bluuebunny/crossref_metadata_2025 huggingface dataset:
2: Tranexamic Acid Is Associated With Decreased Intraoperative Blood Loss And Wound Healing Complication Rate In Penile Inversion Vaginoplasty
Authors: Gunderson Kirsten A. , Edalatpour Armin , Wirth Peter , Rose Katherine , Gast Katherine M.
Published: July 2021

Purpose: Penile inversion vaginoplasty (PIV) is the most common gender affirming genital procedure for transfeminine patients. The purpose of this study was to investigate the impact of tranexamic acid (TXA), an antifibrinolytic, on bleeding and bleeding-related complications in vaginoplasty surgery.

Methods: Retrospective chart review was performed on patients undergoing PIV from February 2018 through March 2020 by the senior author (K.G.) at the University of Wisconsin Hospital and Clinics. Patients who received TXA received a combination of topical and intravenous TXA. Data collected includes patient demographics (age, body mass index, race, comorbidities, and tobacco and illicit drug use), intraoperative data (duration of surgery, estimated blood loss, fluid administration, TXA use and dose, and complications), and postoperative data (drain output, complications within 30 days, and revision surgery). Subgroup analysis on the effect of TXA was performed using independent sample t-test.

Results: Seventy-four patients were included in this study with 56 patients receiving TXA and 18 patients who had surgery prior to initiation of TXA protocol. There were no thromboembolic events observed in the TXA or the non-TXA group. Ninety percent of all complications were Clavien-Dindo Grade 1 and did not require intervention. There was a significantly lower EBL in the TXA group compared to the no TXA cohort (299.1 ± 64.3 vs. 347.2 ± 84.8, p=0.013). Patients who received TXA had significantly fewer wound related complications than those who did not receive TXA (21.4% vs. 66.7%, p<0.0001). Similarly, there were fewer neo-vagina skin graft failures in the TXA group, though this did not reach significance (0.0% vs. 11.1%, p=0.057). There was no significant difference in drain output between the two groups.

Conclusion: No thromboembolic events were observed with intravenous and topical tranexamic acid use in transfeminine patients undergoing penile inversion vaginoplasty surgery. TXA was also associated with lower intraoperative blood loss as well as fewer wound healing complications. Further research is needed to further study its use in gender affirmation surgery.
QS4: Genital Neurosensory Outcomes After Innervated Radial Forearm Phalloplasty
Authors: Oles Norah , Abousy Mya , Eisenbeis Lauren , Lee Dellon A. , Coon Devin
Published: July 2021

Purpose: Radial free forearm flap (RFFF) phalloplasty is the most commonly-used technique for gender-affirming phalloplasty procedures. Microsurgical coaptation of the free flap nerves to branches of the genital nerves aims to provide patients with a sensate neophallus. Return of sensation in the neophallus is poorly understood and has yet to be well characterized in the literature. This study serves to describe sensation in the neophallus, which will assist in setting patient expectations for recovery and improving operative technique and planning, especially in selection of nerves for coaptation.

Methods: A total of 14 patients undergoing RFFF were tested for pressure sensation in the neophallus postoperatively. Testing was conducted via 1-point static (1PS) testing using the Pressure Specified Sensory Device (PSSD). A 100g monofilament was used to screen the neophallus for sensation beginning at 3 cm distal to the base and advancing distally by 1 cm until the patient reported no sensation; the PSSD was then applied at the last point the patient reported sensation for precise pressure measurements. These measurements were taken on the right and left ventral and dorsal shaft 1 cm from the ventral and dorsal midlines, respectively. The right and left urethral meatus was also measured for sensation (representing the ulnar-most skin of the RFFF). Measurements were taken at intervals beginning as early as 1 week postoperatively; the longest patient follow-up thus far has been 17 months.

Results: Of the 14 patients, 13 had tactile pressure sensation at their most recent measurement (range 1-17mos). The remaining patient did not have a measurement beyond one month postoperatively. Of the 14 patients, consistent long-term follow-up measurements were currently available for 7. Among these patients, return of any sensation was measured at an average of 69 days (12-160 days) postoperatively. The earliest time point at which a patient had any sensation was two weeks postoperatively while another patient had sensation through the full length of the neophallus measured at 2.5 months postoperatively; subsequent measurements of this patient showed a decreased threshold (increased sensitivity) for pressure sensation over time.

Conclusions: Preliminary data suggests that innervation of the RFFF neophallus can be accomplished via microsurgical nerve coaptation and that recovery of sensation may occur much faster in some patients than previously thought possible. Further follow-up and a larger patient cohort is necessary to fully characterize nerve recovery and regeneration in gender-affirming phalloplasty patients.
QS6: Improvements In Perceived Age And Attractiveness Following Aesthetic Rhinoplasty Using Facial Recognition And Artificial Intelligence
Authors: Parsaei Yassmin , Peck Connor , Khetpal Sumun , Duan Kaiti , Gowda Arvind , Lopez Joseph , Steinbacher Derek
Published: July 2021

Purpose: Facial recognition software may serve as a more objective tool for measuring aesthetic improvements following facial plastic surgery. This study utilized a novel facial recognition and artificial intelligence software in order to assess perceived changes in age and attractiveness amongst patients receiving rhinoplasty.

