TREM2+ and interstitial macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques

The COVID-19 pandemic remains a global health crisis, yet, the immunopathological mechanisms driving the development of severe disease remain poorly defined. Here, we utilize a rhesus macaque (RM) model of SARS-CoV-2 infection to delineate perturbations in the innate immune system during acute infection using an integrated systems analysis. We found that SARS-CoV-2 initiated a rapid infiltration (two days post infection) of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and induction of interferon-stimulated genes. At this early interval, we also observed a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generated a novel compendium of RM-specific lung macrophage gene expression using a combination of sc-RNA-Seq data and bulk RNA-Seq of purified populations under steady state conditions. Using these tools, we generated a longitudinal sc-RNA-seq dataset of airway cells in SARS-CoV-2-infected RMs. We identified that SARS-CoV-2 infection elicited a rapid recruitment of two subsets of macrophages into the airway: a C206+MRC1-population resembling murine interstitial macrophages, and a TREM2+ population consistent with CCR2+ infiltrating monocytes, into the alveolar space. These subsets were the predominant source of inflammatory cytokines, accounting for ~75% of IL6 and TNF production, and >90% of IL10 production, whereas the contribution of CD206+MRC+ alveolar macrophages was significantly lower. Treatment of SARS-CoV-2 infected RMs with baricitinib (Olumiant(R)), a novel JAK1/2 inhibitor that recently received Emergency Use Authorization for the treatment of hospitalized COVID-19 patients, was remarkably effective in eliminating the influx of infiltrating, non-alveolar macrophages in the alveolar space, with a concomitant reduction of inflammatory cytokines. This study has delineated the major subsets of lung macrophages driving inflammatory and anti-inflammatory cytokine production within the alveolar space during SARS-CoV-2 infection. One sentence summaryMulti-omic analyses of hyperacute SARS-CoV-2 infection in rhesus macaques identified two population of infiltrating macrophages, as the primary orchestrators of inflammation in the lower airway that can be successfully treated with baricitinib

Return to sports after anterior cruciate ligament reconstruction - a review of patients with minimum 5-year follow-up

<p><b>INTRODUCTION</b>It is difficult to counsel the anterior cruciate ligament (ACL) deficient patient considering surgical reconstruction on the likelihood of eventual return to sports as information on this is lacking, especially in the Asian context. We wanted to determine how many of our patients who had ACL surgery returned to their previous levels of sports, 5 years after their surgery. For those that had not returned to their previous levels of sports, we wanted to identify their reasons for not doing so.</p><p><b>MATERIALS AND METHODS</b>Based on our inclusion criteria of a minimum 5-year follow-up after primary ACL reconstruction, 146 patients were identified for assessment. Sixty-four patients were successfully recalled. The mean age of our patients was 24.8 years (range, 18 to 40). The patients completed the Lysholm Knee, Tegner activity and the Subjective International Knee Documentation Committee (IKDC) questionnaires. Clinical examination of the operated knee was performed according to the Objective IKDC evaluation form and with a KT-1000 arthrometer.</p><p><b>RESULTS</b>The mean Lysholm score was 85.2 and the mean subjective IKDC score was 79.5. 81.2% of our patients had normal or nearly normal knees (IKDC A or B) with the remaining 18.8% at IKDC grade C. The mean side-side difference for anterior translation using the KT-1000 arthrometer was 1.2 mm. The median pre-injury Tegner activity level was 7 and the median 5-year post-surgery Tegner activity level was 6. Nineteen patients did not return to their pre-injury sports levels because of social reasons and were excluded. From the remaining 45 patients, 28 patients (62.2%) returned to their previous level of sports and 17 patients (28.8%) did not return to their previous level of sports. Of whom, 9 (20%) said that they did not return due to fear of re-injury and the remaining 8 (17.8%) said they had not returned because of knee instability and pain. At 5 years, the subgroup of patients who had returned to sport had the best scores: Lysholm (88.5), subjective IKDC (84.6) and IKDC Grade A&B (89.3%). When we compared this with the subgroups that did not return to sport because of fear of re-injury and because of an unstable knee, we found that the difference in knee outcome scores between these 3 groups were statistically significant.</p><p><b>CONCLUSION</b>Sixty-two per cent of our patients returned to their previous level of sport at 5 years after ACL reconstruction. Fear of reinjury is an important psychological factor for these patients not returning to sports. Our results would allow the attending surgeon to counsel the ACL deficient patient who is considering surgical reconstruction the likelihood of eventual return to sports.</p>

