bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of rescue medication in placebo-controlled trials of pharmacotherapy for neuropathic pain and low back pain
Authors: Grøvle Lars , Hasvik Eivind , Haugen Anne Julsrud
Published: June 2021

Rescue medication (RM) consumption is commonly used as a secondary outcome in placebo-controlled trials of chronic pain, but its validity has yet to be established. If participants randomized to placebo take more RM than those randomized to an active drug, the difference in pain between the 2 groups may be reduced, potentially masking effects of the active drug. This study assessed proportional RM consumption in the placebo and active groups according to results of 42 randomized controlled trials of neuropathic pain (NeP), and 29 trials of low back pain, which were included in 2 systematic reviews and meta-analyses. Trial results were assessed based on effect size, statistical significance, and whether the drug was recommended as first-line treatment by the systematic reviews. In trials indicating effect of the investigational drug, RM consumption was generally higher in the placebo groups than in the active groups. In trials reporting a small or a medium effect size of the investigational drug, subjects receiving placebo consumed 17% to 30% more RM than subjects receiving active drug, potentially leading to underestimation of the effects of the investigational drugs. Few trials reported a large effect size. Differences in RM consumption between participants receiving placebo and those receiving active drug were seldom taken in account by the individual trials and not at all by the systemic reviews when making treatment recommendations for NeP or low back pain. Elaboration on analytical methods to assess treatment effects in chronic pain trials using RM is warranted.
Oral squamous cell carcinoma–released brain-derived neurotrophic factor contributes to oral cancer pain by peripheral tropomyosin receptor kinase B activation
Authors: Grayson Max , Arris Dominic , Wu Ping , Merlo Jaclyn , Ibrahim Tarek , Fang-Mei Chang , Valenzuela Vanessa , Ganatra Shilpa , Ruparel Shivani
Published: June 2021

Oral cancer pain is debilitating and understanding mechanisms for it is critical to develop novel treatment strategies treatment strategies. Brain-derived neurotrophic factor (BDNF) signaling is elevated in oral tumor biopsies and is involved with tumor progression. Whether BDNF signaling in oral tumors contributes to cancer-induced pain is not known. The current study evaluates a novel peripheral role of BDNF-tropomyosin receptor kinase B (TrkB) signaling in oral cancer pain. Using human oral squamous cell carcinoma (OSCC) cells and an orthotopic mouse tongue cancer pain model, we found that BDNF levels were upregulated in superfusates and lysates of tumor tongues and that BDNF was expressed by OSCC cells themselves. Moreover, neutralization of BDNF or inhibition of TrkB activity by ANA12, within the tumor-bearing tongue reversed tumor-induced pain-like behaviors in a sex-dependent manner. Oral squamous cell carcinoma conditioned media also produced pain-like behaviors in naïve male mice that was reversed by local injection of ANA12. On a physiological level, using single-fiber tongue-nerve electrophysiology, we found that acutely blocking TrkB receptors reversed tumor-induced mechanical sensitivity of A-slow high threshold mechanoreceptors. Furthermore, single-cell reverse transcription polymerase chain reaction data of retrogradely labeled lingual neurons demonstrated expression of full-form TrkB and truncated TrkB in distinct neuronal subtypes. Last but not the least, intra-TG siRNA for TrkB also reversed tumor-induced orofacial pain behaviors. Our data suggest that TrkB activities on lingual sensory afferents are partly controlled by local release of OSCC-derived BDNF, thereby contributing to oral cancer pain. This is a novel finding and the first demonstration of a peripheral role for BDNF signaling in oral cancer pain.
Muscle function, quality, and relative mass are associated with knee pain trajectory over 10.7 years
Authors: Pan Feng , Tian Jing , Scott David , Cicuttini Flavia , Jones Graeme
Published: June 2021

Periarticular muscle plays an important role in the pathogenesis of musculoskeletal pain. We recently reported that pain population consists of distinct subgroups of which the causes and mechanisms may differ. This study aimed to examine the association of lean mass, muscle strength, and quality with 10.7-year pain trajectory. Nine hundred forty-seven participants from a population-based cohort study were analysed. Dual-energy X-ray absorptiometry was used to assess lean and fat mass. Leg strength, knee extensor strength, and lower-limb muscle quality were measured/calculated. Knee pain was assessed by the Western Ontario and McMaster Universities Osteoarthritis Index pain questionnaire. Radiographic knee osteoarthritis was assessed by X-ray. Three distinct pain trajectories were identified: “Minimal pain” (53%), “Mild pain” (34%), and “Moderate pain” (13%). Higher total and lower-limb lean mass were associated with an increased risk of “Mild pain” and “Moderate pain” trajectories relative to the “Minimal pain” trajectory group, but these associations became nonsignificant after further adjustment for fat mass. Total lean mass percentage was associated with a lower risk of “Mild pain” (relative risk ratio [RRR]: 0.95, 95% confidence interval 0.92-0.98) and “Moderate pain” trajectory (RRR: 0.92, 95% confidence interval 0.87-0.96). Greater leg and knee extensor strength and muscle quality were associated with “Mild pain” and “Moderate pain” trajectories (RRR: 0.52-0.65, all P < 0.05). Similar results were found in those with radiographic knee osteoarthritis. Higher lower-limb muscle strength and quality, and relative lean mass, are associated with a reduced risk of severe knee pain trajectories, suggesting that improving muscle function and composition may protect against persistent unfavourable knee pain courses.
Printing a static progressive orthosis for hand rehabilitation
Authors: Huang Li-Ying , Wang Tien-Hsiang , Chang Bao-Chi , Huang Chia-I , Chou Li-Wei , Wang Shyh-Jen , Chen Wei-Ming
Published: June 2021

Background:

Static progressive orthosis is used for the treatment of severe joint contracture after trauma and/or surgery. However, a custom-fabricated static progressive splint would be expensive and labor intensive. Especially, owing to very limited payment under the current Taiwanese National Health Insurance, the incentives to fabricate a patient-specific splint are insufficient for a therapist. To ease splint construction, we introduced three-dimensional (3D)-printed “shark fin”-shaped device works as a static progressive orthosis for the hand rehabilitation. The aim of this study was to describe and demonstrate the newly designed device.

