bluuebunny/crossref_metadata_2025 huggingface dataset:
Blocking P2X7 by intracerebroventricular injection of P2X7-specific nanobodies reduces stroke lesions
Authors: Wilmes Maximilian , Pinto Espinoza Carolina , Ludewig Peter , Stabernack Joschi , Liesz Arthur , Nicke Annette , Gelderblom Mathias , Gerloff Christian , Falzoni Simonetta , Tolosa Eva , Di Virgilio Francesco , Rissiek Björn , Plesnilla Nikolaus , Koch-Nolte Friedrich , Magnus Tim
Published: October 2022

Background

Previous studies have demonstrated that purinergic receptors could be therapeutic targets to modulate the inflammatory response in multiple models of brain diseases. However, tools for the selective and efficient targeting of these receptors are lacking. The development of new P2X7-specific nanobodies (nbs) has enabled us to effectively block the P2X7 channel.

Methods

Temporary middle cerebral artery occlusion (tMCAO) in wild-type (wt) and P2X7 transgenic (tg) mice was used to model ischemic stroke. Adenosine triphosphate (ATP) release was assessed in transgenic ATP sensor mice. Stroke size was measured after P2X7-specific nbs were injected intravenously (iv) and intracerebroventricularly (icv) directly before tMCAO surgery. In vitro cultured microglia were used to investigate calcium influx, pore formation via 4,6-diamidino-2-phenylindole (DAPI) uptake, caspase 1 activation and interleukin (IL)-1β release after incubation with the P2X7-specific nbs.

Results

Transgenic ATP sensor mice showed an increase in ATP release in the ischemic hemisphere compared to the contralateral hemisphere or the sham-treated mice up to 24 h after stroke. P2X7-overexpressing mice had a significantly greater stroke size 24 h after tMCAO surgery. In vitro experiments with primary microglial cells demonstrated that P2X7-specific nbs could inhibit ATP-triggered calcium influx and the formation of membrane pores, as measured by Fluo4 fluorescence or DAPI uptake. In microglia, we found lower caspase 1 activity and subsequently lower IL-1β release after P2X7-specific nb treatment. The intravenous injection of P2X7-specific nbs compared to isotype controls before tMCAO surgery did not result in a smaller stroke size. As demonstrated by fluorescence-activated cell sorting (FACS), after stroke, iv injected nbs bound to brain-infiltrated macrophages but not to brain resident microglia, indicating insufficient crossing of the blood–brain barrier of the nbs. Therefore, we directly icv injected the P2X7-specific nbs or the isotype nbs. After icv injection of 30 µg of P2X7 specific nbs, P2X7 specific nbs bound sufficiently to microglia and reduced stroke size.

Conclusion

Mechanistically, we can show that there is a substantial increase of ATP locally after stroke and that blockage of the ATP receptor P2X7 by icv injected P2X7-specific nbs can reduce ischemic tissue damage.
Clinical analysis of the acromial height-measuring device combined with new-type clavicular hook plate and standard clavicular hook plate in the treatment of Neer type II distal clavicle fractures
Authors: Li Dashuang , Qiao Rui , Yang Na , Zhang Kun , Zhu Yangjun , Song Zhe
Published: October 2022

Background

Distal clavicular fracture is a shoulder joint injury that is common in clinical settings and is generally surgically treated using the clavicular hook plate technique with a confirmed curative effect. However, symptoms, such as shoulder abduction limitation, shoulder discomfort, and postoperative joint pain, may occur in some patients. To overcome these problems, after a previous study we developed an acromial height-measuring device and a new type of clavicular hook plate. This study aimed to investigate whether an acromial height-measuring device combined with an improved new-type clavicular hook plate can better reduce the incidence of complications and improve postoperative function. To provide patients with better treatment effects, an acromion gauge and clavicular hook plate are used.

Methods

A retrospective analysis was performed on 81 patients with distal clavicular fractures admitted to our hospital. They were divided into experimental and control groups according to different plates, and the Constant–Murley score, visual analogue scale score, incidence of acromion osteolysis, and incidence of subacromial impingement syndrome were compared.

Results

Compared with the standard clavicular hook plate, the acromial height-measuring device combined with the new-type clavicular hook plate in the treatment of distal clavicle fractures has a lower incidence of subacromial impingement syndrome with better postoperative functional recovery and quality of life.

Conclusions

We considered the acromial height-measuring device combined with the new clavicular hook plate to be a safe and promising alternative to distal clavicular fractures.
Lateral shift of the femoral condyle after total knee arthroplasty: simulation using 2D-templates of the medial pivot design on knee radiographs of young Japanese patients
Authors: Nakajima Arata , Sonobe Masato , Akatsu Yorikazu , Yamada Manabu , Yamamoto Keiichiro , Saito Junya , Norimoto Masaki , Koyama Keita , Taniguchi Shinji , Takahashi Hiroshi , Aoki Yasuchika , Suguro Toru , Nakagawa Koichi
Published: October 2022

Background

Total knee arthroplasty (TKA) is an established surgical treatment for advanced knee osteoarthritis by which patients can expect improvement of knee pain and function. Although many surgeons have investigated limb alignment after TKA, changes in coronal positional relation between the femur and tibia are not known well.

