bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of ERK-1 and ERK-2 gene polymorphisms in PCOS pathogenesis
Authors: Guney Gurhan , Taşkın Mine Islimye , Sener Nazli , Tolu Ezgi , Dodurga Yavuz , Elmas Levent , Cetin Orkun , Sarigul Cengiz
Published: June 2022

Background

Ovulation is regulated by extracellular signal-regulated kinase-1 (ERK-1) and ERK-2 signaling mechanisms, and ERK-1/2 kinases modulates the function of most of the LH-regulated genes. Defective ERK kinase signaling that is secondary to a genetic problem contributes to both ovulatory dysfunction and metabolic problems in polycystic ovary syndrome (PCOS). We planned to investigate ERK-1 and ERK-2 gene polymorphisms in PCOS for the first time in the Turkish population.

Methods

One hundred two PCOS patients and 102 healthy controls were recruited for this patient control study. HOMA-IR, Ferriman-Gallwey score (FGS), waist-to-hip ratio (WHR), and body mass index (BMI) were assessed. Lipid profile levels, CRP, and total testosterone were determined. ERK-2 rs2276008 (G > C) and ERK-1 rs11865228 (G > A) SNPs were analyzed with a real-time PCR system.

Results

ERK-1 and ERK-2 genotypes were found to differ between the PCOS and control groups. In patients with PCOS, ERK-1 GA and ERK-2 GC genotypes were different in terms of BMI, FGS, HOMA-IR, CRP, total testosterone, and total cholesterol levels.

Conclusions

ERK-1 and ERK-2 genes are involved in PCOS pathogenesis. BMI, FGS, HOMA-IR, and CRP levels are related to the heterozygote polymorphic types of ERK-1 and ERK-2 genes.
Transient post-operative overexpression of CXCR2 on monocytes of traumatic brain injury patients drives monocyte chemotaxis toward cerebrospinal fluid and enhances monocyte-mediated immunogenic cell death of neurons in vitro
Authors: Wang Huayang , Huang Qibing , Zhang Zhijie , Ji Jian , Sun Tao , Wang Donghai
Published: June 2022

Background

After traumatic brain injury (TBI), peripheral monocytes infiltrate into the central nervous system due to disruption of the blood–brain barrier, and play an important role in neuroinflammation. However, the mechanisms regulating the movement and function of peripheral monocytes after TBI have not been fully investigated.

Methods

TBI patients who underwent surgery at our hospital were recruited. CXCR2 expression in CD14+monocytes from peripheral blood and cerebrospinal fluid (CSF) of TBI patients around surgery was analyzed by flow cytometry and compared with that of patients who suffered TBI 2–24 months prior and underwent cranioplasty. In vitro, serum or CSF from TBI/non-TBI patients were used to treat peripheral monocytes isolated from healthy volunteers to evaluate their effect on CXCR2 expression. Transwell experiments were performed to analyze the role of CXCR2 in monocyte chemotaxis toward the CSF. The role of CXCR2 in monocyte-mediated immunogenic cell death (ICD) of nerve cells was explored in an indirect co-culture system.

Results

Transient CXCR2 upregulation in monocytes from the peripheral blood and CSF of TBI patients was detected soon after surgery and was associated with unfavorable outcomes. TBI serum and CSF promoted CXCR2 expression in monocytes, and dexamethasone reversed this effect. Peripheral monocytes from TBI patients showed enhanced chemotaxis toward the CSF and increased inflammatory cytokine secretion. The CXCR2 antagonist SB225002 decreased monocyte chemotaxis toward TBI CSF, and lowered pro-inflammatory cytokine secretion in monocytes treated with TBI serum. SB225002 also relieved ICD in nerve cells co-cultured with TBI serum-treated monocytes.

Conclusions

CXCR2 is transiently overexpressed in the peripheral monocytes of TBI patients post-surgery, and drives peripheral monocyte chemotaxis toward CSF and monocyte-mediated ICD of nerve cells. Therefore, CXCR2 may be a target for monocyte-based therapies for TBI.
“Is the health system ready?” A qualitative exploration of stakeholders’ opinions about the feasibility of preconception care services in the Nigerian health system
Authors: Ojifinni Oludoyinmola O. , Ibisomi Latifat
Published: June 2022

Background

Preconception care (PCC) services aim to improve reproductive health outcomes through the provision of biomedical, behavioural and social health interventions to women and couples before conception occurs. Countries that have deployed PCC services have policies that guide the services provided. In Nigeria, PCC is poorly developed and is often provided in an opportunistic manner with no guidelines in place to direct the provision. This study explored the opinions of policymakers and health workers about the feasibility of deploying PCC services in the country.

Methods

This study was a qualitative exploration of opinions about PCC service deployment within the Nigerian health system in which 39 in-depth interviews were conducted with policymakers at the federal and state tiers of government as well as health workers at the tertiary, secondary and primary levels of health care. The transcripts were analysed thematically using a hybrid of deductive and inductive coding on MAXQDA 2018 qualitative data analysis software.

Results

Four main themes emerged from the data—issues around policy for PCC, service integration and collaboration, health system readiness and challenges to PCC service deployment. While noting that the country has no PCC policy, participants identified existing policies into which PCC can be integrated. The participants also described the importance of policy to PCC provision and provided information on existing collaborations that can help the policy development and implementation process. Although many of the participants believed the health system is prepared for PCC deployment, they identified challenges related to policy formulation and implementation, including financial challenges that could hinder the process.

