SM03, an Anti-CD22 Antibody, Converts Cis-to-Trans Ligand Binding of CD22 against α2,6-Linked Sialic Acid Glycans and Immunomodulates Systemic Autoimmune Diseases.

SM03, an anti-CD22 recombinant IgG1 mAb, is currently in a phase III clinical trial for the treatment of rheumatoid arthritis (NCT04312815). SM03 showed good safety and efficacy in phase I systemic lupus erythematosus and phase II moderate to severe rheumatoid arthritis clinical trials. We propose the success of SM03 as a therapeutic to systemic autoimmune diseases is through the utilization of a novel mechanism of action unique to SM03. CD22, an inhibitory coreceptor of the BCR, is a potential immunotherapeutic target against autoimmune diseases. SM03 could disturb the CD22 homomultimeric configuration through disrupting cis binding to α2,6-linked sialic acids, induce rapid internalization of CD22 from the cell surface of human B cells, and facilitate trans binding between CD22 to human autologous cells. This in turn increased the activity of the downstream immunomodulatory molecule Src homology region 2 domain-containing phosphatase 1 (SHP-1) and decreased BCR-induced NF-κB activation in human B cells and B cell proliferation. This mechanism of action gives rationale to support the significant amelioration of disease and good safety profile in clinical trials, as by enabling the "self" recognition mechanism of CD22 via trans binding to α2,6 sialic acid ligands on autologous cells, SM03 specifically restores immune tolerance of B cells to host tissues without affecting the normal B cell immune response to pathogens.

Voluntary Exercise-Induced Activation of Thyroid Axis and Reduction of White Fat Depots Is Attenuated by Chronic Stress in a Sex Dimorphic Pattern in Adult Rats.

The activity of the hypothalamus-pituitary-thyroid (HPT) axis is inhibited by energy deficit, by acute or chronic stress, but activated by cold exposure or exercise. Because stress curtails acute cold induced activation of HPT, we evaluated the effect of chronic stress on HPT axis response to voluntary exercise, a persistent energy-demanding situation. Adult male and female Wistar rats were exposed to restraint stress, 30 min/day for 2 weeks, or to isolation (Iso) [post-natal day [PND] 30-63]. Exercise was performed (7 p.m.-7 a.m.) in a running wheel, sedentary controls stayed in individual cages (Sed); at 7 a.m. they were housed with their cage mate or individually (Iso); food intake by the exercised group was measured day and night to pair-fed Sed. At sacrifice, hormones, mRNA levels and tissue weights were quantified. Control or restrained adult rats had access to running wheel daily for 2 weeks. Compared to C, exercise decreased white adipose tissue (WAT) mass in females and males, increased hypothalamic paraventricular nucleus (PVN)-Trh expression in males proportionally to exercise performed, and increased TSH and T4 serum concentration in females. These changes were not detected in restrained groups. Starting at PND 63 control (2/cage) and isolated (1/cage) rats either exercised on 10 alternated nights or were sedentary. In control male animals, compared to Sed rats, exercise did not decrease WAT mass, nor changed HPT axis activity, but increased Pomc and deiodinase 2 (Dio2) expression in mediobasal hypothalamus (MBH), adrenergic receptor ß3 and uncoupling protein-1 in brown adipose tissue. In control female animals, exercise decreased WAT mass, increased Pomc, Dio2, and Trhde expression in MBH, and TSH serum concentration. Iso females had lower TSH and T4 serum concentration, Dio2 and Trhde expression in MBH than controls. The stress response was higher in isolated males than females, but in males it did not alter the effects of exercise, in contrast to isolated females that had a blunted response to exercise compared to controls. In conclusion, chronic stress interferes with metabolic effects produced by exercise, such as loss of WAT mass, coincident with dampening of HPT activity.

Cost of Cardiac Surgery in Frail Compared With Nonfrail Older Adults.

BACKGROUND: Frailty is a risk factor for mortality, morbidity, and prolonged length of stay after cardiac surgery, all of which are major drivers of hospitalization costs. The incremental hospitalization costs incurred in frail patients have yet to be elucidated. METHODS: Patients aged ≥ 60 years were evaluated for frailty before coronary artery bypass grafting or heart valve surgery at 2 academic centres between 2013 and 2015 as part of the McGill Frailty Registry. Total costs were summed from the date of the index surgery to the date of hospital discharge. Mutivariable linear regression was used to determine the association between preoperative frailty status and total costs after adjusting for conventional surgical risk factors. RESULTS: Among 235 patients included in the analysis, the median age was 73.0 years (interquartile range [IQR], 70.0-78.0 years) and 68 (29%) were women. The median cost was $32,742 (IQR, $23,221-$49,627) in 91 frail patients compared with $23,370 (IQR, $19,977-$29,705) in 144 nonfrail patients. Seven extreme-cost cases > $100,000 were identified, and all of the patients in these cases exhibited baseline frailty. In the multivariable model, total costs were independently associated with frailty (adjusted additional cost, $21,245; 95% confidence interval [CI], $12,418-$30,073; P < 0.001) and valve surgery (adjusted additional cost, $20,600; 95% CI, $9,661-$31,539; P < 0.001). CONCLUSIONS: Frailty is associated with a marked increase in hospitalization costs after cardiac surgery, an effect that persists after adjusting for age, sex, surgery type, and surgical risk score. Further efforts are needed to optimize care and resource use in this vulnerable population.