Methods:

This study included a 46-year male suffered from a left distal radius fracture and underwent open reduction internal fixation and a 23-year male with the right thumb flexor pollicis longus rupture, requiring tendon repair. Both subjects used this “shark fin”-shaped device to stretch for increasing range of motion (ROM) of wrist extension and the thumb.

Results:

The patient receiving ulnar shortening surgery used this device to stretch for increasing ROM of wrist extension. The active ROM of wrist extension improved from 30° to 50°. The other patient with the right thumb flexor pollicis longus rupture suffered from thumb contracture; the ROMs of the metacarpophalangeal (MCP) joint and interphalangeal (IP) joint were 40°–55° and 20°–25°, respectively. After tenolysis surgery, his ROMs of the MCP and IP joints were improved to 10°–35° and 40°–65°, respectively. Following physical therapy by applying the device, his ROMs of the MCP and IP joints were further increased to 0°–40° and 25°–70°, respectively.

Conclusion:

Incorporating the “shark fin”-shaped orthosis into hand rehabilitation increased the ROM of wrist extension for a patient with distal radius fracture and improved the ROM of the MCP and IP joints in another patient after tenolysis surgery.
Varied impacts on outpatient services among departments and divisions in the early phase of the COVID-19 pandemic: Implications for personnel mobilization and preparatory training
Authors: Chang Ya-Ting , Chiang Shu-Chiung , Lee Wui-Chiang , Chen Tzeng-Ji , Hwang Shinn-Jang
Published: June 2021

Background:

Coronavirus disease 2019 (COVID-19) spread all over the world in 2020. In the face of the sudden pandemic, workforce mobilization has been of critical concern to medical institutions. During the pandemic, the public’s behaviors of seeking medical assistance have also changed. Using the real-world data of a large medical center in Taiwan, this study aimed to analyze the fluctuations of outpatient visits among various departments and divisions in the early phase of the COVID-19 pandemic and to provide suggestions for staff allocation in similar future events.

Methods:

Data of outpatient visits at Taipei Veterans General Hospital were obtained for analysis. The weekly fluctuations of outpatient visits among 36 departments or divisions were computed for 8 weeks from February 3 to March 29, 2020, the early phase of the pandemic. The monthly data of outpatient visits by department and division in March 2020 were also extracted for comparison with those in March 2019. A simple regression equation was used to calculate the weekly trends.

Results:

Average outpatient visits decreased by 26% in 2 months following the outbreak. Among the 36 departments or divisions, ophthalmology, orthopedics, and cardiology underwent marked declines after the outbreak; the slopes of the simple regression equation were −110.8, −100.7, and −99.2, respectively. By contrast, transfusion medicine, toxicology, transplantation surgery, pediatric surgery, chest surgery, technical aid, and oncology were divisions less influenced. In the year-over-year comparison, infection was the only department or division with positive growth (20.5%), whereas all others exhibited negative growth.

Conclusion:

In the future, we can fulfil the additional personnel needs during a pandemic by redeploying physicians from departments experiencing a reduced workload. Hospitals should also establish preparatory employee training programs to ensure that the reassigned personnel are adequately equipped to serve in their new positions.
The Effect of Clozapine on Self-reported Duration of Sleep and Its Interaction With 23 Other Medications
Authors: Fernandez-Egea Emilio , Chen Shanquan , Jenkins Christopher , Turrion Concha , Mitchell Simon P. , Dodwell David J. F. , Mann Louisa M. , Deakin Julia B. , Syed Zahoor H. , Hafizi Sepehr , Zimbron Jorge , Praseedom Asha S. , Cardinal Rudolf N.
Published: June 2021

Background

Sedation is a common and incapacitating clozapine adverse effect, but the factors associated with sedation and its pharmacological management remain poorly studied.

Methods

We conducted a retrospective cohort study based on deidentified electronic clinical records of clozapine-treated patients from the secondary mental health care provider for Cambridgeshire and Peterborough, United Kingdom. We first evaluated cross-sectionally the influence of clozapine dose, clozapine, and norclozapine plasma levels on self-reported hours slept, as a proxy for sedation, using bivariate correlation and then the longitudinal effect of changes in clozapine dose and other 23 medications using linear mixed effect models. We followed 241 clozapine-treated patients for 56 months on average, with 2237 face-to-face assessments in total.