Methods

Radiographs of 105 knees of young Japanese patients between 20 and 49 years-old (60 men and 45 women) without osteoarthritic changes who received arthroscopic surgeries at our hospital were used in this study. Using 2D-templates of the medial pivot design (the FINE total knee), we simulated TKA on a SYNAPSE-PACS software. First, the femoral component was placed in normal knee alignment and then was merged to the medial concave of the insert where the tibial component was placed in neutral alignment. The length of the mediolateral shift of the femoral component was measured as an estimate of lateral shift of the femoral condyle, of which association with radiographic parameters including the femorotibial angle (FTA), lateral distal femoral angle (LDFA), and medial proximal tibial angle (MPTA) was analyzed. Subjects were classified into three groups according to the femoral component size that was chosen in simulation of TKA, and the lateral shift of the femoral condyle was compared between groups.

Results

The estimated mean lateral shift of the femoral condyle was 5.99 ± 1.98 mm and was greater in males than females (p < 0.05). Also, it was most highly correlated with the medial proximal tibial angle (MPTA) (r = − 0.553, p < 0.01). A group receiving larger component sizes significantly shifted more laterally compared with a group receiving smaller component sizes (p < 0.01).

Conclusions

These results suggest that the coronal positional relation between the femur and tibia is altered and subsequent ligament imbalance may occur after mechanically aligned TKA using the medial pivot design.
A functional outcome prediction model of acute traumatic spinal cord injury based on extreme gradient boost
Authors: Sizheng Zhan , Boxuan Huang , Feng Xue , Dianying Zhang
Published: October 2022

Objective

We aimed to construct a nonlinear regression model through Extreme Gradient Boost (XGBoost) to predict functional outcome 1 year after surgical decompression for patients with acute spinal cord injury (SCI) and explored the importance of predictors in predicting the functional outcome.

Methods

We prospectively enrolled 249 patients with acute SCI from 5 primary orthopedic centers from June 1, 2016, to June 1, 2020. We identified a total of 6 predictors with three aspects: (1) clinical characteristics, including age, American Spinal Injury Association (ASIA) Impairment Scale (AIS) at admission, level of injury and baseline ASIA motor score (AMS); (2) MR imaging, mainly including Brain and Spinal Injury Center (BASIC) score; (3) surgical timing, specifically comparing whether surgical decompression was received within 24 h or not. We assessed the SCIM score at 1 year after the operation as the functional outcome index. XGBoost was used to build a nonlinear regression prediction model through the method of boosting integrated learning.

Results

We successfully constructed a nonlinear regression prediction model through XGBoost and verified the credibility. There is no significant difference between actual SCIM and nonlinear prediction model (t = 0.86, P = 0.394; Mean ± SD: 3.31 ± 2.8). The nonlinear model is superior to the traditional linear model (t = 6.57, P < 0.001). AMS and age played the most important roles in constructing predictive models. There is an obvious correlation between AIS, AMS and BASIC score.

Conclusion

We verified the feasibility of using XGBoost to construct a nonlinear regression prediction model for the functional outcome of patients with acute SCI, and proved that the predictive performance of the nonlinear model is better than the traditional linear regression prediction model. Age and baseline AMS play the most important role in predicting the functional outcome. We also found a significant correlation between AIS at admission, baseline AMS and BASIC score.

Trial registration

ClinicalTrials.gov identifier: NCT03103516.
Reduced activity of parvalbumin-positive interneurons in the posterior parietal cortex causes visually dominant multisensory decisions in freely navigating mice
Authors: Choi Ilsong , Lee Seung-Hee
Published: October 2022

Multisensory integration is vital for animals to make optimal decisions in a complicated sensory environment. However, the neural mechanisms for flexible multisensory behaviors are not well understood. Here, we found that mice exhibit auditory-dominant decisions in the head-fixed and stationary state and switch to make visual-dominant decisions in the freely navigating state to resolve audiovisual conflicts. To understand the neural mechanism of the state-dependent switch in multisensory decisions, we performed in vivo calcium imaging of parvalbumin-expressing (PV+) inhibitory neurons in the posterior parietal cortex (PPC), which are known to mediate auditory dominance in the resolution of audiovisual conflicts, in mice on the treadmill. In the stationary state, the PPC PV+neurons showed similar amounts of evoked activity in responses to auditory and visual stimuli and enhanced responses to the multisensory audiovisual stimuli. Conversely, when mice were running on a treadmill, the PV+neurons lost auditory responses and did not show any multisensory enhancement in their activity. When we optogenetically activated the PPC PV+neurons in mice freely navigating the T-maze, the mice made more auditory-dominant decisions without changes in unisensory decisions. Our data demonstrate that the PPC PV+neurons lost their ability to integrate auditory information with the visual one during active navigation. This modulation of the PPC PV+neuron activity is critical for animals to make adaptive multisensory decisions according to their behavioral states.
Analysis of influencing factors of passes in the chinese super league
Authors: Zeng Yue , Zhang Hui
Published: October 2022

Background

In football matches, passing is an important means of organizing attacks, creating shots, changing tactics, and achieving tactical objectives and is a frequently used technique. The purpose of the study was to explore the relevant factors that affect passes in the Chinese Super League (CSL) in different game contexts.

Methods

A total of 1,440 matches (2,880 samples) of 24 teams participating in the CSL in the 2014–2019 seasons were selected as the research object, and a mixed linear model was constructed to analyse the influencing factors of passes.

Results

(a) The passing success rate and the total number of forward passes were greatly affected by the stage of the season; (b) except for the passing success rate in the 30 m attack area, all other pass indicators in the home matches were significantly higher than those in the away matches; (c) the number of passes in the 30 m attack area was mainly affected by the team level (table position quartile); the higher the team level, the greater the number of passes in the 30 m attack area; (d) all passing indices for the matches between the first eight and the last eight were significantly greater than the matches between the first eight; (e) the passing success rate in the 30 m attack area in winning matches was higher than that in drawn matches; (f) the number of forward passes was significantly greater in matches won by two or more goals, and the number of defender passes was significantly greater in losing matches.