Methods: This study was a retrospective evaluation of 3D photographs of patients who underwent aesthetic rhinoplasty alone by the senior author (DS). Both pre- and post-operative (>12-month follow-up) Vectra 3D images (Canfield Scientific, Parsippany, NJ) were assessed using Haystack Artificial Intelligence Software (Haystack AI, New York, NY). Facial attractiveness (score 1-10) and apparent age were predicted. Paired t-tests were used to compare age and attractiveness scores before and after surgery. Multivariate linear regression was performed to identify factors associated with age and attractiveness scores.

Results: Forty patients receiving rhinoplasty met the study criteria (average age 48.3). Overall, rhinoplasty was associated with increases in AI-rated attractiveness (+0.58, p = 0.004) and decreases in perceived age relative to the patient’s true age (-1.62 years, p = 0.021). Greater decreases in post-operative perceived age were achieved in patients who appeared older than their actual age pre-operatively (p = 0.04). AI age predictions were also closer to true patient age post-operatively (+1.71 years) than they were pre-operatively (+3.33 years).

Conclusion: Facial recognition software was successfully implemented to evaluate improvements in perceived age and attractiveness in patients undergoing aesthetic rhinoplasty. Using this technology, patients were found to appear more attractive and younger after rhinoplasty. Additionally, age reversal was greatest among patients who appeared older than their actual age at the time of surgery.
QS11: Does the Processing System Matter? A Comparison of Two Filtration Devices in Autologous Fat Grafting for Breast Reconstruction
Authors: Asaad Malke , Howell Skyler M. , Liu Jun , Reece Gregory P. , Chang Edward , Garvey Patrick B. , Butler Charles E. , Hanson Summer E
Published: July 2021

Purpose: The use of autologous fat grafting (AFG) is becoming increasingly common as an adjunct to breast reconstruction. However, there is a paucity of data comparing the varying processing devices. The goal of this study is to compare the outcomes of two commercially available AFG processing devices.

Methods: The authors conducted a retrospective review of patients who underwent AFG using dual filter (Puregraft®) or single filter (RevolveTM) processing systems between 2016 and 2019. Propensity score matching was utilized to adjust for confounding. A total of 38 breasts from the Puregraft® group were matched with 38 breasts from the RevolveTM system.

Results: Matching was successful in achieving a similar distribution of baseline characteristics between the two groups. The mean number of AFG sessions was comparable between the two groups (p=0.37) with a similar median total volume (Puregraft®, 159 ml vs. RevolveTM, 130 ml, p=0.23). Complication rates were similar between the two devices (Puregraft®, 26%; RevolveTM,18%; p=0.47). Patients with at least one complication had higher overall AFG volume (median, 200 vs.130 ml, p=0.03) and number of sessions (mean, 2.4 vs.1.8, p=0.009) compared to those without any postoperative complication.

Conclusion: The decision for which processing system to use for autologous fat grafting should be based on surgeon preference as overall complication rates were comparable between two commonly used commercially available systems. Future studies are underway to decipher whether either system has superior graft retention, cosmetic or patient reported outcomes.
Effect of Iron Supplementation in Children with Attention-Deficit/Hyperactivity Disorder and Iron Deficiency: A Randomized Controlled Trial
Authors: Pongpitakdamrong Atcha , Chirdkiatgumchai Vilawan , Ruangdaraganon Nichara , Roongpraiwan Rawiwan , Sirachainan Nongnuch , Soongprasit Manas , Udomsubpayakul Umaporn
Published: July 2021

Objectives:

To determine the effectiveness of combined iron supplementation and methylphenidate treatment on attention-deficit/hyperactivity disorder (ADHD) symptoms in children/adolescents with ADHD and iron deficiency compared with methylphenidate alone.

Methods:

In total, 116 children/adolescents with ADHD were screened for iron deficiency. Participants who exhibited iron deficiency were randomized into 2 groups (ferrous supplementation vs placebo). Vanderbilt ADHD rating scales were completed by parents and teachers at prestudy and poststudy periods. Student's t tests were used to determine improvements of Vanderbilt scores between the groups.

Results:

Among 116 children who participated in this study, 44.8% (52/116) met the criteria for iron deficiency. Of the total 52 participants with iron deficiency, 26 were randomized to the ferrous group and 26 to the placebo group. Most participants in each group had been prescribed short-acting methylphenidate twice daily in the morning and at noon. After a 12-week study period, total parents' Vanderbilt ADHD symptom scores showed a significant improvement between the groups (mean decrement = −3.96 ± 6.79 vs 0 ± 6.54, p = 0.037). However, teachers' Vanderbilt ADHD symptom scores showed no difference between the groups.

Conclusion:

Children with ADHD and iron deficiency being on methylphenidate and iron supplementation had shown improvement of ADHD symptoms that were reported by parents.
Effect of intra-operative high inspired fraction of oxygen on postoperative nausea and vomiting in children undergoing surgery
Authors: Behera Bikram Kishore , Misra Satyajeet , Mohanty Manoj Kumar , Srinivasan Anand
Published: July 2021

BACKGROUND

Administration of high inspired fraction of oxygen (FiO2) during anaesthesia has been proposed to decrease postoperative nausea and vomiting (PONV) in adults but has not been extensively studied in children.

OBJECTIVES

The primary objective of this study was to evaluate the effect of 80% FiO2 on the incidence of PONV in children undergoing surgery.

DESIGN

Prospective, randomised, study.

SETTING

Single-centre, teaching hospital.