Results

Patients slept for a mean of 9.35 h/d, with 46% reporting 10 h/d or more. Cross-sectionally, sleep duration did not correlate with clozapine dose (r = 0.14, P = 0.106), but with clozapine plasma levels (r = 0.38, P < 0.0001) and norclozapine plasma levels (r = 0.25, P = 0.005). Longitudinally, the final mixed-effects model revealed 4 pharmacological variables that had a significant impact on hours slept: clozapine, risperidone augmentation, and atenolol were associated with increased sleep, whereas aripiprazole augmentation was associated with decreased sleep. We found that 20 other psychotropic medications measured were not associated with changes in sleep when added to clozapine. Excess sleep is a clozapine level-dependent adverse effect.

Conclusions

The impact of different augmentation strategies might help clinicians decide on the most adequate strategy, albeit further studies should confirm our results.
Crisis Management of Hysteroscopic Surgical Complications in the Office Setting
Authors: Roman Robert A. , Roberts Carey C. , Booth Rachel , Nezhat Camran , Bhagavath Bala , Lindheim Steven R.
Published: June 2021

Importance

As health care providers are increasingly motivated to perform office procedures, there is marginal training and attention related to crisis management (CM).

Objective

We review the CM in office gynecology and illustrate the value of applying the STOP (stop, think, observe, plan) mental framework to acute management of office hysteroscopy complications.

Evidence Acquisition

We performed a literature review on crisis management in gynecology.

Results

Concepts of team leadership, simulation training, awareness of human error, and panic control are implemented in CM.

Conclusions

Health care providers need to be cognizant of the importance of CM for optimizing patient safety and quality improvement and consider its application on office-based procedures.

Relevance

Crisis management has become increasingly relevant in the outpatient setting, seeking to better equip physicians with the skills to manage adverse outcomes while performing office-based procedures.

Target Audience

Obstetricians and gynecologists, family physicians

Learning Objectives

At the completion of this article, physicians should be better able to describe the benefits and risks of office hysteroscopy; evaluate CM principles of human error, simulation training, leadership, and panic control; and assess the STOP mental framework for CM.
Cervical Cancer Screening in the United States: Challenges and Potential Solutions for Underscreened Groups
Authors: Fuzzell Lindsay N. , Perkins Rebecca B. , Christy Shannon M. , Lake Paige W. , Vadaparampil Susan T.
Published: June 2021

(Abstracted from Prev Med 2021;144:106400)

Every year, approximately 13,000 cases and 4000 deaths are attributed to cervical cancer, making it the leading cause of cancer death for women worldwide. Nearly all cases of cervical cancer are caused by human papillomavirus (HPV), making HPV vaccination and screening programs critical for reducing mortality.
Long-Term Physical Activity Levels and Physical Functioning Outcomes After Midurethral Sling
Authors: Shinnick Julia K. , Raker Christina A. , Sung Vivian W.
Published: June 2021

(Abstracted from Female Pelvic Med Reconstr Surg 2021;27:51–56)

Urinary incontinence (UI) affects approximately 15.7% of women and can impact physical activity (PA), often due to a fear of urinary leakage. Studies have reported >60% of women with daily urine leakage reporting a diminished physical functioning (PF), and this is especially predominant in women with stress urinary incontinence (SUI) in their fifth or sixth decades of life.
Associations Between Consumption of Coffee and Caffeinated Soft Drinks and Late Stillbirth—Findings From the Midland and North of England Stillbirth Case-Control Study
Authors: Heazell Alexander E. P. , Timms Kate , Scott Rebecca E. , Rockliffe Lauren , Budd Jayne , Li Minglan , Cronin Robin , McCowan Lesley M. E. , Mitchell Edwin A. , Stacey Tomasina , Roberts Devender , Thompson John M. D.
Published: June 2021

(Abstracted from Eur J Obstet Gynecol Reprod Biol 2021;256:471–477)

The prevention of stillbirth is an enduring problem. Identifying risk factors and developing strategies to minimize their effect can help to reduce the prevalence of stillbirth.
The Role of HLA-B27 in Argentinian Axial Spondyloarthritis Patients
Authors: García-Salinas Rodrigo , Ruta Santiago , Chichande Jessica Torres , Magri Sebastian
Published: June 2021

Background

The prevalence of human leukocyte antigen B27 (HLA-B27) is variable around the world. Our objectives were to estimate the frequency of HLA-B27 in an Argentinian cohort of axial spondyloarthritis (axSpA), to evaluate the differences between HLA-B27–positive and HLA-B27–negative patients, and to analyze its performance as a diagnostic biomarker.

Methods

Observational study including patients older than 18 years, with axSpA diagnosis assessed in a fast track program (Reuma-Check SpA). All patients underwent the following: blood tests, HLA-B27, sacroiliac images, and enthesitis ultrasound. Sociodemographic data and SpA symptoms were also collected. The clinical assessor was blinded to complementary studies. For the sensitivity and specificity analysis, patients with chronic low back pain without axSpA who performed the same circuit in the same period were used as control, paired 1:1 (sex and age).

Results

One hundred fifty patients were included, 75 axSpA and 75 controls. The frequency of HLA-B27 was 43% (95% confidence interval [CI], 30–53). The differences between HLA-B27–positive and HLA-B27–negative patients were observed in age of low back pain onset (36 vs 46 years), BASFI (Bath Ankylosing Spondylitis Functional Index) (4 vs 5), and extra-articular SpA features such as uveitis and inflammatory bowel disease (29% vs 50%). When this frequency was compared (low back pain control group), the difference was 43% versus 9% (odds ratio, 7.7; 95% CI, 2.8–24), and HLA-B27 had a sensitivity of 43%, specificity of 91%, positive predictive value of 85%, negative predictive value of 58%, and likelihood ratio of 4.9 (95% CI, 3–8).

