bluuebunny/crossref_metadata_2025 huggingface dataset:
An Injectable Hyaluronic Acid Hydrogel Promotes Intervertebral Disc Repair in a Rabbit Model
Authors: Inoue Masahiro , Isa Isma Liza Mohd , Orita Sumihisa , Suzuki-Narita Miyako , Inage Kazuhide , Shiga Yasuhiro , Norimoto Masaki , Umimura Tomotaka , Sakai Takayuki , Eguchi Yawara , Watanabe Atsuya , Aoki Yasuchika , Pandit Abhay , Ohtori Seiji
Published: January 2021

Study Design.

An in vivo model to study the effect of an injectable hyaluronic acid (HA) hydrogel following puncture-induced lumbar disc injury in rabbits.

Objectives.

The aim of this study was to determine the efficacy of an injectable HA hydrogel to maintain disc height and tissue hydration, promote structural repair, and attenuate inflammation and innervation in the lumbar discs.

Summary of Background Data.

Previously, we have demonstrated that HA hydrogel alleviated inflammation, innervation, and pain to promote disc repair. Nevertheless, the effect of an injectable HA hydrogel in the lumbar disc in a weight-bearing animal model was not performed.

Methods.

We have adopted a surgically puncture-induced disc injury at lumbar levels in a rabbit model. The discs were grouped into sham, puncture with water injection, and puncture with HA hydrogel injection. Postoperatively, we measured changes in disc height using x-ray. We used magnetic resonance imaging to assess disc degeneration on tissue hydration after euthanasia. Post-mortem, we determined histological changes, innervation (PGP9.5) and inflammation (interleukin [IL]-6, IL-1β, and tumor necrosis factor [TNF]-α) in the discs.

Results.

We have demonstrated a significant reduction of disc height and T2/T1ρ mapping with histological evidence of degenerative discs, increase of innervation and inflammation in puncture-induced disc injury over time. In the HA hydrogel group, disc height was increased at weeks four and eight. A slight increase of T2 mapping, but significantly in T1ρ mapping, was observed in the HA hydrogel group at week 8. We observed homogenous NP distribution and organised AF lamellae at week eight and a slight reduced innervation score in the treatment group. HA hydrogel significantly downregulated IL-6 expression at day 1. This, however, was only slightly reduced for IL-1β and TNF-α.

Conclusion.

An injectable HA hydrogel had the protective effects in suppressing the loss of disc height, promoting tissue hydration for structural repair, and attenuating inflammation and innervation to prevent further disc degeneration.

Level of Evidence: N/A
Evaluating the Severity and Prognosis of Acute Traumatic Cervical Spinal Cord Injury
Authors: Zhu Fengzhao , Liu Yuan , Zeng Lian , Wang Yulong , Kong Xiangchuang , Yao Sheng , Chen Kaifang , Jing Xirui , Yang Lian , Guo Xiaodong
Published: January 2021

Study Design.

Retrospective observational cohort study.

Objective.

We explored the relationship between diffusion tensor imaging (DTI) parameters and prognosis in patients with acute traumatic cervical spinal cord injury (ATCSCI).

Summary of Background Data.

DTI has been used to diagnose spinal cord injury; nevertheless, its role remains controversial.

Methods.

We analyzed retrospectively 24 patients with ATCSCI who were examined using conventional T2-weighted imaging and DTI. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were recorded at the injured site. Diffusion tensor tractography (DTT) was used to measure the spinal cord white matter fiber volume (MWFV). American Spinal Injury Association (ASIA) grades were recorded. Correlations between DTI parameters and ASIA scores were evaluated using Spearman correlation coefficients.

Results.

FA values at injured sites were significantly lower than those of the control group, whereas ADC values in injured and control groups were not significantly different. DTT revealed that ATCSCI could be divided into four types: Type A1—complete rupture of spinal cord white matter fiber (MWF); Type A2—partial rupture of MWF; Type B—most MWF retained with severe compression or abnormal fiber conduction direction; and Type C—MWF basically complete with slight compression. Preoperative physical examinations revealed complete injury (ASIA A) in patients with A1 (n = 4) and A2 (n = 4). The ASIA grades or scores of A2 were improved to varying degrees, whereas there was no significant improvement in A1. FA values and MWFV of ASIA B, C, and D were significantly higher than those of ASIA A. FA and MWFV were correlated with ASIA motor score preoperatively and at final follow-up.

Conclusion.

We propose a classification for the severity of ATCSCI based on DTI and DTT that may explain why some patients with ASIA A recover, whereas others do not.

Level of Evidence: 4
Patient Outcomes After Single-level Coflex Interspinous Implants Versus Single-level Laminectomy
Authors: Zhong Jack , O’Connell Brooke , Balouch Eaman , Stickley Carolyn , Leon Carlos , O’Malley Nicholas , Protopsaltis Themistocles S. , Kim Yong H. , Maglaras Constance , Buckland Aaron J.
Published: January 2021

Study Design

Retrospective cohort analysis.

Objective

The aim of this study was to compare postoperative outcomes of Coflex interspinous device versus laminectomy.

Summary of Background Data

Coflex Interlaminar Stabilization device (CID) is indicated for one- or two-level lumbar stenosis with grade 1 stable spondylolisthesis in adult patients, as an alternative to laminectomy, or laminectomy and fusion. CID provides stability against progressive spondylolisthesis, retains motion, and prevents further disc space collapse.