Conclusion

Deployment of PCC services in the Nigerian health system is achievable as there are existing health-related policies into which the guidelines can be integrated. However, there is a need to consider the possible implementation challenges and address them as part of the planning process.
Association of pre-pregnancy body mass index and gestational weight gain with neonatal anogenital distance in a Chinese birth cohort
Authors: Wang Zhiyang , Niu Jinbo , Ji Honglei , Miao Maohua , Yang Limei , Chen Xia , Li Xiufeng , Song Xiuxia , Chen Aimin , Liang Hong , Yuan Wei
Published: June 2022

Background

This study aimed to investigate the associations of pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with anogenital distance (AGD) among newborns.

Methods

The study included 556 mother-newborn pairs from the Jiashan birth cohort. AGD was measured as AGDAP (from the center of the anus to the anterior base of the penis, where the penile tissue meets the pubic bone) and AGDAS (from the center of the anus to the posterior base of the scrotum, where the skin changes from rugate to smooth) in males and AGDAC (from the center of the anus to the clitoris) and AGDAF (from the center of the anus to the posterior convergence of the fourchette) in females. Multiple linear regression models were used to estimate the associations of pre-pregnancy BMI and GWG, with AGD.

Results

After adjusting for pre-pregnancy BMI and other potential confounders, male newborns whose mothers had excessive GWG had shorter AGDAP than those whose mothers had normal GWG. Male newborns whose mothers had normal pre-pregnancy BMI and inadequate/excessive GWG had shorter AGDAP than the reference group where mothers had normal pre-pregnancy BMI and GWG in stratified analyses.

Conclusion

Gestational weight gain during pregnancy was associated with AGD in newborns in this birth cohort.
Acetazolamide modulates intracranial pressure directly by its action on the cerebrospinal fluid secretion apparatus
Authors: Barbuskaite Dagne , Oernbo Eva K. , Wardman Jonathan H. , Toft-Bertelsen Trine L. , Conti Eller , Andreassen Søren N. , Gerkau Niklas J. , Rose Christine R. , MacAulay Nanna
Published: June 2022

Background

Elevated intracranial pressure (ICP) is observed in many neurological pathologies, e.g. hydrocephalus and stroke. This condition is routinely relieved with neurosurgical approaches, since effective and targeted pharmacological tools are still lacking. The carbonic anhydrase inhibitor, acetazolamide (AZE), may be employed to treat elevated ICP. However, its effectiveness is questioned, its location of action unresolved, and its tolerability low. Here, we determined the efficacy and mode of action of AZE in the rat .

Methods

We employed in vivo approaches including ICP and cerebrospinal fluid secretion measurements in anaesthetized rats and telemetric monitoring of ICP and blood pressure in awake rats in combination with ex vivo choroidal radioisotope flux assays and transcriptomic analysis.

Results

AZE effectively reduced the ICP, irrespective of the mode of drug administration and level of anaesthesia. The effect appeared to occur via a direct action on the choroid plexus and an associated decrease in cerebrospinal fluid secretion, and not indirectly via the systemic action of AZE on renal and vascular processes. Upon a single administration, the reduced ICP endured for approximately 10 h post-AZE delivery with no long-term changes of brain water content or choroidal transporter expression. However, a persistent reduction of ICP was secured with repeated AZE administrations throughout the day.

Conclusions

AZE lowers ICP directly via its ability to reduce the choroid plexus CSF secretion, irrespective of mode of drug administration.
Primary cold atmospheric plasma combined with low dose cisplatin as a possible adjuvant combination therapy for HNSCC cells—an in-vitro study
Authors: Brunner Teresa F. , Probst Florian A. , Troeltzsch Matthias , Schwenk-Zieger Sabina , Zimmermann Julia L. , Morfill Gregor , Becker Sven , Harréus Ulrich , Welz Christian
Published: June 2022

Background

The aim of the present study was to examine the cytostatic effects of cold atmospheric plasma (CAP) on different head and neck squamous carcinoma (HNSCC) cell lines either in isolation or in combination with low dose cisplatin. The effect of CAP treatment was investigated by using three different HNSCC cell lines (chemo-resistant Cal 27, chemo-sensitive FaDu and OSC 19).

Materials and method

Cell lines were exposed to CAP treatment for 30, 60, 90, 120 and 180 s (s). Cisplatin was added concurrently (cc) or 24 h after CAP application (cs). Cell viability, DNA damage and apoptosis was evaluated by dye exclusion, MTT, alkaline microgel electrophoresis assay and Annexin V-Fit-C/PI respectively.

Results

In all cell lines, 120 s of CAP exposure resulted in a significant reduction of cell viability. DNA damage significantly increased after 60 s. Combined treatment of cells with CAP and low dose cisplatin showed additive effects. A possible sensitivity to cisplatin could be restored in Cal 27 cells by CAP application.

Conclusion

CAP shows strong cytostatic effects in HNSCC cell lines that can be increased by concurrent cisplatin treatment, suggesting that CAP may enhance the therapeutic efficacy of low dose cisplatin.
Bookend: precise transcript reconstruction with end-guided assembly
Authors: Schon Michael A. , Lutzmayer Stefan , Hofmann Falko , Nodine Michael D.
Published: June 2022

We developed Bookend, a package for transcript assembly that incorporates data from different RNA-seq techniques, with a focus on identifying and utilizing RNA 5′ and 3′ ends. We demonstrate that correct identification of transcript start and end sites is essential for precise full-length transcript assembly. Utilization of end-labeled reads present in full-length single-cell RNA-seq datasets dramatically improves the precision of transcript assembly in single cells. Finally, we show that hybrid assembly across short-read, long-read, and end-capture RNA-seq datasets from Arabidopsis thaliana, as well as meta-assembly of RNA-seq from single mouse embryonic stem cells, can produce reference-quality end-to-end transcript annotations.
Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome
Authors: Kalinowska Magdalena , van der Lei Mathijs B. , Kitiashvili Michael , Mamcarz Maggie , Oliveira Mauricio M. , Longo Francesco , Klann Eric
Published: June 2022

