TIMELESS mutation alters phase responsiveness and causes advanced sleep phase.

Many components of the circadian molecular clock are conserved from flies to mammals; however, the role of mammalian Timeless remains ambiguous. Here, we report a mutation in the human TIMELESS (hTIM) gene that causes familial advanced sleep phase (FASP). Tim CRISPR mutant mice exhibit FASP with altered photic entrainment but normal circadian period. We demonstrate that the mutation prevents TIM accumulation in the nucleus and has altered affinity for CRY2, leading to destabilization of PER/CRY complex and a shortened period in nonmature mouse embryonic fibroblasts (MEFs). We conclude that TIM, when excluded from the nucleus, can destabilize the negative regulators of the circadian clock, alter light entrainment, and cause FASP.

Pathophysiologic Vasodilation in Cardiogenic Shock and Its Impact on Mortality.

BACKGROUND: Cardiogenic shock (CS) mortality remains near 40%. In addition to inadequate cardiac output, patients with severe CS may exhibit vasodilation. We aimed to examine the prevalence and consequences of vasodilation in CS. METHODS: We analyzed all patients hospitalized at a CS referral center who were diagnosed with CS stages B to E and did not have concurrent sepsis or recent cardiac surgery. Vasodilation was defined by lower systemic vascular resistance (SVR), higher norepinephrine equivalent dose, or a blunted SVR response to pressors. Threshold SVR values were determined by their relation to 14-day mortality in spline models. The primary outcome was death within 14 days of CS onset in multivariable-adjusted Cox models. RESULTS: This study included 713 patients with a mean age of 60 years and 27% females; 14-day mortality was 28%, and 38% were vasodilated. The median SVR was 1308 dynes•s•cm-5 (interquartile range, 870-1652), median norepinephrine equivalent was 0.11 µg/kg per minute (interquartile range, 0-0.2), and 28% had a blunted pressor response. Each 100-dynes•s•cm-5 decrease in SVR below 800 was associated with 20% higher mortality (adjusted hazard ratio, 1.23; P=0.004). Each 0.1-µg/kg per minute increase in norepinephrine equivalent dose was associated with 15% higher mortality (adjusted hazard ratio, 1.12; P<0.001). A blunted pressor response was associated with a nearly 2-fold mortality increase (adjusted hazard ratio, 1.74; P=0.003). CONCLUSIONS: Pathophysiologic vasodilation is prevalent in CS and independently associated with an increased risk of death. CS vasodilation can be identified by SVR <800 dynes•s•cm-5, high doses of pressors, or a blunted SVR response to pressors. Additional studies exploring mechanisms and treatments for CS vasodilation are needed.

Larger Prior Tibial Tunnel Size Is Associated with Increased Failure Risk following Revision Anterior Cruciate Ligament Reconstruction.

We hypothesize that larger prior tunnel size is associated with an increased risk of failure of single-stage revision anterior cruciate ligament reconstruction (ACLR) as defined by the performance of a re-revision (third) ACLR on the index knee. Retrospective review identified 244 patients who underwent single-stage revision ACLR at a single center with available preoperative radiographs. Patient and surgical factors were extracted by chart review. The maximum diameter of the tibial tunnel was measured on lateral radiographs and the maximum diameter of the femoral tunnel was measured on anteroposterior radiographs. Record review and follow-up phone calls were used to identify failure of the revision surgery as defined by re-revision ACLR on the index knee. One hundred and seventy-one patients (70%) were reviewed with a mean of 3.9 years follow-up. Overall, 23 patients (13.4%) underwent re-revision surgery. Mean tibial tunnel size was 12.6 ± 2.8 mm (range: 5.7-26.9 mm) and mean femoral tunnel size was 11.7 ± 2.8 mm (range: 6.0-23.0 mm). Re-revision risk increased with tibial tunnel size. Tibial tunnels 11 mm and under had a re-revision risk of 4.2%, while tunnels > 11 mm had a risk of 17.1% (relative risk: 4.1, p = 0.025). No significant association between femoral tunnel size and re-revision risk was noted. Patients with prior tibial tunnels > 11mm in diameter at revision surgery had significantly increased risk of re-revision ACLR. Further studies are needed to explore the relationship between prior tunnel size and outcomes of revision ACLR.