Methods

Patients ≥18 years’ old with lumbar stenosis and grade 1 stable spondylolisthesis who underwent either primary single-level decompression and implantation of CID, or single-level laminectomy alone were included with a minimum 90-day follow-up at a single academic institution. Clinical characteristics, perioperative outcomes, and postoperative complications were reviewed until the latest follow-up. χ
2 and independent samples t tests were used for analysis.

Results

Eighty-three patients (2007–2019) were included: 37 cases of single-level laminectomy (48.6% female) were compared to 46 single-level CID (50% female). CID cohort was older (CID 69.0 ± 9.4 vs. laminectomy 64.2 ± 11.0, P = 0.042) and had higher American Society of Anesthesiologists (ASA) grade (CID 2.59 ± 0.73 vs. laminectomy 2.17 ± 0.48, P = 0.020). CID patients had higher estimated blood loss (EBL) (97.50 ± 77.76 vs. 52.84 ± 50.63 mL, P = 0.004), longer operative time (141.91 ± 47.88 vs. 106.81 ± 41.30 minutes, P = 0.001), and longer length of stay (2.0 ± 1.5 vs. 1.1 ± 1.0 days, P = 0.001). Total perioperative complications (21.7% vs. 5.4%, P = 0.035) and instrumentation-related complication was higher in CID (10.9% vs. 0% laminectomy group, P = 0.039). There were no other significant differences between the groups in demographics or outcomes.

Conclusion

Single-level CID devices had higher perioperative 90-day complications, longer operative time, length of stay, higher EBL compared to laminectomies alone. Similar overall revision and neurologic complication rates were noted compared to laminectomy at last follow-up.

Level of Evidence: 3
MAPK blockade, toxicities, pathogenesis and management
Authors: Moreira Alvaro , Lebbé Céleste , Heinzerling Lucie
Published: January 2021

Purpose of review

BRAF/MEK inhibitor has changed the treatment landscape in patients with advanced and metastatic melanoma with prolonged overall survival and progression-free survival. Since three treatment combinations exist with similar efficacy therapy decisions are often made based on the side effect profile. Additionally, on-target side effects or class effects have to be properly managed to ensure treatment adherence.

Recent findings

Sequential treatment with BRAF/MEK inhibition and immunotherapy might increase toxicity with a sepsis-like syndrome and triple therapy with concomitant BRAF/MEK inhibition and anti-PD1/PD-L1 antibody therapy induces severe side effects in the vast majority of patients.

Toxicity of combination therapy with BRAF/MEK inhibitors is generally manageable, reversible and infrequently associated with treatment discontinuation. In case of persisting off-target effects the change to another combination therapy can resolve side effects.
MEK inhibitors in RASopathies
Authors: Bergqvist Christina , Wolkenstein Pierre
Published: January 2021

Purpose of review

An early understanding of the role of the Ras/Raf/MEK/ERK signalling pathway in regulating cell proliferation has set the stage for the development of several potent and selective MEK inhibitors (MEKi). MEKi represent promising therapies for RAS-driven neoplasias and RASopathies associated with increased Ras/MAPK activity.

Recent findings

Neurofibromatosis 1 (NF1) is a prototypic RASopathy in which early-phase clinical trials with MEKi have been successful in the treatment of plexiform neurofibromas (pNF) and low-grade gliomas (LGGs). The phase 2 trial (SPRINT) of selumetinib in pNF resulted in at least 20% reduction in the size of pNF from baseline in 71% of patients and was associated with clinically meaningful improvements. On the basis of this trial, selumetinib (Koselugo) received FDA approval for children 2 years of age and older with inoperable, symptomatic pNF. The phase 2 trial of selumetinib in LGG resulted in 40% partial response and 96% of patients had 2 years of progression-free survival.

Given the potential of MEK inhibition as an effective and overall well tolerated medical treatment, the use of targeted agents in the NF1 population is likely to increase considerably. Future work on non-NF1 RASopathies should focus on developing preclinical models and defining endpoints for measurement of efficacy in order to conduct clinical trials.
Distinction Between Hypertrophic Lichen Planus and Squamous Cell Carcinoma Requires Clinicopathologic Correlation in Difficult Cases
Authors: Astudillo Michael G. , Hoang Mai P. , Nazarian Rosalynn M. , Foreman Ruth K.
Published: January 2021

Distinguishing hypertrophic lichen planus (HLP) and squamous cell carcinoma (SCC) can be diagnostically challenging because of overlapping clinical and histopathological features. This study characterizes histopathological features in HLP and SCC, assessing their utility in diagnosing atypical squamous proliferations. We compared 12 histopathological features of 15 HLP and 11 SCC biopsies from the lower extremities. We then reviewed 16 cases that were diagnosed as atypical squamous proliferations with differential diagnoses of HLP versus SCC. Clinical follow-up allowed for retrospective categorization of these difficult cases as HLP or SCC. HLP showed significant differences in hyperorthokeratosis (P = 0.04), wedge-shaped hypergranulosis (P = 0.0033), and irregular psoriasiform hyperplasia (P = 0.004), whereas parakeratosis (P = 0.001), solar elastosis (P = 0.001), deep extension (P = 0.02), and perforating elastic fibers (P = 0.0001) were significant for SCC. A scoring system based on these significant differences was devised to aid the classification of difficult cases. 56% of the difficult cases received an “indeterminate” score. A score favoring HLP had a sensitivity of 44% and a specificity of 71%. Although significant differences were identified between cases of definitive HLP and SCC, these histopathological features were unable to distinguish difficult cases, highlighting the need for clinicopathological correlation in patients with atypical squamous proliferations of the lower extremities. Many difficult cases had histologic features that could not be evaluated because of the superficial nature of the biopsy. Therefore, obtaining a deep wedge or punch biopsy may facilitate a diagnosis in cases with a differential diagnosis of HLP and SCC.
Oral Lichen Planus Associated With Lichen Planus Pigmentosus and Lichen Sclerosus in Monozygotic Twins
Authors: Marques Letícia Côgo , Santos Lílian Rocha , da Silva Natasha Camargo , Cunha Karin Soares , Junior Arley Silva , Conde Danielle Castex
Published: January 2021