Background

Fragile X syndrome (FXS), the most common genetic cause of autism spectrum disorder and intellectual disability, is caused by the lack of fragile X mental retardation protein (FMRP) expression. FMRP is an mRNA binding protein with functions in mRNA transport, localization, and translational control. In Fmr1 knockout mice, dysregulated translation has been linked to pathophysiology, including abnormal synaptic function and dendritic morphology, and autistic-like behavioral phenotypes. The role of FMRP in morphology and function of excitatory neurons has been well studied in mice lacking Fmr1, but the impact of Fmr1 deletion on inhibitory neurons remains less characterized. Moreover, the contribution of FMRP in different cell types to FXS pathophysiology is not well defined. We sought to characterize whether FMRP loss in parvalbumin or somatostatin-expressing neurons results in FXS-like deficits in mice.

Methods

We used Cre-lox recombinase technology to generate two lines of conditional knockout mice lacking FMRP in either parvalbumin or somatostatin-expressing cells and carried out a battery of behavioral tests to assess motor function, anxiety, repetitive, stereotypic, social behaviors, and learning and memory. In addition, we used fluorescent non-canonical amino acid tagging along with immunostaining to determine whether de novo protein synthesis is dysregulated in parvalbumin or somatostatin-expressing neurons.

Results

De novo protein synthesis was elevated in hippocampal parvalbumin and somatostatin-expressing inhibitory neurons in Fmr1 knockout mice. Cell type-specific deletion of Fmr1 in parvalbumin-expressing neurons resulted in anxiety-like behavior, impaired social behavior, and dysregulated de novo protein synthesis. In contrast, deletion of Fmr1 in somatostatin-expressing neurons did not result in behavioral abnormalities and did not significantly impact de novo protein synthesis. This is the first report of how loss of FMRP in two specific subtypes of inhibitory neurons is associated with distinct FXS-like abnormalities.

Limitations

The mouse models we generated are limited by whole body knockout of FMRP in parvalbumin or somatostatin-expressing cells and further studies are needed to establish a causal relationship between cellular deficits and FXS-like behaviors.

Conclusions

Our findings indicate a cell type-specific role for FMRP in parvalbumin-expressing neurons in regulating distinct behavioral features associated with FXS.
Outer trench slope extension to frontal wedge compression in a subducting plate
Authors: Chang Emmy T. , Mozziconacci Laetitia
Published: June 2022

The occurrence of faulting in subducting plates is a major process that changes the mechanical properties of the subducting lithosphere and carries surface materials into mantle wedges. Two ocean-bottom seismometer networks deployed on the frontal accretionary wedge of the northern Manila trench in 2005 and on the outer slope of the trench in 2006 were used to detect earthquakes in the subducting plate. All available P and S manually picked phases and the waveforms of 16 short-period, three-component stations were used. Relocation was performed using the double-difference method with differential times derived from the phase-picked data. Two intraplate earthquake sequences of small-to-moderate magnitudes in the northern Manila subduction system were investigated in this study. The results revealed distinct fault planes, but a contrasting seismogeny over the northern Manila Trench. The seismicity in the frontal wedge (as measured in 2005) was mainly contributed by a fluid overpressure sequence, whereas that in the incoming plate (as measured in 2006) was contributed by the aftershocks of an extensional faulting sequence. The obtained seismic velocity models and Vp/Vs ratios revealed that the overpressure was likely caused by high pore-fluid pressure within the shallow subduction zone. By using the near-field waveform inversion algorithm, we determined focal mechanism solutions for a few relatively large earthquakes. Through the use of data obtained from global seismic observations, we determined that stress transfer may be responsible for the seismic activity in the study area during the period of 2005–2006. In late 2005, the plate interface in the frontal wedge area was unlocked by the overpressure effect due to a thrusting-dominant sequence. This event changed the stress regime across the Manila Trench and triggered a normal fault extension at the outer trench slope in mid-2006. However, in the present study, a hybrid focal mechanism solution indicating reverse and strike–slip mechanisms was implemented, and it revealed that the plate interface locked again in late 2006.

Graphical Abstract
Association of ABO blood groups and ART outcomes among subfertile South Asian women: a retrospective cohort study
Authors: Jayakumar Nithya Panapakkam , Reka Karuppusami , Parimala Chinta , Kunjummen Aleyamma Thayparmbil , Kamath Mohan Shashikant
Published: June 2022

Background

Blood groups are expressed on the surface of the red cells, and their association with the ovarian reserve and pregnancy outcomes has been an area of interest. The aim of the current study is to study the association of blood groups with live birth rates among South Asian women undergoing assisted reproductive technology treatment. It is a retrospective cohort analysis of women undergoing assisted reproductive technology (ART) at Christian Medical College and Hospital, India, between January 2007 and June 2017. All women ≤ 40 years undergoing the first ART cycle with fresh embryo transfer were included and stratified into four groups (A, B, AB, and O) based on the blood group type. The ART outcomes were analyzed among the groups.

Results

A total of 2524 women underwent fresh embryo transfer cycles during the study period, among whom 2079 women were analyzed. There was no statistically significant difference in the live birth rates for women with blood group B (odds ratio, OR 0.96, confidence interval, CI, 95% 0.74–1.24), blood group AB (OR 0.89, 95% CI 0.58–1.35), and blood group O (OR 0.87, 95% CI 0.68–1.12) with blood group A as the reference. After adjusting for important confounders, there was no statistically significant difference in the live birth rates for women with blood group B, AB, and O in comparison with blood group A.

