bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of histone acetyltransferase GCN5 by a transcription factor FgPacC controls fungal adaption to host-derived iron stress
Authors: Gu Qin , Wang Yujie , Zhao Xiaozhen , Yuan Bingqin , Zhang Mengxuan , Tan Zheng , Zhang Xinyue , Chen Yun , Wu Huijun , Luo Yuming , Keller Nancy P , Gao Xuewen , Ma Zhonghua
Published: June 2022

Poaceae plants can locally accumulate iron to suppress pathogen infection. It remains unknown how pathogens overcome host-derived iron stress during their successful infections. Here, we report that Fusarium graminearum (Fg), a destructive fungal pathogen of cereal crops, is challenged by host-derived high-iron stress. Fg infection induces host alkalinization, and the pH-dependent transcription factor FgPacC undergoes a proteolytic cleavage into the functional isoform named FgPacC30 under alkaline host environment. Subsequently FgPacC30 binds to a GCCAR(R = A/G)G element at the promoters of the genes involved in iron uptake and inhibits their expression, leading to adaption of Fg to high-iron stress. Mechanistically, FgPacC30 binds to FgGcn5 protein, a catalytic subunit of Spt-Ada-Gcn5 Acetyltransferase (SAGA) complex, leading to deregulation of histone acetylation at H3K18 and H2BK11, and repression of iron uptake genes. Moreover, we identified a protein kinase FgHal4, which is highly induced by extracellular high-iron stress and protects FgPacC30 against 26S proteasome-dependent degradation by promoting FgPacC30 phosphorylation at Ser2. Collectively, this study uncovers a novel inhibitory mechanism of the SAGA complex by a transcription factor that enables a fungal pathogen to adapt to dynamic microenvironments during infection.
Bi-PE: bi-directional priming improves CRISPR/Cas9 prime editing in mammalian cells
Authors: Tao Rui , Wang Yanhong , Jiao Yaoge , Hu Yun , Li Li , Jiang Lurong , Zhou Lifang , Qu Junyan , Chen Qiang , Yao Shaohua
Published: June 2022

Prime editors consisting of Cas9-nickase and reverse transcriptase enable targeted precise editing of small DNA pieces, including all 12 kinds of base substitutions, insertions and deletions, while without requiring double-strand breaks or donor templates. Current optimized prime editing strategy (PE3) uses two guide RNAs to guide the performance of prime editor. One guide RNA carrying both spacer and templating sequences (pegRNA) guides prime editor to produce ssDNA break and subsequent extension, and the other one produces a nick in the complementary strand. Here, we demonstrated that positioning the nick sgRNA nearby the templating sequences of the pegRNA facilitated targeted large fragment deletion and that engineering both guide RNAs to be pegRNAs to achieve bi-direction prime editing (Bi-PE) further increase the efficiency by up to 16 times and improved the accuracy of editing products by 60 times. In addition, we showed that Bi-PE strategy also increased the efficiency of simultaneous conversion of multiple bases but not single base conversion over PE3. In conclusion, Bi-PE strategy expanded the editing scope and improved the efficiency and the accuracy of prime editing system, which might have a wide range of potential applications.
Outcomes of kidney transplantation in patients with myeloma and amyloidosis in the USA
Authors: Ng Jia H , Izard Stephanie , Murakami Naoka , Jhaveri Kenar D , Sharma Amy , Nair Vinay
Published: June 2022

Background

Recent improvement in treatment and patient survival has opened the eligibility of kidney transplantation to patients who developed end-stage kidney disease (ESKD) from plasma cell dyscrasias (PCDs). Data on clinical outcomes in this population are lacking.

Methods

We conducted a retrospective study of United Network for Organ Sharing/Organ Procurement and Transplantation Network dataset (2006–2018) to compare patient and graft outcomes of kidney transplant recipients with ESKD due to PCD versus other causes.

Results

Among 168 369 adult first kidney transplant recipients, 0.22–0.43% per year had PCD as the cause of ESKD. The PCD group had worse survival than the non-PCD group for both living and deceased donor types {adjusted hazard ratio [aHR] 2.24 [95% confidence interval (CI) 1.67–2.99] and aHR 1.40 [95% CI 1.08–1.83], respectively}. The PCD group had worse survival than the diabetes group, but only among living donors [aHR 1.87 (95% CI 1.37–2.53) versus aHR 1.16 (95% CI 0.89–1.2)]. Graft survival in patients with PCD were worse than non-PCD in both living and deceased donors [aHR 1.72 (95% CI 1.91–2.56) and aHR 1.30 (95% CI 1.03–1.66)]. Patient and graft survival were worse in amyloidosis but not statistically different in multiple myeloma compared with the non-PCD group.