Lichen planus (LP) is a mucocutaneous immune-mediated disease of unknown etiology. It is more prevalent in women and usually occurs between the third and sixth decades of life. Oral lesions may or may not be associated with skin and genital lesions. Although the role of genetic factors is still undetermined, reports of LP in more than one family member are not uncommon. However, the occurrence of LP in monozygotic twins is rare. We report a rare case of 42-year-old female monozygotic twins presenting oral LP. This report is even rarer because one of the patients had cutaneous lesions of an unusual variant of LP (LP pigmentosus) and the other had an uncommon association with lichen sclerosus. The etiology and pathogenesis of LP are still uncertain. However, despite being rare, its occurrence in family members and monozygotic twins suggests that genetic factors are involved in its development.
Value of PD-L1, PD-1, and CTLA-4 Expression in the Clinical Practice as Predictors of Response to Nivolumab and Ipilimumab in Monotherapy in Patients With Advanced Stage Melanoma
Authors: Santos-Briz Angel , Cañueto Javier , Carmen Sofía del , Barrios Beatriz , Yuste Manuela , Bellido Lorena , Ludeña María Dolores , Román Concepción
Published: January 2021

Background:

The introduction of immune checkpoint inhibitors (ICI) has improved the survival outcomes of patients with advanced melanoma. To date, only a few studies have evaluated the immunohistochemical (IHC) expression of PD-1 and CTLA-4 in tumor-infiltrating lymphocytes (TILs) as predictive markers of response to ICI, most of them in the context of clinical trials. Moreover, the predictive value of PD-L1 in melanoma cells in the response to immunotherapy is unclear. The aim of our study was to assess the IHC expression of PD-L1, PD-1, and CTLA-4 in samples of patients with advanced melanoma and to establish their prognostic value as predictors of ICI response in a university hospital.

Methods:

The expression of PD-L1, PD-1, and CTLA-4 was evaluated in pretreatment tumor samples in a series of 35 patients, 21 patients treated with nivolumab and 14 patients with ipilimumab in monotherapy.

Results:

In the nivolumab group, 4 tumors (19%) were positive for PD-L1 and all of them showed a partial response to the treatment. However, 4 patients whose tumors did not express PD-L1 also responded to nivolumab. PD-1 expression was not associated with better progression-free survival (PFS). In the ipilimumab group, 5 patients (35.7%) showed expression of CTLA-4. Positive cases showed a better PFS; however, one negative case responded to ipilimumab.

Conclusions:

Nivolumab produces a better response compared with ipilimumab in patients with melanoma. The IHC expression of PD‐L1 and CTLA-4 are associated with a higher response rate to nivolumab and ipilimumab, respectively, and better PFS, but the existence of responder patients with negative expression suggests that they are not adequate biomarkers to select candidate patients for ICI in the clinical practice.
Keratoacanthoma: Update on the Debate
Authors: Nirenberg Alexander , Steinman Howard , Dixon Anthony
Published: January 2021

Keratoacanthoma (KA) is a cutaneous tumor with a biphasic pattern of growth. A rapidly growing phase is usually followed by involution. KA occurs on sun-damaged skin. There are many listed causative associations, which include some therapeutic agents. Debate continues as to whether KA is a variant of squamous carcinoma (SCC) or a separate entity. Reporting of KA versus SCC is markedly inconsistent. Reasons for inconsistency include overlapping microscopic criteria, variants of KA with more aggressive features, and possibly medicolegal concerns. Genetic studies have shown some differences between the 2 entities. Activation of apoptotic pathways has been demonstrated in KA. Genetic studies have shown a possible role of human polyomavirus 6 in the pathogenesis of at least some KAs. Given that some cases of KA have components that behave as conventional SCCs, KA can be considered as a low-grade variant of SCC with some genetic differences.
Diagnostic Utility of C4d by Direct Immunofluorescence in Bullous Pemphigoid
Authors: Damman Jeffrey , Edwards Gareth , van Doorn Martijn B. , Horvath Barbara , Diercks Gilles F. H.
Published: January 2021

Bullous pemphigoid (BP) is an autoimmune blistering disease that commonly affects elderly patients. Direct immunofluorescence (DIF) for immunoglobulin G (IgG) and C3c on frozen skin biopsies is the gold standard for the diagnosis of BP. In a minority of cases, IgG and/or C3c are found negative, and in these situations, there is a need for a more stable diagnostic marker of BP. C4d is biologically inactive, but has a long half-life, rendering it a long-lived marker for antibody-mediated complement activation. Previous studies already demonstrated that C4d was diagnostically useful in formalin-fixed paraffin-embedded skin biopsies of patients with BP. We hypothesized that C4d detected by DIF could also be a promising diagnostic marker for BP, particularly in IgG and/or C3c DIF-negative cases. In this single-center retrospective study, 69 cases of BP were analyzed for linear deposition of C4d; of the 69 cases, n = 26 were IgG+/C3c−, n = 10 IgG+/C3c+, and n = 33 IgG−/C3c−. Results were compared with n = 39 negative controls. Seven of the 26 (27%) IgG+/C3c− and 3 of the 33 (9%) IgG−/C3c− BP cases were positive for C4d. All 10 IgG+/C3c+ cases were also C4d positive. In the negative control group, 2 of the 39 (5%) were found positive for C4d. In conclusion, the current study shows that C4d is a more sensitive but not a 100% specific marker of BP. We conclude that C4d by DIF could be an interesting diagnostic adjunct for BP, particularly in IgG−/C3c− double negative cases.
Diagnostic Utility of Biplex/Multiplex Polymerase Chain Reaction in Infectious Granulomatous Dermatitis in North Indian Population
Authors: Parkhi Mayur , Kumar S Mukin , De Dipankar , Yadav Rakesh , Sethi Sunil , Radotra Bishan Dass , Saikia Uma Nahar
Published: January 2021

