bluuebunny/crossref_metadata_2025 huggingface dataset:
CoBiToM Project – II. Evolution of contact binary systems close to the orbital period cut-off
Authors: Loukaidou G A , Gazeas K D , Palafouta S , Athanasopoulos D , Zola S , Liakos A , Niarchos P G , Hakala P , Essam A , Hatzidimitriou D
Published: November 2021

Ultra-short orbital period contact binaries (Porb < 0.26 d) host some of the smallest and least massive stars. These systems are faint and rare, and it is believed that they have reached a contact configuration after several Gyrs of evolution via angular momentum loss, mass transfer, and mass loss through stellar wind processes. This study is conducted in the frame of the Contact Binaries Towards Merging (CoBiToM) Project and presents the results from light curve and orbital analysis of 30 ultra-short orbital period contact binaries, with the aim to investigate the possibility of them being red nova progenitors, eventually producing merger events. Approximately half of the systems exhibit orbital period modulations, as a result of mass transfer or mass loss processes. Although they are in contact, their fill-out factor is low (less than 30 per cent), while their mass ratio is larger than the one in longer period contact binaries. This study investigates the orbital stability of these systems and examines their physical and orbital parameters in comparison to those of the entire sample of known and well-studied contact binaries, based on combined spectroscopic and photometric analysis. It is found that ultra-short orbital period contact binaries have very stable orbits, while very often additional components are gravitationally bound in wide orbits around the central binary system. We confirmed that the evolution of such systems is very slow, which explains why the components of ultra-short orbital period systems are still Main Sequence stars after several Gyrs of evolution.
Aberrant Cerebello-Thalamo-Cortical Functional and Effective Connectivity in First-Episode Schizophrenia With Auditory Verbal Hallucinations
Authors: Wei Yarui , Xue Kangkang , Yang Meng , Wang Huan , Chen Jingli , Han Shaoqiang , Wang Xiaoxiao , Li Hong , Zhang Yong , Song Xueqin , Cheng Jingliang
Published: November 2021

The thalamus is known to be impaired in schizophrenia patients with auditory verbal hallucinations (AVHs). Abnormal filtering function of the thalamus has been found in schizophrenia patients with AVHs. However, a whole-structure approach has commonly been adopted when investigating thalamic dysconnectivity in patients with AVHs, and it remains unclear which thalamic nucleus is the critical structure underlying AVHs. Here, we investigated voxel-wise resting-state functional connectivity (rsFC) of the thalamic nucleus in drug-naïve patients with first-episode schizophrenia (FES) with AVHs. In addition, dynamic causal modeling was applied to compute effective connectivity and estimate causal relationships that could explain aberrant rsFC. Compared with the FES patients without AVH (NAVH) and normal controls, patients with AVHs had weaker rsFC of the bilateral medial pulvinar (PuM) nucleus-cerebellum. Moreover, compared with the normal control group, the AVH and NAVH groups had significantly stronger rsFC of the bilateral PuM nucleus-cerebral cortex, as well as weaker rsFC of the right medial geniculate nucleus-cerebral cortex. Compared with the NAVH and normal control groups, dynamic causal modeling revealed significantly stronger effective connectivity from the left PuM nucleus to the right inferior frontal gyrus in the AVH group. These findings indicate that the critical structure in the thalamus underlying AVHs is the PuM nucleus, and provide direct evidence that the cerebello-thalamo-cortical circuit is associated with AVHs.
Phylodynamic analysis and spike protein mutations in porcine deltacoronavirus with a new variant introduction in Taiwan
Authors: Hsueh Fu-Chun , Wu Cheng-Nan , Lin Marco Yung-Cheng , Hsu Feng-Yang , Lin Chuen-Fu , Chang Hui-Wen , Lin Jih-Hui , Liu Hsin-Fu , Chiou Ming-Tang , Chan Kuan Rong , Lin Chao-Nan
Published: November 2021

Porcine deltacoronavirus (PDCoV) is a highly transmissible intestinal pathogen that causes mild to severe clinical symptoms, such as anorexia, vomiting, and watery diarrhea in pigs. By comparing the genetic sequences of the spike glycoprotein between historical and current Taiwanese PDCoV strains, we identified a novel PDCoV variant that displaced the PDCoV responsible for the 2015 epidemic. This PDCoV variant belongs to a young population within the US lineage, and infected pigs carry high concentrations of the virus. It also has several critical point mutations and an amino acid insertion at position 52 that may enhance the affinity between the B-cell epitopes located in the N-terminal domain with its complementarity regions, consequently facilitating binding or penetration between the fusion peptide and cellular membrane. Furthermore, viral protein structure prediction demonstrated that these amino acid changes may change the ability of the virus to bind to the receptor, which may consequently alter virus infectivity. Our results hence suggest the emergence of new PDCoV strains in Taiwan with the potential for greater transmission and pathogenesis.
Lyme carditis
Authors: Stypula M. Arthur , Bright Jeffrey , Beck David C.
Published: November 2021

With the rising prevalence of Lyme disease over the last 2 decades comes an increase in cases of Lyme carditis, a consequence of early disseminated infection. This case report focuses on a young man with a complicated case of Lyme carditis that required advanced therapy.
Reevaluating race and the glomerular filtration rate calculator
Authors: Lyas Claretha , Zuber Kim , Davis Jane
Published: November 2021

