bluuebunny/crossref_metadata_2025 huggingface dataset:
SMMPPI: a machine learning-based approach for prediction of modulators of protein–protein interactions and its application for identification of novel inhibitors for RBD:hACE2 interactions in SARS-CoV-2
Authors: Gupta Priya , Mohanty Debasisa
Published: March 2021

Small molecule modulators of protein–protein interactions (PPIs) are being pursued as novel anticancer, antiviral and antimicrobial drug candidates. We have utilized a large data set of experimentally validated PPI modulators and developed machine learning classifiers for prediction of new small molecule modulators of PPI. Our analysis reveals that using random forest (RF) classifier, general PPI Modulators independent of PPI family can be predicted with ROC-AUC higher than 0.9, when training and test sets are generated by random split. The performance of the classifier on data sets very different from those used in training has also been estimated by using different state of the art protocols for removing various types of bias in division of data into training and test sets. The family-specific PPIM predictors developed in this work for 11 clinically important PPI families also have prediction accuracies of above 90% in majority of the cases. All these ML-based predictors have been implemented in a freely available software named SMMPPI for prediction of small molecule modulators for clinically relevant PPIs like RBD:hACE2, Bromodomain_Histone, BCL2-Like_BAX/BAK, LEDGF_IN, LFA_ICAM, MDM2-Like_P53, RAS_SOS1, XIAP_Smac, WDR5_MLL1, KEAP1_NRF2 and CD4_gp120. We have identified novel chemical scaffolds as inhibitors for RBD_hACE PPI involved in host cell entry of SARS-CoV-2. Docking studies for some of the compounds reveal that they can inhibit RBD_hACE2 interaction by high affinity binding to interaction hotspots on RBD. Some of these new scaffolds have also been found in SARS-CoV-2 viral growth inhibitors reported recently; however, it is not known if these molecules inhibit the entry phase.
Ovarian follicles are resistant to monocyte perturbations—implications for ovarian health with immune disruption
Authors: Sominsky Luba , Younesi Simin , De Luca Simone N , Loone Sophie M , Quinn Kylie M , Spencer Sarah J
Published: March 2021

Monocytes and macrophages are the most abundant immune cell populations in the adult ovary, with well-known roles in ovulation and corpus luteum formation and regression. They are activated and proliferate in response to immune challenge and are suppressed by anti-inflammatory treatments. It is also likely they have a functional role in the healthy ovary in supporting the maturing follicle from the primordial through to the later stages; however, this role has been unexplored until now. Here, we utilized a Cx3cr1-Dtr transgenic Wistar rat model that allows a conditional depletion of circulating monocytes, to investigate their role in ovarian follicle health. Our findings show that circulating monocyte depletion leads to a significant depletion of ovarian monocytes and monocyte-derived macrophages. Depletion of monocytes was associated with a transient reduction in circulating anti-Müllerian hormone (AMH) at 5 days postdepletion. However, the 50–60% ovarian monocyte/macrophage depletion had no effect on ovarian follicle numbers, follicle atresia, or apoptosis, within 5–21 days postdepletion. These data reveal that the healthy adult ovary is remarkably resistant to perturbations of circulating and ovarian monocytes despite acute changes in AMH. These data suggest that short-term anti-inflammatory therapies that transiently impact on circulating monocytes are unlikely to disrupt ovarian follicle health, findings that have significant implications for fertility planning relative to the experience of an immune challenge or immunosuppression.
Reinfection Rates Among Patients Who Previously Tested Positive for Coronavirus Disease 2019: A Retrospective Cohort Study
Authors: Sheehan Megan M , Reddy Anita J , Rothberg Michael B
Published: March 2021

Background

Protection afforded from prior disease among patients with coronavirus disease 2019 (COVID-19) infection is unknown. If infection provides substantial long-lasting immunity, it may be appropriate to reconsider vaccination distribution.

Methods

This retrospective cohort study of 1 health system included 150 325 patients tested for COVID-19 infection via polymerase chain reaction from 12 March 2020 to 30 August 2020. Testing performed up to 24 February 2021 in these patients was included. The main outcome was reinfection, defined as infection ≥90 days after initial testing. Secondary outcomes were symptomatic infection and protection of prior infection against reinfection.

Results

Of 150 325 patients, 8845 (5.9%) tested positive and 141 480 (94.1%) tested negative before 30 August. A total of 1278 (14.4%) positive patients were retested after 90 days, and 62 had possible reinfection. Of those, 31 (50%) were symptomatic. Of those with initial negative testing, 5449 (3.9%) were subsequently positive and 3191 of those (58.5%) were symptomatic. Protection offered from prior infection was 81.8% (95% confidence interval [CI], 76.6–85.8) and against symptomatic infection was 84.5% (95% CI, 77.9–89.1). This protection increased over time.