Psoas Muscle Area and Length of Stay in Older Adults Undergoing Cardiac Operations.

BACKGROUND: Frailty assessment can help predict which older adults will experience adverse events after cardiac surgical procedures. Low muscle mass is a core component of frailty that is suboptimally captured by self-reported weight loss; refined measures using computed tomographic (CT) images have emerged and are predictive of outcomes in noncardiac surgical procedures. The objective of this study was to evaluate the association between CT muscle area and length of stay (LOS) after cardiac surgical procedures. METHODS: Frail patients who had a perioperative abdominal or thoracic CT scan were identified. The CT scans were analyzed to measure cross-sectional lean muscle area at the L4 vertebra (psoas muscle area [PMA], lumbar muscle area [LMA]) and the T4 vertebra (thoracic muscle area [TMA]). The associations of PMA, LMA, and TMA with frailty markers and postoperative LOS were investigated. RESULTS: Eighty-two patients were included; the mean age was 69.2 ± 9.97 years. Low muscle area was correlated with lower handgrip strength and short physical performance battery (SPPB) scores indicative of physical frailty. Postoperative LOS was correlated with PMA (R = -0.47, p = 0.004), LMA (R = -0.41, p = 0.01), and TMA (R = -0.29, p = 0.03). After adjustment for the predicted risk of prolonged LOS, age, sex, and body surface area, PMA remained significantly associated with LOS (ß = -2.35, 95% CI -4.48 to -0.22). The combination of low PMA and handgrip strength, indicative of sarcopenia, yielded the greatest incremental value in predicting LOS. CONCLUSIONS: Low PMA is a marker of physical frailty associated with increased LOS in older adults undergoing cardiac surgical procedures. Further research is necessary to validate PMA as a prognostic marker and therapeutic target in this vulnerable population.

A BMP-Shh negative-feedback loop restricts Shh expression during limb development.

Normal patterning of tissues and organs requires the tight restriction of signaling molecules to well-defined organizing centers. In the limb bud, one of the main signaling centers is the zone of polarizing activity (ZPA) that controls growth and patterning through the production of sonic hedgehog (SHH). The appropriate temporal and spatial expression of Shh is crucial for normal limb bud patterning, because modifications, even if subtle, have important phenotypic consequences. However, although there is a lot of information about the factors that activate and maintain Shh expression, much less is known about the mechanisms that restrict its expression to the ZPA. In this study, we show that BMP activity negatively regulates Shh transcription and that a BMP-Shh negative-feedback loop serves to confine Shh expression. BMP-dependent downregulation of Shh is achieved by interfering with the FGF and Wnt signaling activities that maintain Shh expression. We also show that FGF induction of Shh requires protein synthesis and is mediated by the ERK1/2 MAPK transduction pathway. BMP gene expression in the posterior limb bud mesoderm is positively regulated by FGF signaling and finely regulated by an auto-regulatory loop. Our study emphasizes the intricacy of the crosstalk between the major signaling pathways in the posterior limb bud.

How do we get a perfect complement of digits?

A crucial issue in limb development is how a correct set of precisely shaped digits forms in the digital plate. This process relies on patterning across the anterior-posterior axis of the limb bud, which is under the control of Sonic hedgehog emanating from the zone of polarizing activity. Recently, Sonic hedgehog function in the limb bud has been shown to have a dual character controlling both growth and patterning of the digital field. This finding has prompted the proposal of new models of how these two functions are achieved, and this will be discussed in this review.

Risk factors for prolonged stay in the intensive care unit and on the ward after cardiac surgery.

BACKGROUND: Prolonged length of stay (LOS) after cardiac surgery has been associated with poor outcome and a considerable expenditure of health care resources. As our patient's demographics are changing, a continuing evaluation of the preoperative and intraoperative variables affecting LOS in the intensive care unit (ICU) and on the floor remains important. METHODS: This is a prospective study examining the determinants of prolonged LOS in 426 consecutive patients after cardiac surgery. Univariate and multivariate analyses were performed for an ICU stay > or =2 days and for a stay on the floor >7 days. Secondary outcome was the incidence of postoperative complications. RESULTS: Among all patients, 27.7% had a prolonged stay in the ICU. Univariate analysis revealed 13 perioperative variables that were significantly associated with prolonged stay. Independent predictors for extended ICU LOS included an ejection fraction <40% (RR 1.83; p = 0.04), high Parsonnet score (RR 2.23; p = 0.012), history of renal failure (RR 5.39; p = 0.001), and an emergency surgery (RR 2.43; p = 0.007). Furthermore, 30.5% of patients had an extended stay on the floor with female gender (RR 1.93; p = 0.009) and age (RR 2.55; p = 0.0001) being two independent risk factors. CONCLUSIONS: In this series of 426 consecutive patients, we have identified several perioperative risk factors associated with prolonged hospitalization that can help clinicians in their preoperative patient counseling, risk stratification, and selection. However, the most obvious use of these results is in allowing decision makers to implement specific strategies that would best allocate resources depending on the risk profile of cardiac patients.