Estimated glomerular filtration rate (eGFR) calculators have included a race adjustment to help approximate measured GFR. Over the past several years, as more attention has been directed toward uncovering racial bias, the appropriateness of including race in these calculators has been called into question. The American Society of Nephrology and the National Kidney Foundation convened an expert task force to review the inclusion of race in eGFR. The deliberative review showed that race can be removed from eGFR calculators without causing adverse reactions in any group of patients. This new, refitted CKD-EPI equation can be used immediately by all laboratories in the United States. The task force also recommended greater use of cystatin C nationally in eGFR calculations. This would enable the new CKD-EPI equation to incorporate both creatinine and cystatin C without race and would yield better accuracy than a calculator that uses creatinine alone.
Delivery Technique for Fibular Strut Bone Grafting to Proximal Humerus Nonunion Fractures
Authors: Kane Steven M. , Tanaka Scott , Smith Matt
Published: November 2021

Introduction:

The prevalence of proximal humerus fractures will continue to increase as the population ages. Although the use of fibular strut grafts to treat these fractures is well established and has been used for many years, the authors present an alternative technique that aligns the graft within the intermedullary canal, and proximal segment, allowing for greater fragment and reduction control throughout the procedure.

Materials and Methods:

The technique involves intramedullary reaming and the usage of a #5 suture through the strut graft proximally that allows for easy placement of the graft across the fracture and into the humeral head after reduction.

Results:

The representative case described in this paper demonstrates a simplified technique for placement of a fibular allograft and fracture reduction with locking plate fixation for the treatment of proximal humerus nonunions.

Discussion:

The technique is an effective and simple method for the placement of a fibular strut allograft within the intramedullary canal of the distal and proximal segments of a proximal humeral fracture. The use of an endosteal fibular allograft strut addresses the need to re-establish the medial column of the humerus, provides local bone stock, and helps avoid varus angulation, and allows for improved fixation of the plate in poor quality bone.
Rare driver alterations in nonsmall cell lung cancer: novel targeted drugs
Authors: Kauffmann-Guerrero Diego , Tufman Amanda
Published: November 2021

Purpose of review

The current review presents clinically relevant driver alterations in nonsmall cell lung cancer (NSCLC) and the targeted treatments currently available for clinical use as well as those in clinical trials and advanced stages of drug development.

Recent findings

Mesenchymal–epithelial transition factor, human epidermal growth factor receptor 2, proto-oncogene B-RAF (BRAF), proto-oncogene tyrosine-protein kinase ROS (ROS1), rearranged during transfection (RET) and neurotrophic tyrosine kinase are rare genetic driver alterations, each present in a small subset of patients with NSCLC. Treatments targeting BRAF, ROS1, RET and neurotrophic tyrosine kinase are approved in Europe, and promising treatments targeting mesenchymal–epithelial transition factor and human epidermal growth factor receptor 2 are available in clinical trials and compassionate use programs. The response rates, duration of response and tolerability observed in trials of targeted drugs in this setting are presented in detail here.

While rare driver alterations are, by definition, rare, their recognition can change the course of NSCLC for those patients affected. Targeted treatments for many rare driver alterations are well tolerated and effective. Screening for molecular changes in advanced NSCLC should include screening for rare drivers, and patients should be directed to clinical trials in setting where treatment of the driver alterations is not otherwise available.
Outcome of Lamellar Graft Patching for the Treatment of Noninfectious Corneal Perforations
Authors: Suzuki Takanori , Yamaguchi Takefumi , Tomida Daisuke , Fukui Masaki , Shimazaki Jun
Published: November 2021

Purpose:

The aims of this study were to evaluate the clinical outcome of lamellar graft patching used for treating noninfectious corneal perforations and to determine the clinical factors affecting tectonic integrity.

Methods:

This retrospective study includes a total of 71 eyes of 67 patients who underwent lamellar graft patching for the treatment of corneal perforations due to persistent epithelial defects secondary to limbal stem cell deficiency (LSCD, 21 eyes; 29.6%), peripheral ulcerative keratitis (17 eyes; 23.9%), neurotrophic keratitis due to herpes simplex keratitis (HSK, 14 eyes; 19.7%), and other causes (19 eyes; 26.8%). We evaluated the tectonic integrity of the globe, visual outcomes, and postoperative complications.

Results:

Tectonic integrity was achieved in 53 eyes (74.6%). The survival proportions of eyes that achieved clear grafts were 77.8% and 65.2% at 12 and 24 months, respectively. Graft failure was observed in 19 eyes (26.8%). The survival rate of tectonic integrity and eyes that finally achieved a clear graft was significantly worse in eyes with LSCD compared with those without (P < 0.001). The logarithm of minimal angle resolution improved significantly from 1.79 ± 0.98 to 1.22 ± 0.87 at 12 months and 1.08 ± 0.81 at 24 months. Postoperative complications included cataract formation (32 eyes, 45.1%), intraocular pressure rise (23 eyes, 32.4%), recurrent perforations (15 eyes, 21.1%), infectious keratitis (14 eyes, 19.7%), recurrence of herpes simplex keratitis (7 eyes, 9.9%), and traumatic graft dehiscence (1 eye, 1.4%).

