bluuebunny/crossref_metadata_2025 huggingface dataset:
Superior versus anterior plate fixation for midshaft clavicular fractures – a multicentre analysis
Authors: Buenter I R , Kremo V , van de Wall B J M , Link B-C , Galliker B , Babst R , Beeres F J P
Published: June 2022

Objective

To date it remains unclear whether superior or anterior plating is the best option for treating midshaft clavicular fractures. The aim of this study was to compare both techniques with regard to the need of implant removal due to hardware irritation or uncomforting during daily activities, to healing and to complications.

Methods

This was a retrospective study on all midshaft clavicular fractures treated operatively between 2017 and 2019 in two hospitals different in respect to anterior versus superior plating for midshaft clavicular fractures in Switzerland. The primary outcome was the number of implant removal due to hardware irritation, uncomforting, weather sensitivity or the patients wish for removal, whereas the specific reason was not evaluated. Secondary outcomes were time to union, complications, re-interventions and range-of-motion during the follow-up period of at least 6-months.

Results

In total 171 patients were included in the study of which 89 (52%) received anterior plating and 82 (48%) superior plating. The overall mean age was 45 years (SD 16). There was no significant difference between anterior and superior plating in the number of implant removals (39.3% versus 45.1%), infection rate (1.1% versus 1.2%), implant failure (1.1% versus 0%), non-union (1.1% and 0%) and time to union (mean 40 weeks versus 51 weeks).

Ninty-four patients had a documented range of motion after a follow up from 6 up to 12 months with no significant difference in anteflexion (mean 170 degree anterior versus 178 degree superior) and abduction (mean 166 degree versus 176 degree).

Conclusion

There is no significant difference between anterior and superior plating for midshaft clavicular fractures with regard to implant removal, healing, complications and shoulder function. As both treatment opinions are viable, the decision may depend on surgeons experience.
Anatomical analysis of different helical plate designs for proximal humeral shaft fracture fixation
Authors: Pastor T , Kastner P , Souleiman F , Gehweiler D , Miglorini F , Link B-C , Beeres F J P , Babst R , Nebelung S , Ganse B , Schoeneberg C , Gueorguiev B , Knobe M
Published: June 2022

Objective

Helical plates are preferably used for proximal humeral shaft fracture fixation with metaphyseal extension into the humeral head and potentially avoid radial nerve irritation as compared to straight plates. The aims of this study were: (1) to investigate the safety of applying different long plate designs (straight, 45°-, 90°-helical and ALPS) in MIPO-technique to the humerus and (2) to assess and compare their distances to adjacent anatomical structures at risk.

Methods

MIPO was performed in 16 human cadaveric humeri using either a straight plate (group1), a 45°-helical (group2), a 90°-helical (group3) or an ALPS (group4). Using CT-angiography, distances between brachial arteries and plates were evaluated. Following, all specimens were dissected, and distances to the axillary, radial and musculocutaneous nerve were evaluated.

Results

None of the specimens demonstrated injuries of the anatomical structures at risk after MIPO with all investigated plate designs. Closest overall distance (mm(range)) between each plate and the radial nerve was 1(1–3) in group1, 7(2–11) in group2, 14(7–25) in group3 and 6(3–8) in group4. It was significantly longer in group3 and significantly shorter in group1 as compared to all other groups, p<0.001. Closest overall distance (mm(range)) between each plate and the musculocutaneous nerve was 16(8–28) in group1, 11(7–18) in group2, 3(2–4) in group3 and 6(3–8) in group4. It was significantly longer in group1 and significantly shorter in group3 as compared to all other groups, p<0.001. Closest overall distance (mm(range)) between each plate and the brachial artery was 21(18–23) in group1, 7(6–7) in group2, 4(3–5) in group3 and 7(6–7) in group4. It was significantly longer in group1 and significantly shorter in group3 as compared to all other groups, p<0.021.

Conclusion

MIPO with 45°- and 90°-helical plates as well as ALPS is safely feasible and showed a significant greater distance to the radial nerve compared to straight plates. However, distances remain low, and attention must be paid to the musculocutaneous nerve and the brachial artery when MIPO is used with ALPS, 45°- and 90°-helical implants. Moreover, the anterior part of the deltoid insertion will be detached when using 90°-helical and ALPS implants in MIPO-technique.
Outcomes of oncologic robotic gastrectomy compared with open gastrectomy for early and locoregional advanced gastric cancer
Authors: Jung M K , Chevallay M , Toso C , Mönig S P
Published: June 2022

Objective

Minimally invasive gastrectomy for gastric cancer shows slower adoption in Western countries compared to Asia, probably due to lower incidence, advanced stages and a more frequently proximal localization, which requires a technically more challenging total gastrectomy.

Methods

We retrospectively reviewed a prospectively collected database. A total of 51 patients who underwent oncologic total gastrectomy or subtotal gastrectomy by robotic or open approach of stage pT1-T4a, pN0-3 were identified from June 2016 until June 2020. Nine patients were operated on robotically, and 42 patients by laparotomy. Perioperative outcomes, postoperative 30-day complications as well as pathologic results were compared.