Conclusion

The various passing indices of the CSL were affected by different game contexts (including season stage, venue, team level, match type and match outcome), and understanding these influencing factors of passes will help coaches and players better understand football matches.
PACADI: translation and adaptation of a Swedish-language version of the pancreatic cancer disease impact score
Authors: Andersson Thomas , Fagevik Olsén Monika , Al Nouh Micheline , Bratlie Svein Olav
Published: October 2022

Objective

The Norwegian pancreatic cancer disease impact score (PACADI) is a digitalized analogue questionnaire that assesses different disease-specific symptoms. There is a need of translations of it into other languages. Therefore, the aim of this article is to describe the translation process of a Swedish version of PACADI and present its validity to EORCT QLQ PAN26. The self-administered questionnaire PACADI was translated according to guidelines and assessed by an expert panel of health care personnel. The test of its validity was performed with the disease-specific questionnaire for EORCT QLQ PAN26. Both questionnaires were completed by 66 subjects with pancreatic cancer, either before, at discharge or three months after surgery.

Result

The results between the groups indicate that patients suffer from different symptoms at different times. The correlations between the different symptoms of the two questionnaires were fair to good. In conclusion, PACADI and QLQ PAN 26 have a good correlation and PACADI can be used in clinical practise.
Effect of internet-based counselling with a cognitive-behavioural approach on premenstrual syndrome
Authors: Borji-Navan Sanam , Mohammad-Alizadeh-Charandabi Sakineh , Esmaeilpour Khalil , Mirghafourvand Mojgan
Published: October 2022

Objectives

To assess the effect of internet-based counselling with a cognitive-behavioural approach on symptom severity of women with premenstrual syndrome (PMS) and their quality of life during the perimenstrual and late follicular phases of the menstrual cycle. Moreover, the PMS-related disability and attitude toward menstruation were investigated as secondary outcomes.

Data description

We provide data generated in a randomized controlled trial with two-parallel arms carried out on 92 female university students aged 18–35 years who had moderate to severe PMS, residing at halls of the Tabriz University of Medical Sciences. PMS severity was assessed during two menstrual cycles before intervention (baseline) and during two cycles just after ending the two-month intervention using Daily Record of Severity of Problems (DRSP) and the quality of life using the Quality of Life Enjoyment and Satisfaction Questionnaire—Short Form (Q-LES-Q-SF) on days 1–2 and 11–13 of the menstrual cycle at the baseline and post-intervention. Also, the PMS-related disability was assessed using Sheehan Disability Scale (SDS) and attitude toward menstruation using Menstrual Attitude Questionnaire (MAQ) at the baseline and post-intervention. Participant satisfaction and views on intervention effectiveness were also assessed using a single Likert question.
Diagnostic value of plasma p-tau181, NfL, and GFAP in a clinical setting cohort of prevalent neurodegenerative dementias
Authors: Baiardi Simone , Quadalti Corinne , Mammana Angela , Dellavalle Sofia , Zenesini Corrado , Sambati Luisa , Pantieri Roberta , Polischi Barbara , Romano Luciano , Suffritti Matteo , Bentivenga Giuseppe Mario , Randi Vanda , Stanzani-Maserati Michelangelo , Capellari Sabina , Parchi Piero
Published: October 2022

Background

Increasing evidence supports the use of plasma biomarkers of neurodegeneration and neuroinflammation to screen and diagnose patients with dementia. However, confirmatory studies are required to demonstrate their usefulness in the clinical setting.

Methods

We evaluated plasma and cerebrospinal fluid (CSF) samples from consecutive patients with frontotemporal dementia (FTD) (n= 59), progressive supranuclear palsy (PSP) (n= 31), corticobasal syndrome (CBS) (n= 29), dementia with Lewy bodies (DLB) (n= 49), Alzheimer disease (AD) (n= 97), and suspected non-AD physiopathology (n= 51), as well as plasma samples from 60 healthy controls (HC). We measured neurofilament light chain (NfL), phospho-tau181 (p-tau181), and glial fibrillary acid protein (GFAP) using Simoa (all plasma biomarkers and CSF GFAP), CLEIA (CSF p-tau181), and ELISA (CSF NfL) assays. Additionally, we stratified patients according to the A/T/N classification scheme and the CSF α-synuclein real-time quaking-induced conversion assay (RT-QuIC) results.

Results

We found good correlations between CSF and plasma biomarkers for NfL (rho = 0.668,p< 0.001) and p-tau181 (rho = 0.619,p< 0.001). Plasma NfL was significantly higher in disease groups than in HC and showed a greater increase in FTD than in AD [44.9 (28.1–68.6) vs. 21.9 (17.0–27.9) pg/ml,p< 0.001]. Conversely, plasma p-tau181 and GFAP levels were significantly higher in AD than in FTD [3.2 (2.4–4.3) vs. 1.1 (0.7–1.6) pg/ml,p< 0.001; 404.7 (279.7–503.0) vs. 198.2 (143.9–316.8) pg/ml,p< 0.001]. GFAP also allowed discriminating disease groups from HC. In the distinction between FTD and AD, plasma p-tau181 showed better accuracy (AUC 0.964) than NfL (AUC 0.791) and GFAP (AUC 0.818). In DLB and CBS, CSF amyloid positive (A+) subjects had higher plasma p-tau181 and GFAP levels than A− individuals. CSF RT-QuIC showed positive α-synuclein seeding activity in 96% DLB and 15% AD patients with no differences in plasma biomarker levels in those stratified by RT-QuIC result.