Conclusion

The study data are crucial when determining kidney transplant eligibility and when discussing transplant risks in patients with PCD.
Petrogenesis and Tectonics of Eocene–Oligocene Phonolites of Mecejana, Ceará, NE Brazil: the Role of the Fernando de Noronha Fracture Zone, Equatorial Atlantic
Authors: de Souza Zorano Sérgio , Vilalva Frederico Castro Jobim , Dantas Elton Luiz , Lafon Jean-Michel , Silveira Francisco Valdir , Oliveira Joyce Lorena
Published: June 2022

Located on the western continental tip of the Fernando de Noronha transform fracture (FNTF), northeastern Brazil, the Eocene–Oligocene Mecejana Phonolitic Province (MPP) was subjected to a multi-methodological study, comprising field and microscopic characterization, mineral and whole-rock chemistry, and Sr-Nd isotopes. These rocks intrude the Precambrian crystalline basement, forming mainly plugs oriented in the NE–SW direction. They are composed of alkali basalt, phono-tephrite, tephri-phonolite, and phonolite with phenocrysts of nepheline and sanidine, and minor diopside, aegirine-augite, aegirine, kaersutite, biotite and titanite. Chemically, they are sodic (Na2O/K2O > 1) and display Light Rare Earth Elements (LREE) enrichment, concave upward or flat Heavy Rare Earth Elements (HREE) patterns, weak to strong Eu anomaly, and high contents of Nb, Ta and Zr. They delineate two chemical groups, the less-evolved one comprising basalt to tephri-phonolites and the more evolved constituted by phonolites. Oxide and trace element modeling points out to an evolution by fractional crystallization, leaving olivine-rich gabbro and foidolite/nepheline syenite cumulates, respectively. The analyzed samples have Sr-Nd isotopic ratios akin to ocean island basalt (OIB) rocks (positive εNd of +3.0 to +0.9 at 30 Ma) and low to high 87Sr/86Sri (at 30 Ma) of 0.70264–0.70955. The data suggest a three-stage evolution model for the MPP: (1) <5% partial melting of a metasomatized phlogopite-amphibole-garnet peridotite generates an alkali basalt melt, (2) polybaric differentiation of this melt at crustal level (~570–220 MPa, 1040–645°C) leads firstly to phono-tephrites and tephri-phonolites and then to (3) foidolite and nepheline syenite. Petrographic, chemical, and isotopic characteristics of the MPP and similar rocks of the Fernando de Noronha islands suggest the control by the FNTF and reactivation of NE–SW trending deep-rooted Precambrian faults allowing channeling and emplacement of the alkaline magmas.
Emergent expression of fitness-conferring genes by phenotypic selection
Authors: Ciechonska Marta , Sturrock Marc , Grob Alice , Larrouy-Maumus Gerald , Shahrezaei Vahid , Isalan Mark
Published: June 2022

Genotypic and phenotypic adaptation is the consequence of ongoing natural selection in populations and is key to predicting and preventing drug resistance. Whereas classic antibiotic persistence is all-or-nothing, here we demonstrate that an antibiotic resistance gene displays linear dose-responsive selection for increased expression in proportion to rising antibiotic concentration in growing Escherichia coli populations. Furthermore, we report the potentially wide-spread nature of this form of emergent gene expression (EGE) by instantaneous phenotypic selection process under bactericidal and bacteriostatic antibiotic treatment, as well as an amino acid synthesis pathway enzyme under a range of auxotrophic conditions. We propose an analogy to Ohm’s law in electricity (V = IR), where selection pressure acts similarly to voltage (V), gene expression to current (I), and resistance (R) to cellular machinery constraints and costs. Lastly, mathematical modeling using agent-based models of stochastic gene expression in growing populations and Bayesian model selection reveal that the EGE mechanism requires variability in gene expression within an isogenic population, and a cellular “memory” from positive feedbacks between growth and expression of any fitness-conferring gene. Finally, we discuss the connection of the observed phenomenon to a previously described general fluctuation–response relationship in biology.
Use of biologics to treat relapsing and/or refractory polyarteritis nodosa: data from a European collaborative study
Authors: Hadjadj Jérome , Canzian Alice , Karadag Omer , Contis Anne , Maurier François , Sanges Sébastien , Sartorelli Silvia , Denis Laure , de Moreuil Claire , Durel Cécile-Audrey , Durupt Stéphane , Jachiet Marie , Rouzaud Diane , Salvarani Carlo , Padoan Roberto , Dagna Lorenzo , Bonnet Fabrice , Agard Christian , Moulinet Thomas , Hermet Marion , Sterpu Raluca , Maria Alexandre Thibault Jacques , Keraen Jérémy , Guillevin Loic , Jayne David , Terrier Benjamin
Published: June 2022

Objectives

To describe the effectiveness and safety of biologics for the treatment of relapsing and/or refractory polyarteritis nodosa (PAN).

Methods

A retrospective European collaborative study was conducted in patients with PAN who received biologics for relapsing and/or refractory disease.

Results

Forty-two patients with PAN received a total of 53 biologic courses, including TNF-α blockers in 15 cases, rituximab (RTX) in 18 cases, tocilizumab (TCZ) in 10 cases and other biologics in 10 cases. TNF-α blockers and TCZ were mainly used for refractory diseases whereas RTX was mainly initiated for relapsing disease. After a median follow-up of 29 (8–50) months, remission, partial response, treatment failure and treatment discontinuation due to severe adverse events occurred in, respectively, 40%, 13%, 40% and 7% of patients receiving TNF-α blockers, 50%, none, 30% and 20% of TCZ recipients, and 33%, 11%, 56% and none of the RTX recipients. No remission was noted in patients treated with other biologics. Severe adverse events were observed in 14 (28%) patients without significant differences between the three biologics, leading to early biologics discontinuation in only three cases.

Conclusion

These results suggest that TCZ may be effective in relapsing and/or refractory PAN. Our data warrant further study to confirm these findings.
White-coat effect on orthostatic hypotension: a nationwide survey of Japanese general practitioners
Authors: Yuasa Shohei , Yamamoto Hareaki , Suzuki Yoshiro , Chin Keiichi , Ukai Hiroshi , Kobayashi Yusuke , Yano Yuichiro , Mori Hisao
Published: June 2022

Objective

The relationship between the white-coat effect (WCE), defined as white-coat hypertension under treatment, and the frequency of orthostatic hypotension (OH) is not known. We conducted an orthostatic test in patients with WCE to determine the frequency of OH.