Results

The age of the patients in the robotic group was comparable to that of the open group (64.7 ±9.2 versus 62.8 ±12.9, respectively, p = 0.685). Blood loss was significantly smaller with the robotic approach (185±180 mL versus 425±257 mL, p = 0.038). Pathologic tumor stage included stages pT1–pT4b in the open group, while only stages pT1–pT3 were operated by robotic approach. Fewer tumors were localized in the upper body in the robotic group (0, 0%) than in the open group (12, 28.6%). The length of the proximal margin was comparable in the two groups (104.29 ± 50.29 versus 86.88 ± 64.66, p = 0.516). The mean number of retrieved lymph nodes was comparable in the robotic group and the open group (42.89 ± 12.119 versus 43.22 ± 20.271, p = 0.963). The mean number of metastatic nodes was significantly lower in the robotic group (0.33 ± 0.707 versus 7.02 ± 14.313, p = 0.171). In regards to Lauren classification, diffuse-type cancers were significantly more frequent in the robotic group (3 (33.3%) versus 3 (8.6%), respectively, p = 0.040). Significantly fewer high-grade complications (Clavien/Dindo >3a) appeared in the robotic group (0 (0%) versus 2 (4.8%), p = 0.019). No anastomotic leakage and no death occurred in both groups.

Conclusion

The gold standard of oncologic gastrectomy, especially for advanced stages and bulky lymph nodes, is still the open approach. The minimally invasive approach for gastric cancer may be beneficial in regards to blood loss and postoperative complications but must show comparable pathohistological results in comparison to the open approach in regards to lymph node harvest and proximal tumor margins to be an acceptable alternative to the open approach.
Preliminary experience with the new off-the-shelf 4 inner branches E-nside for the treatment of complex aortic disease
Authors: Ettorre L , Longchamp J , Longchamp A , Trunfio R , D'Amico R , Wuarin L , Côté E , Deslarzes-Dubuis C , Déglise S
Published: June 2022

Objective

In case of complex aortic aneurysmal disease, fenestrated or branched EVAR (b/f-EVAR) is considered as a valid and safe alternative to open surgery. However, one the main limitation is the time required for manufacture, limiting its use in emergent situations. The new off-the-shelf 4 inner branches E-nside (Jotec, Hechingen, Germany) has been developed to offer a solution in such circumstances. The aim of this study was to report our preliminary monocentric experience with this new device.

Methods

Retrospective analysis of prospective data retrieved from 1 center between November 2020 and January 2022 was done. Endpoints were technical success, postoperative morbidity, rate of endoleak and any aneurysm-related re-interventions during follow-up.

Results

In this study, 15 patients (mean age 73 years, range 59–90) were identified. There was a majority of male (9/15) and all of them but 3 were asymptomatic. The mean aneurysmal diameter was 60 mm (range 50–100). There were 3 cases of juxtarenal aortic aneurysms (20%), 1 Crawford type I (7%), 4 type II (27%), 4 type III (27%) and 3 type IV (20%) aneurysms. In 7 cases, a 2-steps procedure was done with a TEVAR first followed by Enside implantation. There was a technical success in 93% with 1 open conversion for a mesenterical bypass. There was no death in the post-operative period. During the post-operative period, 33% of patients (5/15) presented complications with 3 complications related to the femoral or iliac access and 2 cases of spinal cord ischemia (13%). One case occurred in an emergent setting of a type III aneurysm rupture. The other case was the open conversion and the patient also developed a colic ischemia and finally died 4 months alter. The mean length of stay was 9 days. During the follow-up, 2 reinterventions were necessary, 1 for a type Ic endoleak with distal prolongation of the stent and 1 renal stent occlusion treated by relining. The overall target vessel patency was 98%.

Conclusion

The use of the off-the-shelf 4 inner branches E-nside appears to be safe with good technical success for the treatment of complex aortic aneurysmal disease. It is associated with an acceptable rate of complications and allows for treatment of a wide variety of diseases in an emergent setting. Further patients and longer follow-up are required to better evaluate the exact role of this new device.
Inventory of ATP-binding cassette proteins inLithospermum erythrorhizonas a model plant producing divergent secondary metabolites
Authors: Li Hao , Matsuda Hinako , Tsuboyama Ai , Munakata Ryosuke , Sugiyama Akifumi , Yazaki Kazufumi
Published: June 2022

ATP-binding cassette (ABC) proteins are the largest membrane transporter family in plants. In addition to transporting organic substances, these proteins function as ion channels and molecular switches. The development of multiple genes encoding ABC proteins has been associated with their various biological roles. Plants utilize many secondary metabolites to adapt to environmental stresses and to communicate with other organisms, with many ABC proteins thought to be involved in metabolite transport. Lithospermum erythrorhizon is regarded as a model plant for studying secondary metabolism, as cells in culture yielded high concentrations of meroterpenes and phenylpropanoids. Analysis of the genome and transcriptomes of L. erythrorhizon showed expression of genes encoding 118 ABC proteins, similar to other plant species. The number of expressed proteins in the half-size ABCA and full-size ABCB subfamilies was ca. 50% lower in L. erythrorhizon than in Arabidopsis, whereas there was no significant difference in the numbers of other expressed ABC proteins. Because many ABCG proteins are involved in the export of organic substances, members of this subfamily may play important roles in the transport of secondary metabolites that are secreted into apoplasts.
Combining Pentoxifylline With Vedolizumab for Crohn’s Disease: Results of a Randomised, Placebo-controlled Pilot Study
Authors: Berera Shivali , Ioannou Stephanie C , Morillo Diana , Mantero Alejandro M A , Pignac-Kobinger Judith , Colina Niurka , Santander Ana M , Fernandez Irina , Quintero Maria Alejandra , Rodriguez Jennifer , Kerman David H , Damas Oriana M , Czul Frank , Sussman Daniel A , Abreu Maria T , Deshpande Amar R
Published: June 2022

Background and Aims

The efficacy of current biologics may be limited by targeting only one pathway. Pentoxifylline [PTX] interferes with tumour necrosis factor [TNF] gene expression. We performed a randomised, placebo-controlled pilot study to determine if PTX plus vedolizumab [VDZ] in patients with Crohn’s disease [CD] is safe and improves response compared with VDZ monotherapy.

