Circadian rhythms are 24-h temporal patterns of biochemistry, physiology, and behavior that are an integral component of eukaryotic life (1, 2). The molecular circadian clock is a cell autonomous system composed of three conceptual components: a self-sustainable pacemaker that generates 24-h rhythmicity; an input pathway that allows the clock to be reset and entrained by temporal cues in the environment; and mechanisms of output that regulate molecular and biochemical pathways and ultimately translate to rhythms in physiology and behavior. The master circadian pacemaker resides in the suprachiasmatic nucleus (SCN) 2 of the hypothalamus (1). Additionally, peripheral tissues and cell lines contain self-sustaining clocks (3-6). The molecular clock is comprised of a series of transcriptional-translational feedback loops that take ϳ24 h to complete. The positive loop contains the basic helix-loop-helix (bHLH)/PAS (Per-Arnt-Sim) proteins BMAL1 (brain and muscle ARNT-like 1) and CLOCK (Circadian locomotor output cycle kaput) and/or NPAS2 (neuronal PAS domain-containing protein 2). These transcription factors interact through their PAS and HLH regions and bind to the promoter region of their target genes of the negative loop at specific E-box regulatory elements (CACGTG), resulting in transcriptional activation. The negative loop is comprised of the period (mPer1, mPer2, mPer3) and cryptochrome genes (mCry1, mCry2). Rev-ERB␣ and ROR␣ are additional components that close the interlocking loops, and additional loops have been identified (e.g. Dec1, Dec2), which are proposed to increase stability and precision of the clock (1, 2, 7-9).The clock is reset by Zeitgeber stimuli through input pathways that transiently induce or suppress levels of period gene transcripts (1, 2, 10, 11). In the case of the SCN, light activation of retinal photoreceptors and the retinal hypothalamic tract results in stimulation of SCN neurons. Activation of several intracellular signaling pathways culminates in the phosphorylation of Ca 2ϩ /cAMP response element binding protein (CREB) (12-15). Phospho-CREB (pCREB) can then bind to its response element, the CRE, within the promoter region of target genes, such as the immediate early gene c-fos and immediate early gene/clock genes mPer1 and mPer2. Phase shifts of the SCN clock by elements of the photic signaling pathways results in elevation of mPer1 (and sometimes mPer2). Nonphotic (arousal) generated phase shifts result in suppression of mPer1 (1, 11). Furthermore, phase shifts of clocks in peripheral tissues and cell lines by serum, hormone, and nutrient signaling elicit * This work was supported, in whole or in part, by NIGMS, National Institutes of Health Grant GM087508 (to G. E. D.

Summary Variations in the KCNJ6 gene appear to influence both acute and chronic pain phenotypes. G-protein coupled inwardly rectifying potassium (GIRK) channels are effectors determining degree of analgesia experienced upon opioid receptor activation by endogenous and exogenous opioids. The impact of GIRK-related genetic variation on human pain responses has received little research attention. We used a tag SNP approach to comprehensively examine pain-related effects of KCNJ3 (GIRK1) and KCNJ6 (GIRK2) gene variation. Forty-one KCNJ3 and 69 KCNJ6 tag SNPs were selected, capturing the known variability in each gene. The primary sample included 311 Caucasian patients undergoing total knee arthroplasty in whom post-surgical oral opioid analgesic medication order data were available. Primary sample findings were then replicated in an independent Caucasian sample of 63 healthy pain-free individuals and 75 individuals with chronic low back pain (CLBP) who provided data regarding laboratory acute pain responsiveness (ischemic task) and chronic pain intensity and unpleasantness (CLBP Only). Univariate quantitative trait analyses in the primary sample revealed that 8 KCNJ6 SNPs were significantly associated with the medication order phenotype (p < 0.05); overall effects of the KCNJ6 gene (gene set-based analysis) just failed to reach significance (p=.054). No significant KCNJ3 effects were observed. A continuous GIRK Related Risk Score (GRRS) was derived in the primary sample to summarize each individual's number of KCNJ6 “pain risk” alleles. This GRRS was applied to the replication sample, which revealed significant associations (p<.05) between higher GRRS values and lower acute pain tolerance and higher CLBP intensity and unpleasantness. Results suggest further exploration of the impact of KCNJ6 genetic variation on pain outcomes is warranted.

No abstract

Cochlear implantation in canal wall down mastoid (CWD) cavities is fraught with the issue of how best to manage the mastoid cavity. Decision points include whether the external auditory meatus should be overclosed, whether the implantation should be staged, or even if the eustachian tube should be plugged. Given these options, we sought to describe our experience of cochlear implantation in CWD cavities. Among evaluation of subjects ≥18 years of age, 9 had cochlear implants placed in CWD mastoid cavities, 7 of which had the external auditory meatus overclosed, while 2 maintained open cavities following implantation. With an average follow-up of 36.7 months (median, 22.8 months), 2 subjects who had overclosure developed meatal dehiscences requiring further intervention, while no complications were observed in the 2 patients who maintained open cavities.

Objective To determine the preoperative risk factors most predictive of prolonged length of stay (LOS) or admission to a skilled nursing facility (SNF) or inpatient rehabilitation center (IPR) after free flap reconstruction of the head and neck. Study Design Retrospective cohort study. Setting Tertiary academic medical center. Methods Retrospective review of 1008 patients who underwent tumor resection and free flap reconstruction of the head and neck at a tertiary referral center from 2002 to 2019. Results Of 1008 patients (65.7% male; mean age of 61.4 years, SD 14.0 years), 161 (15.6%) were discharged to SNF/IPR, and the median LOS was 7 days. In multiple linear regression analysis, Charlson Comorbidity Index (CCI; P < .001), American Society of Anesthesiologists (ASA) classification ( P = .021), female gender ( P = .023), and inability to tolerate oral diet preoperatively ( P = .006) were statistically significantly related to increased LOS, whereas age, body mass index (BMI), modified frailty index (MFI), a history of prior radiation or chemotherapy, and home oxygen use were not. Multiple logistic regression analysis demonstrated that CCI (odds ratio [OR] = 1.119, confidence interval [CI] 1.023-1.223), age (OR = 1.082, CI 1.056-1.108), and BMI <19.0 (OR = 2.141, CI 1.159-3.807) were the only variables statistically significantly related to posthospital placement in an SNF or IPR. Conclusion Common tools for assessing frailty and need for additional care may be inadequate in a head and neck reconstructive population. CCI appears to be the best of the aggregate metrics assessed, with significant relationships to both LOS and placement in SNF/IPR.