Methods

This was a cross-sectional study of 5631 patients with hypertension visiting general practitioners nationwide, in which 4305 patients with hypertension recorded their home blood pressure (BP) and consented to the orthostatic test. Patients with hypertension were divided into four groups: controlled hypertension (CHT), masked hypertension (MHT), sustained hypertension (SHT), and WCE. The orthostatic test was performed, and BP and pulse rate were measured immediately and 1 min after orthostasis.

Results

The OH frequencies immediately after standing in CHT, WCE, SHT, and MHT patients were 7, 11.7, 12.1, and 6.6%, respectively, and those at 1 min after standing were 7.1, 13.1, 11.6 and 6.9%, respectively (Chi-square test, P < 0.01, respectively). Logistic regression analysis was performed to examine the relationship between WCE and the frequency of OH. The frequency of OH immediately after standing was significantly increased [adjusted odds ratio (AOR), 1.702; 95% confidence interval (CI), 1.246–2.326; P < 0.01]. The frequency of OH at 1 min after standing was also significantly higher (AOR, 1.897; 95% CI, 1.396–2.578; P < 0.01).

Conclusion

When the standing test was performed for patients with WCE, the frequency of OH increased. Thus, it is important to recognize the possibility of OH in patients with WCE to avoid adverse events associated with excessive hypotension.
Spirituality as a Mediator Between Social Support and Benefit Finding Among Advanced Cancer Patients
Authors: Rong Huan , Yin Min , Ren Pan , Li Yanjun , Qu Haimei , Chen Xiaoju
Published: June 2022

Background

Social support and benefit finding (BF) are important for cancer patients. The relationship between social support and BF has not been studied sufficiently in patients with advanced cancer, and the mechanism through which social support might influence BF is unclear.

Objective

This study aimed to investigate the relationship between social support and BF in Chinese patients with advanced cancer as mediated by their perceptions of spirituality.

Methods

This was a correlation study with a cross-sectional design. We recruited advanced-cancer patients (n = 208) from China. Patients’ sociodemographic and clinical characteristics were collected, and they were asked to complete the Benefit Finding Scale, the Multidimensional Scale of Perceived Social Support, and the Spiritual Attitude and Involvement List.

Results

Social support was associated with greater spirituality and greater BF (P < .01). Spirituality was positively correlated with BF (P < .01). Results from mediation analysis identified that both the indirect effect of social support on BF via spirituality (indirect effect, 0.268; 95% confidence interval, 0.147–0.419) and its direct effect on BF (direct effect, 0.233; 95% confidence interval, 0.031–0.429) were statistically significant, suggesting a partial mediatory effect of spirituality between social support and BF.

Conclusions

Our findings supported a positive association between social support and BF among Chinese advanced-cancer patients. The mediatory role of spirituality should provide a new perspective for augmentation of BF in these patients.

Implications for Practice

Interventions that help enhance social support and spirituality in patients with advanced cancer could facilitate their BF.
Analysis of Symptom Characteristics, Influencing Factors, and Their Predictive Value for Posttraumatic Stress Disorder in Nurses
Authors: Xue Mengxin , Yuan Yuan , Chen Hong , Dai Minghui , Sun Huiping , Qu Jiling , Zhou Ting , Zhou Jingxin , Qu Junchao , Bu Yuan , Ji Siqi , Hu Yicheng , Yao Zhenshuai , Feng Yanbing , Gu Xinyi , Liu Yongbing
Published: June 2022

Nurses often face a variety of nursing-related stresses, making them more prone to symptoms of posttraumatic stress disorder (PTSD). We aimed to explore symptom characteristics, influencing factors, and their predictive value for PTSD in nurses, so as to prevent the occurrence of PTSD in nurses. This was a cross-sectional study conducted in two tertiary hospitals in Yangzhou. A total of 1290 valid questionnaires were received in our study, and 190 nurses (14.7%) were positive for PTSD symptoms. The results show that individuals with higher scores on the Perceived Stress Scale-10 (PSS-10), Patient Health Questionnaire-15 (PHQ-15), Generalized Anxiety Disorder Scale-7 (GAD-7), and maladaptive cognitive emotion regulation strategies questionnaire (maladaptive CERS) were more likely to experience PTSD symptoms, whereas those with lower scores on the Perceived Social Support Scale (PSSS) were more likely to experience PTSD symptoms. Compared with the PSS-10, PHQ-15, and PSSS, GAD-7 and maladaptive CERS had higher predictive value. This study provided the optimal threshold of relevant factors that may have a positive effect on the prevention of PTSD symptoms. This has guiding implications for active prevention and intervention in some institutions.
Psychiatrists' Cognitive and Affective Biases and the Practice of Psychopharmacology: Why Do Psychiatrists Differ From One Another in How They View and Prescribe Certain Medication Classes?
Authors: Yager Joel , Ritvo Alexis D. , MacPhee Edward R.
Published: June 2022