Methods

Thirty adult patients with active CD were randomised to VDZ/PTX or VDZ/placebo and followed for 24 weeks. Endoscopic activity and inflammatory cytokines were measured at baseline and Week 24. Descriptive statistics were used to determine estimates of effect.

Results

Demographics were similar but baseline disease activity was higher in the VDZ/PTX group. There was no difference in clinical remission at Week 14 (60.0% vs 66.67%, odds ratio [OR] 0.76, 95% confidence interval [CI] 0.16, 3.51) or steroid-free clinical remission at Week 24 in patients receiving VDZ/PTX. Improved clinical response was noted in the VDZ/PTX group at Weeks 6, 14, and 24 [Week 6: 20% vs 6.67%, Week 14: 26.67% vs 6.67%, Week 24: 40% vs 20%]. The rate of endoscopic remission was similar between the groups [40% vs 33.33%], with a greater mean decrease in Simple Endoscopic Score-CD [SES-CD] and C-reactive protein [CRP] with VDZ/PTX [SES-CD -3.17 vs -0.15, CRP -5.56 vs 0.46]. An increase in serum TNF-α concentration was observed with VDZ/placebo group; PTX mitigated this effect. No serious adverse events occurred.

Conclusions

VDZ/PTX did not provide benefit over VDZ monotherapy in clinical or endoscopic remission but appeared to improve clinical response and was safe. These data should inform a fully powered study.
Presentation cardiac troponin and early computed tomography coronary angiography in patients with suspected acute coronary syndrome: a pre-specified secondary analysis of the RAPID-CTCA trial
Authors: Wang Kang Ling , Roobottom Carl , Smith Jason E , Goodacre Steve , Oatey Katherine , O’Brien Rachel , Storey Robert F , Curzen Nick , Keating Liza , Kardos Attila , Felmeden Dirk , Thokala Praveen , Mills Nicholas L , Newby David E , Gray Alasdair J
Published: June 2022

Aims

To evaluate the potential associations between presentation cardiac troponin and the clinical impact of early computed tomography coronary angiography (CTCA) in intermediate-risk patients with suspected acute coronary syndrome.

Methods and results

In a large multicentre randomized controlled trial of patients with intermediate-risk chest pain due to suspected acute coronary syndrome, early CTCA had no effect on the primary outcome—death or subsequent Type 1 or 4b myocardial infarction—but reduced the rate of invasive coronary angiography. In this pre-specified secondary analysis, cardiovascular testing and clinical outcomes were compared between those with or without cardiac troponin elevation at presentation. Of 1748 patients, 1004 (57%) had an elevated cardiac troponin concentration and 744 (43%) had a normal concentration. Patients with cardiac troponin elevation had a higher Global Registry of Acute Coronary Events score (132 vs. 91; P < 0.001) and were more likely to have obstructive coronary artery disease (59 vs. 33%; P < 0.001), non-invasive (72 vs. 52%; P < 0.001) and invasive (72 vs. 38%; P < 0.001) testing, coronary revascularization (47 vs. 15%; P < 0.001), and the primary outcome (8 vs. 3%; P = 0.007) at 1 year. However, there was no evidence that presentation cardiac troponin was associated with the relative effects of early CTCA on rates of non-invasive (Pinteraction = 0.33) and invasive (Pinteraction = 0.99) testing, coronary revascularization (Pinteraction = 0.57), or the primary outcome (Pinteraction = 0.41).

Conclusion

Presentation cardiac troponin had no demonstrable associations between the effects of early CTCA on reductions in non-invasive and invasive testing, or the lack of effect on coronary revascularization or the primary outcome in intermediate-risk patients with suspected acute coronary syndrome.
Pericardial adiposity is independently linked to adverse cardiovascular phenotypes: a CMR study of 42 598 UK Biobank participants
Authors: Ardissino Maddalena , McCracken Celeste , Bard Andrew , Antoniades Charalambos , Neubauer Stefan , Harvey Nicholas C , Petersen Steffen E , Raisi-Estabragh Zahra
Published: June 2022

Aims

We evaluated independent associations of cardiovascular magnetic resonance (CMR)-measured pericardial adipose tissue (PAT) with cardiovascular structure and function and considered underlying mechanism in 42 598 UK Biobank participants.