PATIENTS

Children of either gender in the age group of 5 to 15 years scheduled for elective surgeries were assessed for eligibility. Emergency surgeries; patients receiving supplemental oxygen pre-operatively or on mechanical ventilation; sepsis; bowel obstruction or ischaemia; poor nutritional status; anaemia (Hb <8 g%) or surgeries lasting less than 1 h or greater than 4 h were excluded from the study.

INTERVENTIONS

After induction of anaesthesia, children were randomised to receive either 30 or 80% oxygen in air, till the end of surgery.

MAIN OUTCOME MEASURES

Incidence of PONV within 24 h; surgical site infections (SSI)s; serum serotonin and TNF-α levels and the incidence of postoperative pulmonary complications (PPC)s were studied.

RESULTS

The overall 24 h incidence of PONV was not different between the low and high FiO2 groups [24 vs. 23%; P = 0.84; odds ratio (OR) 0.92; 95% confidence interval (CI), 0.44 to 2.06]. The incidence of SSIs (15 vs. 12%; P = 0.61; OR 0.77; 95% CI, 0.28 to 2.10) and PPCs (12 vs. 8%; P = 0.38; OR 0.59; 95% CI, 0.18 to 1.92) were not significant between the low and high FiO2 groups, respectively. Intragroup and intergroup comparisons of serum serotonin and TNF-α showed no significant difference either at baseline or at the end of surgery.

CONCLUSION

High intra-operative FiO2 of 80% does not provide additional protection against PONV in children.

TRIAL REGISTRATION

The study was registered with Clinical Trials Registry of India (CTRI) with trial registration no: CTRI/2018/07/014974.
Virtual Interviews for the Integrated Plastic Surgery Residency Match: The Program Director Perspective
Authors: Sarac Benjamin A. , Shen Abra H. , Nassar Amer H. , Maselli Amy M. , Shiah Eric , Lin Samuel J. , Janis Jeffrey E.
Published: July 2021

Background:

Interviews for the integrated plastic surgery residency match took place in a virtual format for the 2020–2021 application cycle. Current literature lacks the perspectives of program directors (PDs) on virtual interviews compared with traditional in-person interviews.

Methods:

Following institutional review board approval, an anonymous 17-question survey was distributed by email to 82 program directors of integrated plastic surgery residency programs in the United States. Participants were asked baseline program information, the number of positions and interview invites offered, and their perspectives on various aspects of the virtual interview process.

Results:

Sixty-two (75.6%) PDs completed the survey. Thirty-seven percent reported increasing the number of interview offers per available residency spot. On a five-point Likert scale (1, not well at all; 5, extremely well), PDs showed no significant differences in their ability judge an applicant’s professionalism (3.1 ± 1.1), interpersonal and communication skills (3.2 ± 1.1), and “fit” with their program (2.9 ± 0.9) during virtual interviews (P = 0.360). Sixty-eight percent reported being satisfied (15.3% extremely satisfied, 52.5% somewhat satisfied) with the virtual interview process, though 76.3% preferred in-person interviews.

Conclusions:

This study is the first to provide insight into PDs’ impressions of virtual residency interviews. Although most reported being satisfied with the virtual interview process, the majority still preferred in-person interviews. Further long-term studies evaluating the pros and cons of each interview modality may provide more information on whether virtual interviews could become a sustainable alternative to the traditional in-person residency interview.
Comparative Analysis of Prepectoral versus Subpectoral Implant-based Breast Reconstruction
Authors: Plachinski Sarah J. , Boehm Lucas M. , Adamson Karri A. , LoGiudice John A. , Doren Erin L.
Published: July 2021

Background:

Recent advances in mastectomy and reconstruction have allowed for an evolution in implant-based breast reconstruction to a muscle-sparing, prepectoral approach. Advantages of this technique may include reductions in postoperative pain, shorter hospitalization, less narcotic usage, and improved aesthetic outcomes. Postoperative complication rates are described as comparable to subpectoral techniques; however, little comparative data exist to adequately assess prepectoral versus subpectoral implant placement.

Methods:

To address this knowledge gap, we performed a single institution retrospective review of 186 (83 prepectoral, 103 subpectoral) consecutive immediate breast reconstructions. All cases were tracked for a minimum of 2 years between 2016 and 2021.

Results:

Prepectoral patients demonstrated an overall higher seroma rate (P = 0.001), with all other postoperative complications being comparable. Prepectoral patients tolerated higher intraoperative tissue expander fill volumes (P < 0.001), shorter hospital stays (P = 0.007), fewer clinic visits for tissue expansion (P < 0.001), and experienced less animation deformity (P = 0.005). Both groups demonstrated similar pain scores (P = 0.65) and needs for narcotics (P = 0.8) as well as comparable scores of capsular contracture (P = 0.791).

Conclusions:

Our comparative analysis of consecutive immediate implant-based breast reconstructions finds prepectoral reconstruction to be safe and effective. Compared with subpectoral reconstruction, the prepectoral approach may offer quicker tissue expansion, less postoperative office visits, less need for muscle relaxants, and a shorter hospital stay with a comparable complication profile.
Noninvasive carotid pressure—diameter loops to identify viscoelastic properties in ageing, hypertension and type 2 diabetes
Authors: Giudici Alessandro , Palombo Carlo , Kozakova Michaela , Morizzo Carmela , Penno Giuseppe , Jamagidze Giuli , Della Latta Daniele , Chiappino Dante , Cruickshank J. Kennedy , Khir Ashraf W.
Published: July 2021

Objectives:

Arterial stiffness as pulse wave velocity (PWV) predicts cardiovascular events independently of blood pressure (BP). PWV does not distinguish between stiffness in systole and diastole. This cross-sectional study aimed to test the hypothesis that viscous and elastic carotid wall properties differ between systole and diastole, distinguishing effects of ageing, hypertension and T2 diabetes (T2DM).