Conclusions

In a single-center clinical cohort, we confirm the high diagnostic value of plasma p-tau181 for distinguishing FTD from AD and plasma NfL for discriminating degenerative dementias from HC. Plasma GFAP alone differentiates AD from FTD and neurodegenerative dementias from HC but with lower accuracy than p-tau181 and NfL. In CBS and DLB, plasma p-tau181 and GFAP levels are significantly influenced by beta-amyloid pathology.
Modifiable and non-modifiable risk factors of dementia on midlife cerebral small vessel disease in cognitively healthy middle-aged adults: the PREVENT-Dementia study
Authors: Low Audrey , Prats-Sedano Maria A. , McKiernan Elizabeth , Carter Stephen F. , Stefaniak James D. , Nannoni Stefania , Su Li , Dounavi Maria-Eleni , Muniz-Terrera Graciela , Ritchie Karen , Lawlor Brian , Naci Lorina , Malhotra Paresh , Mackay Clare , Koychev Ivan , Ritchie Craig W. , Markus Hugh S. , O’Brien John T.
Published: October 2022

Background

Considerable overlap exists between the risk factors of dementia and cerebral small vessel disease (SVD). However, studies remain limited to older cohorts wherein pathologies of both dementia (e.g. amyloid) and SVD (e.g. white matter hyperintensities) already co-exist. In younger asymptomatic adults, we investigated differential associations and interactions of modifiable and non-modifiable inherited risk factors of (future) late-life dementia to (present-day) mid-life SVD.

Methods

Cognitively healthy middle-aged adults (aged 40–59; mean 51.2 years) underwent 3T MRI (n = 630) as part of the PREVENT-Dementia study. To assess SVD, we quantified white matter hyperintensities, enlarged perivascular spaces, microbleeds, lacunes, and computed composite scores of SVD burden and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). Non-modifiable (inherited) risk factors were APOE4 status and parental family history of dementia. Modifiable risk factors were derived from the 2020 Lancet Commission on dementia prevention (early/midlife: education, hypertension, obesity, alcohol, hearing impairment, head injuries). Confirmatory factor analysis (CFA) was used to evaluate the latent variables of SVD and risk factors. Structural equation modelling (SEM) of the full structural assessed associations of SVD with risk factors and APOE4*risk interaction.

Results

In SEM, the latent variable of global SVD related to the latent variable of modifiable midlife risk SVD (β = 0.80, p = .009) but not non-modifiable inherited risk factors of APOE4 or family history of dementia. Interaction analysis demonstrated that the effect of modifiable risk on SVD was amplified in APOE4 non-carriers (β = − 0.31, p = .009), rather than carriers. These associations and interaction effects were observed in relation to the SVD subtype of hypertensive arteriopathy, rather than CAA. Sensitivity analyses using separate general linear models validated SEM results.

Conclusions

Established modifiable risk factors of future (late-life) dementia related to present-day (mid-life) SVD, suggesting that early lifestyle modifications could potentially reduce rates of vascular cognitive impairment attributed to SVD, a major ‘silent’ contributor to global dementia cases. This association was amplified in APOE4 non-carriers, suggesting that lifestyle modifications could be effective even in those with genetic predisposition to dementia.
Baicalin acts as an adjuvant to potentiate the activity of azithromycin against Staphylococcus saprophyticus biofilm: an in vitro, in vivo, and molecular study
Authors: Wang Jinli , Li Siya , Meng Jinwu , Zhu Jinyue , Qiu Tianxin , Wang Wenjia , Ding Jinxue , Liu Zhenguang , Li Kun , lqbal Mujahid , Wang Deyun , Wu Yi , Liu Jiaguo
Published: October 2022

Staphylococcus saprophyticus is frequently involved in various difficult-to-treat infections due to the formation of biofilms. To identify useful antibiofilm strategies, this study explored the efficacy and mechanism of baicalin in enhancing the ability of azithromycin against multidrug-resistant Staphylococcus saprophyticus-Liu-2016-Liyang, China-francolin (MDRSS) biofilms in vitro and in vivo. When azithromycin was used in combination with baicalin, the minimum inhibitory concentration in biofilm (MICB) for azithromycin decreased 4- to 512-fold. Compared with the azithromycin and baicalin groups, the combination of azithromycin and baicalin could not reduce the biofilm biomass, but the dispersion rates of biofilm were decreased and the bactericidal ability was increased. Furthermore, the relative transcript levels of WalK/R system-related genes were upregulated by the addition of baicalin or azithromycin plus baicalin compared with that of the azithromycin and blank control groups. The strong correlation relationship between the WalK/R system and the bactericidal index demonstrated that baicalin enhanced the bactericidal effect of azithromycin on MDRSS biofilms by modulating the WalK/R system. In the mouse cutaneous infection model, the combination of azithromycin and baicalin succeeded in eradicating MDRSS and decreasing pathological injuries. This study indicated that baicalin has the potential to be an adjuvant to enhance the antimicrobial activity of azithromycin against MDRSS in the biofilm form by modulating the WalK/R system.
Chicken miR-126-5p negatively regulates antiviral innate immunity by targeting TRAF3
Authors: Wang Jie , Cheng Yuqiang , Wang Longlong , Sun Aixi , Lin Zhenyu , Zhu Wenxian , Wang Zhaofei , Ma Jingjiao , Wang Henan , Yan Yaxian , Sun Jianhe
Published: October 2022