Conclusion

The current study showed no association of blood groups with the ART treatment outcomes in South Asian women.
Camrelizumab in combination with concurrent chemoradiotherapy as first-line treatment for nonoperative head and neck cancer: A comparative study.
Authors: Liu Feng , Huang Wenxiao , Wang Hui , Jiang Cuihong , Zhang Hailin , Wu Xiangwei , Tan Haolei , Li Jinyun , Tan Pingqing , He Lili , Xiao Shuai
Published: June 2022

6063

Background: We hypothesized that concurrent chemoradiotherapy (CCRT) plus concurrent and adjuvant camrelizumab as first-line treatmentwas associated with improved survival compared with concurrent chemoradiotherapy alone for nonoperative locoregionally advanced head and neck squamous cell carcinoma (HNSCC). The purpose of this comparative study was to compare the efficacy and toxicity of CCRT plus concurrent and adjuvant camrelizumab versus CCRT alone in nonoperative locoregionally advanced HNSCC. Methods: One hundred and eighty patients with nonoperative locoregionally advanced HNSCC (cancer of the oral cavity, oropharyngeal cancer, hypopharyngeal cancer and laryngeal cancer) received either CCRT plus concurrent and adjuvant camrelizumab (camrelizumab + CCRT group, n = 90) or CCRT alone (CCRT alone group, n = 90). Patients in both groups received curative cisplatin-based concurrent chemoradiotherapy. The radiation dose was 70 Gy (2.0 Gy/fraction). In camrelizumab + CCRT group, concurrent camrelizumab (200mg/day on days 1, 22, 43) was added to CCRT, followed by adjuvant camrelizumab (200mg, every 3 weeks for 6 months or until disease progression, unacceptable adverse events or withdrawal of consent). Results: Compared with CCRT alone, the addition of concurrent and adjuvant camrelizumab significantly improved complete response (CR) rates (92.2% vs. 80.0%; P = 0.018), 3-year disease free survival (DFS, 72.2% vs. 56.7%; P = 0.029), locoregional recurrence-free survival (LRRFS, 76.7% vs. 61.1%; P = 0.024), and overall survival (OS, 78.9% vs. 63.3%; P = 0.033). Reactive cutaneous capillary endothelial proliferation was higher in the camrelizumab + CCRT group (6.7% vs. 0.0%; P = 0.013). No statistically significant differences in other acute (mucositis, leukopenia, thrombocytopenia, anemia, etc.) and late toxic effects (mucosal necrosis, trismus, cranial nerve palsy, etc.) were observed between the two groups. The addition of camrelizumab (CCRT plus camrelizumab vs. CCRT alone) was a significant independent prognostic factor for 3-year DFS, LRRFS and OS (P = 0.038, P = 0.032, and P = 0.048, respectively). Conclusions: Concurrent chemoradiotherapy plus concurrent and adjuvant camrelizumab as first-line treatment is associated with a considerable survival benefit, with acceptable adverse events, as compared with concurrent chemoradiotherapy alone, among patients with nonoperative locoregionally advanced head and neck squamous cell carcinoma. Our ongoing prospective clinical trial (registered with chictr.org.cn, number ChiCTR2200056298) will further investigate the efficacy of camrelizumab in combination with chemoradiotherapy for HNSCC.
Transoral robotic surgery (TORS)-guided radiotherapy (RT) volume de-intensification in p16-positive unknown primary squamous cell carcinoma (SCC) of the neck: A phase 2 trial (FIND).
Authors: de Almeida John R , Goldstein David Paul , Martino Rosemary , Su Jie , Hosni Ali , Bratman Scott Victor , Chepeha Douglas Brian , Waldron John , Weinreb Ilan , Perez-Ordonez Bayardo , Yu Eugene , Metser Ur , Hansen Aaron Richard , Xu Wei , Kim John
Published: June 2022

6067

Background: TORS has improved the likelihood of identifying an oropharyngeal cancer for patients presenting with unknown primary. We evaluate the oncologic and functional outcomes after reduction of RT volumes based on TORS findings. Methods: Patients with p16-positive, neck SCC (cN1-N3) with no primary on examination and CT/MRI were included between 08/2017 and 12/2019. All patients underwent PET-CT, surgical evaluation with either therapeutic intent including neck dissection for cN1 without extranodal extension (Group 1, n=9) or diagnostic intent (Group 2, n=13). Patients underwent excision of palatine tonsil (PT) followed by lingual tonsil (LT), if the PT was negative, or excision of PET-CT avid regions. Pharyngeal-sparing radiotherapy (PSRT) was given when no primary was found (pT0) and for primaries completely excised (margins >= 3mm). Unilateral neck radiotherapy (UNRT) was given for lateralized (>1 cm from midline) primaries or pT0 with unilateral disease. The primary outcome was 2-year out-of-treated volume failures (OTVF). Swallowing-related quality of life (SR-QOL) was measured using MD Anderson Dysphagia Inventory (MDADI) composite score. A sample size of 22 was required assuming OTVF cannot exceed 15% (vs. 1% historical), power of 0.8, alpha of 0.05 (one-sided), and loss to follow-up of 10%. Results: All 22 patients [median age 60 (46-68); 86% male; 86% N1, 9% N2, 5% N3] underwent surgical evaluation. PET-CT showed suspicious findings in 12 (55%) [sensitivity = 0.44, specificity = 0.29]. Excision of PT and LT were performed in 14 (64%) and 14 (64%) patients respectively; and 8 (36%) had previous PT. Oropharyngeal primaries were found in 17 patients (77%) [14 (64%) single primary, 3 (13%) two primaries]. RT volume de-intensification was achieved in 11 patients (50%) who had PSRT and 10 (45%) who had UNRT. In Group 1, adjuvant RT was given to 6 (67%) and CRT to 1 (11%). In group 2, 8 (62%) had RT and 5 (38%) had CRT. There were no OTVF, local, or regional failures [median follow-up 29 months]. Two-year OS, DFS, and LRC were 100%, 95%, and 100%. SR-QOL showed good recovery (Table). Grade III/IV surgical as well as acute and late toxicities occurred in 2 (9%), 5 (23%), and 1 (5%) respectively. Conclusions: TORS evaluation for p16-positive unknown primary SCC allowed RT volume de-intensification with excellent disease control and quality of life. Future randomized trials can compare transoral surgery versus existing diagnostic approaches. MDADI composite scores. Clinical trial information: NCT03281499. [Table: see text]
Cabozantinib (C) versus placebo (P) in patients (pts) with radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy: Outcomes in prespecified subgroups based on prior VEGFR-targeted therapy.
Authors: Hernando Jorge , Capdevila Jaume , Robinson Bruce , Sherman Steven I. , Jarząb Barbara , Lin Chia-Chi , Vaisman Fernanda , Hoff Ana , Hitre Erika , Bowles Daniel W. , Sen Suvajit , Oliver Jennifer Wright , Keam Bhumsuk , Brose Marcia S.
Published: June 2022