Background:

A definite diagnosis of infectious granulomatous dermatitis (IGD) is difficult for both practicing dermatologists and dermatopathologists due to overlapping clinical and histomorphological features. We aimed to explore the role of multiplex polymerase chain reaction (PCR) for identifying a definite etiological agent for diagnosis and appropriate treatment in IGD in formalin-fixed paraffin-embedded tissue.

Materials and Methods:

Sixty-two cases of IGD were included, excluding leprosy. The histochemical stains including Ziehl–Neelsen, periodic acid–Schiff, and Giemsa were performed in all cases. A multiplex PCR was designed for detection of tuberculosis (TB) (IS6110 and mpt64), fungal infections (ITS1, ITS2; ZM1, and ZM3), and leishmaniasis (kDNA). The results of histomorphology, histochemical stains, and multiplex PCR were compared.

Results:

Among 62 cases, the sensitivity rate of PCR detection for organisms was 16.7%, 0%, 100%, 72%, 75%, and 66.7% in patients with TB, suggestive of TB, leishmaniasis, fungal infections, and granulomatous dermatitis not otherwise specified and granulomatous dermatitis suggestive of fungus, respectively. The TB PCR using IS6110 primers was negative in all cases; however, PCR using mpt64 primers was positive in 33.33% cases of scrofuloderma. The histochemical stains including Ziehl–Neelsen for acid-fast bacilli, periodic acid–Schiff for fungus, and Giemsa for Leishman-Donovan bodies showed positivity in 11.3%, 43.5%, and 3.2%, respectively.

Conclusion:

A multiplex PCR (Mycobacterium tuberculosis, Leishmania, and panfungal) is highly recommended in all cases of IGD where an etiological agent is difficult to establish by skin biopsy and histochemical stains along with a clinicopathological correlation. This will augment in appropriate treatment and will reduce empirical treatment and morbidity in such patients.
Effects of JL13, a pyridobenzoxazepine compound, in dopaminergic and glutamatergic models of antipsychotic activity
Authors: Andrade Yane C.P. , Ropke Jivago , Viana Thércia G. , Fanelli Chiara , Minaldi Elisa , Batista Luara A. , Issy Ana C. , Del Bel Elaine A. , Rodrigues Lívia C.M. , Liégeois Jean-François , Moreira Fabrício A.
Published: January 2021

The pyridobenzoxazepine compound, 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine (JL13), has been developed as a potential antipsychotic drug. We tested the hypothesis that JL13 is efficacious in both dopaminergic and glutamatergic animal models of schizophrenia. We investigated JL13 for its efficacy to prevent cocaine- and ketamine-induced hyperlocomotion and MK-801-induced deficits in prepulse inhibition (PPI) of the startle reflex. Male Swiss mice received injections of JL13 (0.1–10 mg/kg) and were tested in the open field for basal locomotion. In separate experiments, the animals received injections of JL13 (0.1–3 mg/kg) followed by cocaine (10 mg/kg), ketamine (60 mg/kg), or MK-801 (0.5 mg/kg) and were tested in the open field for hyperlocomotion. In addition, it was also tested if JL13 prevented MK-801-induced disruption of PPI. Only the highest dose of JL13 impaired spontaneous locomotion, suggesting its favorable profile regarding motor side effects. At doses that did not impair basal motor activity, JL13 prevented cocaine-, ketamine-, and MK-801-induced hyperlocomotion. Moreover, JL13 prevented MK-801-induced disruption of PPI. Extending previous findings, this study shows that JL13 exerts antipsychotic-like activity in both dopaminergic and glutamatergic models. This compound has a favorable pharmacological profile, similar to second-generation antipsychotics.
Intermittent dietary supplementation with fish oil prevents high fat diet-induced enhanced sensitivity to dopaminergic drugs
Authors: Beltran Nina M. , Ramos Jeremiah , Galindo Kayla I. , Echeverri Alegre Jose I , Cruz Bryan , Hernandez-Casner Caroline , Serafine Katherine M.
Published: January 2021