Conclusions

The frequency of HLA-B27 in axSpA was 43%; positive patients had an earlier age of onset (36), a higher BASFI, and more SpA features. For the diagnosis of SpA, HLA-B27 had a good specificity but low sensitivity.
Neural response during temporal – and spatial luminance contrast processing and its manifestation in the blood-oxygen-level-dependent-signal in striate and extra-striate cortex
Authors: Marcar Valentine L. , Jäncke Lutz
Published: June 2021

The primate visual system has been the prime site for investigating the relationship between stimulus property, neural response and blood-oxygen-level-dependent (BOLD)-signal; yet this relationship remains ill-understood. Electrophysiological studies have shown that the ability to visualise a neural response is determined by stimulus property and presentation paradigm. The neural response in the human visual cortex consists of a phasic response processing temporal and tonic response processing spatial luminance contrast. We investigated their influence on the BOLD signal from the visual cortex. To do so, we compared BOLD signal amplitude from BA17 and BA18 of 15 human volunteers to visual patterns varying the size of the active neural population and the discharge activity of this population. The BOLD signal amplitude in both areas reflected the discharge activity of the active neural population but not the size of the active neural population. For identical stimuli, BOLD signal amplitude in BA17 exceeded than that of BA18. This indicates that the BOLD signal reflects the tonic neural neuronal response during spatial luminance contrast processing. The difference in BOLD signal amplitude between BA17 and BA18 is accounted for by differences in neurophysiological and cytoarchitectonic differences between the two areas. Our findings offer an understanding of the relationship between stimulus property, neural response and the BOLD signal by considering the cytoarchitectonic, and neurophysiological make-up between different cortical areas and the influence of a phasic and tonic neural response on local deoxyhaemoglobin concentration. Conversely, differences in BOLD signal between brain structures and stimuli provide cues to the influence of different neurophysiological mechanisms on the neural response.
The c.824C>A and c.616dupA mutations in the SLC17a8 gene are associated with auditory neuropathy and lead to defective expression of VGluT3
Authors: Qi Yue , Gong Shusheng , Liu Ke , Song Yueshuai
Published: June 2021

Auditory neuropathy is sensorineural deafness where sound signals cannot be transmitted synchronously from the cochlea to the auditory center. Abnormal expression of vesicle glutamate transporter 3 (VGluT3) encoded by the SLC17a8 gene is associated with the pathophysiology of auditory neuropathy. Although several suspected pathogenic mutations of the SLC17a8 gene have been identified in humans, few studies have confirmed their pathogenicity. Here, we describe the effects of two known suspected pathogenic mutations (c.824C>A and c.616dupA) in the SLC17a8 gene coding VGluT3 protein and analyzed the potential pathogenicity of these mutations. The p.M206Nfs4 and p.A275D changes are caused by c.824C>A and c.616dupA mutations in the cytoplasmic loop, an important structure of VGluT3. To explore the potential pathogenic effects of c.824C>A and c.616dupA mutations, we performed a series of experiments on mRNA levels and protein expression in cell culture. The c.616dupA mutation in the SLC17a8 gene resulted in a significant decrease in transcriptional activity of mRNA, and the expression of VGluT3 was also reduced. The c.824C>A mutation in the SLC17a8 gene resulted in abnormal VGluT3, although this mutation did not affect the transcriptional activity of mRNA. Our results demonstrate that c.824C>A and c.616dupA mutations in the SLC17a8 gene could lead to pathological protein expression of VGluT3 and supported the potential pathogenicity of these mutations.
Discontinuation of Continuation or Maintenance Electroconvulsive Therapy Caused by the COVID-19 Pandemic
Authors: Van de Velde Nele , Geerts Pieter-Jan , Tandt Hannelore , Vanderhasselt Marie-Anne , Titeca Koen , Lemmens Gilbert
Published: June 2021

Background

Continuation or maintenance electroconvulsive therapy (C/M-ECT) is recommended to reduce relapse rates of patients with major depressive disorder. During the ongoing COVID-19 pandemic, ECT services have come under pressure or needed to close because of redirected resources and safety reasons. We investigated the impact of C/M-ECT discontinuation on relapse in patients with unipolar depressive disorder in Flanders, Belgium.

Methods

Between March 30 and June 18, 2020, all patients receiving C/M-ECT in 2 ECT centers were included. Continuation or maintenance electroconvulsive therapy was discontinued in 33 patients and continued in 4 patients. Relapse was defined as the need to restart ECT or the need for hospitalization. Depressive symptoms were assessed every 3 weeks using the Patient Health Questionnaire, the Clinical Global Impression Scale, and 2 additional patient-rated questions.

Results

Relapse in the discontinuation group was 60.6%. All 4 patients who continued ECT remained remitted. Kaplan-Meier survival analysis showed significantly shorter relapse rates for patients receiving bitemporal and/or frequent C/M-ECT (1- to 2-week intervals). Patients older than 60 years showed longer survival rates.

