:

A substudy of HPTN 069/ACTG A5305, 48-week study of three oral candidate preexposure prophylaxis regimens: maraviroc, maraviroc/emtricitabine and maraviroc/tenofovir disoproxil fumarate (TDF) compared with a TDF/emtricitabine control group.

Methods:

Plasma, peripheral blood mononuclear cells and cervical and colorectal tissue biopsies were collected at Baseline (no drug), Week 24 and 48 (on drug), and Week 49 (1-week postdrug). Drug concentrations were assessed in all matrices. HIV infectivity was assessed using tissue biopsy ‘explants’ challenged with HIV ex vivo followed by HIV p24 measurement. Flow cytometry evaluated colorectal cell phenotype.

Results:

Thirty-seven CGW and 54 MSM participated. CGW's colorectal explant p24 was higher than MSM before (0.31 log10, P = 0.046), during (1.01-1.19 log10, P = 0.016) and one week after (0.61 log10, P = 0.011) study drug dosing. Pooling regimens, cervical explant p24 did not differ among visits. CGW had higher plasma maraviroc and colorectal tissue tenofovir diphosphate and lower colorectal tissue emtricitabine (all P < 0.005) compared with MSM. Each study drug's cervical tissue concentrations were more than 10-fold below paired colorectal concentrations (P < 0.001). Cell phenotype sex differences included 4% higher CD38+/CD8+ cells at baseline and 3–7% higher CD69+/CD8+ cells throughout Weeks 24–49 in CGW compared with MSM (P < 0.05).

Conclusion:

Colorectal explants in CGW demonstrated greater HIV infectivity than MSM with and without study drugs. Small differences in adherence, drug concentration and colorectal tissue flow cytometry cannot fully explain this difference.
Incident obstructive lung disease and mortality among people with HIV and a history of injecting drugs
Authors: Kalmin Mariah M. , Westreich Daniel , Drummond Bradley M. , Sun Jing , Mehta Shruti H. , Kirk Gregory D.
Published: April 2021

Objective:

People with HIV (PWH) experience increased prevalence of obstructive lung disease (OLD), regardless of greater observed smoking behaviors. We investigated whether the effect of incident OLD on mortality differed by HIV and HIV viral suppression among persons who inject drugs (PWID) and report smoking history.

Design:

ALIVE is a longitudinal, observational cohort study of HIV-positive and seronegative PWID. This analysis included participants who had at least one spirometry measure to assess OLD between 2007 and 2016, excluding those who never smoked (5%, n = 62) or had baseline OLD (17%, n = 269).

Methods:

Incident OLD occurred when the first prebronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) less than 0.70 during follow-up. The effect of incident OLD on all-cause mortality was estimated in PWH and seronegative participants using inverse-probability-of-treatment-weighted marginal structural models controlling for baseline (age, race, sex, calendar year, smoking pack-years) and time-varying (smoking intensity, viral suppression, and calendar time) confounders.

Results:

Among 1204 participants, 269 (22.3%) and 157 (13.0%) experienced incident OLD and death, respectively, over a median of five person-years of follow-up. There was no effect of OLD on mortality among seronegative participants [hazard ratio = 0.84, 95% confidence interval (CI): 0.47–1.48]; however, PWH diagnosed with OLD experienced an increased mortality risk (hazard ratio = 1.71, 95% CI: 1.04–2.80) during follow-up. HIV viral suppression did not confound or modify the effect of OLD on mortality among PWH.

Conclusion:

There was an apparent effect of OLD on all-cause mortality irrespective of viral suppression among PWH but not among seronegative persons, after accounting for baseline and time-varying confounders. These results highlight the need for enhanced screening and management of OLD among PWH.
Uncovering an Optic Nerve Sheath Meningioma Using 68Ga-DOTATATE PET/CT
Authors: Vay Sabine Ulrike , Werner Jan-Michael , Kabbasch Christoph , Schmidt Matthias , Drzezga Alexander , Fink Gereon R. , Galldiks Norbert , Warnke Clemens
Published: April 2021