Methods:

We examined carotid visco-elasticity in 307 people (180 men), with hypertension alone (n = 69), combined hypertension/T2DM (H-T2DM, n = 99), normotensive (N-T2DM, n = 25) and healthy controls (n = 114). Diameter (D)/pressure (P) waveforms were measured at right /left common carotid arteries, respectively. Local carotid PWV and distensibility in systole and diastole were evaluated by the D

2

P-loop method, and wall viscosity from hysteresis, the area (H
A) within the P--D loop, as a dynamic measure of systolic loading and diastolic unloading.

Results:

Controls’ hysteresis fell quadratically with age (R
2 = 0.23, P < 0.001). Yet mean H
A in hypertensive patients (0.95, 95% CI 0.65–1.23) was six-fold higher than in age-matched controls (0.14, −0.20 to 0.49, P < 0.001) with a 2.5× difference between diastolic (d
Ds) to systolic (s
Ds) distensibility (P < 0.05) in hypertensive patients. H
A was higher in hypertensive patients and H-T2DMs (0.80, 0.58–1.04) than N-T2DMs (0.20, −0.17 to 0.54, P < 0.05), but similar between controls and N-T2DMs. BP-adjusted carotid diameters in all T2DM were significantly greater compared with controls and hypertensive patients.

Conclusion:

Higher BP increased wall viscosity, hysteresis and relative difference between systolic and diastolic distensibility across groups. Carotid diameters were increased in all T2DMs, more in H-T2DM, probably altering BP-flow dynamics in T2DM.
A prospective study of multiple sleep dimensions and hypertension risk among white, black and Hispanic/Latina women: findings from the Sister Study
Authors: Lunyera Joseph , Park Yong-Moon Mark , Ward Julia B. , Gaston Symielle A. , Bhavsar Nrupen A. , Muntner Paul , Sandler Dale P. , Jackson Chandra L.
Published: July 2021

Background:

Poor sleep is associated with increased hypertension risk, but few studies have evaluated multiple sleep dimensions or investigated racial/ethnic disparities in this association among women.

Method:

We investigated multiple sleep dimensions (sleep duration, inconsistent weekly sleep patterns, sleep debt, frequent napping and difficulty falling or staying asleep) and hypertension risk among women, and determined modification by age, race/ethnicity and menopausal status. We used data from the Sister Study, a national cohort of 50 884 women who had sisters diagnosed with breast cancer in the United States enrolled in 2003–2009 and followed through September 2018.

Results:

Of 33 497 women without diagnosed hypertension at baseline (mean age ± standard deviation: 53.9 ± 8.8 years; 88.7% White, 6.4% Black and 4.9% Hispanic/Latina), 23% (n = 7686) developed hypertension over a median follow-up of 10.1 years [interquartile range: 8.2–11.9 years]. Very short, short or long sleep duration, inconsistent weekly sleep patterns, sleep debt, frequent napping, insomnia, insomnia symptoms as well as short sleep and exploratory cumulative poor sleep score were associated with incident hypertension after adjustment for demographics factors. After additional adjustment for lifestyle and clinical factors, insomnia [hazard ratio = 1.09, 95% confidence interval (95% CI): 1.03–1.15] and insomnia symptoms plus short sleep (hazard ratio = 1.13, 95% CI: 1.05–1.21) remained associated with incident hypertension. These associations were stronger in younger (age<54 vs. ≥54 years) and premenopausal vs. postmenopausal women (all P-interaction < 0.05). Associations did not differ by race/ethnicity (all P-interaction > 0.05).

Conclusion:

Thus, screening for multiple sleep dimensions and prioritizing younger and premenopausal women may help identify individuals at high risk for hypertension.
Effects of enhanced versus reduced vasodilating treatment on brachial and central blood pressure in patients with chronic kidney disease: a randomized controlled trial
Authors: Khatir Dinah Sherzad , Carlsen Rasmus Kirkeskov , Ivarsen Per , Jespersen Bente , Pedersen Michael , Christensen Kent Lodberg , Buus Niels Henrik
Published: July 2021

Background:

Blood pressure (BP) control is important in chronic kidney disease (CKD), but a reduction in brachial BP may not mirror changes in central aortic BP (cBP) during antihypertensive medication. We hypothesize that a fall in cBP is better reflected during enhanced vasodilation treatment (EVT) compared with reduced vasodilation treatment (RVT) because of different hemodynamic actions of these interventions.

Methods:

Eighty-one hypertensive CKD stage 3–4 patients (mean measured glomerular filtration rate 36 ml/min per 1.73 m2) were randomized to either EVT based on renin--angiotensin blockade and/or amlodipine or RVT based on nonvasodilating β-blockade (metoprolol). Before randomization and following 18 months of treatment, we performed 24-h ambulatory BP measurements (ABPM) and radial artery pulse wave analysis for estimation of cBP and augmentation index (AIx). Forearm resistance (R
rest) was determined by venous occlusion plethysmography and arterial stiffness by carotid--femoral pulse wave velocity (PWV). Matched healthy controls were studied once for comparison.