6083

Background: Based on the results of the phase 3 COSMIC-311 trial, the multikinase inhibitor C was recently approved by the FDA for the treatment of RAIR DTC pts who progress after prior VEGFR-targeted therapies, such as lenvatinib (L) or sorafenib (S), and for whom there was no standard of care (Brose et al. Lancet Oncol. 2021). In an extended follow-up of the intent-to-treat (ITT) population, C-treated pts achieved a median (m) progression-free survival (PFS) of 11 months (mo) vs 1.9 mo with P (HR 0.22, 96% CI 0.15–0.32, P <.0001); here we present outcomes for prespecified subgroups who received prior L, S, or both. Methods: Pts were randomized 2:1 to C (60 mg QD) or P. P pts could cross over to open-label C upon disease progression per confirmation by blinded independent radiology committee (BIRC). The primary endpoints were PFS (ITT) and objective response rate (first 100 randomized pts), per RECIST v1.1 by BIRC. Pts must have received L or S and progressed during or after 1–2 prior VEGFR inhibitors. Results: After a median follow-up of 10.1 mo, 258 pts (170 C, 88 P) had been randomized (data cutoff 8 Feb 2021); 96 (̃37%) had received prior S (no L), 102 (̃40%) prior L (no S), and 60 (̃23%) prior S and L. Median PFS was 16.6 for C vs 3.2 mo for P in prior S (no L) (HR 0.13, 95% CI 0.06–0.26); 5.8 vs 1.9 mo in prior L (no S) (HR 0.28, 95% CI 0.16–0.48), and 7.6 vs 1.9 mo in prior S and L (HR 0.27, 95% CI 0.13–0.54). In the C arm, 21% of pts in prior S (no L), 3% in prior L (no S), and 8% in S and L subgroups had confirmed partial response, and 1 pt had a confirmed complete response in prior L (no S); there were no responses with P. Stable disease as best response was 67% for C vs 45% for P in prior S (no L), 68% vs 32% in prior L (no S), and 74% vs 38% in prior S and L. Median duration of C-exposure was 7.0 mo in prior S (no L), 5.6 mo in prior L (no S) and 5.9 mo in prior S and L. Grade 3/4 treatment-emergent adverse events (TEAE) occurred in 63% pts in prior S (no L), 57% in prior L (no S), and 69% in prior S and L. Discontinuations of C due to TEAE occurred in 16% of pts in prior S (no L), 13% in prior L (no S), and 23% in prior S and L. There were no treatment-related deaths. Conclusions: In the extended follow-up, C maintained its superior PFS vs P irrespective of prior L and/or S. AEs in each subgroup were consistent with that of the overall population. This is also the first phase 3 study demonstrating a clinical benefit with C after prior L in RAIR DTC pts. Clinical trial information: NCT03690388.
A pilot study of trametinib in combination with paclitaxel in the treatment of anaplastic thyroid cancer.
Authors: Sherman Eric Jeffrey , Michel Loren S. , Kriplani Anuja , Dunn Lara , Haque Sofia , Bang Deborah , Stein Sarah , Pfister David G. , Ho Alan Loh
Published: June 2022