Cognitive and affective biases impact clinical decision-making in general medicine. This article explores how such biases might specifically affect psychiatrists' attitudes and prescribing patterns regarding two medication classes (stimulants and benzodiazepines) and addresses related issues. To supplement personal observations, selective PubMed narrative literature searches were conducted using relevant title/abstract terms, followed by snowballing for additional pertinent titles. Acknowledging that there are many more types of biases, we describe and use clinical vignettes to illustrate 17 cognitive and affective biases that might influence clinicians' psychopharmacological practices. Factors possibly underlying these biases include temperamental differences and both preprofessional and professional socialization. Mitigating strategies can reduce the potentially detrimental impacts that biases may impose on clinical care. How extensively these biases appear, how they differ among psychiatrists and across classes of medication, and how they might be most effectively addressed to minimize harms deserve further systematic study.
Total Metacognitive Capacity Predicts Competitive Employment Acquisition Across 6 Months in Adults With Serious Mental Illness Receiving Psychiatric Rehabilitation Services
Authors: Kukla Marina , Faith Laura A. , Lysaker Paul H. , Wiesepape Courtney , Corbière Marc , Lecomte Tania
Published: June 2022

Deficits in metacognitive capacity are common among people with serious mental illness (SMI), although there is a gap in knowledge regarding how these impairments predict later functioning, especially employment. This study aimed to prospectively examine the relationship between metacognitive capacity and 6-month competitive employment attainment in adults with SMI who were participating in a study testing a cognitive behavioral therapy intervention added to supported employment services. Sixty-seven participants with complete data at baseline and the 6-month follow-up comprised the sample. Data were analyzed using stepwise logistic regression covarying for work history and study assignment. Results indicate that total metacognitive capacity at baseline significantly predicted employment acquisition at 6 months; the final model correctly classified 83.3% of participants who obtained work. In conclusion, these findings suggest that better overall metacognitive capacity may be key for future work functioning. Thus, interventions that target metacognitive capacity may lead to enhancements in community outcomes.
Epidemiological and Psychopharmacological Study About Off-Label Treatment in Child and Adolescent Psychiatric Emergencies
Authors: Minghetti Sara , Vannini Martina , Casula Laura , Asprea Martina , Gori Sara , Calvani Anna Maria , Pisano Tiziana
Published: June 2022

Objective

The study used an epidemiological and pharmacological description of child and adolescent psychiatric emergencies (CAPEs), during which psychotropic medications are frequently administered as off-label therapies.

Methods

We retrospectively describe CAPE in 190 patients (mean age, 14.7 years) referring in the emergency department of a single tertiary center, from June 2016 to June 2018, focusing on off-label administration rate, most of all in emergency setting.

Results

An intrinsic fragility was observed in this population, where 28.4% of patients present a history of self-harm, 24.7% a concomitant neurodevelopmental disorder, and 17.3% a history of substance abuse. Psychomotor agitation was the most frequent referral reason, and it represents an unspecified clinical presentation of several conditions, while self-harm showed a stronger association with depressive disorders (55.2%).

Globally, 811 medications were administered both as baseline therapy (67.8% of off-label rate) and/or in the emergency setting, where the off-label rate raised to 78.3%. Benzodiazepines had the highest rate of off-label use (98.2% as baseline therapy, 92.9% in acute context). Nevertheless, in 83.5% cases of acute administrations, a singular oral benzodiazepine (mostly lorazepam) guaranteed psychomotor agitation resolution, with a lower rate of adverse effects in contrast with atypical antipsychotics.

Conclusions

Off-label drug use in CAPEs is a recurrent clinical practice. An international agreement about off-label drugs is crucial to obtain standard long-term pharmacoepidemiological, safety, and efficacy data. Pharmacological pediatric trials and international guidelines are also required to regulate pharmacological treatments of CAPEs, most of all in emergency settings.
Addition of Midthigh Circumference Improves Predictive Ability of Broselow Tape Weight Estimation
Authors: Saeed Wajeeha , Akbar Amber , Waseem Muhammad , Kuchinski Ann-Marie , Xu Hongyan , Gibson Robert W.
Published: June 2022

Objectives

This study aimed to improve the accuracy of Broselow tape (BT) weight prediction by adding midthigh circumference (MTC) and to compare and standardize the methods for measuring MTC.

Methods

This prospective, observational study was conducted in a pediatric emergency department of a tertiary care children's hospital. Children up to 12 years of age presenting to emergency department were included. Children were excluded if obtaining the data would interfere with their acute management. The data collected included MTC, height, BT weight, and actual weight. Three models were built. Broselow tape–only model and MTC plus BT model used 2 methods for MTC measurements: visual approximation of thigh midpoint (visual MTC1) and Centers for Disease Control and Prevention (CDC)–defined method (CDC MTC2).

Results

A total of 430 children were enrolled during pre–coronavirus disease era. Of these, 234 were boys (54.4%) and 196 (45.6%) were girls. Data were categorized into children younger than 2 years (224 [52.1%]) and older than 2 years (206 [47.9%]). African American constituted 250 (58%); White, 136 (31%); and unspecified, 27 (6%). For the entire cohort, both models that included MTC were significantly better at weight prediction with larger adjusted R
2 (visual MTC1, 0.921; CDC MTC2, 0.928) and smaller root mean squared (RMSE) (visual MTC1, 2.70; CDC MTC2, 2.56) compared with BT-only model (adjusted R
2 = 0.843; RMSE, 3.80). Midthigh circumference plus BT models performed even better in children older than 2 years compared with BT-only model with adjusted R
2 (visual MTC1, 0.859; CDC MTC2, 0.872 vs 0.616) and RMSE (visual MTC1, 3.18; CDC MTC2, 3.03 vs 5.27).