Conclusions:

Lamellar graft patching is an effective and safe surgical treatment for noninfectious corneal perforations; however, careful attention to severe complications is necessary, especially in eyes with LSCD.
Pre-Exposure Prophylaxis Stigma and Beliefs in the Efficacy of Pre-Exposure Prophylaxis: An Analysis of a Cross-Sectional Survey of Male Couples in the United States
Authors: Stephenson Rob , Chavanduka Tanaka M. D. , Sullivan Stephen P. , Mitchell Jason W.
Published: November 2021

Increasing the use of pre-exposure prophylaxis (PrEP) among male couples is critical to the success of the United States' Ending the HIV Epidemic campaign. By leveraging dyadic data from a larger cross-sectional study of male couples, the present analysis examined individual, partner, and relationship characteristics associated with PrEP stigma and perceived efficacy of PrEP. Actor–Partner Independence Models were fit separately for both outcomes. Individual and partner risk behaviors, including substance use, binge drinking, and higher number of condomless casual sex partners, were associated with lower levels of both PrEP stigma and belief in the efficacy of PrEP. Networks that supported PrEP use were associated with decreased PrEP stigma and increased belief in PrEP efficacy. Stigma-informed PrEP interventions for couples should be considered foundational to the success of the United States' Ending the HIV Epidemic campaign.
Electronic Messaging for Gonorrhea and Chlamydia Test Result Notification, Improving Treatment and Patient Satisfaction
Authors: Rahman Mohammad M. , Johnson Chaquetta , Whyte Martha , Ewell Joy , Cope Anna B. , Chandler Yolanda , Bennett Tammy S. , Gray Terri , Gruber DeAnn , Peterman Thomas A.
Published: November 2021

Background

Approximately 20% of chlamydia (CT) and gonorrhea (GC) cases in Louisiana are diagnosed at Parish Health Units. Patient notification of CT and GC test results involves nurses' phone calls and letters to positive patients, which is time-consuming and inefficient.

Methods

In December 2018, electronic results notification was implemented in Caddo Parish Health Unit using Chexout software to notify enrolled patients via text or email when test results are ready to view in a patient portal. We compared the timeliness of GC/CT results notification and treatment pre-Chexout (December 2017 to November 2018) and post-Chexout (December 2018 to November 2019) implementation. A random sample of patients was interviewed to assess acceptability.

Results

During December 2018 to November 2019, 5432 patients were tested for CT/GC, 3924 (72%) enrolled in Chexout, and notifications were sent to 3884 (99%). Among CT-positives, 472 of 568 (83%) viewed results in the portal compared with 2451 of 3356 (73%) CT-negatives. Among GC-positives, 300 of 353 (85%) viewed results compared with 2657 of 3571 (74%) GC-negatives. Treatment success for CT improved from 493 of 670 (74%) to 506 of 568 (89%), and for GC, from 332 of 409 (81%) to 325 of 353 (92%). Mean time to treatment decreased for CT (13.4–10.7 days) and GC (11.3–9.2 days). Enrolled patients found Chexout notification satisfactory in 168 of 169 (99%) and easy to use in 130 of 141 (92%). Reasons for declining electronic notification included lack of personal cell phone for 55 of 86 (64%) and confidentiality concerns for 42 of 86 (49%).

Conclusions

Electronic messaging decreased time to notification and increased treatment success. Nurses spent less time notifying patients leaving more time for patient care.
Pain, numbness, or both? Distinguishing the longitudinal course and predictors of positive, painful neuropathic features vs numbness after breast cancer surgery
Authors: Flowers K. Mikayla , Beck Meghan , Colebaugh Carin , Haroutounian Simon , Edwards Robert R. , Schreiber Kristin L.
Published: November 2021

Introduction:

Both positive (burning, stabbing, and allodynia) and negative (numbness) neuropathic symptoms may arise after surgery but likely contribute differently to patients' postoperative pain experience. Numbness has been identified as divergent from positive neuropathic symptoms and therefore excluded from some neuropathic assessment tools (Neuropathic Pain Scale for PostSurgical patients [NeuPPS]).

Objectives:

In this prospective longitudinal study of patients undergoing breast surgery, we aimed to delineate the time course of numbness and its coincidence with NeuPPS and to contrast the association of surgical, psychosocial, and psychophysical predictors with the development of negative vs positive neuropathic symptoms.

Methods:

Patients reported surgical area sensory disturbances at 2 weeks and 3, 6, and 12 months postoperatively. Association of baseline demographic, surgical, psychosocial, and psychophysical factors with NeuPPS and numbness across time was investigated using generalized estimating equation linear and logistic regression.

Results:

Numbness was consistently reported by 65% of patients; positive neuropathic symptoms were less common, often decreasing over time. Neuropathic Pain scale for PostSurgical patients and numbness co-occurred in half of patients and were both associated with greater clinical pain severity and impact, younger age, axillary surgery, and psychosocial factors. More extensive surgery and chemotherapy were only associated with numbness. Conversely, other chronic pain, lower physical activity, perioperative opioid use, negative affect, and lower baseline pressure pain threshold and tolerance were only associated with NeuPPS. Patients reporting numbness alone did not endorse substantial clinical pain.

Conclusions:

Differentiation of predictors, prevalence, and time course of numbness vs NeuPPS in breast surgical patients revealed important distinctions, suggesting that their independent assessment is worthwhile in future studies of postsurgical pain.
Selection of Optimal Functional Lymphatic Vessel Cutoff Size in Supermicrosurgical Lymphaticovenous Anastomosis in Lower Extremity Lymphedema
Authors: Yang Johnson Chia-Shen , Wu Shao-Chun , Hayashi Akitatsu , Lin Wei-Che , Wang Yu-Ming , Luo Sheng-Dean , Chiang Min-Hsien , Hsieh Ching-Hua
Published: November 2021

Background:

Functional lymphatic vessels are essential for supermicrosurgical lymphaticovenous anastomosis. Theoretically, the larger the lymphatic vessel, the better the flow. However, large lymphatic vessels are not readily available. Since the introduction of lymphaticovenous anastomosis, no guidelines have been set as to how small a lymphatic vessel is still worthwhile for anastomosis.