6088

Background: Anaplastic Thyroid Cancer (ATC) is a rare and highly aggressive tumor with extremely poor prognosis. Outside of the recent approval of dabrafenib/trametinib for BRAF mutant tumors, there are no other standard treatment available for metastatic ATC. The majority of ATC is driven through the MAPK pathway. Data in lung cancer suggested synergy with trametinib, a MEK inhibitor, and taxanes. Methods: In this pilot study we used Trametinib (2 mg) daily with Paclitaxel (80 mg/m2) administered weekly for the first 3 weeks out the 4 week-cycle. Restaging imaging was performed every 6-8 weeks (1.5-2 cycles). Eligible patients had ATC with baseline ECOG performance status ≤ 1 and were enrolled at Memorial Sloan Kettering Cancer Center. Prior treatment allowed. Prior brain metastases were allowed if treated and stable off of steroids. Primary objective was PFS at 6 months with the target of > 2 subjects out of 12 at the time point. Results: 12 patients (6 men and 6 women) were enrolled between 11/2017 and 10/2021. Seven (58%) had prior radiation to the neck; 4 (33%) had prior treatment (not including with radiation) for ATC; 1 (8%) had prior brain metastases. Three (25%) partial responses were reported, and five (41.67%) reported stable disease. Subjects with partial responses had a BRAF V600E mutation (1), BRAF fusion gene (1), and a RAS mutation (1). Median time on treatment was 10.5 weeks (3-47+ weeks). Median overall survival was 26 weeks (3-59+). Six-month progression free survival (PFS) was achieved in 3 patient (25%), one of whom remains on study. 2 patients discontinued treatment due to unacceptable toxicity. The most frequent adverse events observed (all grades) were anemia (75%), increased AST, diarrhea and leukopenia (all 50%). Grade 3/4 AEs included neutropenia (25%), with anemia, AST increased, febrile neutropenia, and lymphopenia, all 16.67%. Grade 4 reactions included lymphopenia (n = 2) and leukopenia (n = 1). Conclusions: Our target progression-free survival (PFS) at 6 months was observed on this study. The combination of trametinib and paclitaxel should be evaluated in a larger cohort of patients in the future. Clinical trial information: NCT03085056.
Apatinib versus placebo in patients with locally advanced or metastatic, radioactive iodine-refractory, differentiated thyroid cancer: Post hoc analyses from the REALITY randomized clinical trial.
Authors: Lin Yan-Song , Qin Shukui , Li Zhiyong , Yang Hui , Fu Wei , Li Shaohua , Chen Wenxin , Gao Zairong , Miao Weibing , Xu Huiqin , Zhang Qing , Zhao Xinming , Bao Jiandong , Li Linfa , Ren Yuan , Lin Chenghe , Jing Shanghua , Ma Qingjie , Liang Jun , Chen Guang
Published: June 2022

6095

Background: In the multicenter, double-blind, randomized, phase 3 REALITY study, apatinib significantly improved clinical benefits in terms of progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) compared to placebo with a tolerable safety profile in patients with progressive locally advanced or metastatic radioactive iodine-refractory, differentiated thyroid cancer (RAIR-DTC). Here, we investigate the association between baseline characteristics and survival endpoints. Methods: Post-hoc analyses of PFS and OS were done in patients treated with apatinib according to the following subgroups: ECOG performance status (PS) (0 vs 1-2), thyroglobulin (Tg) ( < 223 vs ≥ 223 ng/mL), and tumor target lesions diameter ( < 33.2 vs ≥ 33.2 cm). Results: Among 92 patients with RAIR-DTC included in the study, 46 patients received apatinib. As of December 3, 2021, median PFS was 25.77 (95% CI 11.14-not reached [NR]) vs 11.08 months (95% CI 7.17-NR) for ECOG PS 0 / 1-2, though no statistical significance (HR 0.454, 95% CI 0.161-1.285, p = 0.1373). The median OS was significant prolonged in patients with ECOG PS of 0 compared with those ECOG 1-2 (not reached vs 29.42 months, 95% CI 18.87-NR; HR 0.199, 95% CI 0.054-0.733, p = 0.0152). In subgroups by Tg, median PFS was 25.77 (95% CI 9.11-NR) vs 11.08 (95% CI 5.65-NR) months for Tg < 223 / ≥ 223 ng/mL. A trend towards improved PFS was observed (HR 0.444, 95% CI 0.145-1.361, p = 0.1556). The median OS was significantly improved in patients with Tg < 223 in contrast to those Tg ≥ 223 ng/mL (NR vs 25.87 months, 95% CI 13.58-NR; HR 0.151, 95% CI 0.033-0.689, p = 0. 0147). The median PFS for tumor target lesions diameter < 33.2 cm was significantly improved relative to those ≥33.2 cm (25.77, 95% CI 11.14-NR vs 9.11 months, 95% CI 5.65-NR) with a significant difference (HR 0.289, 95% CI 0.097- 0.859, p = 0.0255); OS data in two subgroups were not mature (NR, 95% CI 29.42-NR vs NR, 95% CI 17.95-NR; HR 0.364, 95% CI 0.112-1.184, p = 0.0932). Conclusions: Post-hoc analysis indicated that among patients receiving apatinib, longer OS benefits were associated with better ECOG PS, lower Tg levels; longer PFS benefits were associated with smaller tumor diameter. These results suggest a better prognosis for early initiation of apatinib treatment in patients with RAIR-DTC. Clinical trial information: NCT03048877.
Photoresponse of porous silicon for potential optical sensing
Authors: Ahmed Shahzad , Khatun Sehba , Sallam Sahar , Ansari Arshiya , Ansari Zeeshan Alam , Kumar Rishi Ranjan , Hakami Jabir , Khan Afzal
Published: June 2022

In this work, porous silicon (P-Si) structures were fabricated by anodizing n-type monocrystalline Si into an ethanoic-HF solution. Anisotropic electrochemical etching with constant time and current density was carried out to fabricate pores and their average diameter was found to be

. Raman spectra exhibited widened peaks for red, blue, and green wavelengths. The widened photoluminescence (PL) spectrum was blue-shifted owing to the quantum confinement effect. The P-Si exhibited an energy gap of 1.80 eV and manifested a direct bandgap. The photoresponse of the fabricated P-Si based device was studied at different laser irradiation wavelengthsin the range of 400–1100 nm. The best photoresponse was observed for 785 nm wavelength and the corresponding sensitivity was determined to be 9.4%. Hence, the P-Si can potentially be used for visible range photodetectors.
Fibrosis Risk in Nonalcoholic Fatty Liver Disease Is Related to Chronic Kidney Disease in Older Type 2 Diabetes Patients
Authors: Sun Yifan , Hong Liang , Huang Zhe , Wang Lihong , Xiong Yanqin , Zong Shuhang , Zhang Rui , Liu Jun , Zang Shufei
Published: June 2022

Context

Nonalcoholic fatty liver disease (NAFLD) is a multisystem disease, associated with fibrosis and an increased risk of type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD).