Conclusions

The inclusion of MTC with BT resulted in a more accurate weight prediction in children especially greater than 2 years old. Midthigh circumference model using CDC-defined method was slightly better predictor of actual weight than visual approximation.
Peak age and performance trajectories in Para powerlifters
Authors: Severin Anna Cecilia , Baumgart Julia Kathrin , Haugen Thomas , Hogarth Luke
Published: June 2022

Objective

This study established the age-related performance trajectories in Para powerlifters, thereby presenting valuable information for athlete development.

Design

Data on athlete date-of-birth, body mass, and weight lifted in competition were analyzed for 2079 athletes between 1994 and 2019.

Results

Age-related performance trajectories showed that men and women lift their heaviest weights in competition at 36 and 41 years of age, respectively. This correspond to the mean age of competitors in the heaviest bodyweight categories at elite competitions (men 36 years, women 43 years), who were older than competitors in lighter bodyweight categories. It is possible that Para powerlifters ‘move up’ bodyweight categories as they get older and before lifting their heaviest weights in competition. High performing athletes lifted their heaviest weight in competition 2.6 years earlier than lower performing peers, and the best performances in most bodyweight categories were achieved by athletes between 31 and 35 years of age.

Conclusions

These results suggest that Para powerlifters should reach their peak performance in their early- to mid-thirties and before age-related changes to neural and hormonal processes impact muscular strength. This information can help coaches and athletes evaluate their strategies for achieving success in Para powerlifting.
The Impact of the Early COVID-19 Pandemic On Inpatient Clinical Experience for Physical Medicine and Rehabilitation Resident Physicians
Authors: Deo Prabhav , Sliwa James
Published: June 2022

The objective of this retrospective, observational study was to quantitatively study the impact of the early COVID-19 pandemic on the inpatient clinical experience of Physical Medicine and Rehabilitation (PM&R) resident physicians in an inpatient rehabilitation facility (IRF) setting. Inpatient clinical experience as evidenced by admissions, rehabilitation diagnosis, medical emergencies, acute care transfers, and resident work hours from January to June 2019 (pre-pandemic) were compared January to June 2020 (immediately before and during pandemic). There was a statistically significant decrease in the mean daily admissions in April 2020 and a significant increase in medically complex admissions in June 2020, reflective of medical patterns due to the pandemic. There was a decrease in mean work hours during the pandemic, but no statistically significant difference in admission rate of other rehabilitation diagnoses, medical emergencies or transfers to acute care. This study demonstrates no substantial pandemic related impact on inpatient clinical experience for PM&R residents in the studied program.
Teaching and Assessing Cognitive Competencies in Aesthetic and Plastic Surgery
Authors: Al-Halabi Becher , Vassiliou Melina , Gilardino Mirko
Published: June 2022

Background:

Cognition, part of surgical competence, employs forward planning, error prevention, and orchestration of technical skills. Thus, an understanding of mental processes used by experts throughout patient care is essential to teaching such competencies. The authors’ study aimed to analyze and compare mental models of two distinct procedures in plastic surgery—breast augmentation and flexor tendon repair—to develop a framework to define cognitive competencies in plastic surgery aided by a review of the literature.

Methods:

Based on data from a priori cognitive task analyses, literary sources, and field observations of breast augmentation surgery and flexor tendon repair, task lists were produced for each procedure. Two mental models were developed using fuzzy logic cognitive maps to visually illustrate and analyze cognitive processes used in either procedure. A comparison of the models aided by literature was used to define the cognitive competencies employed, identify differences in the decision-making process, and provide a guiding framework for understanding cognitive competencies.

Results:

Five distinct cognitive competency domains were identified from the literature applicable to plastic surgery: situation awareness, decision-making, task management, leadership, and communication and teamwork. Differences in processes of decision-making utilized between an elective and a trauma setting were identified. A framework to map cognitive competencies within a generic mental model in surgical care was synthesized, and methods were suggested for training on such competencies.

Conclusion:

Cognitive competencies in different settings in plastic surgery are introduced using a comparative study of two mental models of distinct procedures to guide the teaching and assessment of such competencies.
Brief Report: Quantifiable Plasma Tenofovir Among South African Women Using Daily Oral Pre-exposure Prophylaxis During the ECHO Trial
Authors: Beesham Ivana , Mansoor Leila E. , Joseph Davey Dvora L. , Palanee-Phillips Thesla , Smit Jenni , Ahmed Khatija , Selepe Pearl , Louw Cheryl , Singata-Madliki Mandisa , Kotze Philip , Heffron Renee , Parikh Urvi M. , Wiesner Lubbe , Rees Helen , Baeten Jared M. , Beksinska Mags
Published: June 2022

Background:

HIV endpoint–driven clinical trials provide oral pre-exposure prophylaxis (PrEP) as HIV prevention standard of care. We evaluated quantifiable plasma tenofovir among South African women who used oral PrEP during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial.

Methods:

ECHO, a randomized trial conducted in 4 African countries between 2015 and 2018, assessed HIV incidence among HIV-uninfected women, aged 16–35 years, randomized to 1 of 3 contraceptives. Oral PrEP was offered onsite as part of the HIV prevention package at the South African trial sites. We measured tenofovir in plasma samples collected at the final trial visit among women reporting ongoing PrEP use. We used bivariate and multivariate logistical regression to assess demographic and sexual risk factors associated with plasma tenofovir quantification.