Conclusions

Prior infection in patients with COVID-19 was highly protective against reinfection and symptomatic disease. This protection increased over time, suggesting that viral shedding or ongoing immune response may persist beyond 90 days and may not represent true reinfection. As vaccine supply is limited, patients with known history of COVID-19 could delay early vaccination to allow for the most vulnerable to access the vaccine and slow transmission.
The friendship paradox in real and model networks
Authors: Cantwell George T , Kirkley Alec , Newman M E J
Published: March 2021

The friendship paradox is the observation that the degrees of the neighbours of a node in any network will, on average, be greater than the degree of the node itself. In common parlance, your friends have more friends than you do. In this article, we develop the mathematical theory of the friendship paradox, both in general as well as for specific model networks, focusing not only on average behaviour but also on variation about the average and using generating function methods to calculate full distributions of quantities of interest. We compare the predictions of our theory with measurements on a large number of real-world network datasets and find remarkably good agreement. We also develop equivalent theory for the generalized friendship paradox, which compares characteristics of nodes other than degree to those of their neighbours.
Non-invasive peripheral vascular function, incident cardiovascular disease, and mortality in the general population
Authors: Schnabel Renate B , Magnussen Christina , Schulz Andreas , Ojeda Francisco M , Schmitt Volker H , Arnold Natalie , Sinning Christoph R , Beutel Manfred E , Schmidtmann Irene , Pfeiffer Norbert , Leuschner Anja , Lackner Karl J , Gori Tommaso , Benjamin Emelia J , Binder Harald , Wild Philipp S , Blankenberg Stefan , Münzel Thomas ,   for the Gutenberg Health Study investigators
Published: March 2021

Aims 

Evidence suggests that peripheral vascular function is related to cardiovascular disease (CVD) and mortality. We evaluated the associations of non-invasive measures of flow-mediated dilatation and peripheral arterial tonometry with incident CVD and mortality.

Methods and results 

In a post-hoc analysis of the community-based Gutenberg Health Study, median age 55 years (25th/75th percentile 46/65) and 49.5% women, we measured brachial artery flow-mediated dilatation (N=12 599) and fingertip peripheral arterial tonometry (N=11 125). After a follow-up of up to 11.7 years, we observed 595 incident CVD events, 106 cardiac deaths, and 860 deaths in total. Survival curves showed decreased event-free survival with higher mean brachial artery diameter and baseline pulse amplitude and better survival with higher mean flow-mediated dilatation and peripheral arterial tonometry ratio (all Plog rank <0.05). In multivariable-adjusted Cox regression analyses only baseline pulse amplitude was inversely related to mortality [hazard ratio (HR) per standard deviation increase, 0.86, 95% confidence interval (95% CI), 0.79–0.94; P=0.0009]. After exclusion of individuals with prevalent CVD the association was no longer statistically significant in multivariable-adjusted models (HR 0.91, 95% CI 0.81–1.02; P=0.11). None of the vascular variables substantially increased the C-index of a model comprising clinical risk factors.

Conclusions 

In our cohort, non-invasive measures of peripheral vascular structure and function did not reveal clinically relevant associations with incident CVD or mortality. Whether determination of pulse amplitude by peripheral arterial tonometry improves clinical decision-making in primary prevention needs to be demonstrated.
In vitro activity and resistance rates of topical antimicrobials fusidic acid, mupirocin and ozenoxacin against skin and soft tissue infection pathogens obtained across Canada (CANWARD 2007–18)
Authors: Zhanel George G , Adam Heather J , Baxter Melanie , Lagace-Wiens Philippe R S , Karlowsky James A
Published: March 2021

Background

Current antimicrobial susceptibility/resistance data versus skin and soft tissue infection (SSTI) pathogens help to guide empirical treatment using topical antimicrobials.

Objectives

To assess the in vitro activity and resistance rates of fusidic acid, mupirocin, ozenoxacin and comparator agents against pathogens isolated from patients with SSTIs in Canada.

Methods

SSTI isolates of MSSA (n = 422), MRSA (n = 283) and Streptococcus pyogenes (n = 46) obtained from CANWARD 2007–18 were tested using CLSI broth microdilution. Fusidic acid low-level resistance was defined as an MIC of ≥2 mg/L and high-level resistance as an MIC ≥512 mg/L. Mupirocin high-level resistance was defined as an MIC ≥512 mg/L and low-level resistance was an MIC of 2–256 mg/L.

Results

Low-level and high-level fusidic acid resistance in MSSA was 10.9% and 1.7%, respectively. Low-level and high-level fusidic acid resistance in MRSA was 10.6% and 3.5%, respectively. High-level mupirocin resistance was identified in 1.4% of MSSA and 14.1% of MRSA, respectively. Versus MSSA, ozenoxacin demonstrated MIC50 and MIC90 of 0.004 and 0.25 mg/L, respectively. Against MRSA, ozenoxacin inhibited all isolates at an MIC of ≤0.5 mg/L, including isolates with ciprofloxacin MICs >2 mg/L, clarithromycin-resistant, clindamycin-resistant, high-level fusidic acid-resistant and high-level mupirocin-resistant isolates.

Conclusions

We conclude that fusidic acid low-level resistance exceeded 10% for both MSSA and MRSA while fusidic acid high-level resistance was ≤3.5%. Mupirocin high-level resistance exceeded 10% in MRSA. Ozenoxacin is active versus SSTI pathogens including MRSA resistant to fluoroquinolones, macrolides, clindamycin, fusidic acid and mupirocin.
Improving visual communication of discriminative accuracy for predictive models: the probability threshold plot
Authors: Johnston Stephen S , Fortin Stephen , Kalsekar Iftekhar , Reps Jenna , Coplan Paul
Published: March 2021

Objectives

To propose a visual display—the probability threshold plot (PTP)—that transparently communicates a predictive models’ measures of discriminative accuracy along the range of model-based predicted probabilities (Pt).

Materials and Methods

We illustrate the PTP by replicating a previously-published and validated machine learning-based model to predict antihyperglycemic medication cessation within 1–2 years following metabolic surgery. The visual characteristics of the PTPs for each model were compared to receiver operating characteristic (ROC) curves.