Methods and results

We extracted PAT and selected CMR metrics using automated pipelines. We estimated associations of PAT with each CMR metric using linear regression adjusting for age, sex, ethnicity, deprivation, smoking, exercise, processed food intake, body mass index, diabetes, hypertension, height cholesterol, waist-to-hip ratio, impedance fat measures, and magnetic resonance imaging abdominal visceral adiposity measures. Higher PAT was independently associated with unhealthy left ventricular (LV) structure (greater wall thickness, higher LV mass, more concentric pattern of LV hypertrophy), poorer LV function (lower LV global function index, lower LV stroke volume), lower left atrial ejection fraction, and lower aortic distensibility. We used multiple mediation analysis to examine the potential mediating effect of cardiometabolic diseases and blood biomarkers (lipid profile, glycaemic control, inflammation) in the PAT-CMR relationships. Higher PAT was associated with cardiometabolic disease (hypertension, diabetes, high cholesterol), adverse serum lipids, poorer glycaemic control, and greater systemic inflammation. We identified potential mediation pathways via hypertension, adverse lipids, and inflammation markers, which overall only partially explained the PAT-CMR relationships.

Conclusion

We demonstrate association of PAT with unhealthy cardiovascular structure and function, independent of baseline comorbidities, vascular risk factors, inflammatory markers, and multiple non-invasive and imaging measures of obesity. Our findings support an independent role of PAT in adversely impacting cardiovascular health and highlight CMR-measured PAT as a potential novel imaging biomarker of cardiovascular risk.
Moral Hazard Versus Liquidity and the Optimal Timing of Unemployment Benefits
Authors: Campos Rodolfo G , García-Pérez J Ignacio , Reggio Iliana
Published: June 2022

We develop a novel way of identifying the liquidity and moral hazard effects of unemployment insurance exclusively from how job-finding rates respond to unemployment benefits that vary over an unemployment spell. We derive a sufficient statistics formula for the dynamically optimal level of unemployment benefits based on these two effects. Using a regression kink design (RKD) that simultaneously exploits two kinks in the schedule of unemployment benefits, we apply our method to Spain for the years 1992–2012 and find that moral hazard effects dominated liquidity effects, suggesting that Spanish unemployment benefits exceeded the optimal level in that period.
CommensalBacillus subtilisfrom cow milk inhibitsStaphylococcus aureusbiofilm formation and mastitis in mice
Authors: Qiu Min , Feng Lianjun , Zhao Caijun , Gao Siyuan , Bao Lijuan , Zhao Yihong , Fu Yunhe , Hu Xiaoyu
Published: June 2022

The colonization and virulence production of Staphylococcus aureus (S. aureus), a known pathogen that induces mastitis, depend on its quorum-sensing (QS) system and biofilm formation. It has been reported that Bacillus can inhibit the QS system of S. aureus, thereby reducing S. aureus colonization in the intestine. However, whether Bacillus affects S. aureus biofilm formation and consequent colonization during mastitis is still unknown. In this study, the differences in the colonization of S. aureus and Bacillus were first analyzed by isolating and culturing bacteria from milk samples. It was found that the colonization of Bacillus and S. aureus in cow mammary glands was negatively correlated. Secondly, we found that although Bacillus did not affect S. aureus growth, it inhibited the biofilm formation of S. aureus by interfering its QS signaling. The most significant anti-biofilm effect was found in Bacillus subtilis H28 (B. subtilis H28). Finally, we found that B. subtilis H28 treatment alleviated S. aureus-induced mastitis in a mice model. Our results rerealed that bovine milk derived commensal Bacillus inhibited S. aureus colonization and alleviated S. aureus-induced mastitis by influencing biofilm formation, suggesting a potential targeted strategy to limit the colonization of S. aureus in vivo.
From blood to stress—my life investigating cell differentiation
Authors: Breitenbach Michael , Cooper Terrance G
Published: June 2022

This short retrospective covers more than 50 years of research. I spent most of it doing yeast genetics and genetic engineering. It has been my great privilege to be part of the international group of yeast genetics researchers. With many of them named in this retrospective, I am connected in lifelong friendships and the same is true for my students and collaborators. The question which we wanted to ask is “How does the genome of the cell and cell differentiation adapt to changing and stressful environmental conditions?” The two examples we studied were sporulation and pseudohyphal growth. Both forms of differentiation are triggered by the stress of starvation. In the pathway of regulation of pseudohyphal growth, a yeast NADPH oxidase (discovered by our group) plays a major role.
Ancestral State Reconstructions Trace Mitochondria But Not Phagocytosis to the Last Eukaryotic Common Ancestor
Authors: Bremer Nico , Tria Fernando D. K. , Skejo Josip , Garg Sriram G. , Martin William F.
Published: June 2022