Methods:

In this longitudinal cohort study, unilateral lower limb lymphedema patients who underwent lymphaticovenous anastomosis between March of 2016 and January of 2019 were included. Demographic data and intraoperative findings including the number and size of lymphatic vessels were recorded. The cutoff size was determined by receiver operating characteristic curve analysis, based on the functional properties of lymphatic vessels. Clinical correlation was made with post–lymphaticovenous anastomosis volume measured by magnetic resonance volumetry.

Results:

A total of 141 consecutive patients (124 women and 17 men) with a median age of 60.0 years (range, 56.7 to 61.2 years) were included. The cutoff size for a functional lymphatic vessel was determined to be 0.50 mm (i.e., lymphatic vessel0.5) from a total of 1048 lymphatic vessels. Significant differences were found between the number of lymphatic vessels0.5 anastomosed (zero to one, two to three, and greater than over equal to four lymphatic vessels0.5), the median post–lymphaticovenous anastomosis volume reduction (in milliliters) (p < 0.001), and the median percentage volume reduction (p = 0.012).

Conclusions:

Lymphatic vessel0.5 can be a valuable reference for lymphaticovenous anastomosis. Post–lymphaticovenous anastomosis outcome can be enhanced with the use of lymphatic vessel0.5 for anastomoses.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, II.
Prognostic Values of Platelet Distribution Width and Platelet Distribution Width-to-Platelet Ratio in Severe Burns
Authors: Lin Jian-Chang , Wu Guo-Hua , Zheng Jian-Jun , Chen Zhao-Hong , Chen Xiao-Dong
Published: November 2021

Background:

Platelet distribution width (PDW) and PDW-to-platelet ratio (PPR) have been proven to be good prognostic indicators for many diseases. However, their prognostic values in severe burns have not been reported.

Objective:

To investigate the early time course of PDW and PPR in severe burn patients and investigate their prognostic values.

Methods:

This is a 16-year, single-center retrospective study of 590 severe burn patients. The complete blood count parameters on day 1, day 3, and day 7 postburn, including PDW and PPR, were collected. Receiver operating characteristic curves (ROC) analysis, multiple logistic regression analysis and Kaplan–Meier survival analysis were performed to evaluate the prognostic values of PDW and PPR in severe burn patients.

Results:

According to 120-day follow-up records, 96 patients were nonsurvivors and 494 patients were survivors. ROC and area under the curve (AUC) analysis showed that, for predicting 120-day prognosis, the AUC of PDW (0.782) and PPR (0.816) on day 3 was the highest, followed by the AUC of PDW (0.764) and PPR (0.750) on day 7. The ROC–AUC of PPR (0.816) on day 3 was very close to that of the ABSI score (0.818). Multiple logistic regression analysis showed that the PDW (P = 0.033 and P = 0.009) and PPR (P = 0.052 and P = 0.046) on day 3 and day 7 were all significantly independently positively associated with 120-day mortality. Kaplan–Meier survival analysis showed that high PDW and PPR were both significantly associated with a high 120-day mortality rate on day 3 and day 7.

Conclusion:

PDW and PPR on day 3 and day 7 were independent risk factors for 120-day mortality in severe burn patients. These objective and readily available prognostic indicators may be more clinically favored.
Ophthalmological Evaluation in Children Presenting With a Primary Brain Tumor
Authors: Nuijts Myrthe A. , Stegeman Inge , Porro Giorgio L. , Duvekot Josje C. , van Egmond-Ebbeling Michelle B. , van der Linden Denise C. P. , Hoving Eelco W. , Schouten-van Meeteren Antoinette Y. N. , Imhof Saskia M.
Published: November 2021

Background:

Children with a brain tumor are prone to develop visual impairment, which to date is often underestimated and unrecognized. Our aim was to assess the prevalence of ophthalmological evaluation and abnormal ophthalmological findings, and investigate whether demographic and tumor-related characteristics are associated with abnormal ophthalmological findings in children presenting with a primary brain tumor.

Methods:

Medical records of all 90 children diagnosed with a primary brain tumor between June 2018 and May 2019 and treated at the Princess Máxima Center for Pediatric Oncology, a tertiary referral center in the Netherlands, were retrospectively reviewed. Univariate regression analysis was used to investigate associations between demographic, tumor-related and clinical characteristics, and abnormal ophthalmological findings.

Results:

Sixty children (34 male [56.7%]; median [range] age, 9.3 [0–16.9] years) underwent ophthalmological evaluation within 6 weeks before or after diagnosis, 11 children (5 male [45.5%]; median [range] age, 5.7 [0.1–17.2] years) were seen more than 6 weeks before or after diagnosis, and 19 children (7 male [36.8%]; median [range] age, 7.2 [1.9–16.6] years) did not receive ophthalmological evaluation within at least 6 months from diagnosis. A total of 19 children (21.1%) presented with visual symptoms as first sign leading to the diagnosis of a brain tumor. Children who presented with visual symptoms (odds ratio [OR], 22.52; 95% confidence interval [CI], 4.90–103.60) and/or hydrocephalus (OR, 3.60; 95% CI, 1.38–9.36) at diagnosis were more often seen for ophthalmological evaluation. The most common abnormal ophthalmological findings were eye movement disorders (66.0%), papilledema (44.1%), and visual field defects (58.1%). Eye movement disorders occurred more frequently in patients with an infratentorial tumor (OR, 4.71; 95% CI, 1.03–21.65). The risk of papilledema was associated with older age (OR, 1.19; 95% CI, 1.05–1.34), hydrocephalus (OR, 9.63; 95% CI, 2.68–34.61), and infratentorial (OR, 9.11; 95% CI, 1.77–46.78) and supratentorial (OR, 13.13; 95% CI, 1.92–89.52) tumors.