Results

A total of 18 887 patients were included for analysis. Whereas during testing each predictive model had nearly identical ROC curves and corresponding area under the curve values (0.672 and 0.673), the visual characteristics of the PTPs revealed substantive between-model differences in sensitivity, specificity, PPV, and NPV across the range of Pt.

Discussion and Conclusions

The PTP provides improved visual display of a predictive model’s discriminative accuracy, which can enhance the practical application of predictive models for medical decision making.
LncRNA PART1 promotes cell proliferation and inhibits apoptosis of oral squamous cell carcinoma by blocking EZH2 degradation
Authors: Yu Qiongqiong , Du Yajing , Wang Suping , Zheng Xiaofei
Published: March 2021

Long non-coding RNAs (lncRNAs) have been considered as novel regulators in oral squamous cell carcinoma (OSCC). Enhancer of zeste homolog 2 (EZH2) can act as an oncogene in OSCC. This study intended to investigate whether lncRNA prostatic androgen-regulated transcription 1 (PART1) can exert its role in OSCC by regulating EZH2. The expression of PART1 in OSCC samples, tumour tissues or OSCC cell lines was detected by qRT-PCR. The proliferation and apoptosis of OSCC cells were detected by CCK-8 and flow cytometry assays, respectively. The expression of PART1 and EZH2 was highly expressed in clinical OSCC tumours and cell lines. The expression level of PART1 was positively correlated to the size, clinical stage and node metastasis of OSCC patients. Functionally, PART1 knockdown inhibited proliferation and facilitated apoptosis of OSCC cells. Mechanically, fused in sarcoma/translocated in liposarcoma (FUS) interacted with PART1 and EZH2. In addition, PART1 knockdown reduced the mRNA expression of EZH2, which was offset by FUS overexpression. The overexpression of FUS abrogated the effects of PART1 silence on proliferation and apoptosis of OSCC cells. The in vivo experiment revealed that PART1 knockdown inhibited tumour growth of OSCC cells in nude mice. This study indicated that PART1 exerts a carcinogenic role in OSCC by enhancing the stability of EZH2 protein.
Effects of Dehumidification on the Survivorship of Four Psocid Species
Authors: Ocran Abena F , Opit George P , Noden Bruce H , Arthur Frank H , Kard Bradford M
Published: March 2021

Psocids are damaging stored-product pests. In this study, eggs and early-instar nymphs, adults, and all life stages of Liposcelis entomophila, L. decolor, L. bostrychophila, and L. paeta were subjected to 43, 50, or 75% (Control) relative humidity (RH) for 2, 4, 6, 8, 10, 12, 14, or 16 d at 30.0°C. All adults of these species died within 8 d at both 43 and 50% RH, except for L. bostrychophila, which required 12 d at 50% RH for 100% mortality to occur. For all life stages and eggs and early-instar nymphs, maximum survival times (times to 100% mortality) at 43 or 50% RH for L. entomophila, L. decolor, L. bostrychophila, and L. paeta, were 8 and 10 d, 8 and 12 d, 12 and 14 d, and 12 and 16 d, respectively. During this study, numbers of nymphs and adults of all species 14 d after the RH treatments increased within the 75% RH Control arenas. Different species and life stages responded differently to 43 and 50% RH, as time to kill all stages of the four psocid species was 8–12 and 10–16 d, respectively. Results indicate that using a specific RH environment may be effective in psocid management.
CUSUM-Based Monitoring for Explosive Episodes in Financial Data in the Presence of Time-Varying Volatility
Authors: Astill Sam , Harvey David I , Leybourne Stephen J , Taylor A M Robert , Zu Yang
Published: March 2021

We generalize the Homm and Breitung (2012) CUSUM-based procedure for the real-time detection of explosive autoregressive episodes in financial price data to allow for time-varying volatility. Such behavior can heavily inflate the false positive rate (FPR) of the CUSUM-based procedure to spuriously signal the presence of an explosive episode. Our modified procedure involves replacing the standard variance estimate in the CUSUM statistics with a nonparametric kernel-based spot variance estimate. We show that the sequence of modified CUSUM statistics has a joint limiting null distribution which is invariant to any time-varying volatility present in the innovations and that this delivers a real-time monitoring procedure whose theoretical FPR is controlled. Simulations show that the modification is effective in controlling the empirical FPR of the procedure, yet sacrifices only a small amount of power to detect explosive episodes, relative to the standard procedure, when the shocks are homoskedastic. An empirical illustration using Bitcoin price data is provided.
Pontine Arteriolosclerosis and Locus Coeruleus Oxidative Stress Differentiate Resilience from Mild Cognitive Impairment in a Clinical Pathologic Cohort
Authors: Kelly Sarah C , Nelson Peter T , Counts Scott E
Published: March 2021

Locus coeruleus (LC) neurodegeneration is associated with cognitive deterioration during the transition from normal cognition to mild cognitive impairment (MCI) and Alzheimer disease (AD). However, the extent to which LC degenerative processes differentiate cognitively normal, “resilient” subjects bearing a high AD pathological burden from those with MCI or AD remains unclear. We approached this problem by quantifying the number of LC neurons and the percentage of LC neurons bearing AT8 tau pathology, TDP-43 pathology, or a marker for DNA/RNA oxidative damage, in well-characterized subjects diagnosed as normal cognition-low AD pathology (NC-LP), NC-high AD pathology (NC-HP), MCI, or mild/moderate AD. In addition, the severity of pontine arteriolosclerosis in each subject was compared across the groups. There was a trend for a step-wise ∼20% loss of LC neuron number between the NC-LP, NC-HP and MCI subjects despite a successive, significant ∼80%–100% increase in tau pathology between these groups. In contrast, increasing pontine arteriolosclerosis severity scores and LC oxidative stress burden significantly separated the NC-LP/HP and MCI/AD groups via comparative, correlation, and regression analysis. Pontine perfusion, as well as LC neuronal metabolic and redox function, may impact noradrenergic LC modulation of cognition during the preclinical and prodromal stages of AD.
Logic of defeasible permission and its dynamics
Authors: Dong Huimin
Published: March 2021