Innate immunity plays an essential role in preventing the invasion of pathogenic microorganisms. However, innate immunity is a double-edged sword, whose excessive activation is detrimental to immune homeostasis and even leads to a “cytokine storm” of the infected host. The host develops a series of negative regulatory mechanisms to balance the immune response. Here, we report a negative regulatory mechanism of chicken innate immunity mediated by miRNA. In the GEO database, we found that miR-126-5p was markedly up-regulated in chickens infected by RNA viruses. Upregulation of miR-126-5p by RNA virus was then further shown via both a cell model and in vivo tests. Overexpression of miR-126-5p significantly inhibited the expression of interferon and inflammatory cytokine-related genes induced by RNA viruses. The opposite result was achieved after the knockdown of miR-126-5p expression. Bioinformatics analysis identified TRAF3 as candidate target gene of miR-126-5p. Experimentally, miR-126-5p can target TRAF3, as shown by the effects of miR-126-5p on the endogenous expression of TRAF3, and by the TRAF3 3'UTR driven luciferase reporter assay. Furthermore, we demonstrated that miR-126-5p negatively regulated innate immunity by blocking the MAVS-TRAF3-TBK1 axis, with a co-expression assay. Overall, our results suggest that miR-126-5p is involved in the negative regulation of chicken innate immunity, which might contribute to maintaining immune balance.
Local time and longitudinal variation of the ionospheric radial current: swarm observations and TIE–GCM simulations
Authors: Wang Hui , Xia Hao , Zhang Kedeng , Zhong Yunfang , Qian Chenyu
Published: October 2022

Based on the high-precision vector magnetic field data of Swarm A and C satellites, we perform a statistical analysis of the diurnal and longitudinal variations of the ionospheric radial current (IRC) in the F layer at the magnetic equator from 2014 to 2018. The observations are compared with the simulations based on the Thermosphere–Ionosphere Electrodynamics–General Circulation Model (TIE–GCM). It is found that the noon IRC is radially outward, whereas the dusk IRC is radially inward. The time of the change from the inward to the outward direction occurred is earlier in June than in other seasons. The TIE–GCM results show that low atmospheric tides have an important effect on the seasonal change in the reverse time. The noon IRC is weakened primarily by the polarization current from migrating tides. The dusk IRC is mainly weakened by polarization current from nonmigrating tides in the equinox and December solstice and by dynamo current from migrating tides in the June solstice. Geomagnetic field configuration is the main reason for the longitudinal variation of IRC. The noon IRC have a wave-4 zonal structure, which is mainly caused by the outward propagation of migrating and nonmigrating tides. The dusk IRC in the western hemisphere shows a larger current density than that in the eastern hemisphere, resulting mainly from the neutral wind dynamo current. The competing effect of the wind dynamo current and polarization current determined the peak location of the total current in the western hemisphere.

Graphical Abstract
Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non–Small-Cell Lung Cancer in CheckMate 227
Authors: Brahmer Julie R. , Lee Jong-Seok , Ciuleanu Tudor-Eliade , Bernabe Caro Reyes , Nishio Makoto , Urban Laszlo , Audigier-Valette Clarisse , Lupinacci Lorena , Sangha Randeep , Pluzanski Adam , Burgers Jacobus , Mahave Mauricio , Ahmed Samreen , Schoenfeld Adam J. , Paz-Ares Luis G. , Reck Martin , Borghaei Hossein , O'Byrne Kenneth J. , Gupta Ravi G. , Bushong Judith , Li Li , Blum Steven I. , Eccles Laura J. , Ramalingam Suresh S.
Published: October 2022

PURPOSE

We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non–small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status.

METHODS

Adults with stage IV/recurrent non–small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life.

RESULTS

At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed.

CONCLUSION

With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non–small-cell lung cancer.

[Media: see text]
Implications of an HbA1c-based Diabetes Screening on Prevalence and Effect of Dysglycemia in Patients With COVID-19
Authors: Van Baal Lukas , Reinold Johanna , Benson Sven , Diehl Anke , Witzke Oliver , Fuehrer Dagmar , Tan Susanne
Published: October 2022

Context

In patients with severe acute respiratory syndrome coronavirus type 2 infection, diabetes is associated with poor COVID-19 prognosis. However, case detection strategy is divergent and reported prevalence varies from 5% to 35%.

Objective

We examined how far the choice of screening tools affects the detection rate of dysglycemia and in consequence the estimation of diagnosis-associated risk for moderate (mo) or severe (s) COVID-19.

Methods

Non–intensive care unit inpatients with COVID-19 were screened systematically at admission for diabetes (D) and prediabetes (PreD) by glycated hemoglobin A1c (HbA1c) (A), random blood glucose (B), and known history (C) from November 1, 2020 to March 8, 2021. Dysglycemia rate and effect on COVID-19 outcome were analyzed in 2 screening strategies (ABC vs BC).

Results

A total of 578 of 601 (96.2%) of admitted patients were screened and analyzed. In ABC, prevalence of D and PreD was 38.2% and 37.5%, respectively. D was significantly associated with an increased risk for more severe COVID-19 (adjusted odds ratio [aOR] [moCOVID-19]: 2.27, 95% CI, 1.16-4.46 and aOR [sCOVID-19]: 3.26, 95% CI, 1.56-6.38). Patients with PreD also presented more often with more severe COVID-19 than those with normoglycemia (aOR [moCOVID-19]: 1.76, 95% CI, 1.04-2.97 and aOR [sCOVID-19]: 2.41, 95% CI, 1.37-4.23). Screening with BC failed to identify only 96% of PreD (206/217) and 26.2% of D diagnosis (58/221) and missed associations of dysglycemia and COVID-19 severity.