Results:

Of 260 women included, 52% were ≤24 years and 22% had Chlamydia trachomatis at enrollment. At PrEP initiation, 68% reported inconsistent/nonuse of condoms. The median duration of PrEP use was 90 days (IQR: 83–104). Tenofovir was quantified in 36% (n = 94) of samples. Women >24 years had twice the odds of having tenofovir quantified vs younger women (OR = 2.12; 95% confidence interval = 1.27 to 3.56). Women who reported inconsistent/nonuse of condoms had lower odds of tenofovir quantification (age-adjusted OR = 0.47; 95% confidence interval = 0.26 to 0.83).

Conclusions:

Over a third of women initiating PrEP and reporting ongoing use at the final trial visit had evidence of recent drug exposure. Clinical trials may serve as an entry point for PrEP initiation among women at substantial risk for HIV infection with referral to local facilities for ongoing access at trial end.

Clinical trial number:

NCT02550067.
Revealing human sensitivity to a latent temporal structure of changes
Authors: Marković Dimitrije , Reiter Andrea M.F. , Kiebel Stefan J.
Published: June 2022

Precisely timed behaviour and accurate time perception plays a critical role in our everyday lives, as our well-being and even survival can depend on well-timed decisions. Although the temporal structure of the world around us is essential for human decision making, we know surprisingly little about how representation of temporal structure of our everyday environment impacts decision making. How does the representation of temporal structure affect our ability to generate well-timed decisions? Here we address this question by using a well-established dynamic probabilistic learning task. Using computational modelling, we found that human subjects’ beliefs about temporal structure are reflected in their choices to either exploit their current knowledge or to explore novel options. The model-based analysis illustrates a large within-group and within-subject heterogeneity. To explain these results, we propose a normative model for how temporal structure is used in decision making, based on the semi-Markov formalism in an active inference framework. We discuss potential key applications of the presented approach to the fields of cognitive phenotyping and computational psychiatry.
Patient Clusters and Cost Trajectories in Atrial Fibrillation: Evidence from the Swiss Atrial Fibrillation Cohort
Authors: Helena Aebersold , Miquel Serra-Burriel , Fabienne Foster-Witassek , Giorgio Moschovitis , Stefanie Aeschbacher , Angelo Auricchio , Beer Jürg H. , Eva Blozik , Bonati Leo H. , David Conen , Stefan Felder , Huber Carola A. , Michael Kühne , Andreas Müller , Jolanda Oberle , Paladini Rebecca E. , Tobias Reichlin , Nicolas Rodondi , Anne Springer , Annina Stauber , Christian Sticherling , Thomas Szucs , Stefan Osswald , Matthias Schwenkglenks
Published: June 2022

Aims

Evidence on long-term costs of atrial fibrillation (AF) and associated factors is scarce. As part of the Swiss-AF prospective cohort study we aimed to characterise AF costs and their development over time, and to assess specific patient clusters and their cost trajectories.

Methods

Swiss-AF enrolled 2,415 patients with variable duration of AF between 2014 and 2017. Patient clusters were identified using hierarchical cluster analysis of baseline characteristics. Ongoing yearly follow-ups include health insurance clinical and claims data. An algorithm was developed to adjudicate costs to AF and related complications.

Results

Hierarchical analysis identified three patient clusters. “Cardiovascular-dominated” (CV-dominated) patients had the highest proportions of prior myocardial infarction and presence of diabetes. “Heart failure-dominated” (HF-dominated) patients had the highest occurrence of heart failure and permanent AF. “Isolated symptomatic” (IS) patients were younger and had the highest occurrence of paroxysmal AF. A subpopulation of 1,024 Swiss-AF patients with available claims data was followed up for a median [interquartile range] of 3.24 [1.09] years. Average yearly AF-adjudicated costs amounted to CHF 5,679, remaining stable across the observation period. CV-dominated (N = 253 with claims data) and HF-dominated patients (N = 185) depicted similarly high costs across all cost outcomes, the IS (N = 586) patients accrued the lowest costs.

Conclusion

Our results highlight three well-differentiated patient clusters with specific costs that could be used for stratification in both clinical and economic studies. Patient characteristics associated with adjudicated costs as well as cost trajectories may enable an early understanding of the magnitude of upcoming AF-related healthcare costs.

What is already known on this topic

Atrial fibrillation (AF) is a complex disease and constitutes a major economic and societal challenge due to its high prevalence worldwide.

What this study adds

This study, based on a large prospective cohort study, provides evidence on real-world AF costs and their development over time. Data-derived patient clusters are linked to costs and their respective cost trajectories are assessed.

How this study might affect research, practice or policy

The identified patient clusters and their characteristics may help clinicians and payers to gain an early insight and understanding of the magnitude of the expected AF-related healthcare costs.
Associations between prenatal alcohol and tobacco exposure and cortical and subcortical brain measures in South African children: a pilot study
Authors: Uban Kristina A. , Jonker Deborah , Donald Kirsten A. , Brooks Samantha J. , Bodison Stefanie C. , Kan Eric , Butler-Kruger Letitia , Roos Annerine , Steigelmann Babette , Melly Brigitte , Adise Shana , Marshall Andrew , Narr Katherine L. , Joshi Shantanu H. , Odendaal Hein J. , Sowell Elizabeth R. , Stein Dan J.
Published: June 2022

Objective

The aim of this pilot study was to assess associations of prenatal alcohol exposure (PAE), prenatal tobacco exposure (PTE), and their interaction and quantity on subsequent cortical and subcortical measures at age 6 years.