This paper develops a deontic logic for defeasible permission and studies norm change in various updated semantics. When one grants that $\varphi $ or $\psi $ is permitted, normally, it goes together with the conjunction of a permission of $\varphi $ and that of $\psi $. In the monotonic reasoning on this permission, a permission of $\varphi $ leads to a permission of $\varphi $ and $\psi $; however, if a prohibition of $\psi $ is introduced, we get into trouble. We face a paradox of free choice permission. Many solutions have been proposed, but a systematic account of handling norm change is still needed. This paper first introduces the notion of normality to develop a sound and complete deontic logic for defeasible permission, which can be used to analyse several notions in natural language and in game theory. Further, following Lewis’ idea of norm change, a systematic way to capture various dynamics for updating permission and obligation is proposed.
‘Water Has Aroused the Girls’ Hearts’: Gendering Water and Soil Conservation in 1950s China
Authors: Muscolino Micah S
Published: March 2021

Water and soil conservation in the village of Dengjiabao in Gansu province, north-west China, gained nationwide renown through state-led campaigns against erosion during the 1950s. This was deeply interconnected with shifting conceptions of women’s work and had far-reaching effects on their everyday lives. Investigation of these conservation programmes adds to recent efforts to integrate gender and environmental history. Since the gendered division of labour in rural China dictated that women should do the work of acquiring fuel and water, measures that conserved these resources brought genuine improvements for them. They also reshaped local marriage patterns by making previously resource-starved villages more attractive to young women from other areas. However, a dissonance existed between the official propaganda and the experience of conservation for rural women. Oral history interviews and archival documents show that balancing the demands of conservation work with household responsibilities intensified the pressures placed upon women. Mobilization for the highly militarized conservation campaigns that were an integral part of the Great Leap Forward (1958–61), and the famine they helped to precipitate, subjected women to unprecedented burdens that affected their domestic lives and had an enduring effect on their health and well-being.
The Rate of Return on Real Estate: Long-Run Micro-Level Evidence
Authors: Chambers David , Spaenjers Christophe , Steiner Eva
Published: March 2021

Real estate—housing in particular—is a less profitable investment in the long run than previously thought. We hand-collect property-level financial data for the institutional real estate portfolios of four large Oxbridge colleges over the period 1901–1983. Gross income yields initially fluctuate around 5%, but then trend downward (upward) for agricultural and residential (commercial) real estate. Long-term real income growth rates are close to zero for all property types. Our findings imply annualized real total returns, net of costs, ranging from approximately 2.3% for residential to 4.5% for agricultural real estate.
Methodological Variation in Empirical Corporate Finance
Authors: Mitton Todd
Published: March 2021

I document large variation in empirical methodology in corporate finance regressions in top finance journals. Although methodological variation allows for customization of empirical tests to fit specific theories, it can also enable excessive reporting of statistically significant results. For example, given discretion over 10 routine methodological decisions, a researcher could report that over 70% of randomly generated variables are statistically significant determinants of leverage at the 5% level. The methodological decisions that affect statistical significance the most are dependent variable selection, variable transformation, and outlier treatment. I discuss remedies that can mitigate the negative effects of methodological variation.
Tumour necrosis factor receptor-1 associated periodic syndrome (TRAPS)-related AA amyloidosis: a national case series and systematic review
Authors: Delaleu Jérémie , Deshayes Samuel , Rodrigues Francois , Savey Lea , Rivière Etienne , Silva Nicolas Martin , Aouba Achille , Amselem Serge , Rabant Marion , Grateau Gilles , Giurgea Irina , Georgin-Lavialle Sophie
Published: March 2021

Objectives

TNF receptor-1-associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder associated with mutations in the TNF receptor super family 1 A (TNFRSF1A) gene. AA amyloidosis (AA) is the most severe complication of TRAPS. To study the occurrence and prognosis of AA in TRAPS, we conducted a retrospective study of all French cases and a systematic literature review.

Methods

This case series includes TRAPS patients followed by our centre from 2000 to 2020 presenting with histologically confirmed AA. We conducted a systematic literature review on the PubMed and EMBASE databases for articles published up to February 2021 following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and using the keywords: amyloidoisis, amyloid, TNF receptor-associated periodic syndrome, TNF receptor-associated periodic syndrome, tumor necrosis factor receptor-associated periodic syndrome, TRAPS, TNFRSF1A, familial hibernian fever and hibernian familial fever.

Results

A total of 41 TRAPS with AA were studied: three new patients and 38 cases from the literature. AA diagnosis preceded that of TRAPS in 96% of cases, and 17/36 (47%) required renal replacement therapy. Death occurred in 5/36 (14%) with a median follow-up of 23 months. Effect of biologics on AA were available for 21 regimens in 19 patients: 10 improved renal function, seven stabilized and four worsened. Four patients (36% of transplanted patients) relapse AA on kidney graft (only one under etanercept).