Two main theories have been put forward to explain the origin of mitochondria in eukaryotes: phagotrophic engulfment (undigested food) and microbial symbiosis (physiological interactions). The two theories generate mutually exclusive predictions about the order in which mitochondria and phagocytosis arose. To discriminate the alternatives, we have employed ancestral state reconstructions (ASR) for phagocytosis as a trait, phagotrophy as a feeding habit, the presence of mitochondria, the presence of plastids, and the multinucleated organization across major eukaryotic lineages. To mitigate the bias introduced by assuming a particular eukaryotic phylogeny, we reconstructed the appearance of these traits across 1789 different rooted gene trees, each having species from opisthokonts, mycetozoa, hacrobia, excavate, archeplastida, and Stramenopiles, Alveolates and Rhizaria. The trees reflect conflicting relationships and different positions of the root. We employed a novel phylogenomic test that summarizes ASR across trees which reconstructs a last eukaryotic common ancestor that possessed mitochondria, was multinucleated, lacked plastids, and was non-phagotrophic as well as non-phagocytic. This indicates that both phagocytosis and phagotrophy arose subsequent to the origin of mitochondria, consistent with findings from comparative physiology. Furthermore, our ASRs uncovered multiple origins of phagocytosis and of phagotrophy across eukaryotes, indicating that, like wings in animals, these traits are useful but neither ancestral nor homologous across groups. The data indicate that mitochondria preceded the origin of phagocytosis, such that phagocytosis cannot have been the mechanism by which mitochondria were acquired.
The Evolution of Widespread Recombination Suppression on the Dwarf Hamster (Phodopus) X Chromosome
Authors: Moore Emily C. , Thomas Gregg W. C. , Mortimer Sebastian , Kopania Emily E. K. , Hunnicutt Kelsie E. , Clare-Salzler Zachary J. , Larson Erica L. , Good Jeffrey M.
Published: June 2022

The X chromosome of therian mammals shows strong conservation among distantly related species, limiting insights into the distinct selective processes that have shaped sex chromosome evolution. We constructed a chromosome-scale de novo genome assembly for the Siberian dwarf hamster (Phodopus sungorus), a species reported to show extensive recombination suppression across an entire arm of the X chromosome. Combining a physical genome assembly based on shotgun and long-range proximity ligation sequencing with a dense genetic map, we detected widespread suppression of female recombination across ∼65% of the Phodopus X chromosome. This region of suppressed recombination likely corresponds to the Xp arm, which has previously been shown to be highly heterochromatic. Using additional sequencing data from two closely related species (P. campbelli and P. roborovskii), we show that recombination suppression on Xp appears to be independent of major structural rearrangements. The suppressed Xp arm was enriched for several transposable element families and de-enriched for genes primarily expressed in placenta, but otherwise showed similar gene densities, expression patterns, and rates of molecular evolution when compared to the recombinant Xq arm. Phodopus Xp gene content and order was also broadly conserved relative to the more distantly related rat X chromosome. These data suggest that widespread suppression of recombination has likely evolved through the transient induction of facultative heterochromatin on the Phodopus Xp arm without major changes in chromosome structure or genetic content. Thus, substantial changes in the recombination landscape have so far had relatively subtle influences on patterns of X-linked molecular evolution in these species.
Expression Plasticity of Transposable Elements Is Highly Associated with Organismal Re-adaptation to Ancestral Environments
Authors: Liu Yan-Nan , Chen Rong-Mei , Pu Qi-Ting , Nneji Lotanna M. , Sun Yan-Bo
Published: June 2022

Understanding the roles of phenotypic plasticity in adaptive evolution has gained recognition for decades. Studies involving multiple taxa have shown that gene expression plasticity serves as “long-term memory” to facilitate re-adaptations to ancestral environments. Nevertheless, the general pattern and the underlying genetic basis of expression plasticity remain unclear. The transposable elements (TEs) play crucial roles in gene expression regulation and are widely distributed within the genome. Given this, we re-analyzed the transcriptomic data of chicken (Gallus gallus) generated from a reciprocal transplant experiment to examine whether expression shifts of TEs are involved in the re-adaptation process. Similar to the protein-coding genes, the plastic changes of TEs overwhelmingly exceed the genetic changes in the re-adaptation process. Further, the associated TEs co-expressed with diverse genes to perform a regulatory activity. Thus, our study supports the general function of phenotypic plasticity in adaptive evolution, and suggests a regulatory functions of TEs in this process.
Long-term Risk of Herpes Zoster Infection in Patients With Ulcerative Colitis Receiving Tofacitinib
Authors: Winthrop Kevin L , Vermeire Séverine , Long Millie D , Panés Julian , Ng Siew C , Kulisek Nicole , Mundayat Rajiv , Lawendy Nervin , Vranic Ivana , Modesto Irene , Su Chinyu , Melmed Gil Y
Published: June 2022

Background

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We report herpes zoster (HZ) incidence and risk factors in the tofacitinib UC clinical program (up to 7.8 years).

Methods

Proportions and incidence rates (IRs; unique patients with events/100 patient-years) of HZ were evaluated in 4 cohorts: Induction (phase 2 and 3 induction study data), Maintenance (phase 3 maintenance study data), Overall (data from all phase 2, 3, and open-label, long-term extension studies), and Overall plus interim 6-month phase 3b and 4 data. Herpes zoster risk factors were assessed by Cox regression analysis.

Results

In the Induction and Maintenance Cohorts, IRs for HZ (nonserious and serious) were numerically higher with tofacitinib 10 mg twice daily (BID) vs placebo and tofacitinib 10 vs 5 mg BID, respectively. With all tofacitinib doses (5 or 10 mg BID), IRs (95% confidence intervals) for HZ in the Overall and Overall plus phase 3b/4 Cohorts (total exposure, 2814.4 and 2999.7 patient-years, respectively) were 3.38 (2.73-4.15) and 3.30 (2.67-4.04), respectively. In the Overall plus phase 3b/4 Cohort, >90% of HZ were nonserious; >90% were mild/moderate; >90% resolved without discontinuing tofacitinib; 0.6% of patients had multiple HZ events. Herpes zoster IRs were stable when analyzed by 6-month intervals up to >30 months. Herpes zoster risk factors included older age, lower weight, geographic region, and prior tumor necrosis factor inhibitor (TNFi) failure.

