Πέμπτη 14 Ιουλίου 2022

Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1

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‘Reduced Cell Surface Levels of C-C Chemokine Receptor 5 and Immunosuppression in Long Coronavirus Disease 2019 Syndrome’

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to the editor—Gaylis et al offer "an unexpected mechanism of abnormal immune downmodulation in some persons that is normalized by leronlimab" [1]. The disclosure of a public statement [2] and a Warning Letter [3] on leronlimab (PubChem SID 384585377) by the Food and Drug Administration (FDA) is appropriate. Gaylis et al offer no biostatistical methods but cite the clinical trial record. Using the Supplementary Data provided by Gaylis et al [1] with nonparametric Wilcoxon signed ranked test for change (Weeks 8–0), the 2-sided P-values for Figure 1A are .003 (leronlimab) and .0139 (placebo) and for Figure 1B are .0002 (leronlimab, Improving), .7344 (leronlimab, not improving), .0640 (placebo, not improving), and .1272 (placebo, not improving). Paired t-test results were not meaningfully different. Reporting nonsignificance (NS) for the latter 2 P-values with the given sample sizes is not advised, but the NS for placebo (Figure 1A) is significant and affects the conclusion. They do not define "responder" or state if the definition was made a priori. Some of the symptoms may not be independent (eg, cough/sore throat, headache/sleep disturbance) so using them all to generate a "responder" score should be explained. They fail to provide a mechanism of action or gene expression results to explain how a monoclonal antibody to CCR5, a G-protein-coupled receptor (GPCR), might increase the proportion of CD45+/CCR5+ T cells relative to total cell counts or increase expression of CCR5 in T cells. The authors should report the time between positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) test and enrollment, duration of COVID-19 infection, re-exposure to SARS-CoV-2, especially to variants different from the original infecting viruses, other factors that affect immune responses, distribution of severity of COVID-19 among the treatment groups, the results by age and sex, the receptor occupancy, and the potential effects of the half-life of leronlimab. Galanti and Shaman [4] report multiple (re-)infections per year in the same subjects with other coronaviruses. Lee et al [5] reported that "granulocyte macrophage colony-stimulating factor caused a marked decrease of CXCR4 (from ∼5000 ABS to <500) while up-regulating CCR5 expression (from ∼5000 to ∼20 000 ABS)." Jacobson et al [6] reported 'mean terminal half-lives (PRO 140 Serum Concentration) were 3.4 and 3.7 days, but Yang et al [7] suggested an "estimated half-life of about 10 days." With T-cell proliferation and the potential increase in CCR5 expression, the half-life and receptor occupancy need to be appropri ately addressed in different patient populations. Roche and Futura state that "plasma membrane of eukaryotic cells is constantly being internalized" [8]; how long a 146.7 kDa [9] antibody bound to the 62 kDa [10] transmembrane CCR5 (NP_001381712.1) remains at the surface or, when it is internalized, whether it is trafficked back to surface or to the lysosomes is of interest. T-cell exhaustion [11] could help explain the results; with small sample sizes, imbalances can occur so duration, sev erity, and time from PCR test for each patient is important. Finally, genotypes of CCR5, which may affect binding of leronlimab, and of the ligands of CCR5, such as CCL3L1 with copy number variants [12], and any antidrug antibodies (ADA) against leronlimab would help elucidate this finding.
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Cervical Pneumatocele Following Total Thyroidectomy Presenting as an Air Thyrogram

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jamanetwork.com

This case report describes a woman in her 30s who presented with delayed cervical pneumatocele after thyroidectomy.
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Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1

alexandrossfakianakis shared this article with you from Inoreader

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International Journal of Oral Science, Published online: 14 July 2022; doi:10.1038/s41368-022-00190-4

Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1
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Thyroid Surgeries in Asymptomatic Patients