Conclusion

TRAPS is revealed by AA in most cases. Therefore, clinical features of TRAPS should be screened for in AA patients. IL-1 antagonist can help to normalize inflammation and to preserve renal function.
Globally Bred Chinese Talents Returning Home: An Analysis of a Reverse Brain-Drain Flagship Policy
Authors: Marini Giulio , Yang Lili
Published: March 2021

China has launched a series of talent-recruitment policies in the last years, in order to attract back Chinese nationals who stayed abroad. Yet, little is known about the effect of such policies. This paper examines whether researchers recruited in one of the Chinese flagship talent-recruitment policies—the ‘Young Thousand Talents’ policy (Y1000T)—had, in the following years after recruitment, better research performance. We compare these recipients against other Chinese nationals who got PhDs in equally prestigious non-Chinese universities but continued to work abroad (mostly in the USA). Results of difference-in-differences regressions show that returning to China has an effect of positioning returnees both at the bottom and at the very summit of the distribution of quality of publications. Nevertheless, some Y1000T researchers seem to have prioritized the quantity of outputs, arguably to the detriment of quality. This is probably due to certain research evaluation criteria in place until recent times.
Long-Read Genome Sequence Resources of Xanthomonas citri pv. punicae Strain Bagalkot Causing Pomegranate Bacterial Blight
Authors: Radhika Dattatraya Hegde , Gunnaiah Raghavendra , Lamani Ashwini , Peerjade Dadapeer , Jagadeesha Rudrappa Chandrashekhar
Published: March 2021

Xanthomonas citri pv. punicae causing bacterial blight is a devastating disease of pomegranate in India and Pakistan. Most xanthomonads use the type III secretion system to inject transcription activator-like effector (TALE) proteins into the host cell. TALEs bind to the effector-binding elements in the promoter of host susceptibility genes, triggering disease development. PacBio single-molecule real-time long-read sequencing technology was used to identify the TALE-encoding genes, which is otherwise not possible using next-generation short-read sequencers. In all, 1.74 Gb of raw data containing 368,980 subreads, with an average read length of 4,724 bp and longest read length of 77,471, were generated. Subreads were assembled into 15 scaffolds generating approximately 5.4 Mb (348×) of genome. X. citri pv. punicae exhibited close lineage with X. citri pv. citri with 98.78% average nucleotide identity. Of the 4,263 protein-coding genes, 11 non-TALE type III effectors and 2 TALE-encoding genes were identified.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
The emerging and diverse roles of the SLy/SASH1‐protein family in health and disease—Overview of three multifunctional proteins
Authors: Jaufmann Jennifer , Franke Fabian Christoph , Sperlich Andreas , Blumendeller Carolin , Kloos Isabel , Schneider Barbara , Sasaki Daisuke , Janssen Klaus‐Peter , Beer‐Hammer Sandra
Published: March 2021

Intracellular adaptor proteins are indispensable for the transduction of receptor‐derived signals, as they recruit and connect essential downstream effectors. The SLy/SASH1‐adaptor family comprises three highly homologous proteins, all of them sharing conserved structural motifs. The initial characterization of the first member SLy1/SASH3 (SH3 protein expressed in lymphocytes 1) in 2001 was rapidly followed by identification of SLy2/HACS1 (hematopoietic adaptor containing SH3 and SAM domains 1) and SASH1/SLy3 (SAM and SH3 domain containing 1). Based on their pronounced sequence similarity, they were subsequently classified as one family of intracellular scaffold proteins. Despite their obvious homology, the three SLy/SASH1‐members fundamentally differ with regard to their expression and function in intracellular signaling. On the contrary, growing evidence clearly demonstrates an important role of all three proteins in human health and disease. In this review, we systematically summarize what is known about the SLy/SASH1‐adaptors in the field of molecular cell biology and immunology. To this end, we recapitulate current research about SLy1/SASH3, SLy2/HACS1, and SASH1/SLy3, with an emphasis on their similarities and differences.
Value in Scoliosis Surgery
Authors: Stanton Robert P. , Grauer Jordan , Le Robert V. , Reutebuch Kirsten , Saunders Kevin J. , Kiebzak Gary M.
Published: March 2021

Study Design.

Retrospective chart review.

Objective.

The aim of this study was to document the impact of coordinated surgical and anesthetic techniques on estimated blood loss (EBL) and subsequent need for transfusion.

Summary of Background Data.

Scoliosis surgery is typically associated with large quantities of blood loss, and consequently blood transfusion may be necessary. Many strategies have been employed to minimize blood loss, including blood collection with reinfusion (“cell-saver”) and the use of antifibrinolytic drugs. We reviewed our experience with methods to minimize blood loss to show that transfusion should be a rare event.

Methods.

One hundred and thirty consecutive cases of spine fusion for adolescent idiopathic scoliosis utilizing pedicle screw fixation were reviewed from March 2013 to October 2019. The senior author was the primary surgeon for all cases. Data were collected from the electronic medical record, including age, sex, weight, number of instrumented levels, EBL, total fluids administered during surgery, pre- and postoperative hemoglobin, and procedure duration.

Results.

The average EBL was 232 ± 152 mL (range 37–740 mL). The average preoperative hemoglobin was 13.4 ± 1.2 g/dL and the average postoperative hemoglobin (last measured before discharge) was 9.0 ± 1.2 g/dL. One patient received a transfusion of 270 mL homologous blood. Blood salvage and reinfusion (“cell-saver”) was not used. No patient was managed with antifibrinolytic drugs.

Conclusion.

Minimizing blood loss using a combination of surgical and anesthesia techniques can effectively eliminate the need for blood transfusion. The elimination of costly adjuncts increases the value of a complex orthopedic procedure.