Conclusions:

In this study, most children with a primary brain tumor underwent ophthalmological evaluation around diagnosis, 21% of the children were not evaluated. The high prevalence of abnormal ophthalmological findings stresses the importance of early standardized ophthalmological evaluation to detect visual impairment and provide timely treatment to potentially prevent permanent visual loss.
Translation of scientific evidence into cardiovascular guidelines
Authors: Koller Akos , Takács Johanna
Published: November 2021

Introduction and aims:

Research evidence is the basis of guidelines used by healthcare professionals to make difficult decisions every day. We hypothesized that due to the available evidence the four selected cardiovascular guidelines have different degrees of certainty for making efficient decisions.

Methods:

We conducted an analytic study on the guidelines on arterial hypertension (AH), myocardial revascularization, syncope and cardiovascular diseases during pregnancy to assess the levels of evidence (LEVEL) and the classes of the recommendations (CLASS).

Results:

A total of 636 LEVEL and CLASS data were analyzed. To define certainty, LEVEL areas under CLASS were calculated. The frequency of LEVEL by CLASS showed that AH had the highest rate of evidence A in each CLASS. Myocardial revascularization showed a frequency pattern similar to that of AH. In syncope and pregnancy, the percentage of evidence B and/or C was the highest in each class; the percentages of certainty were 24.3% – pregnancy and 75.7% – AH. Deviations from an optimal decision revealed that the observed percentages of certainty were significantly lower on higher LEVEL than the expected percentages.

Conclusion:

Analyzing recommended procedures for diagnosis and treatments revealed a great disparity of certainty among the guidelines, and that the guideline of AH is superior to other guidelines, probably due to the substantial scientific evidence available in this field. Revealing the ratio of certainty/uncertainty in guidelines can identify issues to be clarified and investigated in future studies.
Overprotection and overcontrol in childhood: An evaluation on reliability and validity of 33-item Expanded Childhood Trauma Questionnaire (CTQ-33), Chinese version
Authors: Wu Zhipeng , Liu Zhening , Jiang Zhengqian , Fu Xingzi , Deng Qian , Palaniyappan Lena , Xiang Zhibiao , Huang Danqing , Long Yicheng
Published: November 2021

Overprotection and overcontrol from parents or other family members, which are not rare in the Chinese culture, have been suggested to be traumatic experiences for some children. However, research on overprotection/overcontrol is much rarer in China compared with other childhood trauma subtypes. One of the possible reasons for this is the lack of easy and feasible screening tools. In this study, we therefore translated and validated a Chinese version of the 33-item Childhood Trauma Questionnaire (CTQ-33), which was expanded from the widely-used 28-item CTQ with an additional overprotection/overcontrol subscale. A total of 248 young healthy participants were recruited and completed the Chinese version of CTQ-33, and 50 of them were retested after an interval of two weeks. At baseline, all participants also completed the 9-item Patient Health Questionnaire and the 7-item Generalized Anxiety Disorder Scale to assess their depression and anxiety, respectively. Our main findings include that: (1) the Chinese version of CTQ-33 showed a good internal consistency (Cronbach’s α coefficient = 0.733) and an excellent test-retest reliability over a two-week period (ICC = 0.861); (2) the previously reported significant associations between the overprotection/overcontrol and other subtypes of childhood trauma (abuse and neglect), as well as psychopathological conditions such as depression can all be replicated using the Chinese version of CTQ-33. These results suggest that the Chinese version of CTQ-33 would be a promising tool for assessing various subtypes of childhood adversities, especially the overprotection/overcontrol experiences in Chinese populations.
Pausing methotrexate improves immunogenicity of COVID-19 vaccination in elderly patients with rheumatic diseases
Authors: Arumahandi de Silva AN , Frommert LM , Albach FN , Klotsche J , Scholz V , Jeworowski LM , Schwarz T , ten Hagen A , Zernicke J , Corman VM , Drosten C , Burmester GR , Biesen R
Published: November 2021

Objective

To study the effect of methotrexate (MTX) and its discontinuation on the humoral immune response after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD).

Methods

In this retrospective study, neutralising SARS-CoV-2 antibodies were measured after second vaccination in 64 rheumatic patients on methotrexate therapy, 31 of whom temporarily paused medication without a fixed regimen. The control group consisted of 21 AIRD patients without immunosuppressive medication.

Results

MTX patients showed a significantly lower mean antibody response compared to AIRD patients without immunosuppressive therapy (71.8 % vs 92.4 %, p<0.001). For patients taking MTX, age correlated negatively with immune response (r=-0.49; p<0.001). All nine patients with antibody levels below the cut-off were older than 60 years. Patients who held MTX during at least one vaccination showed significantly higher mean neutralising antibody levels after second vaccination, compared to patients who continued MTX therapy during both vaccinations (83.1 % vs 61.2 %, p=0.001). This effect was particularly pronounced in patients older than 60 years (80.8 % vs 51.9 %, p=0.001). The impact of the time period after vaccination was greater than of the time before vaccination with the critical cut-off being 10 days.