Conclusions

Our results confirm earlier prospective and retrospective data regarding the efficacy and importance of C/M-ECT as relapse prevention. After treatment discontinuation, close monitoring of early warning signs for relapse is crucial, especially in the first few months. With the COVID-19 pandemic continuing, our data provide an indication of the necessity to ensure adequate care and access to ECT not only for the acutely ill but also for the vulnerable patients who are depending on C/M-ECT.
Benefits of Surveillance Testing and Quarantine in a SARS-CoV-2 Vaccinated Population of Students on a University Campus
Authors: Motta Francis C. , McGoff Kevin A. , Deckard Anastasia , Wolfe Cameron R. , Moody M. Anthony , Cavanaugh Kyle , Denny Thomas N. , Harer John , Haase Steven B.
Published: June 2021

Surveillance testing and quarantine have been effective measures for limiting SARS-CoV-2 transmission on university campuses. However, the importance of these measures needs to be re-evaluated in the context of a complex and rapidly changing environment that includes vaccines, variants, and waning immunity. Also, recent guidelines from the CDC suggest that vaccinated students do not need to participate in surveillance testing. We used an agent-based SEIR model to evaluate the utility of surveillance testing and quarantine in a fully vaccinated student population where vaccine effectiveness may be impacted by the type of vaccination, the presence of variants, and the loss of vaccine-induced or natural immunity over time. We found that weekly surveillance testing at 90% vaccine effectiveness only marginally reduces viral transmission as compared to no testing. However, at 50%-75% effectiveness, surveillance testing can provide over 10-fold reduction in the number of infections on campus over the course of the semester. We also show that a 10-day quarantine protocol for exposures has limited effect on infections until vaccine effectiveness drops to 50%, and that increased surveillance testing for exposures is at least as effective as quarantine at limiting infections. Together these findings provide a foundation for universities to design appropriate mitigation protocols for the 2021-2022 academic year.
Use of real-world evidence data to evaluate the comparative effectiveness of second-line type 2 diabetes medications on chronic kidney disease
Authors: Deng Yu , Ghamsari Farhad , Lu Alice , Yu Jingzhi , Zhao Lihui , Kho Abel N
Published: June 2021

Chronic kidney disease (CKD) is a common complication of type 2 diabetes mellitus (T2DM). Approximately one-third of patients with T2DM also have CKD. In clinical trial studies, several anti-diabetic medications (ADM) show evidence of preventing the progression of CKD. Biguanides (e.g., metformin) are widely accepted as the first line medication. However, the comparativeness effectiveness of second line ADMs on CKD outcomes in T2DM is unclear. In addition, results from clinical trials may not generalize into routine clinical practice. In this study, we aimed to investigate the association of second line ADMs with incident CKD and CKD hospitalization in T2DM patients using real-world data from electronic health records. Our study found that treatment with sodium-glucose cotransporter 2 (SGLT-2) inhibitors was significantly associated with a lower risk of CKD incidence in both primary analysis (hazard ratio, 0.43; 95% CI, [0.22;0.87]; p-value,0.02) (SU) as a second-line ADM. Treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor was significantly associated with lower CKD incidence (hazard ratio, 0.7; 95% CI, [0.53;0.96]; p-value, 0.03) and lower CKD hospitalization events (hazard ratio, 0.6; 95% CI, [0.37; 0.96]; p-value, 0.04) in the primary analysis. However, both associations were not significant in the sensitivity analysis. We did not observe significant association between use of GLP-1, TZD, insulin and CKD incidence or hospitalization compared to use of SU as the second-line ADM.
A novel hyperinflammation clinical risk tool, HI5-NEWS2, predicts mortality following early dexamethasone use in an observational cohort of hospitalised COVID-19 patients
Authors: Ardern-Jones Michael R , Phan Hang T.T. , Borca Florina , Stammers Matt , Batchelor James , Reading Isabel C. , Fletcher Sophie V. , Smith Trevor , Duncombe Andrew S
Published: June 2021

Background

The success of early dexamethasone therapy for hospitalised COVID-19 cases in treatment of Sars-CoV-2 infection may predominantly reflect its anti-inflammatory action against a hyperinflammation (HI) response. It is likely that there is substantial heterogeneity in HI responses in COVID-19.

Methods

Blood CRP, ferritin, neutrophil, lymphocyte and platelet counts were scored to assess HI (HI5) and combined with a validated measure of generalised medical deterioration (NEWS2) before day 2. Our primary outcome was 28 day mortality from early treatment with dexamethasone stratified by HI5-NEWS2 status.

Findings

Of 1265 patients, high risk of HI (high HI5-NEWS2) (n=367, 29.0%) conferred a strikingly increased mortality (36.0% vs 7.8%; Age adjusted hazard ratio (aHR) 5.9; 95% CI 3.6-9.8, p<0.001) compared to the low risk group (n= 455, 36.0%). An intermediate risk group (n= 443, 35.0%) also showed significantly higher mortality than the low risk group (17.6% vs 7.8%), aHR 2.2, p=0.005). Early dexamethasone treatment conferred a 50.0% reduction in mortality in the high risk group (36.0% to 18.0%, aHR 0.56, p=0.007). The intermediate risk group showed a trend to reduction in mortality (17.8% to 10.3%, aHR 0.82, p=0.46) which was not observed in the low risk group (7.8% to 9.2%, aHR 1.4, p =0.31).

Interpretation

The HI5-NEWS2 measured at COVID-19 diagnosis, strongly predicts mortality at 28 days. Significant reduction in mortality with early dexamethasone treatment was only observed in the high risk group. Therefore, the HI5-NEWS2 score could be utilised to stratify randomised clinical trials to test whether intensified anti-inflammatory therapy would further benefit high risk patients and whether alternative approaches would benefit low risk groups. Considering its recognised morbidity, we suggest that early dexamethasone should not be routinely prescribed for HI5-NEWS2 low risk individuals with COVID-19 and clinicians should cautiously assess the risk benefit of this intervention.