Results:

Compared with controls, CKD patients had elevated ABPM, cBP and PWV. Although ABPM remained unchanged from baseline to follow-up in both treatment groups, cBP decreased 4.7/2.9 mmHg (systolic/diastolic) during EVT and increased 5.1/1.5 mmHg during RVT (Δ=9.8/4.4 mmHg, P=0.02 for SBP, P = 0.05 for DBP). At follow-up, the difference between systolic cBP and 24-h ABPM (ΔBPsyst) was negatively associated with heart rate and positively associated with AIx and Rrest (all P < 0.01) but not PWV (P = 0.32).

Conclusion:

In CKD patients, EVT and RVT have opposite effects on cBP and the difference between cBP and ambulatory BP is larger for EVT than RVT.
Precontrast Magnetic Resonance Imaging Findings and Assessment of Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Low- and High-Flow Vascular Malformations
Authors: Berger Sigurd , Andersen Rune , Jakobsen Jarl Åsbjørn , Geier Oliver Marcel , Abildgaard Andreas , Dorenberg Eric
Published: July 2021

Objectives:

To evaluate magnetic resonance imaging (MRI) findings in vascular malformations by assessing (1) the prevalence of phleboliths and flow voids and (2) dynamic contrast enhancement characteristics in early and delayed contrast phases.

Methods:

Ninety-eight patients (median age 27 years) were included. MRI analyses were performed by 2 radiologists that were blinded to clinical information. Phleboliths and flow-voids were assessed with T1 and short tau inversion recovery. Artery-lesion enhancement time (ALET) was assessed with time-resolved MRI angiography. Contrast accumulation until 15 minutes postinjection was assessed using subtraction techniques based on volumetric interpolated breath-hold examination. Standard statistical methods were applied.

Results:

Eighty-nine patients had low-flow malformations and 9 patients had high-flow malformations. Phleboliths were present in 13.5% of low-flow malformations, and 0% of high-flow malformations (P = .60). Flow voids were observed in 16.9% of low-flow malformations and 55.6% of high-flow malformations (P < .05). Median ALET of low-flow malformations was 9.2 seconds and of high-flow malformations (n = 8) was 0.8 seconds (P < .05). Twenty-one low-flow malformations had ALET that overlapped with ALET of high-flow malformations (≤6.3 seconds). Contrast accumulation between preinjection and 2 minutes postinjection was observed in 97.5% of low-flow malformations and 100% of high-flow malformations, whereas contrast accumulation between 2 and 15 minutes postinjection was observed in 92.6% of low-flow malformations and 62.5% of high-flow malformations (P < .05).

Conclusion:

Our data suggest that phleboliths are infrequent in vascular malformations and that flow voids may be unreliable markers of high-flow malformations. Both high- and low-flow malformations may present with considerable overlap regarding flow dynamics, implying vascular heterogeneity within both malformation types.
Social Model Hospice Home
Authors: Farrar Helen Mavis , Scott Kelley Easterling , Clifton Shari , Clark Jennifer K.
Published: July 2021

The term social model hospice first appeared late in the 20th century as a label for a complementary model to medical hospice care. Two decades later, the term is inconsistently defined and used by scholars, health care providers, public consumers, and those within the movement. The purpose of this review is to trace the development of the concept and confirm an evolving definition based on Rodgers' evolutionary method. Database and hand searching was done for the years 1975 to 2020, resulting in 25 publications for analysis. Unique antecedents include presence of a resource crisis, unmet needs falling outside the scope of medical hospice care, and desire to experience death outside the medical system and/or personal home. Attributes include a dedicated home, round-the-clock, individualized end-of-life care; care option when dying at home becomes unmanageable; collaboration with medical hospice services; nonprofit organization funded by community philanthropy; environment to support loved ones; and community volunteer involvement. Noted consequences are effective end-of-life care for dying patients and their families, innovative health care design, nationwide network of like-minded providers, and platform for end-of-life community education. Clarity of the concept will facilitate access to end-of-life care, further the model's development, formalize research endeavors, and foster community education.
Data-driven identification of complex disease phenotypes
Authors: Strauss Markus J. , Niederkrotenthaler Thomas , Thurner Stefan , Kautzky-Willer Alexandra , Klimek Peter
Published: July 2021

Disease interaction in multimorbid patients is relevant to treatment and prognosis, yet poorly understood. In the present work, we combine approaches from network science, machine learning and computational phenotyping to assess interactions between two or more diseases in a transparent way across the full diagnostic spectrum. We demonstrate that health states of hospitalized patients can be better characterized by including higher-order features capturing interactions between
more
than two diseases. We identify a meaningful set of higher-order diagnosis features that account for synergistic disease interactions in a population-wide (
N
= 9 M) medical claims dataset. We construct a
generalized disease network
where (higher-order) diagnosis features are linked if they predict similar diagnoses across the whole diagnostic spectrum. The fact that specific diagnoses are generally represented multiple times in the network allows for the identification of putatively different disease phenotypes that may reflect different disease aetiologies. At the example of obesity, we demonstrate the purely data-driven detection of two complex phenotypes of obesity. As indicated by a matched comparison between patients having these phenotypes, we show that these phenotypes show specific characteristics of what has been controversially discussed in the medical literature as metabolically healthy and unhealthy obesity, respectively. The findings also suggest that metabolically healthy patients show some progression towards more unhealthy obesity over time, a finding that is consistent with longitudinal studies indicating a transient nature of metabolically healthy obesity. The disease network is available for exploration at https://disease.network/.
Role of body temperature variations in bat immune response to viral infections
Authors: Fumagalli Maria Rita , Zapperi Stefano , La Porta Caterina A. M.
Published: July 2021