Conclusion

MTX reduces the immunogenicity of SARS-CoV-2 vaccination in an age-dependent manner. Our data further suggest that holding MTX for at least 10 days after vaccination significantly improves the antibody response in patients over 60 years of age.
Self-assembling short immunostimulatory duplex RNAs with broad spectrum antiviral activity
Authors: Si Longlong , Bai Haiqing , Oh Crystal Yuri , Zhang Tian , Hong Fan , Jiang Amanda , Ye Yongxin , Jordan Tristan X. , Logue James , McGrath Marisa , Belgur Chaitra , Nurani Atiq , Cao Wuji , Prantil-Baun Rachelle , Gygi Steven P , Powers Rani K. , Frieman Matthew , tenOever Benjamin R. , Ingber Donald E.
Published: November 2021

The current COVID-19 pandemic highlights the need for broad-spectrum antiviral therapeutics. Here we describe a new class of self-assembling immunostimulatory short duplex RNAs that potently induce production of type I and type III interferon (IFN-I and IFN-III), in a wide range of human cell types. These RNAs require a minimum of 20 base pairs, lack any sequence or structural characteristics of known immunostimulatory RNAs, and instead require a unique conserved sequence motif (sense strand: 5’-C, antisense strand: 3’-GGG) that mediates end-to-end dimer self-assembly of these RNAs by Hoogsteen G-G base-pairing. The presence of terminal hydroxyl or monophosphate groups, blunt or overhanging ends, or terminal RNA or DNA bases did not affect their ability to induce IFN. Unlike previously described immunostimulatory siRNAs, their activity is independent of TLR7/8, but requires the RIG-I/IRF3 pathway that induces a more restricted antiviral response with a lower proinflammatory signature compared with poly(I:C). Immune stimulation mediated by these duplex RNAs results in broad spectrum inhibition of infections by many respiratory viruses with pandemic potential, including SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza A, as well as the common cold virus HCoV-NL63 in both cell lines and human Lung Chips that mimic organ-level lung pathophysiology. These short dsRNAs can be manufactured easily, and thus potentially could be harnessed to produce broad-spectrum antiviral therapeutics at low cost.
Novel markers to detect HER2 amplification in Breast cancer
Authors: Mudgal Shikha , Kalra Arnav , Ravi Bina , Rao Shalinee , Chowdhury Nilotpal
Published: November 2021

Overexpression of HER2 in breast cancer is an important prognostic and predictive biomarker, assessed using immunohistochemistry (IHC) and in situ hybridization (ISH). More than 20% of tumours are graded equivocal on IHC and is send for reflex testing via ISH. In situ hybridization (ISH) is an expensive assay and is not available widely in resource limiting areas. Therefore, we propose that genes found significantly co-expressed with HER2 in breast cancer can be used as surrogate markers for HER2 in breast cancer which can detect HER2 positivity on IHC itself. This hypothesis is based on analysis of publicly available datasets from the Gene Expression Omnibus (GEO) database. The genes found most significantly correlated with HER2 expression were PGAP3 (r = 0.85), GRB7 (r = 0.82), STARD3 (r = 0.78), CDK12 (r= 0.68), PSMD3 (r =0.67) and GSDMB (r = 0.63). We hypothesize that these identified surrogate markers for HER2 amplification which can be detected on IHC can detect HER2 amplification status in HER2 equivocal tumors based on IHC staining alone and will reduce the number of HER2 2+ (equivocal) category tumours.
Decidual immune response following COVID-19 during pregnancy varies by timing of maternal SARS-CoV-2 infection
Authors: Juttukonda Lillian J. , Wachman Elisha M. , Boateng Jeffery , Jain Mayuri , Benarroch Yoel , Taglauer Elizabeth S.
Published: November 2021

While COVID-19 infection during pregnancy is common, fetal transmission is rare, suggesting that intrauterine mechanisms form an effective blockade against SARS-CoV-2. Key among these is the decidual immune environment of the placenta. We hypothesized that decidual leukocytes are altered by maternal SARS-CoV-2 infection in pregnancy and that this decidual immune resonse is shaped by the timing of infection during gestation. To address this hypothesis, we collected decidua basalis tissues at delivery from women with symptomatic COVID-19 during second (2nd Tri COVID, n=8) or third trimester (3rd Tri COVID, n=8) and SARS-CoV-2-negative controls (Control, n=8). Decidual natural killer (NK) cells, macrophages and T cells were evaluated using quantitative microscopy, and pro- and anti-inflammatory cytokine mRNA expression was evaluated using quantitative reverse transcriptase PCR (qRT-PCR). When compared with the Control group, decidual tissues from 3rd Tri COVID exhibited significantly increased macrophages, NK cells and T cells, whereas 2nd Tri COVID only had significantly increased T cells. In evaluating decidual cytokine expression, we noted that IL-6, IL-8, IL-10 and TNF-α were significantly correlated with macrophage cell abundance. However, in 2nd Tri COVID tissues, there was significant downregulation of IL-6, IL-8, IL-10, and TNF-α. Taken together, these results suggest innate and adaptive immune responses are present at the maternal-fetal interface in maternal SARS-CoV-2 infections late in pregnancy, and that infections earlier in pregnancy show evidence of a resolving immune response. Further studies are warranted to characterize the full scope of intrauterine immune responses in pregnancies affected by maternal COVID-19.
Visual Attention in The Fovea and The Periphery during Visual Search
Authors: Zhang Jie , Zhu Xiaocang , Wang Shanshan , Ma Zhengyu , Esteky Hossein , Tian Yonghong , Desimone Robert , Zhou Huihui
Published: November 2021