Objective

This work aimed to investigate the association of NAFLD fibrosis with the development of CKD in aged patients with T2DM.

Methods

This cross-sectional study enrolled 13 915 participants. A further 1734 individuals who had been followed annually for 5 years comprised the retrospective cohort study. Noninvasive markers, NAFLD fibrosis score (NFS), and fibrosis index based on 4 factors (FIB-4) were applied to determine NAFLD fibrosis risk.

Results

In the cross-sectional study, there was an additive interaction for NAFLD with increased risk of fibrosis and T2DM on CKD incidence. Logistic regression demonstrated that as NAFLD fibrosis risk progressed from low to intermediate and high, there was a stepwise increase in CKD in patients with NAFLD, T2DM, and those with coexistent NAFLD and T2DM when stratified by diabetes and fibrosis stage. FIB-4 had a much higher odds ratio (OR) value than NFS for prediction of CKD incidence. In the cohort study, individuals were grouped according to FIB-4 and NFS. Cox regression analysis showed that FIB-4 intermediate risk (hazard ratio [HR] 1.268; 95% CI, 1.056-1.521) and high risk (HR 2.516; 95% CI, 1.970-3.214) were significant predictors of CKD progression. When NFS was applied, only high risk was a significant predictor.

Conclusion

NAFLD with an increased risk of fibrosis and presence of T2DM had an additive interaction on CKD incidence. Increased risk of NAFLD fibrosis was closely associated with CKD incidence and progression in aged T2DM patients. FIB-4 outperformed NFS as a noninvasive means to predict CKD development.
Vitamin D Metabolites Are Associated with Physical Performance in Young Healthy Adults
Authors: CARSWELL ALEXANDER T. , JACKSON SARAH , SWINTON PAUL , O’LEARY THOMAS J. , TANG JONATHAN C. Y. , OLIVER SAMUEL J. , SALE CRAIG , IZARD RACHEL M. , WALSH NEIL P. , FRASER WILLIAM D. , GREEVES JULIE P.
Published: June 2022

Purpose

This study aimed to determine vitamin D metabolites and vitamin D receptor (VDR) single-nucleotide polymorphism (SNP) relationships with physical performance.

Methods

In 1205 men and 322 women (94.8% White Caucasian, 22.0 ± 2.8 yr) commencing military training, we measured serum vitamin D metabolites (25-hydroxyvitamin D (25(OH)D) and 24,25-dihydroxyvitamin D (24,25(OH)2D) by high-performance liquid chromatography tandem mass spectrophotometry and 1,25-dihydroxyvitamin D (1,25(OH)2D) by immunoassay), VDR SNPs (rs2228570, rs4516035, and rs7139166 by polymerase chain reaction genotyping), and endurance performance by 2.4-km run, muscle strength by maximal dynamic lift, and muscle power by maximal vertical jump.

Results

Serum 25(OH)D was negatively associated with 2.4-km run time and positively associated with muscle power (β = −12.0 and 90.1), 1,25(OH)2D was positively associated with run time and negatively associated with strength and muscle power (β = 5.6, −1.06, and −38.4), and 24,25(OH)2D was negatively associated with run time (β = −8.9; P < 0.01), after controlling for age, sex, smoking, alcohol, physical activity, time outdoors, season, and body mass index. Vitamin D metabolites (25(OH)D, 1,25(OH)2D, and 24,25(OH)2D) together explained variances of 5.0% in run time, 0.7% in strength, and 0.9% in muscle power (ΔF P < 0.001). All performance measures were superior with low 1,25(OH)2D:24,25(OH)2D ratio (P < 0.05). VDR SNPs were not associated with physical performance (ΔFP ≥ 0.306).

Conclusions

Vitamin D metabolites accounted for a small portion of variance in physical performance. Associations between vitamin D metabolites and run time were the most consistent. VDR SNPs explained no variance in performance. Greater conversion of 25(OH)D to 24,25(OH)2D, relative to 1,25(OH)2D (i.e., low 1,25(OH)2D:24,25(OH)2D ratio), was favorable for performance, indicating 24,25(OH)2D may have a role in optimizing physical performance.
Monopsony in the US Labor Market
Authors: Yeh Chen , Macaluso Claudia , Hershbein Brad
Published: June 2022

This paper quantifies employer market power in US manufacturing and how it has changed over time. Using administrative data, we estimate plant-level markdowns—the ratio between a plant’s marginal revenue product of labor and its wage. We find most manufacturing plants operate in a monopsonistic environment, with an average markdown of 1.53, implying a worker earning only 65 cents on the marginal dollar generated. To investigate long-term trends for the entire sector, we propose a novel, theoretically grounded measure for the aggregate markdown. We find that it decreased between the late 1970s and the early 2000s, but has been sharply increasing since. (JEL J24, J31, J38, J42, L13, L60)
Treat to transmural healing: how to incorporate intestinal ultrasound into the treatment of inflammatory bowel disease
Authors: Al-Ani Aysha H. , Vaughan Rose , Christensen Britt , Bryant Robert V. , Novak Kerri L.
Published: June 2022