The ability of bats to coexist with viruses without being harmed is an interesting issue that is still under investigation. Here we use a mathematical model to show that the pattern of body temperature variations observed in bats between day and night is responsible for their ability to keep viruses in check. From the dynamical systems point of view, our model displays an intriguing quasi-periodic behaviour that might be relevant in making the system robust by avoiding viral escape due to perturbations in the body temperature cycle.
Mutations in two SARS-CoV-2 variants of concern reflect two distinct strategies of antibody escape
Authors: Fiedler Sebastian , Denninger Viola , Morgunov Alexey S. , Ilsley Alison , Worth Roland , Meisl Georg , Xu Catherine K. , Piziorska Monika A. , Ricci Francesco , Malik Anisa Y. , Devenish Sean R. A. , Schneider Matthias M. , Kosmoliaptsis Vasilis , Aguzzi Adriano , Iwasaki Akiko , Fiegler Heike , Knowles Tuomas P. J.
Published: July 2021

Understanding the factors that contribute to antibody escape of SARS-CoV-2 and its variants is key for the development of drugs and vaccines that provide broad protection against a variety of virus variants. Using microfluidic diffusional sizing, we determined the dissociation constant (KD) for the interaction between receptor binding domains (RBDs) of SARS-CoV-2 in its original version (WT) as well as alpha and beta variants with the host-cell receptor angiotensin converting enzyme 2 (ACE2). For RBD-alpha, the ACE2-binding affinity was increased by a factor of ten when compared with RBD-WT, while ACE2-binding of RBD-beta was largely unaffected. However, when challenged with a neutralizing antibody that binds to both RBD-WT and RBD-alpha with low nanomolar KD values, RBD-beta displayed no binding, suggesting a substantial epitope change. In SARS-CoV-2 convalescent sera, RBD-binding antibodies showed low nanomolar affinities to both wild-type and variant RBD proteins—strikingly, the concentration of antibodies binding to RBD-beta was half that of RBD-WT and RBD-alpha, again indicating considerable epitope changes in the beta variant. Our data therefore suggests that one factor contributing to the higher transmissibility and antibody evasion of SARS-CoV-2 alpha and beta is a larger fraction of viruses that can form a complex with ACE2. However, the two variants employ different mechanisms to achieve this goal. While SARS-CoV-2 alpha RBD binds with greater affinity to ACE2 and is thus more difficult to displace from the receptor by neutralizing antibodies, RBD-beta is less accessible to antibodies due to epitope changes which increases the chances of ACE2-binding and infection.
Multivariate mining of an alpaca immune repertoire identifies potent cross-neutralising SARS-CoV-2 nanobodies
Authors: Hanke Leo , Sheward Daniel J. , Pankow Alec , Vidakovics Laura Perez , Karl Vivien , Kim Changil , Urgard Egon , Smith Natalie L. , Astorga-Wells Juan , Ekström Simon , Coquet Jonathan M. , McInerney Gerald M. , Murrell Ben
Published: July 2021

Conventional approaches to isolate and characterize nanobodies are laborious and cumbersome. Here we combine phage display, multivariate enrichment, and novel sequence analysis techniques to annotate an entire nanobody repertoire from an immunized alpaca. We combine this approach with a streamlined screening strategy to identify numerous anti-SARS-CoV-2 nanobodies, and use neutralization assays and Hydrogen/Deuterium exchange coupled to mass spectrometry (HDX-MS) epitope mapping to characterize their potency and specificity. Epitope mapping revealed that the binding site is a key determinant of neutralization potency, rather than affinity alone. The most potent nanobodies bind to the receptor binding motif of the RBD, directly preventing interaction with the host cell receptor ACE2, and we identify two exceptionally potent members of this category (with monomeric IC50s around 13 and 16 ng/ml). Other nanobodies bind to a more conserved epitope on the side of the RBD, and are able to potently neutralize the SARS-CoV-2 founder virus (42 ng/ml), the beta variant (B.1.351/501Y.V2) (35 ng/ml), and also cross-neutralize the more distantly related SARS-CoV-1 (0.46 μg/ml). The approach presented here is well suited for the screening of phage libraries to identify functional nanobodies for various biomedical and biochemical applications.
The peroxisomal transporter ABCD3 plays a major role in dicarboxylic fatty acid metabolism
Authors: Ranea-Robles Pablo , Chen Hongjie , Stauffer Brandon , Yu Chunli , Bhattacharya Dipankar , Friedman Scott L. , Puchowicz Michelle , Houten Sander M.
Published: July 2021