Visual search depends on both the foveal and peripheral visual system, yet the foveal attention mechanisms is still lack of insights. We simultaneously recorded the foveal and peripheral activities in V4, IT and LPFC, while monkeys performed a category-based visual search task. Feature attention enhanced responses of Face-selective, House-selective, and Non-selective foveal cells in visual cortex. While foveal attention effects appeared no matter the peripheral attention effects, paying attention to the foveal stimulus dissipated the peripheral feature attentional effects, and delayed the peripheral spatial attentional effects. When target features appeared both in the foveal and the peripheral, feature attention effects seemed to occur predominately in the foveal, which might not distribute across the visual field according to common view of distributed feature attention effects. As a result, the parallel attentive process seemed to occur during distractor fixations, while the serial process predominated during target fixations in visual search.
Simplified, Shear Induced Generation of Double Emulsions for Robust Compartmentalization during Single Genome Analysis
Authors: Cowell Thomas W. , Dobria Andrew , Han Hee-Sun
Published: November 2021

Drop microfluidics has driven innovations for high throughput, low input analysis techniques such as single-cell RNA-seq. However, the instability of single emulsion (SE) drops occasionally causes significant merging during drop processing, limiting most applications to single-step reactions in drops. Here, we show that double emulsion (DE) drops address this critical limitation and completely prevent content mixing, which is essential for single entity analysis. DEs show excellent stability during thermal cycling. More importantly, DEs undergo rupture into the continuous phase instead of merging, preventing content mixing and eliminating unstable drops from the downstream analysis. Due to the lack of drop merging, the monodispersity of drops is maintained throughout a workflow, enabling the deterministic manipulation of drops downstream. We also developed a simple, one-layer fabrication method for DE drop makers. This design is powerful as it allows robust production of single-core DEs at a wide range of flow rates and better control over the shell thickness, both of which have been significant limitations of conventional two-layer devices. This approach makes the fabrication of DE devices much more accessible, facilitating its broader adoption. Finally, we show that DE droplets effectively maintain the compartmentalization of single virus genomes during PCR-based amplification and barcoding, while SEs mixed contents due to merging. With their resistance to content mixing, DE drops have key advantages for multistep reactions in drops, which is limited in SEs due to merging and content mixing.
Sampling the conformational landscapes of transporters and receptors with AlphaFold2
Authors: del Alamo Diego , Sala Davide , Mchaourab Hassane S. , Meiler Jens
Published: November 2021

Equilibrium fluctuations and triggered conformational changes often underlie the functional cycles of membrane proteins. For example, transporters mediate the passage of molecules across cell membranes by alternating between inward-facing (IF) and outward-facing (OF) states, while receptors undergo intracellular structural rearrangements that initiate signaling cascades. Although the conformational plasticity of these proteins has historically posed a challenge for traditional de novo protein structure prediction pipelines, the recent success of AlphaFold2 (AF2) in CASP14 culminated in the modeling of a transporter in multiple conformations to high accuracy. Given that AF2 was designed to predict static structures of proteins, it remains unclear if this result represents an underexplored capability to accurately predict multiple conformations and/or structural heterogeneity. Here, we present an approach to drive AF2 to sample alternative conformations of topologically diverse transporters and G-protein coupled receptors (GPCRs) that are absent from the AF2 training set. Whereas models generated using the default AF2 pipeline are conformationally homogeneous and nearly identical to one another, reducing the depth of the input multiple sequence alignments (MSAs) by stochastic subsampling led to the generation of accurate models in multiple conformations. In our benchmark, these conformations spanned the range between two experimental structures of interest, with models at the extremes of these conformational distributions observed to be among the most accurate (average template modeling (TM)-score of 0.94). These results suggest a straightforward approach to identifying native-like alternative states, while also highlighting the need for the next generation of deep learning algorithms to be designed to predict ensembles of biophysically relevant states.
Induction and inhibition of Drosophila X chromosome gene expression are both impeded by the dosage compensation complex
Authors: Meisel Richard P. , Asgari Danial , Schlamp Florencia , Unckless Robert L.
Published: November 2021

Sex chromosomes frequently differ from the autosomes in the frequencies of genes with sexually dimorphic or tissue-specific expression. Multiple hypotheses have been put forth to explain the unique gene content of the X chromosome, including selection against male-beneficial X-linked alleles, expression limits imposed by the haploid dosage of the X in males, and interference by the dosage compensation complex (DCC) on expression in males. Here, we investigate these hypotheses by examining differential gene expression in Drosophila melanogaster following several treatments that have widespread transcriptomic effects: bacterial infection, viral infection, and abiotic stress. We found that genes that are induced (up-regulated) by these biotic and abiotic treatments are frequently under-represented on the X chromosome, but so are those that are repressed (down-regulated) following treatment. We further show that whether a gene is bound by the DCC in males can largely explain the paucity of both up- and down-regulated genes on the X chromosome. Specifically, genes that are bound by the DCC, or close to a DCC high-affinity site, are unlikely to be up- or down-regulated after treatment. This relationship, however, could partially be explained by a correlation between differential expression and breadth of expression across tissues. Nonetheless, our results suggest that DCC binding, or the associated chromatin modifications, inhibit both up- and down-regulation of X chromosome gene expression within specific contexts. We propose multiple possible mechanisms of action for the effect, including a role of Males absent on the first (Mof), a component of the DCC, as a dampener of gene expression variance in both males and females. This effect could explain why the Drosophila X chromosome is depauperate in genes with tissue-specific or induced expression, while the mammalian X has an excess of genes with tissue-specific expression.
Co-Delivery of Synergistic Antimicrobials with Polyelectrolyte Nanocomplexes to Treat Bacterial Biofilms and Lung Infections
Authors: Finbloom Joel A. , Raghavan Preethi , Kwon Michael , Kharbikar Bhushan N. , Yu Michelle A. , Desai Tejal A.
Published: November 2021