Conclusion

Pandemic conditions may hamper dysglycemia detection rate and in consequence the awareness of individual patient risk for COVID-19 severity. A systematic diabetes screening including HbA1c reduces underdiagnosis of previously unknown or new-onset dysglycemia, and enhances the quality of risk estimation and access of patients at risk to a diabetes-specific intervention.
Prodromal α-Synucleinopathies
Authors: Chahine Lana M.
Published: October 2022

PURPOSE OF REVIEW

This article describes prodromal α-synucleinopathies.

RECENT FINDINGS

The pathology underlying α-synucleinopathies, which include Parkinson disease, multiple system atrophy, and dementia with Lewy bodies, begins years before the presence of the full syndrome that is the basis for the clinical diagnosis of each of these disorders. This “prodromal” phase may manifest with various signs or symptoms. In addition to individuals in the prodromal phase, some individuals are asymptomatic but are at risk for α-synucleinopathies owing to genetic predisposition or other risk factors.

Clinicians are increasingly seeing patients in the clinical setting who are prodromal or at risk for α-synucleinopathies, and this article reviews the approach to these patient populations, which includes identifying clinical features, assessment, and counseling.
Progressive Supranuclear Palsy and Corticobasal Syndrome
Authors: Pantelyat Alexander
Published: October 2022

PURPOSE OF REVIEW

The differential diagnosis of parkinsonism (tremor, rigidity, bradykinesia, and gait difficulty/postural instability) is broad and includes two neurodegenerative conditions that exist on a clinicopathologic spectrum: progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). Early in their clinical course, PSP and CBS may be difficult to distinguish from Parkinson disease and several other illnesses, but it is crucial to do so because of implications for management and prognosis.

RECENT FINDINGS

Early accurate diagnosis of PSP and CBS remains a challenge because of heterogeneity in presenting symptoms and high frequency of coexisting pathologies (especially Alzheimer disease and vascular disease). It is increasingly recognized that patients with PSP, CBS, and other parkinsonian disorders require multidisciplinary care for optimal outcomes. With the recent proliferation of biomarker studies and therapeutic trials for tauopathies, there is growing hope that better treatments for PSP and CBS are on the horizon.

Although PSP and CBS currently lack disease-modifying therapies, it is important to diagnose them as early as possible so that the patient can benefit from the many available symptomatic therapies, support groups, and a growing number of clinical trials.
The Dystonias
Authors: Stephen Christopher D.
Published: October 2022

PURPOSE OF REVIEW

This article discusses the most recent findings regarding the diagnosis, classification, and management of genetic and idiopathic dystonia.

RECENT FINDINGS

A new approach to classifying dystonia has been created with the aim to increase the recognition and diagnosis of dystonia. Molecular biology and genetic studies have identified several genes and biological pathways involved in dystonia.

Dystonia is a common movement disorder involving abnormal, often twisting, postures and is a challenging condition to diagnose. The pathophysiology of dystonia involves abnormalities in brain motor networks in the context of genetic factors. Dystonia has genetic, idiopathic, and acquired forms, with a wide phenotypic spectrum, and is a common feature in complex neurologic disorders. Dystonia can be isolated or combined with another movement disorder and may be focal, segmental, multifocal, or generalized in distribution, with some forms only occurring during the performance of specific tasks (task-specific dystonia). Dystonia is classified by clinical characteristics and presumed etiology. The management of dystonia involves accurate diagnosis, followed by treatment with botulinum toxin injections, oral medications, and surgical therapies (mainly deep brain stimulation), as well as pathogenesis-directed treatments, including the prospect of disease-modifying or gene therapies.
Chorea
Authors: Stimming Erin Furr , Bega Danny
Published: October 2022

PURPOSE OF REVIEW

This article provides an overview of the diagnostic and therapeutic approach to a patient with chorea. The phenomenology of chorea is described in addition to other common hyperkinetic movements that may be mistaken for or coexist with chorea. Chorea can be acquired or hereditary. Key historical and clinical features that can aid in determining the etiology are reviewed, and pharmacologic and nonpharmacologic treatment strategies are discussed.

RECENT FINDINGS

Clinical investigations are under way to target transcription and translation of the mutant huntingtin protein as a potential disease-modifying strategy in Huntington disease (HD). Additional heritable factors have been revealed through genome-wide association studies. Symptom-focused treatments for HD are are being studied, including a third vesicular monoamine transporter-2 (VMAT2) inhibitor for chorea attenuation and drugs to target irritability and cognitive impairment. Increased availability of genetic testing has led to increased awareness of HD mimics (eg,C9orf72and IgLON5).