Funding

No external funding.
Mendelian randomization suggests a bidirectional, causal relationship between physical inactivity and obesity
Authors: Carrasquilla Germán D. , García-Ureña Mario , Fall Tove , Sørensen Thorkild I.A. , Kilpeläinen Tuomas O.
Published: June 2021

Physical inactivity is associated with excess weight gain in observational studies. However, some longitudinal studies indicate reverse causality where weight gain leads to physical inactivity. As observational studies suffer from reverse causality, it is challenging to assess the true causal directions. Here, we assess the bidirectional causality between physical inactivity and obesity by bidirectional Mendelian randomization analysis. We used results from genome-wide association studies for accelerometer-based physical activity and sedentary time in 91,105 individuals and for body mass index (BMI) in 806,834 individuals. We implemented Mendelian randomization using CAUSE method that accounts for pleiotropy and sample overlap using full genome-wide data. We also applied inverse variance-weighted, MR-Egger, weighted median, and weighted mode methods using genome-wide significant variants only. We found evidence of bidirectional causality between sedentary time and BMI: longer sedentary time was causally associated with higher BMI [beta (95%CI) from CAUSE method: 0.11 (0.02, 0.2), P=0.02], and higher BMI was causally associated with longer sedentary time (0.13 (0.08, 0.17), P=6.3.×10-4). Our analyses suggest that higher moderate and vigorous physical activity are causally associated with lower BMI (moderate: -0.18 (-0.3,-0.05), P=0.006; vigorous: -0.16 (-0.24,-0.08), P=3.8×10-4), but indicate that the association between higher BMI and lower levels of physical activity is due to horizontal pleiotropy. The bidirectional, causal relationship between sedentary time and BMI suggests that decreasing sedentary time is beneficial for weight management, but also that targeting obesity may lead to additional health benefits by reducing sedentary time.
Identification of essential genes in Caenorhabditis elegans through whole genome sequencing of legacy mutant collections
Authors: Li-Leger Erica , Feichtinger Richard , Flibotte Stephane , Holzkamp Heinke , Schnabel Ralf , Moerman Donald G.
Published: June 2021

It has been estimated that 15-30% of the ∼20,000 genes in C. elegans are essential, yet many of these genes remain to be identified or characterized. With the goal of identifying unknown essential genes, we performed whole genome sequencing on complementation pairs from legacy collections of maternal-effect lethal and sterile mutants. This approach uncovered maternal genes required for embryonic development and genes with putative sperm-specific functions. In total, 58 essential genes were identified on chromosomes III, IV, and V, of which 49 genes are represented by novel alleles in this collection. Of these 49 genes, 19 (40 alleles) were selected for further functional characterization. The terminal phenotypes of embryos were examined, revealing defects in cell division, morphogenesis, and osmotic integrity of the eggshell. Mating assays with wild-type males revealed previously unknown male-expressed genes required for fertilization and embryonic development. The result of this study is a catalogue of mutant alleles in essential genes that will serve as a resource to guide further study toward a more complete understanding of this important model organism. As many genes and developmental pathways in C. elegans are conserved and essential genes are often linked to human disease, uncovering the function of these genes may also provide insight to further our understanding of human biology.
Claustral Projections to Anterior Cingulate Cortex Modulate Engagement with the External World
Authors: Atlan Gal , Matosevich Noa , Peretz-Rivlin Noa , Yvgi Idit , Chen Eden , Kleinman Timna , Bleistein Noa , Sheinbach Efrat , Groysman Maya , Nir Yuval , Citri Ami
Published: June 2021

Engagement is a major determinant of performance. Hyper-engagement risks impulsivity and is fatiguing over time, while hypo-engagement could lead to missed opportunities. Even in sleep, when engagement levels are minimal, sensory responsiveness varies. Thus, maintaining an optimal engagement level with the environment is a fundamental cognitive ability. The claustrum, and in particular its reciprocal connectivity with executive regions in the frontal cortex, has been associated with salience, attention and sleep. These apparently disparate roles can be consolidated within the context of engagement. Here we describe the activity of claustro-frontal circuits in a task imposing a tradeoff between response inhibition and sensory acuity (‘ENGAGE’). Recording calcium fiber photometry during >80,000 trials, we characterize claustrum recruitment during salient behavioral events, and find that a moderate level of activity in claustro-cingulate projections defines optimal engagement. Low activity of this pathway is associated with impulsive actions, while high activity is associated with behavioral lapses. Chemogenetic activation of cingulate-projecting claustrum neurons suppressed impulsive behavior and reduced the engagement of mice in the task. This relationship became even clearer upon addressing individual variability in the strategy mice employed during the ENGAGE task. Furthermore, this association of claustrum activity and engagement extends into sleep. Using simultaneous EEG and photometry recordings in the claustrum, we find that cingulate projecting claustrum neurons are most active during deep unresponsive slow-wave sleep, when mice are less prone to awakening by sensory stimuli.
Stromal cell sialylation suppresses T cells in inflammatory tumour microenvironments: A new tumour stromal cell immune checkpoint?
Authors: Egan Hannah , Treacy Oliver , Lynch Kevin , Leonard Niamh A , O’Malley Grace , De Veirman Kim , Vanderkerken Karin , Craughwell Michael , Egan Laurence J , Ritter Thomas , Hogan Aisling M , Redmond Keara , Sheehan Margaret , Canney Aoife , Hynes Sean , Kerr Emma , Dunne Philip D , O’Dwyer Michael E , Ryan Aideen E
Published: June 2021

Immunosuppressive tumour microenvironments (TME) reduce the effectiveness of immune responses in cancer. Non-haematopoietic mesenchymal stromal cells (MSC), the precursor to cancer associated fibroblasts (CAFs), dictate tumour progression by enhancing immune cell suppression. Hyper-sialylation of glycans promotes immune evasion in cancer, but the role of sialyation in stromal cell-mediated immunosuppression is unknown.