New approaches are needed to treat bacterial biofilm infections, particularly those of Pseudomonas aeruginosa (PA), which have high rates of antimicrobial resistance and are commonly found in chronic wound and cystic fibrosis lung infections. Combination therapeutics that act synergistically can overcome resistance; however, the delivery of multiple therapeutics at relevant dosages remains a challenge. We therefore developed a new nanoscale drug carrier for antimicrobial co-delivery by combining approaches from polyelectrolyte nanocomplex (NC) formation and layer-by-layer electrostatic self-assembly. This strategy led to NC drug carriers loaded with tobramycin antibiotics and antimicrobial silver nanoparticles (AgTob-NCs). AgTob-NCs displayed synergistic enhancements in antimicrobial activity against both planktonic and biofilm PA cultures, with positively charged NCs leading to complete biofilm eradication. NCs were evaluated in mouse models of lung infection, leading to reduced bacterial burden and improved survival outcomes. This approach therefore shows promise for nanoscale therapeutic co-delivery to overcome antimicrobial resistant bacterial infections.
Mechanically induced nuclear shuttling of β-catenin requires co-transfer of actin
Authors: Sen Buer , Xie Zhihui , Howard Sean , Styner Maya , van Wijnen Andre J , Uzer Gunes , Rubin Janet
Published: November 2021

Mesenchymal stem cells (MSC) respond to environmental forces with both cytoskeletal re-structuring and activation of protein chaperones of mechanical information, β-catenin and Yes-Associated Protein 1 (YAP1). To function, MSCs must differentiate between dynamic forces such as cyclic strains of extracellular matrix due to physical activity and static strains due to ECM stiffening. To delineate how MSCs recognize and respond differently to both force types, we compared effects of dynamic (200 cycles x 2%) and static (1 × 2% hold) strain on nuclear translocation of β-catenin and YAP1 at 3h after force application. Dynamic strain induced nuclear accumulation of β-catenin, and increased cytoskeletal actin structure and cell stiffness, but had no effect on nuclear YAP1 levels. Critically, both nuclear actin and nuclear stiffness increased along with dynamic strain-induced β-catenin transport. Augmentation of cytoskeletal structure using either static strain or lysophosphatidic acid (LPA) did not increase nuclear content of β–catenin or actin, but induced robust nuclear increase in YAP1. As actin binds β-catenin, we considered whether β-catenin, which lacks a nuclear localization signal, was dependent on actin to gain entry to the nucleus. Knockdown of cofilin-1 (Cfl1) or importin-9 (Ipo9), which co-mediate nuclear transfer of G-actin, prevented dynamic strain-mediated nuclear transfer of both β-catenin and actin. In sum, dynamic strain induction of actin re-structuring promotes nuclear transport of G-actin, concurrently supporting nuclear access of β-catenin via mechanisms utilized for actin transport. Thus, dynamic and static strain activate alternative mechanoresponses reflected by differences in the cellular distributions of actin, β-catenin and YAP1.

Significance statement

Cells integrate both static and dynamic mechanical signals through the actin cytoskeleton which is attached to the nuclear envelope, affecting nuclear transport of β-catenin and YAP1. Dynamic strain induces nuclear translocation of β-catenin, but not YAP1, while static strain causes nuclear translocation of YAP1, but not β-catenin. Importantly, nuclear transport of actin is induced by dynamic but not static force. Furthermore, nuclear import of β-catenin depends on cofilin/importin-9 dependent actin transport mechanisms. Thus the presence of β-catenin and YAP1 in the nucleus represent specific responses to regulatory mechanical signals.
Beetle bioluminescence outshines aerial predators
Authors: Powell Gareth S. , Saxton Natalie A. , Pacheco Yelena M. , Stanger-Hall Kathrin F. , Martin Gavin J. , Kusy Dominik , Da Silveira Luiz Felipe Lima , Bocak Ladislav , Branham Marc A. , Bybee Seth M.
Published: November 2021

Bioluminescence is found across the tree of life and has many functions. Yet we understand very little about its timing and origins, particularly as a predator avoidance strategy. Understanding the timing between bioluminescence and predator origins has yet to be examined and can help elucidate the evolution of this ecologically important aposematic signal. Using the most prevalent bioluminescent group, fireflies, where bioluminescence primarily functions as aposematic and sexual signals, the timing for the origins of both potential predators of fireflies and bioluminescence is explored. Divergence time estimations were performed using genomic-scale phylogenetic reconstructions, and multiple fossil calibration points, allowing for a robust estimate for the origin of lampyrid bioluminescence as a terrestrial and as an aerial signal. Our results recover the origins of terrestrial beetle bioluminescence at 141.17 (122.63–161.17) mya and firefly aerial bioluminescence at 133.18 (117.86–152.47) mya with a large dataset focused on Lampyridae; and terrestrial bioluminescence as 148.03 (130.12–166.80) mya, with the age of aerial bioluminescence at 104.97 (99.00–120.90) mya with a complementary broad Elateroidea dataset. These ages predate the origins of all known extant aerial predators (i.e., bats and birds) and support the much older terrestrial predators (assassin bugs, frogs, ground beetles, lizards, snakes, hunting spiders, and harvestmen) as the most likely drivers of terrestrial bioluminescence in beetles, and sexual signaling likely being the original function in aerial fireflies.