Eating a high fat diet can lead to obesity, type 2 diabetes, and dopamine system dysfunction. For example, rats eating high fat chow are more sensitive than rats eating standard chow to the behavioral effects (e.g., locomotion and yawning) of dopaminergic drugs (e.g., quinpirole and cocaine). Daily dietary supplementation with 20% (w/w) fish oil prevents high fat diet-induced enhanced sensitivity to quinpirole-induced yawning and cocaine-induced locomotion; however, doctors recommend that patients take fish oil just two to three times a week. To test the hypothesis that intermittent (i.e., 2 days per week) dietary supplementation with fish oil prevents high fat diet-induced enhanced sensitivity to quinpirole and cocaine, rats eating standard chow (17% kcal from fat), high fat chow (60% kcal from fat), and rats eating standard or high fat chow with 20% (w/w) intermittent (e.g., 2 days per week) dietary fish oil supplementation were tested once weekly with quinpirole [0.0032–0.32 mg/kg, intraperitoneally (i.p.)] or cocaine (1.0–17.8 mg/kg, i.p.) using a cumulative dosing procedure. Consistent with previous reports, eating high fat chow enhanced sensitivity of rats to the behavioral effects of quinpirole and cocaine. Intermittent dietary supplementation of fish oil prevented high fat chow-induced enhanced sensitivity to dopaminergic drugs in male and female rats. Future experiments will focus on understanding the mechanism(s) by which fish oil produces these beneficial effects.
Granisetron, a selective 5-HT3 antagonist, reduces L-3,4-dihydroxyphenylalanine-induced abnormal involuntary movements in the 6-hydroxydopamine-lesioned rat
Authors: Kwan Cynthia , Frouni Imane , Bédard Dominique , Hamadjida Adjia , Huot Philippe
Published: January 2021

Administration of L-3,4-dihydroxyphenylalanine (L-DOPA) provides Parkinson’s disease patients with effective symptomatic relief. However, long-term L-DOPA therapy is often marred by complications such as dyskinesia. We have previously demonstrated that serotonin type 3 (5-HT3) receptor blockade with the clinically available and highly selective antagonist ondansetron alleviates dyskinesia in the 6-hydroxydopamine (6-OHDA)-lesioned rat. Here, we sought to explore the antidyskinetic efficacy of granisetron, another clinically available 5-HT3 receptor antagonist. Rats were rendered hemi-parkinsonian by 6-OHDA injection in the medial forebrain bundle. Following induction of stable abnormal involuntary movements (AIMs), granisetron (0.0001, 0.001, 0.01, 0.1 and 1 mg/kg) or vehicle was acutely administered in combination with L-DOPA and the severity of AIMs, both duration and amplitude, was determined. We also assessed the effect of granisetron on L-DOPA antiparkinsonian action by performing the cylinder test. Adding granisetron (0.0001, 0.001, 0.01, 0.1 and 1 mg/kg) to L-DOPA resulted in a significant reduction of AIMs duration and amplitude, with certain parameters being reduced by as much as 38 and 45% (P < 0.05 and P < 0.001, respectively). The antidyskinetic effect of granisetron was not accompanied by a reduction of L-DOPA antiparkinsonian action. These results suggest that 5-HT3 blockade may reduce L-DOPA-induced dyskinesia without impairing the therapeutic efficacy of L-DOPA. However, a U-shaped dose-response curve obtained with certain parameters may limit the therapeutic potential of this strategy and require further investigation.
Blockade of orexin receptors in the ventral tegmental area reduced the extinction period of the lateral hypothalamic-induced conditioned place preference in rats
Authors: Mahmoudi Maedeh , Maleki-Roveshti Mehrdad , Haghparast Amir , Karimi-Haghighi Saeideh , Haghparast Abbas
Published: January 2021

The orexinergic connection between the lateral hypothalamus (LH) and the ventral tegmental area (VTA) is involved in modulating the reward circuit. The conditioned place preference (CPP) can be induced by microinjection of carbachol, a cholinergic agonist, into the LH. The current research was conducted to understand whether intra-VTA orexin receptors (OXRs) could influence the duration of the extinction period or maintenance of the intra-LH carbachol-induced CPP. To this end, the rats unilaterally received intra-LH carbachol (250 nM) within a 3-day conditioning period. Animals that have already passed the conditioning test were unilaterally administered by intra-VTA microinjection of SB334867, an OX1R antagonist, or TCS OX2 29, an OX2R antagonist during the extinction phase of the LH stimulation-induced CPP. For the first time, our data indicated that daily intra-VTA administration of either SB334867 (30 nM) or TCS OX2 29 (10 and 30 nM) during the extinction period decreased the maintenance of intra-LH carbachol-induced CPP. In conclusion, OXRs in the VTA play crucial roles in the maintenance of reward processes.
Ligand-specific pharmacogenetic effects of nonsynonymous mutations
Authors: Morningstar-Kywi Noam , Haworth Ian S. , Mosley Scott A.
Published: January 2021

In pharmacogenomics, variable receptor phenotypes, resulting from genetic polymorphisms, are often described as a change in protein function or regulation observed upon exposure to a drug. However, in some instances, phenotypes are defined using a class of medications rather than individual drugs. This paradigm assumes that a variation associated with a drug response phenotype will retain the magnitude and direction of the effect for other drugs with the same mechanism of action. However, nonsynonymous polymorphisms may have ligand-specific effects. The purpose of this study was to investigate the potential for point mutations to asymmetrically affect the binding of different drugs to a common target. Ligand binding data from site-directed mutagenesis studies on five G-protein coupled receptors (beta-1 and -2 adrenergic, dopamine D2, angiotensin II and mu-opioid receptor) were collected and analyzed. Binding data from 81 studies for 253 ligands with 447 mutant proteins, including 10 naturally occurring human variants, were analyzed, yielding 1989 mutation–ligand pairs. Fold change in binding affinity for mutant proteins, relative to the wild-type, for different drugs was examined for ligand-specific effects, with a fold-change difference of one or more orders of magnitude between agents considered significant. Of the mutations examined, 49% were associated with ligand-specific effects. One human variant (T164I, beta-2 adrenergic receptor) showed ligand-specific effects for antiasthmatic agents. These results indicate that ligand-specific changes in binding are a possible consequence of missense mutations. This implies that caution needs to be exercised when grouping drugs together during design or interpretation of genotype–phenotype association studies.
Influence of CMTM8 polymorphisms on lung cancer susceptibility in the Chinese Han population
Authors: Wu Jiamin , Sun Yao , Xiong Zichao , Niu Fanglin , Liu Yuanwei , Li Haiyue , Liu Jianfeng , Wu Junsheng , Liu Qiufang , Jin Tianbo
Published: January 2021

Background

Lung cancer is the leading cause of cancer-related mortality worldwide and CMTM8 is a potential tumor suppressor gene, which is down-regulated in lung cancer. The objective of this research was to assess the association of CMTM8 genetic polymorphisms with lung cancer risk.