Peroxisomes metabolize a specific subset of fatty acids, which include dicarboxylic fatty acids (DCAs) generated by ω-oxidation. Data obtained in vitro suggest that the peroxisomal transporter ABCD3 (also known as PMP70) mediates the transport of DCAs into the peroxisome, but in vivo evidence to support this role is lacking. In this study, we studied an Abcd3 KO mouse model generated by CRISPR-Cas9 technology using targeted and untargeted metabolomics, histology, immunoblotting, and stable isotope tracing technology. We show that ABCD3 functions in DCA metabolism and uncover a novel role for this peroxisomal transporter in lipid metabolic homeostasis. The Abcd3 KO mouse presents with lipodystrophy, increased circulating free fatty acids, decreased ketone bodies, enhanced hepatic cholesterol synthesis and decreased hepatic de novo lipogenesis. Moreover, our study suggests that DCAs are metabolized by mitochondrial β-oxidation when ABCD3 is not functional, reflecting the importance of the metabolic compartmentalization and communication between peroxisomes and mitochondria. In summary, this study provides data on the role of the peroxisomal transporter ABCD3 in hepatic lipid homeostasis and DCA metabolism, and the consequences of peroxisomal dysfunction for the liver.
Increased aerosol transmission for B.1.1.7 (alpha variant) over lineage A variant of SARS-CoV-2
Authors: Port Julia R. , Yinda Claude Kwe , Avanzato Victoria A. , Schulz Jonathan E. , Holbrook Myndi G. , van Doremalen Neeltje , Shaia Carl , Fischer Robert J. , Munster Vincent J.
Published: July 2021

Airborne transmission, a term combining both large droplet and aerosol transmission, is thought to be the main transmission route of SARS-CoV-2. Here we investigated the relative efficiency of aerosol transmission of two variants of SARS-CoV-2, B.1.1.7 (alpha) and lineage A, in the Syrian hamster. A novel transmission caging setup was designed and validated, which allowed the assessment of transmission efficiency at various distances. At 2 meters distance, only particles <5 µm traversed between cages. In this setup, aerosol transmission was confirmed in 8 out of 8 (N = 4 for each variant) sentinels after 24 hours of exposure as demonstrated by respiratory shedding and seroconversion. Successful transmission occurred even when exposure time was limited to one hour, highlighting the efficiency of this transmission route. Interestingly, the B.1.1.7 variant outcompeted the lineage A variant in an airborne transmission chain after mixed infection of donors. Combined, this data indicates that the infectious dose of B.1.1.7 required for successful transmission may be lower than that of lineage A virus. The experimental proof for true aerosol transmission and the increase in the aerosol transmission potential of B.1.1.7 underscore the continuous need for assessment of novel variants and the development or preemptive transmission mitigation strategies.
Svep1 orchestrates distal airway patterning and alveolar differentiation in murine lung development
Authors: Foxworth N , Wells J , Ocaña-Lopez S , Muller S , Bhayani P , Denegre J , Palmer K , Memishian W , McGee T , Murray SA , Donahoe PK , Bult CJ , Loscertales M
Published: July 2021

Disruptions in airway branching or alveolar differentiation during lung development can lead to severe respiratory deficiencies and neonatal death. The molecular mechanisms governing branching patterning and early alveolar formation remain elusive. Loss ofSvep1function in mice results in various developmental defects, including lung hypoplasia and perinatal lethality. Our examination of the lungs ofSvep1knockout (Svep1-/-)mouse embryos, bothin vivoandin vitro, revealed thatSvep1mutants exhibit an increase in the number of disorganized distal airway tips and progressively greater disruption of lung lobe morphology over time and saccular development.Svep1interacts with FGF signaling to regulate smooth muscle differentiation and, together withFgf9,guides airway branching patterning. Transcriptomic data from the lungs ofSvep1-/-embryos revealed dysregulated gene expression affecting saccular maturation. Our findings demonstrate thatSvep1is a key extracellular matrix player shaping airway morphology and influencing alveolar fate. These insights offer potential avenues for therapeutic interventions in congenital lung disorders.
Self-supervised contrastive learning for integrative single cell RNA-seq data analysis
Authors: Han Wenkai , Cheng Yuqi , Chen Jiayang , Zhong Huawen , Hu Zhihang , Chen Siyuan , Zong Licheng , King Irwin , Gao Xin , Li Yu
Published: July 2021

Single-cell RNA-sequencing (scRNA-seq) has become a powerful tool to reveal the complex biological diversity and heterogeneity among cell populations. However, the technical noise and bias of the technology still have negative impacts on the downstream analysis. Here, we present a self-supervised Contrastive LEArning framework for scRNA-seq (CLEAR) profile representation and the downstream analysis. CLEAR overcomes the heterogeneity of the experimental data with a specifically designed representation learning task and thus can handle batch effects and dropout events. In the task, the deep learning model learns to pull together the representations of similar cells while pushing apart distinct cells, without manual labeling. It achieves superior performance on a broad range of fundamental tasks, including clustering, visualization, dropout correction, batch effect removal, and pseudo-time inference. The proposed method successfully identifies and illustrates inflammatory-related mechanisms in a COVID-19 disease study with 43,695 single cells from peripheral blood mononuclear cells. Further experiments to process a million-scale single-cell dataset demonstrate the scalability of CLEAR. This scalable method generates effective scRNA-seq data representation while eliminating technical noise, and it will serve as a general computational framework for single-cell data analysis.
Affinity maturation for an optimal balance between long-term immune coverage and short-term resource constraints
Authors: Chardès Victor , Vergassola Massimo , Walczak Aleksandra M. , Mora Thierry
Published: July 2021