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jamanetwork.com

In this issue of JAMA Otolaryngology−Head & Neck Surgery, Dr Sajisevi and colleagues report the findings of a retrospective analysis of 1328 patients in 16 centers in 4 countries who underwent thyroid surgery for thyroid pathology in 2019. Patients were classified by the mode of detection of the thyroid findings that led to surgery: endocrinopathic condition, patient-requested screening, clinician-screening physical examination, radiologic serendipity, diagnostic cascade, symptomatic thyroid disease, and under surveillance. The primary outcomes were the mode of detection and the proportion and size of thyroid cancers discovered in patients who were asymptomatic. The authors found that 41% of patients were asymptomatic at the time of the detection of the thyroid condition, while 34% of patients had structural thyroid symptoms at the time of detection. The remaining 25% of patients were either under surveillance for known thyroid pathology, such as thyroid nodules, or had an endocrinopathic condition, such as hyperthyroidism, hyperparathyroidism, or multiple endocrine neoplasia syndrome. Of the 1328 cases, 613 (46%) revealed thyroid cancer. The authors also found that 51% of these cancers were in asymptomatic patients, while only 30% were in symptomatic patients. Finally, the mean tumor size was significantly larger in symptomatic compared with asymptomatic patients (3.2 cm vs 2.1 cm).
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Postoperative Gabapentin's Effect on Opioid Consumption and Pain Control Following Sinonasal Surgery

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Objective

This study investigates the impact of postoperative gabapentin on opioid consumption and pain control following endoscopic sinus surgery (ESS) and/or septoplasty.

Methods

Patients who underwent ESS and/or septoplasty at a single institution from 2021 to 2022 were enrolled. All patients received postoperative hydrocodone-acetaminophen for pain control. Half of the patients were also prescribed gabapentin for the first postoperative day in addition to hydrocodone-acetaminophen. Subjects completed the Revised American Pain Society Patient Outcome Questionnaire 24 h and 7 days after surgery. We conducted a multivariable regression analysis to assess opioid consumption and improvement in pain scores in the first week between gabapentin and non-gabapentin groups.

Results

A total of 102 subjects, 51 in each arm, were enrolled. The mean age was 52 years and 53% of participants were female. Controlling for important baseline demographic, clinical, and surgically related variables, the addition of postoperative gabapentin was associated with a 44% (9.5 mg from 21.6 mg) reduction in opioids consumed in the first postoperative week (B = −9.54, 95% C.I. = [−17.84, −1.24], p = 0.025). In addition, patients in both arms exhibited similar improvement in pain severity and sleep interference in the first 7 days (B = −1.59, 95% C.I. = [−5.03, 1.84], p = 0.36).

Conclusion

To the best of our knowledge, this is the first study to investigate the impact of postoperative gabapentin on opioid consumption and pain control following ESS and/or septoplasty. Our analysis demonstrated that postoperative gabapentin effectively reduced opioid use during the first postoperative week without compromising pain control.

Level of Evidence

3 Laryngoscope, 2022
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Image‐Guided Surgical Device Failures in Functional Endoscopic Sinus Surgery: A MAUDE Analysis

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Image-Guided Surgical Device Failures in Functional Endoscopic Sinus Surgery: A MAUDE Analysis

Image-guided surgery (IGS) devices have become widely used for anatomic localization during functional endoscopic sinus surgery (FESS). However, there are no studies that analyze the post-market complications associated with IGS device use during FESS. This study queried the US Food and Drug Administration's Manufacturer and User Facility Device Experience database for event reports associated with neurological stereotaxic devices utilized in IGS between the dates of January 1, 2016 and December 31, 2020. Of the medical device reports between 2016 and 2020, less than 3% resulted in adverse events.


Objective

Image-guided surgery (IGS) devices have become widely used for anatomic localization during functional endoscopic sinus surgery (FESS). However, there are no studies that analyze the post-market complications associated with IGS device use during FESS. The objective of this study was to better characterize post-market complications associated with the use of IGS devices during sinus surgery.

Methods

The US Food and Drug Administration's Manufacturer and User Facility Device Experience database was queried for event reports associated with neurological stereotaxic devices utilized in IGS between the dates of January 1, 2016 and December 31, 2020. Medical device reports that were analyzed for this study pertained strictly to FESS.

Results

There were 1873 reports involving IGS devices for FESS included in this study. Fifty-five reports involved adverse events to patients (2.9%) and 1818 (97.1%) involved device malfunctions. Of the adverse events to patients, the most common included cerebrospinal fluid leakage (45.6%), tissue damage (12.7%), and nervous system injury (3.6%). The most commonly reported device malfunction was imprecision (21.1%).