Coefficient Variations of Serum Levels of Phenytoin, Carbamazepine, and Valproic Acid in Compliant Epileptics

Compliance of epileptic patients is one of the most important factors for adequate therapy. Recently, it had been shown that the variability of three serial measurement of the serum levels of antiepileptic drug(AED) may be used as an indication of the degree of compliance. Coefficient variation(CV) of serum drug levels calculated by only one AED had been used to determine the compliance in epileptic patients who took multiple AEDs. We attempted to evaluate the CV of AEDs and then find the objective clue of compliance and the compatible therapeutic planing according to CV. Ninety seven epileptic patients of outpatients department of the Gyengsang National University Hospital were entered to this study. All patients were taking medication at least for 6 months without any changes of drug regimen. Patient's information was acquired by reviewing the chart and interview with questionnaire. With these informations, we determined the compliance of the patients. Antiepileptic serum levels were measured three times at intervals of at least two to four weeks apart, and their CV was calculated. We compared the CV between the compliant and non-compliant group in each AED(phenytoin, carbamazepine , valproic acid) and three drugs in the compliant group. The mean CVs of phenytoin, carbamazepine and valproic acid in the compliant group were 18.3+/-13.0, 15.2+/-10.2 and 23.8+/-8.9, respectively(mean+/-SD). The mean of CV in the compliant and the non-compliant group were 17.9+/-10.9 and 38.8+/-27.2, respectively. The CVs of the compliant group were significantly lower than those of the non-compliant group(p<0.05). However, CVs had no significant difference between three antiepileptic drugs. This study showed that CVs of AEDs were not different between each AEDs, even though they possess different pharmacokinetic properties. Therefore, the CV of one AED can be used in determining the compliance of the epileptics who are taking multiple AEDs.

A non-invasive protocol for the determination of lumbar spine mobility.

OBJECTIVE: This article presents a non-invasive protocol for the determination of lumbar spine mobility and compares intersegmental lumbar spinal mobility data from 45 subjects using both radiographic (invasive) and videographic (non-invasive) techniques. DESIGN: Non-linear mathematical models were developed to transfer skin marker coordinates into corresponding vertebral body positions. BACKGROUND: To relate skin surface motion with that of the underlying vertebrae and to enhance the reliability of using the non-invasive technique relied on a model of transformation. METHODS: This set of models was developed by taking the L(4) skinfold, the L(1)-S(1) skin distraction, and the non-linear difference between the lumbar spinal profile and the skin profile into consideration. Based on the digitized and model transformed data, the intersegmental joint angles (ISA) and intersegmental joint mobilities (ISM) were calculated and compared. RESULTS: In this study the non-invasive and invasive coordinate differences ranged from 0.485 to 1.099 cm; the mean ISA differences ranged from 0.29 to 2.08 degrees the mean ISM differences ranged from 0.62 to 1.88 degrees. CONCLUSIONS: With these small differences, the quality of the non-invasive protocol and the application of the transformation model were justified sufficient.

Predictive model of intersegmental mobility of lumbar spine in the sagittal plane from skin markers.

This article describes a sagittal motion model that transforms skin marker coordinates into corresponding vertebral body coordinates. Coordinate data were obtained from 45 subjects with radiopaque skin markers over the vertebral spinous processes. Data of 30 subjects were used for model development while data of the other Fifteen subjects were used for model validation. The subjects were subjected to lateral spinal radiographs in positions of neutral, flexion, and extension. The model was developed by taking the non-linear difference between lumbar spinal profile and skin profile, the L(4) skin-fold, and the difference of L(1)-S(1) skin distraction into consideration. Regression analysis shows high coefficients of determination (range, 62.43-99.86%; mean, 86.41%) in comparing the estimated position data with the actual data in all vertebral body positions. Based on the estimated coordinates, both the intersegmental joint angles and intersegmental joint mobilities were calculated. The result of this study using the non-invasive protocol and the transformation matrices demonstrated that the intersegmental sagittal motion of lumbar spine can be obtained with error ranged from 0.05 to 0.56 degrees.