Methods

To evaluate the correlation between CMTM8 polymorphisms and lung cancer risk, Agena MassArray platform was used for genotype determination among 509 lung cancer patients and 506 controls. Multiple genetic models, stratification analysis and Haploview analysis were used by calculating odds ratio (OR) and 95% confidence intervals (CIs).

Results

Significant associations were detected between CMTM8 rs6771238 and an increased lung cancer risk in codominant (adjusted OR = 1.57, 95% CI: 1.01–2.42, P = 0.044) and dominant (adjusted OR = 1.54, 95% CI: 1.01–2.36, P = 0.047) models. After sex stratification analysis, we observed that rs6771238 was related to an increased risk of lung squamous cell carcinoma, while rs6771238 was associated with an increased risk of lung adenocarcinoma. Rs9835916 was linked to increased risk of lymph node metastasis in lung cancer patients.

Conclusion

Our study first reported that CMTM8 polymorphisms were a risk factor for lung cancer, which suggested the potential roles of CMTM8 in the development of lung cancer.
Resurgence of the edge-to-edge repair of the mitral valve
Authors: Makhdoum Ahmad , Dokollari Aleksander , Elbatarny Malak , Verma Subodh , Yanagawa Bobby
Published: January 2021

Purpose of review

To provide a critical review of the application and outcomes of surgical edge-to-edge (E2E) or Alfieri repair for mitral valvulopathy.

Recent findings

The E2E repair is a surgical technique to address mitral regurgitation, particularly suited when the responsible mechanism is bileaflet prolapse combined with enlarged annular area. It can also be used for a range of mitral valve pathologies. Surgically, the technique has been employed as a bailout for unsuccessful repair including residual mitral regurgitation because of systolic anterior motion (SAM). E2E repair should be accompanied by a ring annuloplasty for long-term repair durability. The simplicity of this approach makes it an ideal strategy during minimally-invasive mitral valve repair. It may also be performed via a transaortic approach at the time of aortic valve surgery to address less-than-severe mitral regurgitation or to address residual SAM following myectomy for hypertrophic obstructive cardiomyopathy. We review the surgical indication, potential complications including risk of mitral stenosis and the long-term outcomes of E2E repair.

The E2E surgical repair is a simple and effective surgical strategy to address a wide range of mitral regurgitation. This is an important technique in the surgical armamentarium especially in cases of minimally-invasive mitral valve surgery.
Ambulatory advanced heart failure patients: timing of mechanical circulatory support – delaying the inevitable?
Authors: Rajapreyar Indranee , Kumar Sachin , Rao Roopa A.
Published: January 2021

Purpose of review

Current indications for continuous-flow left ventricular assist device (cfLVAD) implantation is for patients in cardiogenic shock or inotrope-dependent advanced heart failure. Risk stratification of noninotrope dependent ambulatory advanced heart failure patients is a subject of registries designed to help shared-decision making by clinicians and patients regarding the optimal timing of mechanical circulatory support (MCS).

Recent findings

The Registry Evaluation of Vital Information for VADs in Ambulatory Life enrolled ambulatory noninotrope dependent advanced systolic heart failure patients who had 25% annualized risk of death, MCS, or heart transplantation (HT). Freedom from composite clinical outcome at 1-year follow-up was 23.5% for the entire cohort. Seattle Heart Failure Model Score and Natriuretic pepides were predictors with modest discriminatory power. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 4 patients had the highest risk (3.7-fold) of death, MCS or HT compared to INTERMACS profile 7.

We propose individualized risk stratification for noninotrope dependent ambulatory advanced heart failure patients and include serial changes in end-organ function, nutritional parameters, frailty assessment, echocardiographic and hemodynamic data. The clinical journey of a patient with advanced heart failure should be tracked and discussed at each clinic visit for shared decision-making regarding timing of cfLVAD.
Advances in medical therapy for glaucoma
Authors: Ostler Erik , Rhee Douglas , Burney Edward , Sozeri Yasemin
Published: January 2021

Purpose of review

To discuss a new class of medication that has recently become available for the treatment of glaucoma; as well as share insights into developments in glaucoma medicine administration which has the potential to revolutionize medical therapy for glaucoma.

Recent findings

Newly available eye drops, netarsudil 0.02% and latanoprostene bunod 0.024%, are improving aqueous outflow through the conventional outflow tract. Other new developments in medical glaucoma are focused on alternative methods for sustained glaucoma medication delivery.

Newer medications may be able to extend the duration of medically controlled glaucoma, delaying or possibly eliminating the need of glaucoma surgery for some patients. Alternative methods of delivery for glaucoma medications may be a key factor in improving outcomes with currently available medications.
Qualitative Study of Long-Haul Truck Drivers’ Health and Healthcare Experiences
Authors: Johnson Jennifer K. , Vingilis Evelyn , Terry Amanda L.
Published: January 2021

Objective:

Long-haul truck drivers suffer increased health risk, but how they use healthcare is unknown. The objectives of this study were to explore the health experiences of these drivers, their healthcare experiences, and their relationship with their main medical provider.