Conclusion

IGS devices are widely utilized in FESS. Of the medical device reports between 2016 and 2020, less than 3% resulted in adverse events. Further studies of the infrequent post-market complications of IGS devices used in FESS can help guide surgeons on the risks of their clinical use.

Level of Evidence

4—Retrospective database survey without controls Laryngoscope, 2022
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Systematic review of head and neck lymphedema assessment

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Abstract

Head and neck lymphedema (HNL) is an increasingly recognized complication of head and neck cancer and its treatment. However, no consensus exists on the "gold-standard" assessment tool for the purposes of diagnosis, classification, or monitoring of HNL. We conducted a systematic review of the literature regarding HNL assessment to determine the optimal method/s of assessment for patients with HNL. A review of publications between January 2000 and September 2021 was undertaken on four electronic databases. Studies were excluded if no clear assessment method of HNL was documented. Sixty-seven articles were included in the study. A wide range of assessment methods for HNL have been reported in the literature. For the purposes of diagnosis and classification of physical findings, computed tomography (CT) appears the most promising tool available for both external and internal HNL. In terms of monitoring, ultrasound appears optimal for external HNL, while a clinician-reported ratin g scale on laryngoscopy is the gold standard for internal HNL. Patient-reported assessment must be considered alongside objective methods to classify symptom burden and monitor improvement with treatment.
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Acute toxicity in patients treated with concurrent chemoradiotherapy with proton versus intensity‐modulated radiation therapy for nonmetastatic head and neck cancers

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Abstract

Background

We evaluated if proton therapy is associated with decreased acute toxicities compared to intensity-modulated radiation therapy (IMRT) in patients receiving concurrent chemoradiotherapy for head and neck cancers.

Methods

We analyzed 580 patients with nonmetastatic head and neck cancers. Primary endpoint was any 90-day grade ≥3 toxicity, prospectively collected and graded per CTCAEv4. Modified Poisson regression models were used.

Results

Ninety-five patients received proton and 485 IMRT. The proton group had more HPV-positive tumors (65.6 vs. 58.0%, p = 0.049), postoperative treatment (76.8 vs. 62.1%, p = 0.008), unilateral neck treatment (18.9 vs. 6.6%, p < 0.001) and significantly lower doses to organs-at-risk compared to IMRT group. Adjusted for patient and treatment characteristics, the proton group had decreased grade 2 dysgeusia (RR0.67, 95%CI 0.53–0.84, p = 0.004) and a trend toward lower grade ≥3 toxicities (RR0.60, 95%CI 0.41–0.88, p = 0.06).

Conclusions

Proton therapy was associated with significantly reduced grade 2 dysgeusia and nonstatistically significant decrease in acute grade ≥3 toxicities compared to IMRT.
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Safety and Immunogenicity of COVID‐19 Vaccination in Patients with Hepatocellular Carcinoma (CHESS‐NMCID 2101): A Multicenter Prospective Study

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ABSTRACT

Data on safety and immunogenicity of coronavirus disease 2019 (COVID-19) vaccinations in hepatocellular carcinoma (HCC) patients are limited. In this multicenter prospective study, HCC patients received 2 doses of inactivated whole-virion COVID-19 vaccines. The safety and neutralizing antibody were monitored. Totally, 74 patients were enrolled from 10 centers in China, and 37 (50.0%), 25 (33.8%), and 12 (16.2%) received the CoronaVac, BBIBP-CorV, and WIBP-CorV, respectively. The vaccines were well tolerated, the injection site pain (6.8% [5/74]) and anorexia (2.7% [2/74]) were the most frequently local and systemic adverse events. The median level of neutralizing antibody was 13.5 (interquartile range [IQR]: 6.9-23.2) AU/mL at 45 (IQR: 19-72) days after the second dose of vaccinations, and 60.8% (45/74) of patients had positive neutralizing antibody. Additionally, lower gamma-glutamyl transpeptidase level was related to positive neutralizing antibody (odds r atio = 1.022 [1.003-1.049], p = 0.049). In conclusion, this study found that inactivated COVID-19 vaccinations are safe and the immunogenicity is acceptable or hyporesponsive in patients with HCC. Given that the potential benefits may outweigh the risks and the continuing emergences of novel severe acute respiratory syndrome coronavirus 2 variants, we suggest HCC patients to be vaccinated against COVID-19. Future validation studies are warranted.

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