Intestinal ultrasound (IUS) is emerging as a key tool to achieving the therapeutic target of transmural healing in inflammatory bowel disease (IBD). IUS is a non-invasive, radiation-free, imaging modality comparable to MRI, CT and ileocolonoscopy (IC). With the appropriate training and equipment, IUS can be an easily repeatable bedside test for IBD diagnosis and disease monitoring, including treatment response. Core to successful high quality IUS employment are appropriate training and expert techniques; however, the training pathway will not be explored in this review. Given the increasing shift towards objective assessment for tight disease control, gastroenterologist-led IUS should be incorporated into the armamentarium of imaging modalities alongside radiologists, to enhance our diagnostic and monitoring toolbox. This comprehensive review aims to outline the current literature around IUS and propose the placement of IUS in a treat-to-target algorithm in IBD. Ultimately, IUS facilitates timely management decisions to optimise patient care with potential to revolutionise patient outcomes, moving towards transmural healing as the holy grail of therapy in IBD.
Brain iron accumulation on MRI revealing aceruloplasminemia: a rare cause of simultaneous brain and systemic iron overload
Authors: Touarsa Firdaous , Ali Mohamed Daoud , Onka Behyamet , Rostoum Soufiane , Ech-Cherif El Kettani Najwa , Fikri Meriem , Jiddane Mohamed
Published: June 2022

Aceruloplasminemia is a rare autosomal recessive disorder of iron accumulation in the brain. It is one of the subtypes of Neurodegeneration with brain iron accumulation and is characterized by the uniform involvement of all basal ganglia, thalami, dentate nuclei, and cortex. Aceruloplasminemia is the only known iron overload disorder in which brain and systemic iron overload are combined. Here, we present a 53-year-old female who had progressive cognitive disorders with motor deficits. MRI showed extensive and abundant iron deposited in the brain and in the liver.
Paradox of Concessions in Developing Countries
Authors: Bugarin Mauricio Soares , Ribeiro Frederico
Published: June 2022

This paper presents a game-theoretic analysis of concessions that explicitly considers both the concession auction and the subsequent operation game. The concession contract requires investment to be made, but the concessionaire may benefit from underinvesting and ex-post renegotiating with the regulator. The paper highlights the “Paradox of Concession”: the more successful the auction is, the higher is the probability of underinvestment. We propose a new mechanism, based on benefits for investment rather than punishment for underinvestment. The new mechanism: (i) is efficient; (ii) increases auction bids; (iii) eliminates the “paradox of concessions”; (iv) and can be fine-tuned to reduce the likelihood of underinvestment.
Universal Basic Income in a DevelopingEconomy with a Large Informal Sector
Authors: Rubião Otavio , Santos Cezar
Published: June 2022

We analyze the implication of a Universal Basic Income (UBI) policy introduction in a country with a large informal sector. The model features frictions in the labor market, incomplete markets, risk-averse workers, and heterogeneity in occupation and asset position. A payroll tax on formal firms finances policies to insure workers. We calibrate the model to the Brazilian economy. The introduction of a budget-neutral UBI that replaces an existing Unemployment Insurance (UI) policy reduces welfare by around 1%. However, introducing UBI together with the UI policy increases the welfare of workers by around 0.8%. Poorer households are the ones that benefit the most from the UBI. The maximum welfare gain is achieved with a combined UBI+UI policy with an ex-post payroll tax of 20%. When replacing UI, UBI cannot increase aggregate welfare for any value of the transfer.
The influence of specialization and the level of physical activism on leisure options for students of the Faculty of Physical Education and Sports
Authors: Mocanu George-Danut , Onu Ilie
Published: June 2022

Leisure activities, their dynamics in ontogenesis and the way of managing the time allocated to them are a topic that is frequently researched. Purpose: to investigate students' attitudes, aiming at aspects related to forms of leisure, depending on specialization and level of physical activism, by applying a questionnaire. Material and method: The research took place in the academic year 2019-2020, on a number of 180 students of the Faculty of Physical Education and Sports in Galați. The differences for the pairs of independent specialty variables (PES / physical education and sport and PT / physical therapy), respectively physical activity (HLPA / high level of physical activity, and LLPA / low level of physical activity were analyzed, by applying the techniques of MANOVA and ANOVA calculation. Results: Multivariate analysis indicates significant effects of the physical activity variable on the items of the questionnaire for leisure budget factors, preferred leisure activities, leisure sports activities, and for the specialty variable significant effects are determined only at leisure sports activities, so the level of physical activism will generate more differences between the opinions expressed compared to the specialization of students. Univariate test results indicate significant F values (P <0.05) for a number of items, with weaker values, dominant for PT and LLPA groups. Sports activities and socializing on the internet (defining variant of young people) are at the top, so they do not exclude each other. Conclusion: the students from the PES and HLPA groups stand out through a better organization of free time, high satisfaction of its capitalization, a greater involvement in the variants of active leisure and superior socialization, and those from the PT and LLPA groups allocate more time to watching on TV and using the internet.
Keywords: physical activism, specialization, questionnaire, active and passive leisure options, opinions
The social environment of the personality and its influence on criminal behavior
Authors: Zlokazov Kirill
Published: June 2022

The study examines influence of the social environment on offender and criminal behavior. The relevance of study of social environment for prevention of deviant and delinquent behavior are showed. The organization of social environment of individual is considered. It is shown that it consists of socio-structural, referential and interactive components.

Socio-structural relations reveal a person's positions in social groups, communities and institutions, roles and functions is performed. Referent relations act as a basis for recognition of importance of people included in social environment. Interactive relations determine the possibilities of joint activity, resources of help and support, which the participants of the social environment can present to the person. It is noted that the social environment of the individual affects the involvement in criminal activity, determining the attitude to the criminal way of life. Concepts that reveal the instrumental and value influences of those around them on the decision to commit a crime are examined. The psychological consequences of social disorganization and social categorization that predetermine a person's attitude toward the criminal social environment are described. The influence of social environment on the termination of antisocial lifestyle is explained through the creation of conditions to change the person's perceptions of himself.

The results of the study is a conceptualization of the social environment of the individual, revealing its organization in a set of socio-structural, referential and interactive aspects. The model expands the understanding of the role of other people in the regulation of criminal behavior.