Level of Evidence: 5
Impact of Depression on Patient Reported Outcomes Following Primary Versus Revision ACDF
Authors: Lynch Conor P. , Cha Elliot D.K. , Jadczak Caroline N. , Mohan Shruthi , Geoghegan Cara E. , Singh Kern
Published: March 2021

Study Design.

Retrospective cohort.

Objective.

To assess the relationship of depressive symptoms with patient reported outcome measures (PROMs) in patients undergoing either primary or revision anterior cervical discectomy and fusion (ACDF) procedures.

Summary of Background.

Depression has been associated with poorer outcomes following ACDF. However, research examining the relationship between depression and PROMs in revision ACDF procedures is limited.

Methods.

A prospective database was retrospectively reviewed for primary or revision, single- or multilevel ACDF procedures from 2016 to 2019. Patients lacking preoperative Patient Health Questionnaire-9 (PHQ-9) surveys were excluded. Demographic and perioperative characteristics were recorded and analyzed using Fisher's exact test or t test. Patient-reported outcome measures were collected preoperatively and postoperatively. Postoperative improvement from baseline scores (ΔPROM) was calculated at all postoperative timepoints. Differences in mean PROM and ΔPROM between groups and changes from baseline PROM scores within groups were assessed using Student's t test. Linear regression analyzed the impact of preoperative PHQ-9 on ΔPROM.

Results.

A total of 143 patients (121 primary and 22 revision) were included. Significant differences between groups were demonstrated at the preoperative timepoint for Neck Disability Index (NDI) (P = 0.022). ΔPROM values did not significantly differ between groups. Regression analysis revealed significant relationships between preoperative PHQ-9 and ΔPHQ-9 at all timepoints, ΔVAS neck at 6-weeks and 6-months, ΔVAS arm at 6-months, and ΔNDI at 6-weeks and 6-months for the primary group (all P < 0.05). Regression analysis revealed no significant associations for the revision group.

Conclusion.

Primary or revision ACDF procedures did not significantly differ in depressive symptoms through 1-year. Primary ACDF patients significantly improved in all PROMs through all timepoints, while revision patients had limited improvement in PROMs. Preoperative depression may have a stronger association on postoperative outcomes for primary procedures.

Level of Evidence: 3
Appropriate Risk Stratification and Accounting for Age-Adjusted Reciprocal Changes in the Thoracolumbar Spine Reduces the Incidence and Magnitude of Distal Junctional Kyphosis in Cervical Deformity Surgery
Authors: Passias Peter G. , Bortz Cole , Pierce Katherine E. , Kummer Nicholas A. , Lafage Renaud , Diebo Bassel G. , Line Breton G , Lafage Virginie , Burton Douglas C. , Klineberg Eric O. , Kim Han Jo , Daniels Alan H. , Mundis Gregory M , Protopsaltis Themistocles S. , Eastlack Robert K. , Sciubba Daniel M. , Bess Shay , Schwab Frank J. , Shaffrey Christopher I. , Smith Justin S. , Ames Christopher P.
Published: March 2021

Study Design.

Retrospective cohort study of a prospective cervical deformity (CD) database.

Objective.

Identify factors associated with distal junctional kyphosis (DJK); assess differences across DJK types.

Summary of Background Data.

DJK may develop as compensation for mal-correction of sagittal deformity in the thoracic curve. There is limited understanding of DJK drivers, especially for different DJK types.

Methods.

Included: patients with pre- and postoperative clinical/radiographic data. Excluded: patients with previous fusion to L5 or below. DJK was defined per surgeon note or DJK angle (kyphosis from LIV to LIV-2)<-10°, and pre- to postoperative change in DJK angle by<-10°. Age-specific target LL-TK alignment was calculated as published. Offset from target LL-TK was correlated to DJK magnitude and inclination. DJK types: severe (DJK<−20°), progressive (DJK increase>4.4°), symptomatic (reoperation or published disability thresholds of NDI ≥ 24 or mJOA≤14). Random forest identified factors associated with DJK. Means comparison tests assessed differences.

Results.

Included: 136 CD patients (61 ± 10 yr, 61%F). DJK rate was 30%. Postop offset from ideal LL-TK correlated with greater DJK angle (r = 0.428) and inclination of the distal end of the fusion construct (r = 0.244, both P < 0.02). Seven of the top 15 factors associated with DJK were radiographic, four surgical, and four clinical. Breakdown by type: severe (22%), progressive (24%), symptomatic (61%). Symptomatic had more posterior osteotomies than asymptomatic (P = 0.018). Severe had worse NDI and upper-cervical deformity (CL, C2 slope, C0-C2), as well as more posterior osteotomies than nonsevere (all P < 0.01). Progressive had greater malalignment both globally and in the cervical spine (all P < 0.03) than static. Each type had varying associated factors.

Conclusion.

Offset from age-specific alignment is associated with greater DJK and more anterior distal construct inclination, suggesting DJK may develop due to inappropriate realignment. Preoperative clinical and radiographic factors are associated with symptomatic and progressive DJK, suggesting the need for preoperative risk stratification.

Level of Evidence: 3
Neglected Painful Chronic Achilles Tendon Rupture With No Palpable Gap: A Report of 3 Cases
Authors: Tiwari Punit , Kaur Harmeet , Bansal Nitish , Leonchuk Sergey S.
Published: March 2021

Purpose:

The purpose of this study was to bring to the attention of orthopedic surgeon community of our new technique of quadruple hamstrings graft in neglected Achilles tendon rupture.