A 56-year-old woman was initially diagnosed with optic neuritis. However, several “red flags” were present: older age at presentation, no multiple sclerosis suspicious findings on MRI, and negative oligoclonal bands. 68Ga-DOTATATE PET/CT confirmed the differential diagnosis of an optic sheath meningioma. Our case stresses the value of the somatostatin receptor ligand PET/CT in patients with suspected optic neuritis if the diagnostic workup does not support immune-mediated pathogenesis.
Elevated 68Ga-FAPI Activity in the Plasmacytoma of the Ribs
Authors: Tang Wenxin , Wang Qixin , Yang Songsong , Chen Yue
Published: April 2021

68Ga-labeled quinoline-based fibroblast activation protein inhibitors (68Ga-FAPIs) has been used in the evaluation of a variety of malignancies. We report the case of a patient with rib plasmacytoma, which showed elevated 68Ga-FAPI activity. This case indicated fibroblast activation protein overexpression and some degree of fibrosis in the plasmacytoma lesion. Therefore, 68Ga-FAPI can be a potential tracer in the evaluation of plasmacytoma.
68Ga-FAPI Uptake of Thyroiditis in a Patient With Breast Cancer
Authors: Can Canan , Gündoğan Cihan , Güzel Yunus , Kaplan İhsan , Kömek Halil
Published: April 2021

68Ga–fibroblast activation protein–specific inhibitor (FAPI)-04 PET/CT was performed in a 49-year-old woman diagnosed with breast cancer. In PET/CT imaging, intense 68Ga-FAPI uptake was observed in the primary tumor, axillary lymph nodes, and also in the thyroid gland, whereas pathological 18F-FDG uptake was not observed in the thyroid gland. On thyroid ultrasonography, parenchyma was heterogeneous, and an area of focal thyroiditis was observed in the superior part of the right lobe. Biochemical parameters were found to be consistent with thyroiditis. This case shows that FAPI uptake in the thyroid gland may be associated with thyroiditis and should be evaluated clinically.
Elevated 68Ga-FAPI Activity in Splenic Hemangioma and Pneumonia
Authors: Liu Huipan , Wang Yingwei , Zhang Wei , Cai Liang , Chen Yue
Published: April 2021

A 59-year-old woman with newly diagnosed pulmonary nodules underwent both 18F-FDG and 68Ga-FAPI PET/CT. Both studies showed similarly increased uptake in pneumonia. However, only 68Ga-FAPI PET/CT showed increased uptake in splenic hemangioma, whereas FDG uptake in the splenic lesion is low. Our case illustrates that splenic hemangioma can also reveal increased FAPI activity.
68Ga-PSMA PET/CT Scan on Postoperative Assessment of Sinonasal Glomangiopericytoma
Authors: Sakthivel Pirabu , Kumar Arunav , Arunraj Sreedharan Thankarajan , Singh Chirom Amit , Kumar Rakesh
Published: April 2021

Prostate-specific membrane antigen (PSMA) is expressed on the endothelial cells of tumor-associated neovasculature of various nonprostatic benign and malignant neoplasms. Positive intense uptake on PET/CT imaging with 68Ga-labeled PSMA is noted in a patient with sinonasal glomangiopericytoma, and the same is noted to be absent following complete surgical excision. 68Ga-PSMA PET/CT may be a useful tool for early recurrence identification, differentiating recurrence from surgical site reparative tissues, and peptide receptor radionuclide therapy of residual lesions.
Magnetic Resonance Imaging of the Oral Cavity and Oropharynx
Authors: Varghese Jerrin , Kirsch Claudia
Published: April 2021

Understanding oral cavity and oropharyngeal anatomy is important to identify various pathologies that may afflict them. This article reviews normal magnetic resonance imaging anatomy of these vital spaces and structures, with special attention to the complex musculature, mucosal surfaces, relevant osseous structures, salivary glands, and nerves. Anatomic awareness of these spaces and critical potential pathways for perineural tumoral spread are important to recognize to improve diagnostic evaluation and treatment.
Autologous Fat Grafting and the Occurrence of Radiation-Induced Capsular Contracture
Authors: Martin Shanique , Cai Lawrence , Beniwal Amit , Tevlin Ruth , Lee Gordon , Nazerali Rahim S.
Published: April 2021

Introduction

Radiation therapy is a known risk factor for capsular contracture formation after implant-based breast reconstruction. Although autologous fat grafting (AFG) has been shown to reverse radiation-induced tissue fibrosis, its use as a prophylactic agent against capsular contraction has not been assessed in the clinical setting. In the setting of 2-stage implant-based reconstruction and postmastectomy radiation therapy, we explored the effect AFG has on the prevalence of capsular contracture.