Conclusions

Most HZ events were mild/moderate. Herpes zoster IRs remained stable over 7.8 years of exposure. Older age, lower weight, geographic region, and prior TNFi failure were associated with increased HZ risk.

ClinicalTrials.gov

NCT00787202;NCT01465763;NCT01458951;NCT01458574;NCT01470612;NCT03281304
When Defenses Fail: Atelopus zeteki Skin Secretions Increase Growth of the Pathogen Batrachochytrium dendrobatidis
Authors: Gass Jordan , Voyles Jamie
Published: June 2022

To combat the threat of emerging infectious diseases in wildlife, ecoimmunologists seek to understand the complex interactions among pathogens, their hosts, and their shared environments. The cutaneous fungal pathogen Batrachochytrium dendrobatidis (Bd), has led to the decline of innumerable amphibian species, including the Panamanian golden frog (Atelopus zeteki). Given that Bd can evade or dampen the acquired immune responses of some amphibians, nonspecific immune defenses are thought to be especially important for amphibian defenses against Bd. In particular, skin secretions constitute a vital component of amphibian innate immunity against skin infections, but their role in protecting A. zeteki from Bd is unknown. We investigated the importance of this innate immune component by reducing the skin secretions from A. zeteki and evaluating their effectiveness against Bd in vitro and in vivo. Following exposure to Bd in a controlled inoculation experiment, we compared key disease characteristics (e.g., changes in body condition, prevalence, pathogen loads, and survival) among groups of frogs that had their skin secretions reduced and control frogs that maintained their skin secretions. Surprisingly, we found that the skin secretions collected from A. zeteki increased Bd growth in vitro. This finding was further supported by infection and survival patterns in the in vivo experiment where frogs with reduced skin secretions tended to have lower pathogen loads and survive longer compared to frogs that maintained their secretions. These results suggest that the skin secretions of A. zeteki are not only ineffective at inhibiting Bd but may enhance Bd growth, possibly leading to greater severity of disease and higher mortality in this highly vulnerable species. These results differ from those of previous studies in other amphibian host species that suggest that skin secretions are a key defense in protecting amphibians from developing severe chytridiomycosis. Therefore, we suggest that the importance of immune components cannot be generalized across all amphibian species or over time. Moreover, the finding that skin secretions may be enhancing Bd growth emphasizes the importance of investigating these immune components in detail, especially for species that are a conservation priority.
Metabarcoding Approaches in Amphibian Disease Ecology: Disentangling the Functional Contributions of Skin Bacteria on Disease Outcome
Authors: Longo Ana V
Published: June 2022

Molecular technologies have revolutionized the field of wildlife disease ecology, allowing the detection of outbreaks, novel pathogens, and invasive strains. In particular, metabarcoding approaches, defined here as tools used to amplify and sequence universal barcodes from a single sample (e.g., 16S rRNA for bacteria, ITS for fungi, 18S rRNA for eukaryotes), are expanding our traditional view of host–pathogen dynamics by integrating microbial interactions that modulate disease outcome. Here, I provide an analysis from the perspective of the field of amphibian disease ecology, where the emergence of multi-host pathogens has caused global declines and species extinctions. I reanalyzed an experimental mesocosm dataset to infer the functional profiles of the skin microbiomes of coqui frogs (Eleutherodactylus coqui), an amphibian species that is consistently found infected with the fungal pathogen Batrachochytrium dendrobatidis and has high turnover of skin bacteria driven by seasonal shifts. I found that the metabolic activities of microbiomes operate at different capacities depending on the season. Global enrichment of predicted functions was more prominent during the warm-wet season, indicating that microbiomes during the cool-dry season were either depauperate, resistant to new bacterial colonization, or that their functional space was more saturated. These findings suggest important avenues to investigate how microbes regulate population growth and contribute to host physiological processes. Overall, this study highlights the current challenges and future opportunities in the application of metabarcoding to investigate the causes and consequences of disease in wild systems.
Revisiting TSHβ’s Role in Avian Seasonal Reproduction, Insights, and Challenges from Mammalian Models
Authors: Pérez Jonathan H
Published: June 2022

The core neuroendocrine pathways regulating seasonal reproduction in vertebrates were characterized over a decade ago. This has led to the development of a “consensus” model of seasonal reproduction that appears to be largely conserved across mammals, birds, amphibians, reptile and fish. This model centers around the photoinduced increase in TSHβ expression in the pars tuberalis of the anterior pituitary gland as the key transducer of photic information from sensory cells to the critical switch in hypothalamic deiodinase enzyme expression that drives changes in localized thyroid hormone signaling. These changes in localized thyroid hormone signaling in the medial basal hypothalamus ultimately activate the reproductive axis. This model has in turn, been consistently supported by studies in a variety of taxa. As such, it has become the standard against which subsequent work is compared, particularly in the non-mammalian literature. However, as new studies move away from the handful of canonical model systems and begin to explore the effects of naturalistic rather than artificial photoperiod manipulations, a more nuanced picture has begun to emerge. Yet, progress in elucidating the detailed events of reproductive photostimulation has been uneven across the research community. In this perspective, I draw on emerging data from studies in free living animals that challenges some of the established assumptions of the avian consensus model of reproduction. Specifically, the role of TSHβ and its dissociation from deiodinase signaling. I then discuss how these apparently surprising findings can be contextualized within the context of the mammalian seasonal literature. In turn, this ability to contextualize from the mammalian literature highlights the breadth of the current gap versus our understanding of the molecular neuroendocrine mechanisms of seasonality in mammals versus birds and other non-mammalian seasonal breeders.
Different Traits at Different Rates: The Effects of Dynamic Strain Rate on Structural Traits in Biology
Authors: Anderson Philip S L , Kawano Sandy M
Published: June 2022