Materials and Methods:

In this technique article we present results of treatment of 3 cases with neglected painful chronic Achilles tendon rupture with no palpable gap using our new surgical technique. Our method uses semitendinosus and gracilis tendon as autograft which are passes through 2 bone tunnels in calcaneum and tied over a button.

Results:

At least after 1 year each patient was satisfied with result of our treatment. Patients were able to stand on their forefoot without pain. There was no infection or other complications.

Conclusions:

Our results show that new surgical technique may be use in similar cases and should be evaluated with better analytical studies.
Goal-Directed Care Using Invasive Neuromonitoring Versus Standard of Care After Cardiac Arrest: A Matched Cohort Study*
Authors: Fergusson Nicholas A. , Hoiland Ryan L. , Thiara Sonny , Foster Denise , Gooderham Peter , Rikhraj Kiran , Grunau Brian , Christenson Jim , Ainslie Philip N. , Griesdale Donald E. G. , Sekhon Mypinder S.
Published: March 2021

PURPOSE:

Following return of spontaneous circulation after cardiac arrest, hypoxic ischemic brain injury is the primary cause of mortality and disability. Goal-directed care using invasive multimodal neuromonitoring has emerged as a possible resuscitation strategy. We evaluated whether goal-directed care was associated with improved neurologic outcome in hypoxic ischemic brain injury patients after cardiac arrest.

DESIGN:

Retrospective, single-center, matched observational cohort study.

SETTING:

Quaternary academic medical center.

PATIENTS:

Adult patients admitted to the ICU following return of spontaneous circulation postcardiac arrest with clinical evidence of hypoxic ischemic brain injury defined as greater than or equal to 10 minutes of cardiac arrest with an unconfounded postresuscitation Glasgow Coma Scale of less than or equal to 8.

INTERVENTIONS:

We compared patients who underwent goal-directed care using invasive neuromonitoring with those treated with standard of care (using both total and matched groups).

MEASUREMENTS AND MAIN RESULTS:

Goal-directed care patients were matched 1:1 to standard of care patients using propensity scores and exact matching. The primary outcome was a 6-month favorable neurologic outcome (Cerebral Performance Category of 1 or 2). We included 65 patients, of whom 21 received goal-directed care and 44 patients received standard of care. The median age was 50 (interquartile range, 35–61), 48 (74%) were male, and seven (11%) had shockable rhythms. Favorable neurologic outcome at 6 months was significantly greater in the goal-directed care group (n = 9/21 [43%]) compared with the matched (n = 2/21 [10%], p = 0.016) and total (n = 8/44 [18%], p = 0.034) standard of care groups. Goal-directed care group patients had higher mean arterial pressure (p < 0.001 vs total; p = 0.0060 vs matched) and lower temperature (p = 0.007 vs total; p = 0.041 vs matched).

CONCLUSIONS:

In this preliminary study of patients with hypoxic ischemic brain injury postcardiac arrest, goal-directed care guided by invasive neuromonitoring was associated with a 6-month favorable neurologic outcome (Cerebral Performance Category 1 or 2) versus standard of care. Significant work is required to confirm this finding in a prospectively designed study.
Systematic Review of Treatments for Colorectal Metastases in Elderly Patients to Guide Surveillance Cessation Following Hepatic Resection for Colorectal Liver Metastases
Authors: Alabraba Edward , Gomez Dhanny
Published: March 2021

Background:

Although included in surveillance programmes for colorectal cancer (CRC) metastases, elderly patients are susceptible to declines in health and quality of life that may render them unsuitable for further surveillance. Deciding when to cease surveillance is challenging.

Methods:

There are no publications focused on surveillance of elderly patients for CRC metastases. A systematic review of studies reporting treatment outcomes for CRC metastases in elderly patients was performed to assess the risk-benefit balance of the key objectives of surveillance; detecting and treating CRC metastases.

Results:

Sixty-eight eligible studies reported outcomes for surgery and chemotherapy in the elderly. Liver resections and use of chemotherapy, including biologics, are more conservative and have poorer outcomes in the elderly compared with younger patients. Selected studies demonstrated poorer quality-of-life (QoL) following surgery and chemotherapy. Studies of ablation in elderly patients are limited.

Discussion:

The survival benefit of treating CRC metastases with surgery or chemotherapy decreases with advancing age and QoL may decline in the elderly. The relatively lower efficacy and detrimental QoL impact of multimodal therapy options for detected CRC metastases in the elderly questions the benefit of surveillance in some elderly patients. Care of elderly patients should thus be customized based on their preference, formal geriatric assessment, natural life-expectancy, and the perceived risk-benefit balance of treating recurrent CRC metastases. Clinicians may consider surveillance cessation in patients aged 75 years and above if geriatric assessment is unsatisfactory, patients decline surveillance, or patient fitness deteriorates catastrophically.
Clinical Outcomes of Patients With pT1-T2N0 Oral Tongue Squamous Cell Carcinoma
Authors: Wilson Jessica M. , Lumley Catherine , Tan Xianming , Shen Colette , Coniglio Andrew , Weissler Mark , Yarbrough Wendell G. , Hackman Trevor , Blumberg Jeffrey , Zanation Adam , Thorp Brian , Patel Samip N. , Chera Bhishamjit S.
Published: March 2021

Objective:

The objective of this study was to evaluate the clinical outcomes in a cohort of patients with early-stage oral tongue squamous cell carcinoma (OTSCC).