Materials and Methods

A retrospective chart review of patients who underwent immediate tissue expander (TE) placement followed by postmastectomy radiation therapy and secondary implant-based reconstruction at our institution between January 2012 and December 2019 was performed. Patients were divided into 2 cohorts based on whether or not AFG was performed at the time of secondary reconstruction. The primary outcome of interest was the occurrence of capsular contracture after TE exchange.

Results

Overall 57 patients (57 breasts) were included, 33 of whom received AFG at the time of TE exchange. All but 1 patient underwent submuscular implant placement, and the mean follow-up was 1.96 years. There was no significant difference in the prevalence of medical comorbidities between the study groups.

Capsular contracture occurred in 24 patients (42.1%). Seventeen of these patients had undergone AFG at the time of TE exchange (17/33 patients, 51.5%), and 7 of these patients had not (7/24 patients, 29.2%). Most of the capsular contracture cases were Baker grades III or IV (14 patients, 58.3%), and 50% of patients with capsular contracture of any grade ultimately required operative intervention. Multivariate logistic regression analysis demonstrated that AFG did not significantly influence the occurrence or severity of capsular contracture, or did not impact the need for operative intervention in this patient population.

Conclusions

Implant-based reconstruction of the irradiated breast is associated with high postoperative capsular contracture rates. Although AFG has shown promise in reversing radiation-induced dermal fibrosis, no protective effect on the development of capsular contracture after stage 2 reconstruction was observed in this study population. Further investigation in the form of randomized, prospective studies is needed to better assess the utility of AFG in preventing capsular contracture in irradiated patients.
Evaluation of Research Opportunities and Limitations for Plastic Surgery Residents
Authors: Navia Alfonso , Berner Juan Enrique , Ramirez Joaquin , Will Patrick , Tejos Rodrigo , Dagnino Bruno , Searle Susana , Cuadra Alvaro
Published: April 2021

Background

Conducting research during specialty training provides an opportunity to develop critical thinking and leadership skills along with a better understanding of the scientific literature. However, trainees often find it difficult to undertake research, in the context of labor-intensive surgical training. The aim of this study is to evaluate the research output and limitations of plastic surgery residents in different countries.

Methods

An international cross-sectional study involving plastic surgery trainees and recent postgraduates from Brazil, Chile, Germany, and the United Kingdom was conducted. A survey inquiring into academic productivity, limitations to conducting research, and working-hours patterns was distributed among eligible participants.

Results

From September to December 2019, 106 surveys were retrieved. Most respondents declared having participated in at least 1 project that resulted in a presentation or publication during their training (90.6% in national presentations, 68% international presentations, 67% in national publications, and 66% international publications). Having completed a previous research fellowship was associated with a statistically higher academic output (P < 0.05). Seventy-nine percent of respondents felt that their participation in research activities would have been greater if limiting factors had been addressed, including lack of time (72.5%) and insufficient supervision and mentoring (55%).

Conclusions

Optimizing plastic surgery trainees' participation in scientific research is beneficial both for residents and their mentors. Research fellowships can provide an opportunity for academically oriented trainees to further develop their research skills. Protected time and adequate mentoring can help not only to increase residents' research output, but also to recruit the next generation of academic plastic surgeons.
Age and Sex Differences in the Genetics of Cardiomyopathy
Authors: Akinrinade Oyediran ,   Genomics England Research Consortium, Lougheed Jane , Mondal Tapas , Smythe John , Altamirano-Diaz Luis , Oechslin Erwin , Mital Seema
Published: April 2021

Aims

Cardiomyopathy is a clinically and genetically heterogeneous disorder with age and sex-related differences in severity and outcomes. The aim of our study was to identify age and sex-related differences in the genetic architecture of cardiomyopathy.