Phenotypic diversity is influenced by physical laws that govern how an organism's morphology relates to functional performance. To study comparative organismal biology, we need to quantify this diversity using biological traits (definable aspects of the morphology, behavior, and/or life history of an organism). Traits are often assumed to be immutable properties that need to be measured only a single time in each adult. However, organisms often experience changes in their biotic and abiotic environments that can alter trait function. In particular, structural traits represent the physical capabilities of an organism and may be heavily influenced by the rate at which they are exposed to physical demands (“loads”). For instance, materials tend to become more brittle when loaded at faster rates which could negatively affect structures trying to resist those loads (e.g., brittle materials are more likely to fracture). In the following perspective piece, we address the dynamic properties of structural traits and present case studies that demonstrate how dynamic strain rates affect the function of these traits in diverse groups of organisms. First, we review how strain rate affects deformation and fracture in biomaterials and demonstrate how these effects alter puncture mechanics in systems such as snake strikes. Second, we discuss how different rates of bone loading affect the locomotor biomechanics of vertebrates and their ecology. Through these examinations of diverse taxa and ecological functions, we aim to highlight how rate-dependent properties of structural traits can generate dynamic form–function relationships in response to changing environmental conditions. Findings from these studies serve as a foundation to develop more nuanced ecomechanical models that can predict how complex traits emerge and, thereby, advance progress on outlining the Rules of Life.
Invasive Widow Spiders Perform Differently at Low Temperatures from Conspecifics from the Native Range
Authors: Mowery Monica A , Anthony Susan E , Dorison Alexandra N , Mason Andrew C , Andrade Maydianne C B
Published: June 2022

Temperature challenges are one of the leading abiotic causes of success or failure of non-native species in a novel environment, and this is particularly true for low temperatures. Establishing and reproducing in a novel thermal environment can alter survival, behavior, and traits related to fitness. It has been proposed that plasticity or adaptation of thermal tolerance may allow an introduced species to thrive, or that successful invaders may be those with a thermal breadth in their native habitat that encompasses their new environment. Here, we tested these hypotheses using native and invasive populations of Australian redback spiders (Latrodectus hasselti). We measured how exposure to temperatures common to invasive and native range habitats (exposure to 15 and 25°C, respectively) affected behavioral and life-history traits and trade-offs that may underlie fitness in an invasive population detected in 1995 in Japan and a native population from Australia. We found that the critical thermal minimum (CTmin) was higher in the invasive population from Japan than in the native population, but critical thermal maximum (CTmax) did not differ between populations. Compared to the invasive population, eggs from the native population had a longer development time and lower hatching success at 15°C. Both populations performed equally well at 25°C, as measured by egg development time and hatching success. Invasive juveniles tested at 15°C were faster to explore a novel environment and bolder compared to those tested at 25°C. In comparison, the native population showed faster average exploration, with no differences in boldness or exploration at the two development or testing temperatures. Overall, L. hasselti from Japan maintained hatching success and development across a wider temperature range than the native population, indicating greater thermal breadth and higher behavioral plasticity. These results support the importance of plasticity in thermal tolerance and behavior for a successful invasion under novel environmental temperatures.
Aripiprazole and Risperidone Present Comparable Long-Term Metabolic Profiles: Data From a Pragmatic Randomized Controlled Trial in Drug-Naïve First-Episode Psychosis
Authors: Vázquez-Bourgon Javier , Ortiz-García de la Foz Víctor , Gómez-Revuelta Marcos , Mayoral-van Son Jacqueline , Juncal-Ruiz María , Garrido-Torres Nathalia , Crespo-Facorro Benedicto
Published: June 2022

Objective

Aripiprazole and risperidone are 2 of the most used second-generation antipsychotics (SGAs) worldwide. Previous evidence shows a similar effect of these SGAs on weight and metabolic changes in the short term. However, a longer period is necessary for a better assessment of the SGA´s metabolic profile. We aimed to compare the long-term (1-year) metabolic profile of these 2 antipsychotics on a sample of drug-naïve first episode-psychosis (FEP) patients.

Methods

A total 188 drug-naïve patients, suffering from a first episode of non-affective psychosis (FEP), were randomly assigned to treatment with either aripiprazole or risperidone. Weight and glycemic/lipid parameters were recorded at baseline and after 1-year follow-up.

Results

We observed significant weight increments in both groups (9.2 kg for aripiprazole and 10.5 kg for risperidone) after 1 year of treatment. Despite this, weight and body mass index changes did not significantly differ between treatment groups (P > .05). Similarly, both treatment groups presented similar metabolic clinical impact with a comparable increase in the proportion of participants meeting criteria for metabolic disorders such as obesity or hypercholesterolemia, but not for metabolic syndrome (Δ9.2% vs Δ4.3%) or hypertriglyceridemia (Δ21.9% vs Δ8.0%), where aripiprazole showed worse outcomes than risperidone.