Chorea is a relatively common hyperkinetic disorder with a broad differential. The first step in the approach to a patient with chorea is accurately defining the phenomenology. Once it has been determined that the patient has chorea, the investigation into determining an etiology can begin. Factors such as age of onset, time course, family history, unique clinical features, and imaging and laboratory findings can guide the diagnosis. Treatments for most causes of chorea are purely symptomatic, although it is important to recognize causes that are reversible or have disease-modifying interventions.
Neurodegenerative Cerebellar Ataxia
Authors: Rosenthal Liana S.
Published: October 2022

PURPOSE OF REVIEW

Neurodegenerative cerebellar ataxia is a diverse collection of diseases that are unified by gait and balance abnormalities, appendicular incoordination, and abnormalities of eye movement and speech. The differential diagnosis is broad, ranging from paraneoplastic syndromes that progress quite rapidly to unidentified genetic disorders that progress slowly over the course of decades. This article highlights the diagnostic process, including the differential diagnosis, as well as treatment approaches and symptomatic management. The pillars of treatment are physical, occupational, and speech therapy as well as counseling and discussions of disease prognosis, genetics, and reproductive choices. There are many ways to help patients with neurodegenerative cerebellar ataxia and improve their quality of life.

RECENT FINDINGS

Recent years have seen significant improvements in genetic testing, with reductions in cost of both Sanger sequencing and whole exome sequencing and increasing availability of the latter. These improvements increase clinicians’ ability to identify the etiology of neurodegenerative cerebellar ataxia and suggest future treatments. Although no medication has been approved by the US Food and Drug Administration (FDA) for treatment of cerebellar ataxia, research and clinical trials for these diseases are increasing.

Neurodegenerative cerebellar ataxia is characterized by dysarthria, dysmetria, oculomotor abnormalities, and ataxic gait. It has a broad differential diagnosis, and numerous options exist for managing symptoms. Although no medications have been approved specifically for cerebellar ataxia, treatment options are available to improve patients’ quality of life.
The Poetics of Protest, from Africa to Minneapolis
Authors: Judy R. A.
Published: October 2022

Offering an itinerary of the thinking that led to Sentient Flesh: Thinking in Disorder, Poiēsis in Black, R. A. Judy explains the concept of “poetic socialities” mentioned in it. This explanation begins with an account of the Muslim peripatetic philosophers’ reception of Aristotle’s Poetics, focusing on ibn Sīnā’s conception of the role poetic expression’s cognitive as well as affective force plays in the instantiation of what he calls الأمة الشعرية (al-umma al-sh’irīya), “the poetic or aesthetic community.” Elaborating how and why the phrase poetic socialities is the paraphrastic translation of ibn Sīnā’s, the essay tracks the study of poetic socialites from its initial formulation regarding the 2010 Tunisian Revolution to it becoming the reference point of orientation for an interrogation of the modern concepts of sovereignty, revolution, and civic republicanism. With respect to these concepts, the study of poetic socialities enacts a critique of imperial neoliberal tendency of socialization; whereby the only tenable norm of general subjectivity is a function of speculative market value as the absolute measure not just of human progress but existence as well. Along these lines, poetic socialities is an attempt at understanding something of what is at play in te current era of popular unrest.
The role of adipose tissue in metabolic disorders and molecular pathways that affect its function
Authors: Βλιώρα Μαρία
Published: October 2022

Στόχος της παρούσας διατριβής είναι η διεύρυνση της τρέχουσας γνώσης σχετικά με το ρόλο του λιπώδους ιστού στις μεταβολικές διαταραχές και η έρευνα των μοριακών μονοπατιών που επηρεάζουν τη λειτουργία του. Υπό αυτό το πρίσμα, πραγματοποιήθηκαν δύο βιβλιογραφικές μελέτες. Αρχικά, διερευνήθηκε πώς η αλληλεπίδραση μεταξύ του λιπώδους ιστού και του αγγειακού συστήματος μπορεί να επηρεάσει την εμφάνιση και την εξέλιξη των μεταβολικών ασθενειών. Στη δεύτερη ανασκόπησή που πραγματοποιήθηκε, περιγράφονται οι αγγειογόνοι παράγοντες που επηρεάζουν το λιπώδη ιστό και οι φαρμακολογικές προσεγγίσεις που θα μπορούσαν να χρησιμοποιηθούν στη θεραπεία της παχυσαρκίας και των συνοδών νοσηροτήτων της. Επιπλέον, προτείνονται τρέχουσες προσεγγίσεις της εμβιομηχανικής που θα μπορούσαν να χρησιμοποιηθούν για την καταπολέμηση της παχυσαρκίας και των συνακόλουθων μεταβολικών ασθενειών. Αυτές οι πληροφορίες οδήγησαν στη δοκιμή των ιδιοτήτων ενός νέου, φυσικού, βιολογικού ικριώματος με βάση το Histogel που υποστηρίζει τον πολλαπλασιασμό και τη διαφοροποίηση του λευκού λίπους σε μπεζ, μια μεταβολικά πιο ενεργή εκδοχή του λίπους. Καθώς ο λιπώδης ιστός επηρεάζεται από τις κυτοκίνες άλλων ιστών, ερευνήθηκε η ιρισίνη, μια μυοκίνη, και ο ρόλος της στις μεταβολικές διαταραχές. Με βάση τη βιβλιογραφία σχετικά με το ρόλο της ιρισίνης στον καρκίνο, πραγματοποιήθηκε μια συστηματική ανασκόπηση της βιβλιογραφίας, με στόχο να διευκρινιστεί πώς η ιρισίνη εμπλέκεται στην εξέλιξη του καρκίνου και εάν μπορεί να αποτελέσει έγκυρο βιοδείκτη για τη διάγνωσή του. Τέλος, διερευνήθηκε ο ρόλος της ιρισίνης στο λιπώδη ιστό και πώς επηρεάζει τη μεταβολική του κατάσταση. Τα αποτελέσματα της παρούσας διατριβής προτείνουν ότι η επικοινωνία μεταξύ αγγειακού συστήματος και λιπώδους ιστού θα πρέπει να λαμβάνεται υπόψη, όταν χρησιμοποιούνται φαρμακολογικές προσεγγίσεις για τη θεραπεία μεταβολικών διαταραχών. Επιπλέον, προτείνεται η χρήση βιολογικών ικριωμάτων, που θα μπορούσαν να οδηγήσουν σε αύξηση του καφέ λιπώδους ιστού (αυξημένη μεταβολική δραστηριότητα) και να αποτελούν μέρος της θεραπείας της παχυσαρκίας και των συνοδών μεταβολικών διαταραχών. Φαίνεται επίσης ότι η ιρισίνη εμπλέκεται στον καρκίνο, ρυθμίζοντας τον κυτταρικό πολλαπλασιασμό και την μετάσταση των όγκων, μέσω διαφόρων σηματοδοτικών μονοπατιών και μπορεί επίσης να είναι ένας καλός βιοδείκτης για τη διάγνωση του καρκίνου. Τέλος, φαίνεται ότι η ιρισίνη μπορεί να ρυθμίσει τη λιπόλυση και τη θερμογένεση in vitro. Συνοψίζοντας, τα παραπάνω αποτελέσματά δείχνουν ότι ο λιπώδης ιστός είναι ένα εξαιρετικό μέσο για φαρμακολογικές ή βιοϊατρικές παρεμβάσεις σχετικά με τη θεραπεία των μεταβολικών διαταραχών.
Panda Games: Corporate Disclosure in the Eclipse of Search
Authors: Wang Kemin , Yu Xiaoyun , Zhang Bohui
Published: October 2022