Materials and Methods:

We conducted a retrospective analysis of patients with pT1-T2N0 (American Joint Committee on Cancer [AJCC] seventh edition) OTSCC treated from 2000 to 2018. Two-year actuarial rates of local regional control, cancer-specific survival, and overall survival were calculated for the entire cohort and patients with/without adjuvant radiation.

Results:

Ninety-six patients met the criteria with a median follow-up of 4 years; 14 had adjuvant radiation, while 82 had surgery alone. Two-year local regional control was 82.7% (75.4% to 90.8%) for the entire cohort, 84.9% (77.8% to 93.2%) for surgery only, and 70.7% (50.2% to 99.6%) for patients with adjuvant radiation. Two-year progression-free survival was 82.7% (75.3% to 90.8%). Of the 20 patients with recurrence, 11 (55%) were successfully salvaged.

Conclusion:

Local regional recurrence remains modest in early-stage OTSCC, but salvage is possible with high survival rates.

Level of Evidence:

Level III—retrospective cohort study.
Intercostobrachial Nerve (ICBN) Preservation Versus Sacrifice in Axillary Dissection
Authors: Melhem Jamal , Amarin Marzouq , Odeh Ghada , Al-Bustami Nadwa , Al-Lauzy Hatem , Ayoub Rami
Published: March 2021

Objectives:

Whether to preserve or sacrifice the intercostobrachial nerves (ICBN) is a controversial issue. In this trial, we aim to assess the effects of preservation of the ICBN during axillary dissection for patients with breast cancer in terms of pain score immediately postoperatively and several hours later, need for simple analgesia and narcotics, numbness and arm swelling.

Materials and Methods:

This is a single-institution, single-surgeon randomized controlled trial where a sample of 48 patients with breast cancer, of various age groups, were allocated randomly to any of the 2; preservation or sacrifice categories. Postoperatively, patients were asked by a physician to fill a predesigned questionnaire to assess the studied items during hospitalization and after discharge.

Results:

Among the 48 included patients, ICBN was sacrificed in 24 patients; of which 18 patients (75%) developed numbness in the inner aspect of the arm. While in the ICBN preservation group (24 patients) only 6 patients suffered numbness (25%) with a significant P-value of 0.001. Estimated duration of surgery with ICBN preservation was 100±22.02 minutes, while it is significantly shorter in the ICBN sacrifice group (83.48±21.55). However, with regard to other variables of pain, seroma formation, need of simple analgesia and narcotics, hospital admission days and arm swelling, there was no significant difference between the 2 groups.

Conclusion:

This study can conclude that preservation of ICBN during axillary dissection in patients with breast CA can save these patients’ additional suffering from inner arm numbness. That is at the expense of surgery duration, around 20 minutes longer, for the surgeon to take his/her time in carefully dissecting the axilla properly without injuring these ICBN.
Antinociceptive effects of minor cannabinoids, terpenes and flavonoids in Cannabis
Authors: Rodriguez Carl Erwin B. , Ouyang Lisa , Kandasamy Ram
Published: March 2021

Cannabis has been used for centuries for its medicinal properties. Given the dangerous and unpleasant side effects of existing analgesics, the chemical constituents of Cannabis have garnered significant interest for their antinociceptive, anti-inflammatory and neuroprotective effects. To date, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) remain the two most widely studied constituents of Cannabis in animals. These studies have led to formulations of THC and CBD for human use; however, chronic pain patients also use different strains of Cannabis (sativa, indica and ruderalis) to alleviate their pain. These strains contain major cannabinoids, such as THC and CBD, but they also contain a wide variety of cannabinoid and noncannabinoid constituents. Although the analgesic effects of Cannabis are attributed to major cannabinoids, evidence indicates other constituents such as minor cannabinoids, terpenes and flavonoids also produce antinociception against animal models of acute, inflammatory, neuropathic, muscle and orofacial pain. In some cases, these constituents produce antinociception that is equivalent or greater compared to that produced by traditional analgesics. Thus, a better understanding of the extent to which these constituents produce antinociception alone in animals is necessary. The purposes of this review are to (1) introduce the different minor cannabinoids, terpenes, and flavonoids found in Cannabis and (2) discuss evidence of their antinociceptive properties in animals.
Management of hypertension in heart failure with preserved ejection fraction: is there a blood pressure goal?
Authors: Myhre Peder L. , Selvaraj Senthil , Solomon Scott D.
Published: March 2021

Purpose of review

Hypertension remains a leading risk factor for heart failure with preserved ejection fraction (HFpEF), and elevated blood pressure (BP) portends an adverse prognosis in patients with established HFpEF. We summarize current evidence for mechanisms linking hypertension to HFpEF and management of hypertension in HFpEF.

Recent findings

Data suggest a complex, multifactorial pathophysiology driving the association between hypertension and HFpEF, including left ventricular hypertrophy, diastolic dysfunction, atrial dysfunction, coronary microvascular disease, endothelial dysfunction, myocardial injury and fibrosis. Although intensive BP control may attenuate these processes, this hypothesis has not been tested on clinical outcomes in a dedicated randomized controlled trial (RCT) in HFpEF. Antihypertensive therapies variably improve key surrogate markers in HFpEF, though BP reduction generally does not account for these benefits. Accordingly, BP targets are extrapolated from observational studies and RCTs testing heart failure therapies that affect BP in addition to dedicated RCT data in patients at elevated risk (without heart failure).

Clinicians should recognize the risk of disease progression and poor outcomes associated with uncontrolled hypertension in HFpEF. Intensive BP control, preferably by therapies known to improve outcomes in heart failure, may slow key pathways in disease progression. Future RCTs testing intensified BP control strategies in HFpEF are warranted.