Here we study changes in sialyltransferase (ST) enzymes and associated surface expressed sialic acid in stromal cells following inflammatory and tumour secretome conditioning. We show that tumour conditioned stromal cells have increased levels of sialyltransferases, α2,3/6 linked sialic acid and siglec ligands. In tumour models of solid (colorectal cancer) and haematological (multiple myeloma) stromal rich tumours, stromal cell sialylation is associated with enhanced immunosuppression. Using datasets and patient samples, we confirm that targeting sialylation in tumour stromal cells reverses immune cell exhaustion. Targeting stromal cell sialylation may represent a novel immune checkpoint to reactivate anti-tumour immunity.
Arabidopsis stomatal polarity protein BASL mediates distinct processes before and after cell division to coordinate cell size and fate asymmetries
Authors: Gong Yan , Alassimone Julien , Muroyama Andrew , Amador Gabriel , Varnau Rachel , Liu Ao , Bergmann Dominique C.
Published: June 2021

In many land plants, asymmetric cell divisions (ACDs) create and pattern differentiated cell types on the leaf surface. In the Arabidopsis stomatal lineage, BREAKING OF ASYMMETRY IN THE STOMATAL LINEAGE (BASL) regulates multiple aspects of ACD including division plane placement and cell fate enforcement. Polarized subcellular localization of BASL is initiated before the ACD and persists for many hours after the division in one of the two daughters. Untangling the respective contributions of polarized BASL before and after division is essential to gain a better understanding of its roles in regulating stomatal lineage ACDs and to uncover the rules that guide leaf pattern. Here we combine quantitative imaging and lineage tracking with genetic tools that provide temporally-restricted BASL expression. We find that pre-division BASL is required for division orientation, whereas BASL polarity post-division ensures proper cell fate commitment. These genetic manipulations allowed us to uncouple daughter-cell size asymmetry from polarity crescent inheritance, revealing independent effects of these two asymmetries on subsequent cell behavior. Finally, we show that there is coordination between the division frequencies of sister cells produced by ACDs, and this coupling requires BASL as an effector of peptide signaling.
Exploration of molecular mechanism underlying the self-flocculation of Zymomonas mobilis through comparative omics analyses and experimental validations for developing robust production systems
Authors: Cao Lian-Ying , Yang Yongfu , Liu Chen-Guang , Chen Yunhao , Zhang Xue , Wang Xia , Xia Juan , Yang Shihui , Bai Feng-Wu
Published: June 2021

Zymomonas mobilis metabolizes sugar through the Entner-Doudoroff pathway with less ATP generated for lower biomass accumulation and more substrate to product formation with improved yield, since ATP is dissipated predominately through growth for intracellular energy homeostasis, making it a platform to be engineered as microbial cell factories, particularly for producing bulk commodities with major cost from feedstock consumption. ZM401, a self-flocculating mutant, presents advantages for production including cost-effective biomass recovery through gravity sedimentation, self-immobilization within bioreactors for high cell density to improve productivity and enhanced tolerance to environmental stresses for high product titers, but molecular mechanism underlying this phenotype is largely unknown. In this work, we sequenced and assembled the genome of ZM401 to explore genetic basis for the self-flocculation of the bacterial cells through comparative genomic and transcriptomic analyses, molecular docking simulations for enzymes encoded by functional genes and their substrates/activators, and experimental validations. Our results demonstrated that the single nucleotide deletion in ZMO1082 disrupted its stop codon for the putative gene being fused with ZMO1083, which created an exciting gene encoding the subunit A of the bacterial cellulose synthase with unique function for synthesizing cellulose microfibrils to flocculate the bacterial cells, and the single nucleotide mutation in ZMO1055 compromised the function of bifunctional diguanylate cyclase/phosphodiesterase encoded by the gene on the degradation of c-di-GMP for its intracellular accumulation to activate the cellulose biosynthesis. These discoveries are significant not only for optimizing the self-flocculation of Z. mobilis, but also engineering other bacteria with the self-flocculating phenotype for robust production.
Genomic islands targeting dusA in Vibrio species are distantly related to Salmonella Genomic Island 1 and mobilizable by IncC conjugative plasmids
Authors: Durand Romain , Deschênes Florence , Burrus Vincent
Published: June 2021