Conclusion

This study shows that aripiprazole and risperidone share a similar long-term metabolic profile. After 1 year of antipsychotic treatment, drug-naïve FEP patients in both treatment groups presented a significant increase in weight and metabolic changes, leading to a greater prevalence of metabolic disorders.
Corrigendum to: “Growth of Unbounded Subsets in Nilpotent Groups, Random Mapping Statistics, and Geometry of Group Laws”
Authors: Greenfeld Be’eri , Lavner Hagai
Published: June 2022

We fix Lemma 6.2 in our recent paper [1] and correct the constants derived from it, appearing in Theorems 1.1, 1.3, and 1.4 and Corollary 6.5.
Supercuspidal Support of Irreducible Modulo ℓ-Representations of SLn(F)
Authors: Cui Peiyi
Published: June 2022

Let $p$ be a prime number and $k$ an algebraically closed field with characteristic $\ell \neq p$. We show that the supercuspidal support of irreducible smooth $k$-representations of Levi subgroups $\textrm {M}^{\prime}$ of $\textrm {SL}_n(F)$ is unique up to $\textrm {M}^{\prime}$-conjugation, where $F$ is either a finite field of characteristic $p$ or a non-Archimedean locally compact field of residual characteristic $p$.
Forecasting the future clinical events of a patient through contrastive learning
Authors: Zhang Ziqi , Yan Chao , Zhang Xinmeng , Nyemba Steve L , Malin Bradley A
Published: June 2022

Objective

Deep learning models for clinical event forecasting (CEF) based on a patient’s medical history have improved significantly over the past decade. However, their transition into practice has been limited, particularly for diseases with very low prevalence. In this paper, we introduce CEF-CL, a novel method based on contrastive learning to forecast in the face of a limited number of positive training instances.

Materials and Methods

CEF-CL consists of two primary components: (1) unsupervised contrastive learning for patient representation and (2) supervised transfer learning over the derived representation. We evaluate the new method along with state-of-the-art model architectures trained in a supervised manner with electronic health records data from Vanderbilt University Medical Center and the All of Us Research Program, covering 48 000 and 16 000 patients, respectively. We assess forecasting for over 100 diagnosis codes with respect to their area under the receiver operator characteristic curve (AUROC) and area under the precision-recall curve (AUPRC). We investigate the correlation between forecasting performance improvement and code prevalence via a Wald Test.

Results

CEF-CL achieved an average AUROC and AUPRC performance improvement over the state-of-the-art of 8.0%–9.3% and 11.7%–32.0%, respectively. The improvement in AUROC was negatively correlated with the number of positive training instances (P < .001).

Conclusion

This investigation indicates that clinical event forecasting can be improved significantly through contrastive representation learning, especially when the number of positive training instances is small.
In vivo investigation of ruminant placenta function and physiology—a review
Authors: Tanner Amelia R , Kennedy Victoria C , Lynch Cameron S , Hord Taylor K , Winger Quinton A , Rozance Paul J , Anthony Russell V
Published: June 2022

The placenta facilitates the transport of nutrients to the fetus, removal of waste products from the fetus, immune protection of the fetus and functions as an endocrine organ, thereby determining the environment for fetal growth and development. Additionally, the placenta is a highly metabolic organ in itself, utilizing a majority of the oxygen and glucose derived from maternal circulation. Consequently, optimal placental function is required for the offspring to reach its genetic potential in utero. Among ruminants, pregnant sheep have been used extensively for investigating pregnancy physiology, in part due to the ability to place indwelling catheters within both maternal and fetal vessels, allowing for steady-state investigation of blood flow, nutrient uptakes and utilization, and hormone secretion, under non-stressed and non-anesthetized conditions. This methodology has been applied to both normal and compromised pregnancies. As such, our understanding of the in vivo physiology of pregnancy in sheep is unrivalled by any other species. However, until recently, a significant deficit existed in determining the specific function or significance of individual genes expressed by the placenta in ruminants. To that end, we developed and have been using in vivo RNA interference (RNAi) within the sheep placenta to examine the function and relative importance of genes involved in conceptus development (PRR15 and LIN28), placental nutrient transport (SLC2A1 and SLC2A3), and placenta-derived hormones (CSH). A lentiviral vector is used to generate virus that is stably integrated into the infected cell’s genome, thereby expressing a short-hairpin RNA (shRNA), that when processed within the cell, combines with the RNA Induced Silencing Complex (RISC) resulting in specific mRNA degradation or translational blockage. To accomplish in vivo RNAi, day 9 hatched and fully expanded blastocysts are infected with the lentivirus for 4 to 5 h, and then surgically transferred to synchronized recipient uteri. Only the trophectoderm cells are infected by the replication deficient virus, leaving the inner cell mass unaltered, and we often obtain ~70% pregnancy rates following transfer of a single blastocyst. In vivo RNAi coupled with steady-state study of blood flow and nutrient uptake, transfer and utilization can now provide new insight into the physiological consequences of modifying the translation of specific genes expressed within the ruminant placenta.