Methods:

In-depth semi-structured interviews were conducted with 13 Canadian long-haul truck drivers. The majority (85%) were men and recruited at a truck stop on a major transport corridor between Canada and the United States.

Results:

Through phenomenological analysis of the transcribed interviews, themes of perseverance, isolation, dehumanization, and working in a hidden world emerged as major influences on the health experiences of these drivers. Barriers to their medical provider were also revealed.

Conclusions:

Continuous exposure to a stressful work environment and inadequate access to primary care likely negatively affect the health of long-haul truck drivers. Given the experiences of this small group of drivers, improved healthcare and health resource availability might mitigate the risk of this occupational group.
Parental Occupation and Risk of Childhood Retinoblastoma in Denmark
Authors: Omidakhsh Negar , Hansen Johnni , Ritz Beate , Coleman Anne L. , McKean-Cowdin Roberta , Olsen Jorn , Heck Julia E.
Published: January 2021

Objective:

Retinoblastoma is the most common primary intraocular tumor affecting children. We examine the role of parental occupational exposures and risk of retinoblastoma among offspring.

Methods:

Our population-based case-control study linked data from four nationwide Danish registries and included all cases of retinoblastoma diagnosed in Danish children (<5 y, n = 144) between 1975 and 2014. We focused on two biologically relevant time periods: 90 days preconception to conception for fathers; conception to birth for mothers. Parents were grouped into major industry headings created from Danish industry codes.

Results:

We observed increased risk of all retinoblastoma for children of fathers in the food and drink industry and iron and metal industry. Bilateral disease was associated with paternal work in manufacturing and land transportation.

Conclusion:

Our results suggest that some occupational exposures may increase the risk of childhood sporadic retinoblastoma.
Perceived Health Risks Among Firefighters; The New Jersey Firefighter Health Survey
Authors: Maloney Sean R. , Udasin Iris G. , Black Taylor M. , Shah Nimit N. , Steinberg Michael B. , Pratt Michael E. , Graber Judith M.
Published: January 2021

Objective:

There is a growing literature on the risk of chronic disease among firefighters, including cardiovascular disease (CVD) and cancer. However there is little information on firefighter's perception thereof.

Methods:

Firefighters attending a union convention in New Jersey completed a survey with four domains: firefighting experience; perceived additional risk for chronic diseases (six-point Likert scale); cancer screening history; demographics, and risk behaviors.

Results:

Among 167 enrolled firefighters, all were men and 86.6% active career. Median perceived risk ranged from high risk (colon, hematologic, breast, prostate, and testicular cancers) to very high risk (CVD, pulmonary diseases, all cancers, lung and oral cancer).

Conclusions:

NJ Firefighters attributed considerable additional risk to acquiring chronic disease as a result of their firefighting activities. Understanding firefighter perceptions of their own morbidity and mortality will help develop future firefighter preparatory programs.
What Industrial Categories Are Workers at Excess Risk of Filing a COVID-19 Workers’ Compensation Claim? A Study Conducted in 11 Midwestern US States
Authors: Bernacki Edward J. , Hunt Dan L. , Yuspeh Larry , Lavin Robert A. , Kalia Nimisha , Leung Nina , Tsourmas Nicholas F. , Williams Leila , Tao Xuguang (Grant)
Published: January 2021

Objective:

Determine the industries with the highest proportion of accepted COVID-19 related workers’ compensation (WC) claims.

Methods:

Study included 21,336 WC claims (1898 COVID-19 and 19,438 other claims) that were filed between January 1, 2020 and August 31, 2020 from 11 states in the Midwest United States.

Result:

The overwhelming proportion of all COVID-19 related WC claims submitted and accepted were from healthcare workers (83.77%). Healthcare was the only industrial classification that was at significantly higher COVID-19 WC claim submission risk (odds ratio [OR]: 4.00; 95% confidence intervals [CI]: 2.77 to 5.79) controlling for type of employment, sex, age, and presumption of COVID-19 work-relatedness. Within healthcare employment, WC claims submitted by workers in medical laboratories had the highest risk (crude rate ratio of 8.78).

Conclusion:

Healthcare employment is associated with an increased risk of developing COVID-19 infections and submitting a workers’ compensation claim.
Depressive Symptoms and Suicidal Ideation Among Lawyers and Other Law Professionals
Authors: Thiese Matthew S. , Allen Joseph A. , Knudson Martha , Free Kim , Petersen Paige
Published: January 2021

Law professionals are an understudied population that is integral to society. Limited research indicates lawyers experience poor mental health, decreased wellbeing, and suicidality. This cross-sectional study recruited 654 law professionals and responses to a depression scale, the patient health questionnaire 9 (PHQ-9) were compared with the general working population. Lawyers were significantly more likely to report suicidal ideation “several days” and “more than half the days” as compared with the general working population, with odds ratios (OR) of 6.54 (95% confidence interval [CI] 4.16 to 10.29) and 5.50 (95% CI 2.23 to 13.53) respectively. Lawyers were more likely reported mild (OR = 3.89, 95% CI 3.04 to 4.96), moderate (OR = 5.29, 95% CI 3.61 to 7.76), moderately severe (OR = 9.71, 95% CI 5.50 to 17.14), and severe (OR = 18.34, 95% CI 6.00 to 56.11) depressive symptoms. 17.5% of lawyers in this study were experiencing symptoms equivalent to a diagnosis of a major depressive disorder.
Effectiveness of a Mobile Health Management Program With a Challenge Strategy for Improving the Cardiovascular Health of Workers
Authors: Ryu Hosihn , Jung Jiyeon , Moon Jihyun
Published: January 2021

Background:

Workers’ cardiovascular health can be influenced by individual willingness to practice healthy behaviors. A mobile health management program with a challenge strategy was administered to promote workers’ healthy behaviors among small to medium-sized enterprises.