In order to target threatening pathogens, the adaptive immune system performs a continuous reorganization of its lymphocyte repertoire. Following an immune challenge, the B cell repertoire can evolve cells of increased specificity for the encountered strain. This process of affinity maturation generates a memory pool whose diversity and size remain difficult to predict. We assume that the immune system follows a strategy that maximizes the long-term immune coverage and minimizes the short-term metabolic costs associated with affinity maturation. This strategy is defined as an optimal decision process on a finite dimensional phenotypic space, where a pre-existing population of naive cells is sequentially challenged with a neutrally evolving strain. We unveil a trade-off between immune protection against future strains and the necessary reorganization of the repertoire. This plasticity of the repertoire drives the emergence of distinct regimes for the size and diversity of the memory pool, depending on the density of naive cells and on the mutation rate of the strain. The model predicts power-law distributions of clonotype sizes observed in data, and rationalizes antigenic imprinting as a strategy to minimize metabolic costs while keeping good immune protection against future strains.
Kveik brewing yeasts demonstrate wide flexibility in beer fermentation temperature and flavour metabolite production and exhibit enhanced trehalose accumulation
Authors: Foster Barret , Tyrawa Caroline , Ozsahin Emine , Lubberts Mark , Krogerus Kristoffer , Preiss Richard , van der Merwe George
Published: July 2021

Abstract

Traditional Norwegian Farmhouse ale yeasts, also known as kveik, have captured the attention of the brewing community in recent years. Kveik were recently reported as fast fermenting thermo- and ethanol tolerant yeasts with the capacity to produce a variety of interesting flavour metabolites. They are a genetically distinct group of domesticated beer yeasts of admixed origin with one parent from the “Beer 1” clade and the other unknown. While kveik are known to ferment wort efficiently at warmer temperatures, its range of fermentation temperatures and corresponding flavour metabolites produced, remain uncharacterized. In addition, the characteristics responsible for its increased thermotolerance remain largely unknown. Here we demonstrate variation in kveik strains at a wide range of fermentation temperatures and show not all kveik strains are equal in fermentation performance, flavour metabolite production and stress tolerance. Furthermore, we uncovered an increased capacity of kveik strains to accumulate intracellular trehalose, which likely contributes to its increased thermo- and ethanol tolerances. Taken together our results present a clearer picture of the future opportunities presented by Norwegian kveik yeasts and offer further insight into their applications in brewing.
Functional buffering via cell-specific gene expression promotes tissue homeostasis and cancer robustness
Authors: Lin Hao-Kuen , Cheng Jen-Hao , Wu Chia-Chou , Hsieh Feng-Shu , Dunlap Carolyn , Chen Sheng-hong
Published: July 2021

Functional buffering that ensures biological robustness is critical for maintaining tissue homeostasis, organismal survival, and evolution of novelty. However, the mechanism underlying functional buffering, particularly in multicellular organisms, remains largely elusive. Here, we developed an inference index (C-score) for Cell-specific Expression- BUffering (CEBU), whereby functional buffering is mediated via expression of buffering genes in specific cells and tissues in humans. By computing C-scores across 684 human cell lines using genome-wide CRISPR screens and transcriptomic RNA-seq, we report that C- score-identified putative buffering gene pairs are enriched for members of the same duplicated gene family, pathway, and protein complex. Furthermore, CEBU is especially prevalent in tissues of low regenerative capacity (e.g., bone and neuronal tissues) and is weakest in highly regenerative blood cells, linking functional buffering to tissue regeneration. Clinically, the buffering capacity enabled by CEBU can help predict patient survival for multiple cancers. Our results reveal CEBU as a buffering mechanism contributing to tissue homeostasis and cancer robustness in humans.

Summary blurb

We unveil a genome-wide functional buffering mechanism, termed Cell-specific Expression Buffering (CEBU), whereby gene expression contributes to functional buffering in specific cell types and tissues. We link CEBU to genetic interactions, tissue homeostasis and cancer robustness.
Different Contribution of the Monkey Prefrontal and Premotor Dorsal Cortex in Decision Making during a Transitive Inference task
Authors: Ramawat S , Mione V , Di Bello F , Bardella G , Genovesio A , Pani P , Ferraina S , Brunamonti E
Published: July 2021

Several studies have reported similar neural modulations between brain areas of the frontal cortex, such as the dorsolateral prefrontal (DLPFC) and the premotor dorsal (PMd) cortex, in tasks requiring encoding of the abstract rules for selecting the proper action. Here we compared the neuronal modulation of the DLPFC and PMd of monkeys trained to choose the higher rank from a pair of abstract images (target item), selected from an arbitrarily rank-ordered set (A>B>C>D>E>F) in the context of a transitive inference task. Once acquired by trial-and-error, the ordinal relationship between pairs of adjacent images (i.e., A>B; B>C; C>D; D>E; E>F), monkeys were tested in indicating the ordinal relation between items of the list not paired during learning. During these decisions, we observed that the choice accuracy increased and the reaction time decreased as the rank difference between the compared items enhanced. This result is in line with the hypothesis that after learning, the monkeys built an abstract mental representation of the ranked items, where rank comparisons correspond to the items’ position comparison on this representation. In both brain areas, we observed higher neuronal activity when the target item appeared in a specific location on the screen with respect to the opposite position and that this difference was particularly enhanced at lower degrees of difficulty. By comparing the time evolution of the activity of the two areas, we observed that the neural encoding of target item spatial position occurred earlier in the DLPFC than in the PMd.