Methods and Results

We analyzed whole genome sequence data from 471 pediatric and 926 adult cardiomyopathy patients from our Heart Centre Biobank and from the Genomics England cohort. Overall yield of rare deleterious coding variants was higher in pediatric compared to adult onset cardiomyopathy, but not different by sex.MYH7, TNNT2, MYL3, andVCLvariants were more frequent in pediatric patients;TTNandOBSCNvariants were more frequent in adult patients, withMYH7(Odds ratio 3.6; CI 2.1-6.3) andOBSCN(Odds ratio 5.5, CI 2.0-21.4) remaining significant after adjusting for multiple testing. Variants in early-onset cardiomyopathy clustered in highly constrained coding regions compared to those in adult patients (p=3.9×10−3). There were also differences between pediatric and adult patients in variant location withinMYH7andTTNgenes. When analyzed by sex, variants in female compared to male patients were in more highly constrained coding regions (p=0.002).

Conclusion

Our findings highlight under-appreciated genetic differences in early versus late onset cardiomyopathy. Variants in childhood cardiomyopathy and in female patients were in highly constrained coding regions of the genome suggesting greater deleterious effects and strong purifying selection in the general population. Knowledge of the affected gene, variant location within the gene, and variant constraint scores may be useful in predicting early versus late onset cardiomyopathy.
Rapid neural encoding of the contrast between native and nonnative speech in the alpha band
Authors: Tavano Alessandro , Nagels Arne , Gagl Benjamin , Muralikrishnan R.
Published: April 2021

More than half of the world’s population is multilingual, yet it is not known how the human brain encodes the perception of native vs. nonnative speech. To find out, we asked German native speakers to detect the onset of native and nonnative (English and Turkish) vowels in a roving standard stimulation. Using EEG, we show that nonnativeness is robustly registered by an increase in phase coherence in the alpha band (8-12 Hz), beginning as early as ∼100 ms after stimulus onset and lasting more than 200 ms. The alpha band effect is speech-specific, successfully predicts the response speed advantage of nonnative speech, and grants ∼90% decoding accuracy in distinguishing native vs. nonnative speech irrespective of language familiarity. We propose alpha phase coherence as a candidate neural channel for the online resolution of the native-nonnative contrast in the adult brain.

Significance Statement

We show that the human brain takes only ∼ 100 ms to distinguish native vs. nonnative speech. This difference is neurally encoded in the alpha band in a reliable and specific way, supporting a processing model in which the mixture of top-down and bottom-up information represented in the speech signal is concurrently partitioned into different frequency channels.
Stable motifs delay species loss in simulated food webs
Authors: Cirtwill Alyssa R. , Wootton Kate
Published: April 2021

Some three-species motifs (unique patterns of interactions between three species) are both more stable when modeled in isolation and over-represented in empirical food webs. This suggests that these motifs may reduce extinction risk for species participating in them, ultimately stabilizing the food web as a whole. We test whether a species’ time to extinction following a perturbation is related to its participation in stable and unstable motifs and assess how motif roles co-vary with a species’ degree or trophic level. We found that species’ motif roles are related to their times to extinction following a disturbance. Specifically, participating in many omnivory motifs (whether in absolute terms, as a proportion of the species’ role, or relative to other species in the network) was associated with more rapid extinction, even though omnivory has previously been identified as a stable motif. Participating in the other three stable motifs (three-species chain, apparent competition, and direct competition) was associated with longer times to extinction. While motif roles were associated with extinction risk, they also varied strongly with degree and trophic level. This means that these simpler measures of a species’ role may be sufficient to roughly predict which species are most vulnerable to disturbance, but the additional information encapsulated in a motif role can further refine predictions of vulnerability. Moreover, where researchers area prioriinterested in motif roles, our results confirm that these roles can be interpreted with respect to extinction risk.
Identification of decondensed large-scale chromatin regions by TSA-seq and their localization to a subset of chromatin domain boundaries
Authors: Gholamalamdari Omid , Zhang Liguo , Chen Yu , Belmont Andrew
Published: April 2021