Salmonella Genomic Island 1 (SGI1) and its variants are significant contributors to the spread of antibiotic resistance among Gammaproteobacteria. All known SGI1 variants integrate at the 3’ end of trmE, a gene coding for a tRNA modification enzyme. SGI1 variants are mobilized specifically by conjugative plasmids of the incompatibility groups A and C (IncA and IncC). Using a comparative genomics approach based on genes conserved among members of the SGI1 group, we identified diverse integrative elements distantly related to SGI1 in several species of Vibrio, Aeromonas, Salmonella, Pokkaliibacter, and Escherichia. Unlike SGI1, these elements target two alternative chromosomal loci, the 5’ end of dusA and the 3’ end of yicC. Although they share many features with SGI1, they lack antibiotic resistance genes and carry alternative integration/excision modules. Functional characterization of IMEVchUSA3, a dusA-specific integrative element, revealed promoters that respond to AcaCD, the master activator of IncC plasmid transfer genes. Quantitative PCR and mating assays confirmed that IMEVchUSA3 excises from the chromosome and is mobilized by an IncC helper plasmid from Vibrio cholerae to Escherichia coli. IMEVchUSA3 encodes the AcaC homolog SgaC that associates with AcaD to form a hybrid activator complex AcaD/SgaC essential for its excision and mobilization. We identified the dusA-specific recombination directionality factor RdfN required for the integrase-mediated excision of dusA-specific elements from the chromosome. Like xis in SGI1, rdfN is under the control of an AcaCD-responsive promoter. Although the integration of IMEVchUSA3 disrupts dusA, it provides a new promoter sequence and restores the reading frame of dusA for proper expression of the tRNA-dihydrouridine synthase A. Phylogenetic analysis of the conserved proteins encoded by SGI1-like elements targeting dusA, yicC, and trmE gives a fresh perspective on the possible origin of SGI1 and its variants.

Author summary

We identified integrative elements distantly related to the Salmonella Genomic Island 1 (SGI1), a key vector of antibiotic resistance genes in Gammaproteobacteria. SGI1 and its variants reside at the 3’ end of trmE, share a large, highly conserved core of genes, and carry a complex integron that confers multidrug resistance phenotypes to their hosts. Unlike members of the SGI1 group, these novel genomic islands target the 5’ end dusA or the 3’ end of yicC, lack multidrug resistance genes, and seem much more diverse. We showed here that, like SGI1, these elements are mobilized by conjugative plasmids of the IncC group. Based on comparative genomics and functional analyses, we propose a hypothetical model of the evolution of SGI1 and its siblings from the progenitor of IncA and IncC conjugative plasmids via an intermediate dusA-specific integrative element through gene losses and gain of alternative integration/excision modules.
GOLPH3 and GOLPH3L are broad-spectrum COPI adaptors for sorting into intra-Golgi transport vesicles
Authors: Welch Lawrence G. , Peak-Chew Sew-Yeu , Begum Farida , Stevens Tim J. , Munro Sean
Published: June 2021

Glycosylation is a diverse and abundant modification of proteins, lipids and RNA. The fidelity of glycosylation is, in part, assured by the correct compartmentalisation of Golgi-resident glycosylation enzymes within the Golgi stack. The COPI adaptor GOLPH3 has been shown to interact with the cytoplasmic tails of a subset of Golgi enzymes and direct their retention in the Golgi. However, other mechanisms of retention, and other roles for GOLPH3, have been proposed, and a comprehensive characterisation of the clientele of GOLPH3 and its paralogue GOLPH3L has been lacking. The role of GOLPH3 is of particular interest as it is frequently amplified in several solid tumour types. Here, we combine two orthogonal proteomic analyses to identify a diverse range of GOLPH3+3L clients and find that they act in a wide spectrum of glycosylation pathways, or have other roles in the Golgi. Using binding studies, bioinformatics and an in vivo Golgi retention assay, we show that GOLPH3+3L interact with the cytoplasmic tails of their clients through membrane-proximal positively-charged residues. Furthermore, deletion of GOLPH3+3L causes diverse defects in glycosylation. Thus, GOLPH3+3L are major COPI adaptors that impinge on most, if not all, of the glycosylation pathways of the Golgi.
Social experience and pheromone receptor activity reprogram behavioral switch and neuromodulatory gene expression in sensory neurons
Authors: Deanhardt Bryson , Duan Qichen , Du Chengcheng , Soeder Charles , Morlote Alec , Garg Deeya , Jones Corbin D. , Volkan Pelin Cayirlioglu
Published: June 2021

Social experience and pheromone signaling in olfactory neurons affect neuronal responses and male courtship behaviors in Drosophila. We previously showed that social experience and pheromone signaling modulate chromatin around behavioral switch gene fruitless, which encodes a transcription factor necessary and sufficient for male behaviors. Fruitless drives social experience dependent modulation of courtship behaviors and pheromone responses in sensory neurons, however, the molecular mechanisms underlying this neuromodulation remain less clear. To identify the molecular mechanisms driving social experience-dependent neuromodulation, we performed RNA-seq from antennal samples of mutants in pheromone receptors and fruitless, as well as grouped or isolated wild-type males. We found that loss of pheromone detection differentially alters the levels of fruitless exons suggesting changes in splicing patterns. In addition, many Fruitless target neuromodulatory genes, such as neurotransmitter receptors, ion channels, ion and membrane transporters, and odorant binding proteins are differentially regulated by social context and pheromone signaling. Recent studies showed that social experience and juvenile hormone signaling coregulate fru chromatin to modify pheromone responses in olfactory neurons. Interestingly, genes involved in juvenile hormone metabolism are also misregulated in different social contexts and mutant backgrounds. Our results suggest that modulation of neuronal activity and behaviors in response to social experience and pheromone signaling likely arise due to large-scale changes in transcriptional programs for neuromodulators downstream of behavioral switch gene function.