We show that firms strategically alter their disclosures when investors’ access to information via search engines is interrupted. We conduct a textual analysis and exploit an exogenous event—Google’s 2010 surprising withdrawal from mainland China, which significantly hampered domestic investors’ ability to search for foreign information but did not affect their cost to access domestic information. Following Google’s exit, Chinese firms’ announcements on foreign transactions become more bullish relative to domestic transactions. Optimism in disclosure is especially rosy if the press releases are conveying negative news or are issued by poorly governed firms. This effect is mitigated in the presence of foreign investors or analysts affiliated with foreign brokers who are not subject to foreign information censorship by the government. The increase in search cost also appears to leave domestic news media and financial analysts more vulnerable to the influence of corporate disclosure. These optimistic announcements allow insiders to harvest higher returns from selling their shares and are associated with a higher likelihood of corporate misconduct.

This paper was accepted by Gustavo Manso, finance.

Funding: This work was supported by the National Natural Science Foundation of China [Grants 71272072 and 71572042]. X. Yu gratefully acknowledges financial support from the Arthur M. Weimer Fellowship.

Supplemental Material: The data files and online appendix are available at https://doi.org/10.1287/mnsc.2022.4521 .
Lagrangian Dual Decision Rules for Multistage Stochastic Mixed-Integer Programming
Authors: Daryalal Maryam , Bodur Merve , Luedtke James R.
Published: October 2022

On Decision Rules for Multistage Stochastic Programs with Mixed-Integer Decisions

Multistage stochastic programming is a field of stochastic optimization for addressing sequential decision-making problems defined over a stochastic process with a given probability distribution. The solution to such a problem is a decision rule (policy) that maps the history of observations to the decisions. Design of the decision rules in the presence of mixed-integer decisions is quite challenging. In “Lagrangian Dual Decision Rules for Multistage Stochastic Mixed-Integer Programming,” Daryalal, Bodur, and Luedtke introduce Lagrangian dual decision rules, where linear decision rules are applied to dual multipliers associated with Lagrangian duals of a multistage stochastic mixed-integer programming (MSMIP) model. The restricted decisions are then used in the development of new primal- and dual-bounding methods. This yields a new general-purpose approximation approach for MSMIP, free of strong assumptions made in the literature, such as stagewise independence or existence of a tractable-sized scenario-tree representation.
Association between leisure activities and sleep disturbances among children with and without cerebral palsy
Authors: Amiri Alireza , Kalantari Minoo , Gharebashloo Farzad
Published: October 2022

Background/Aims

Sleep disturbances are common among children with cerebral palsy, resulting in adverse consequences. Investigating the association between leisure activities and sleep disturbances could help to develop ways to promote their sleep quality. This study primarily aimed to investigate the association between leisure activities and sleep disturbances among children with and without cerebral palsy. The secondary aim was to study the prevalence of sleep disturbances and some of its associated factors.

Methods

A total of 75 children with cerebral palsy (study group) (mean age 10.0 ± 2.5 years) and 75 typically developing children (control group) (mean age 10.5 ± 2.9 years) were randomly selected to completed the Children's Assessment of Participation and Enjoyment. Sleep disturbances were assessed using the Sleep Disturbance Scale for Children. Factors associated with sleep disturbances (age, gender, school attendance, bedroom sharing, type of cerebral palsy, motor functions, eating and drinking ability and communication functions) were statistically analysed and the prevalence of sleep disturbances was calculated.

Results

Overall frequency of leisure participation was strongly correlated with overall sleep disturbances (P<0.001) among both groups. The prevalence of overall sleep disturbances was 17.1% and 10.6% among the study and the control groups respectively. Eating and drinking ability and spastic quadriplegia emerged as the strongest predictors of overall negative scores on the Sleep Disturbance Scale for Children.

Conclusions

Greater participation in leisure activities is associated with better sleep. Occupational therapists are encouraged to consider this association when planning for occupation-based interventions aimed at enhancing occupational performance.