Methods

Mothers with varying levels of alcohol and tobacco exposure at different trimesters during pregnancy were approached when their children (born participating in the Safe Passage Study) were approximately 6 years old. 72 mothers agreed to participate, and 51 children completed brain magnetic resonance imaging (MRI). Brain regions of interest (ROIs) that were significantly associated prior to multiple comparison testing, were examined for associations related to exposure quantity, frequency, and timing (QFT), to explore how patterns of PAE and PTE influence brain outcomes in children. Linear regression was used to identify associations between PAE, PTE, and their interaction with cortical (n = 68 ROIs) and subcortical (n = 40 ROIs) measures.

Results

Prior to correction for multiple comparison testing, both PAE and PTE, as well as their interaction, were associated with a range of cortical and subcortical measures. However, none of these findings survived correction for multiple comparisons. Nevertheless, when exploring quantity of PAE, the total amount of standard drinks consumed during pregnancy and the average number of drinks per drinking day were positively associated with cortical volume in the right fusiform gyrus.

Conclusion

These trend results in this pilot study provide preliminary evidence that PAE impacts brain development in unique ways from PTE, and their interactive co-exposure is not a straight forward synergistic or additive effect on the brain.
Measures of Implicit and Explicit Adaptation Do Not Linearly Add
Authors: ’t Hart Bernard Marius , Taqvi Urooj , Gastrock Raphael Q. , Ruttle Jennifer E. , Modchalingam Shanaathanan , Henriques Denise Y.P.
Published: June 2022

Moving effectively is essential for any animal. Thus, many different kinds of brain processes likely contribute to learning and adapting movement. How these contributions are combined is unknown. Nevertheless, the field of motor adaptation has been working under the assumption that measures of explicit and implicit motor adaptation can simply be added in total adaptation. While this has been tested, we show that these tests were insufficient. We put this additivity assumption to the test in various ways, and find that measures of implicit and explicit adaptation are not additive. This means that future studies should measure both implicit and explicit adaptation directly. It also challenges us to disentangle how various motor adaptation processes do combine when producing movements, and may have implications for our understanding of other kinds of learning as well. (data and code:https://osf.io/dh86e)
Conscientiousness associated with efficiency of the salience/ventral attention network: Replication in three samples using individualized parcellation
Authors: Sassenberg Tyler A. , Burton Philip C. , Mwilambwe-Tshilobo Laetitia , Jung Rex E. , Rustichini Aldo , Spreng R. Nathan , DeYoung Colin G.
Published: June 2022

Previous research in the field of personality neuroscience has identified associations of conscientiousness and related constructs like impulsivity and self-control with structural and functional properties of particular regions in the prefrontal cortex (PFC) and insula. Network- based conceptions of brain function suggest that these regions probably belong to a single large- scale network, labeled the salience/ventral attention network (SVAN). The current study tested associations between conscientiousness and resting-state functional connectivity in this network using two community samples (N = 244 and 239) and data from the Human Connectome Project (N = 1000). Individualized parcellation was used to improve the accuracy of functional localization and to facilitate replication. Functional connectivity was measured using an index of network efficiency, a graph theoretical measure quantifying the capacity for parallel information transfer within a network. Efficiency of a set of parcels in the SVAN was significantly associated with conscientiousness in all samples. Findings are consistent with a theory of conscientiousness as a function of variation in neural networks underlying effective prioritization of goals.
Age-related learning and working memory impairment in the common marmoset
Authors: Glavis-Bloom Courtney , Vanderlip Casey R , Reynolds John H
Published: June 2022

Aging is the greatest risk factor for the development of neurodegenerative diseases, yet we still do not understand how the aging process leads to pathological vulnerability. The research community has relied heavily on mouse models, but the considerable anatomical, physiological, and cognitive differences between mice and humans limit their translational relevance. Ultimately, these barriers necessitate the development of novel aging models. As a non-human primate, the common marmoset (Callithrix jacchus) shares many features in common with humans and yet has a significantly shorter lifespan (10 years) than other primates, making it ideally suited to longitudinal studies of aging. Our objective was to evaluate the marmoset as a model of age-related cognitive impairment. To do this, we utilized the Delayed Recognition Span Task (DRST) to characterize age-related changes in working memory capacity in a cohort of sixteen marmosets varying in age from young adult to geriatric. These monkeys performed thousands of trials over periods of time ranging up to 50 percent of their adult lifespan. To our knowledge, this represents the most thorough cognitive profiling of any marmoset aging study conducted to-date. By analyzing individual learning curves, we found that aged animals exhibited delayed onset of learning, slowed learning rate after onset, and decreased asymptotic working memory performance. These findings are not accounted for by age-related impairments in motor speed and motivation. This work firmly establishes the marmoset as a model of age-related cognitive impairment.