Large-scale chromatin compaction is nonuniform across the human genome and correlates with gene expression and genome organization. Current methodologies for assessing large-scale chromatin compaction are indirect and largely based on assays that probe lower levels of chromatin organization, primarily at the level of the nucleosome and/or the local compaction of nearby nucleosomes. These assays assume a one-to-one correlation between local nucleosomal compaction and large-scale compaction of chromosomes that may not exist. Here we describe a method to identify interphase chromosome regions with relatively high levels of large-scale chromatin decondensation using TSA-seq, which produces a signal proportional to microscopic-scale distances relative to a defined nuclear compartment. TSA-seq scores that change rapidly as a function of genomic distance, detected by their higher slope values, identify decondensed large-scale chromatin domains (DLCDs), as then validated by 3D DNA-FISH. DLCDs map near a subset of chromatin domain boundaries, defined by Hi-C, which separate active and repressed chromatin domains and correspond to compartment, subcompartment, and some TAD boundaries. Most DLCDs can also be detected by high slopes of their Hi-C compartment score. In addition to local enrichment in cohesin (RAD21, SMC3) and CTCF, DLCDs show the highest local enrichment to super-enhancers, but are also locally enriched in transcription factors, histone-modifying complexes, chromatin mark readers, and chromatin remodeling complexes. The localization of these DLCDs to a subset of Hi-C chromatin domain boundaries that separate active versus inactive chromatin regions, as measured by two orthogonal genomic methods, suggests a distinct role for DLCDs in genome organization.
ALT Neuroblastoma Chemoresistance due to ATM Activation by Telomere Dysfunction is Reversible with the ATM Inhibitor AZD0156
Authors: Koneru Balakrishna , Farooqi Ahsan , Nguyen Thinhh H. , Chen Wan Hsi , Hindle Ashly , Eslinger Cody , Makena Monish Ram , Burrow Trevor A. , Wilson Joanne , Smith Aaron , Reddy Venkatesh Pilla , Cadogan Elaine , Durant Stephen T. , Reynolds C. Patrick
Published: April 2021

Cancers overcome replicative immortality by activating either telomerase or an alternative lengthening of telomeres (ALT) mechanism. ALT occurs in ∼ 25% of high-risk neuroblastomas and relapse or progression in ALT neuroblastoma patients during or after front-line therapy is frequent and almost uniformly fatal. Temozolomide + irinotecan is commonly used as salvage therapy for neuroblastoma. Patient-derived cell-lines and xenografts established from relapsed ALT neuroblastoma patients demonstratedde novoresistance to temozolomide + irinotecan (as SN-38in vitro, P<0.05)andin vivo(mouse event-free survival (EFS)P<0.0001) relative to telomerase-positive neuroblastomas. We observed that ALT neuroblastoma cells manifest constitutive ATM kinase activation due to spontaneous telomere dysfunction while telomerase- positive tumors lacked constitutive ATM activation or spontaneous telomere DNA damage. We demonstrated that induction of telomere dysfunction resulted in ATM activation that in turn conferred resistance to temozolomide + SN-38 (4.2 fold-change in IC50,P<0.001). ATM kinase shRNA knock-down or inhibition using a clinical-stage small molecule inhibitor (AZD0156) reversed resistance to temozolomide + irinotecan in ALT neuroblastoma cell-linesin vitro(P<0.001) and in 4 ALT xenograftsin vivo(EFSP<0.0001). AZD0156 showed modest to no enhancement of temozolomide + irinotecan activity in telomerase-positive neuroblastoma cell lines and xenografts. ATR inhibition using AZD6738 did not enhance temozolomide + SN-38 activity in ALT neuroblastoma cell lines. Thus, resistance to chemotherapy in ALT neuroblastoma occurs via ATM kinase activation and was reversed with the ATM inhibitor AZD0156. Combining AZD0156 with temozolomide + irinotecan warrants clinical testing in neuroblastoma.

One Statement Summary

ATM activation at telomeres confers resistance to DNA damaging chemotherapy in ALT neuroblastoma that was reversed with ATM knockdown or inhibition.