Methods:

A 12-week program consisted of health communication with a challenge strategy was administered to the workers.

Results:

The intervention group showed significantly improved scores for cardiovascular disease-related health behavior (Z = −2.44, P = 0.013), the job stress contributing factor of inadequate social support (F = 4.10, P = 0.049), and the cardiovascular disease-related health status of waist circumference (t = 3.22, P = 0.004), body fat (Z = −2.23, P = 0.024), and triglycerides (Z = −3.04, P = 0.001).

Conclusion:

This study's significance is its potential for increasing the convenience and joy of participating in intervention programs and acquiring health information through mobile platforms, which are easily accessible to the workers.
Sun Protection Use at Work and Leisure by Outdoor Workers in Alberta, Canada
Authors: Rydz Ela , Harper Andrew , Leong Brandon , Arrandale Victoria H. , Kalia Sunil , Forsman-Phillips Lindsay , Holness D. Linn , Tenkate Thomas , Peters Cheryl E.
Published: January 2021

Objective:

To assess the prevalence and determinants of sun protection behaviours among outdoors workers at work and leisure in Alberta, Canada.

Methods:

We collected outdoor workers’ demographics, skin cancer risk factors, job information, and sun habits at work and leisure using self-completed questionnaires. For both settings, we compared use of specific behaviours and modelled determinants of sun protection behaviour scores.

Results:

At work, wearing a sleeved shirt (81% often/always) and hat (73%) were most prevalent, while seeking shade (12%) and applying sunscreen (36%) were least prevalent. Workers had higher sun protection scores at work than leisure. Hours spent outdoors was a strong determinant for both models. Additional leisure model predictors were eye colour, sex, skin type, and job group.

Conclusions:

Differences in behaviours across settings were observed and should be considered when developing solar UVR exposure reduction initiatives.
Severe infections in neurocritical care
Authors: Martin-Loeches Ignacio , Blake Alan , Collins Daniel
Published: January 2021

Purpose of review

We have highlighted the recent advances in infection in neurocritical care.

Recent findings

Central nervous system (CNS) infections, including meningitis, encephalitis and pyogenic brain infections represent a significant cause of ICU admissions. We underwent an extensive review of the literature over the last several years in order to summarize the most important points in the diagnosis and treatment of severe infections in neurocritical care.

Acute brain injury triggers an inflammatory response that involves a complex interaction between innate and adaptive immunity, and there are several factors that can be implicated, such as age, genetic predisposition, the degree and mechanism of the injury, systemic and secondary injury and therapeutic interventions. Neuroinflammation is a major contributor to secondary injury. The frequent and challenging presence of fever is a common denominator amongst all neurocritical care patients.
How do we identify the crashing traumatic brain injury patient – the neurosurgeon's view
Authors: Posti Jussi P. , Raj Rahul , Luoto Teemu M.
Published: January 2021

Purpose of review

To provide an overview on recent advances in the field of assessment and monitoring of patients with severe traumatic brain injury (sTBI) in neurocritical care from a neurosurgical point of view.

Recent findings

In high-income countries, monitoring of patients with sTBI heavily relies on multimodal neurocritical parameters, nonetheless clinical assessment still has a solid role in decision-making. There are guidelines and consensus-based treatment algorithms that can be employed in both absence and presence of multimodal monitoring in the management of patients with sTBI. Additionally, novel dynamic monitoring options and machine learning-based prognostic models are introduced. Currently, the acute management and treatment of secondary injury/insults is focused on dealing with the objective evident pathology. An ongoing paradigm shift is emerging towards more proactive treatment of neuroworsening as soon as premonitory signs of deterioration are detected.

Based on the current evidence, serial clinical assessment, neuroimaging, intracranial and cerebral perfusion pressure and brain tissue oxygen monitoring are key components of sTBI care. Clinical assessment has a crucial role in identifying the crashing patient with sTBI, especially from a neurosurgical standpoint. Multimodal monitoring and clinical assessment should be seen as complementary evaluation methods that support one another.
Overcoming challenges to enteral nutrition delivery in critical care
Authors: Wischmeyer Paul E.
Published: January 2021

Purpose of review

Existing data and all ICU nutrition guidelines emphasize enteral nutrition (EN) represents a primary therapy leading to both nutritional and non-nutritional benefits. Unfortunately, iatrogenic malnutrition and underfeeding is virtually ubiquitous in ICUs worldwide for prolonged periods post-ICU admission. Overcoming essential challenges to EN delivery requires addressing a range of real, and frequently propagated myths regarding EN delivery.

Recent findings

Key recent data addresses perceived challenges to EN including: Adequately resuscitated patients on vasopressors can and likely should receive trophic early EN and this was recently associated with reduced mortality; Patients paralyzed with neuromuscular blocking agents can and should receive early EN as this was recently associated with reduced mortality/hospital length of stay; Proned patients can safely receive EN; All ICU nutrition delivery, including EN, should be objectively guided by indirect calorimetry (IC) measures. This is now possible with the new availability of a next-generation IC device.

It is the essential implementation of this new evidence occurs to overcome real and perceived EN challenges. This data should lead to increased standardization/protocolization of ICU nutrition therapy to ensure personalized nutrition care delivering the right nutrition dose, in the right patient, at the right time to optimize clinical outcome.