Significance Statement

Understanding the normal aging process is fundamental to identifying therapeutics for neurodegenerative diseases for which aging is the biggest risk factor. Historically, the aging field has relied on animal models that differ markedly from humans, constraining translatability. Here, we firmly establish a short-lived non-human primate, the common marmoset, as a key model of age-related cognitive impairment. We demonstrate, through continuous testing over a substantial portion of the adult marmoset lifespan, that aging is associated with both impaired learning and working memory capacity, unaccounted for by age-related changes in motor speed and motivation. Characterizing individual cognitive aging trajectories reveals inherent heterogeneity, which could lead to earlier identification of the onset of impairment, and extended timelines during which therapeutics are effective.
Prediction of cancer treatment response from histopathology images through imputed transcriptomics
Authors: Hoang Danh-Tai , Dinstag Gal , Hermida Leandro C. , Ben-Zvi Doreen S. , Elis Efrat , Caley Katherine , Sammut Stephen-John , Sinha Sanju , Sinha Neelam , Dampier Christopher H. , Stossel Chani , Patil Tejas , Rajan Arun , Lassoued Wiem , Strauss Julius , Bailey Shania , Allen Clint , Redman Jason , Beker Tuvik , Jiang Peng , Golan Talia , Wilkinson Scott , Sowalsky Adam G. , Pine Sharon R. , Caldas Carlos , Gulley James L. , Aldape Kenneth , Aharonov Ranit , Stone Eric A. , Ruppin Eytan
Published: June 2022

Advances in artificial intelligence have paved the way for leveraging hematoxylin and eosin (H&E)-stained tumor slides for precision oncology. We present ENLIGHT-DeepPT, an approach for predicting response to multiple targeted and immunotherapies from H&E-slides. In difference from existing approaches that aim to predict treatment response directly from the slides, ENLIGHT-DeepPT is an indirect two-step approach consisting of (1) DeepPT, a new deep-learning framework that predicts genome-wide tumor mRNA expression from slides, and (2) ENLIGHT, which predicts response based on the DeepPT inferred expression values. DeepPT successfully predicts transcriptomics in all 16 TCGA cohorts tested and generalizes well to two independent datasets. Importantly, ENLIGHT-DeepPT successfully predicts true responders in five independent patients’ cohorts involving four different treatments spanning six cancer types with an overall odds ratio of 2.44, increasing the baseline response rate by 43.47% among predicted responders, without the need for any treatment data for training. Furthermore, its prediction accuracy on these datasets is comparable to a supervised approach predicting the response directly from the images, trained and tested on the same cohort in cross validation. Its future application could provide clinicians with rapid treatment recommendations to an array of different therapies and importantly, may contribute to advancing precision oncology in developing countries.

Statement of Significance

ENLIGHT-DeepPT is the first approach shown to successfully predict response tomultipletargeted and immune cancer therapies from H&E slides. In distinction from all previous H&E slides prediction approaches, it does not require supervised training on a specific cohort for each drug/indication treatment but is trained to predict expression on the TCGA cohort and then can predict response to an array of treatments without any further training. ENLIGHT-DeepPT can provide rapid treatment recommendations to oncologists and help advance precision oncology in underserved regions and low-income countries.
Discovery of synapse-specific RNA N6-methyladenosine readers associated with the consolidation of fear extinction memory
Authors: Madugalle Sachithrani U. , Liau Wei-Siang , Zhao Qiongyi , Li Xiang , Gong Hao , Marshall Paul R. , Periyakaruppiah Ambika , Zajackowski Esmi L. , Leighton Laura J. , Ren Haobin , Musgrove Mason , Davies Joshua , Rauch Simone , He Chuan , Dickinson Bryan C. , Fletcher Lee , Fulopova Barbora , Williams Stephen R. , Spitale Robert C. , Bredy Timothy W.
Published: June 2022

The RNA modification N6-methyladenosine (m6A) is critically involved in the regulation of gene activity underlying experience-dependent plasticity, and is necessary for the functional interplay between RNA and RNA binding proteins (RBPs) in the nucleus. However, the complete repertoire of m6A-modified RNA interacting RBPs in the synaptic compartment, and whether they are involved in fear extinction, have yet to be revealed. Using RNA immunoprecipitation followed by mass spectrometry, we discovered 12 novel, synapsespecific, learning-induced m6A readers in the medial prefrontal cortex of male C57/B6 mice. m6A RNA-sequencing also revealed a unique population of learning-related m6A-modified RNAs at the synapse, which includes a variant of the long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (Malat1). m6A-modified Malat1 binds to a subset of novel m6A readers, including cytoplasmic FMR1 interacting protein 2 (CYFIP2) and dihydropyrimidase-related protein 2 (DPYSL2) and a cell-type-specific, state-dependent, and synapse-specific reduction in m6A-modified Malat1 disrupts the interaction between Malat1 and DPYSL2 and impairs fear extinction. The consolidation of fear-extinction memory therefore relies on an interaction between m6A-modified Malat1 and select RBPs in the synaptic compartment.
A model of coevolution and local adaptation between hosts and parasites in continuous space
Authors: Week Bob , Bradburd Gideon
Published: June 2022

Previous host-parasite coevolutionary theory has focused on understanding the determinants of local adaptation using spatially discrete models. However, these studies fall short of describing patterns of host-parasite local adaptation across spatial scales. In contrast, empirical work demonstrates patterns of adaptation depend on the scale at which they are measured. Here, we propose a model of host-parasite coevolution in continuous space that naturally leads to a scale-dependent definition of local adaptation and a formal definition for the spatial scale of coevolution. In agreement with empirical findings, our model implies patterns of adaptation vary across spatial scales. When measured on spatial scales shorter than the scale of coevolution, we find the farther dispersing species is locally adapted. However, when measured at longer spatial scales, the opposite pattern is observed. We discuss our results in relation to those found using spatially discrete models and to conclusions drawn from empirical studies, and provide an example of our how our results can be used to inform the design of empirical studies.