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Frailty has been noted as a powerful predictive preoperative tool for 30-day postoperative complications. We sought to evaluate the association between frailty and postoperative outcomes after colectomy for Clostridium difficile colitis. The National Surgical Quality and Improvement Program cross-institutional database was used for this study. Data from 470 patients with a diagnosis of C. difficile colitis were used in the study. Modified frailty index (mFI) is a previously described and validated 11-variable frailty measure used with the National Surgical Quality and Improvement Program to assess frailty. Outcome measures included serious morbidity, overall morbidity, and Clavien IV (requiring ICU) and Clavien V (mortality) complications. The median age was 70 years and body mass index was 26.9 kg/m2. 55.6 per cent of patients were females. 98.5 per cent of patients were assigned American Society of Anesthesiologists Class III or higher. The median mFI was 0.27 (0-0.63). Because mFI increased from 0 (non-frail) to 0.55 and above, the overall morbidity increased from 53.3 per cent to 84.4 per cent and serious morbidity increased from 43.3 per cent to 78.1 per cent. The Clavien IV complication rate increased from 30.0 per cent to 75.0 per cent. The mortality rate increased from 6.7 per cent to 56.2 per cent. On a multivariate analysis, mFI was an independent predictor of overall morbidity (AOR: 13.0; P < 0.05), mortality (AOR: 8.8; P = 0.018), cardiopulmonary complications (AOR: 6.8; P = 0.026), and prolonged length of hospital stay (AOR: 6.6; P = 0.045). Frailty is associated with increased risk of complications in C. difficile colitis patients undergoing colectomy. mFI is an easy-to-use tool and can play an important role in the risk stratification of these patients who generally have significant morbidity and mortality to begin with.

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The rate of ulcerative colitis (UC), an inflammatory bowel disease, has been on the rise in the United States for the last several decades. Colectomy can be performed when other treatment options cannot provide a reasonable quality of life to patients with UC. Frailty has been shown to be a strong tool for evaluating preoperative risk factors for poor postoperative outcomes. The National Surgical Quality and Improvement Program cross-institutional database was used for this study. Data from 943 patients who underwent colectomy for UC between 2005 and 2012 were evaluated. Modified frailty index (mFI) is a previously described and validated 11-variable frailty measure used in the National Surgical Quality and Improvement Program to assess frailty. Outcome measures included serious morbidity; overall morbidity; cardiopulmonary, septic, and wound complications; and Clavien class IV (requiring ICU) and V (mortality) complications. Median age was 46 years and median body mass index was 25.5 Kg/m2. In all, 54.3 per cent of patients were male and 39.38 per cent of patients were American Society of Anesthesiologists Class lll or higher. The median mFI was 0 (0-0.54). As the mFI increased from 0 (nonfrail) to 0.18 and above, the overall morbidity increased from 25.40 to 52.1 per cent (P < 0.05), serious morbidity increased from 14.9 to 42.1 per cent (P < 0.05), septic complications increased from 9.87 to 21.49 per cent (P < 0.05), cardiopulmonary complications increased from 2.98 to 23.14 per cent (P < 0.05), Clavien class IV complications increased from 3.5 to 26.5 per cent (P < 0.05), and Clavien V complications increased from 0.16 to 6.61 per cent (P < 0.05). On multivariate analysis, mFI was an independent predictor of septic complications [Adjusted Odds Ratio (AOR): 31.26; P = 0.006], cardiopulmonary complications (AOR: 216.3; P ≤ 0.001), serious morbidity(AOR: 66.8; P ≤ 0.001), overall morbidity (AOR: 25.5; P ≤ 0.001), Clavien class IV (AOR: 204.9; P ≤ 0.001) complications, and return to the operating room (AOR: 14.29; P = 0.048). Frailty is associated with an increase in morbidity and mortality after colectomy in patients with UC. mFI is an easy-to-use tool and can play an important role in the risk stratification of these patients.

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Migraine is one of the world's most common neurological disorders. Current acute migraine treatments have sub-optimal efficacy and new therapeutic options are needed. Approaches targeting calcitonin gene related peptide (CGRP) signaling are clinically effective but small molecule antagonists have not been advanced due to toxicity. In this study, we explored the axonal growth/specification collapsin response mediator protein 2 (CRMP2) as a novel "druggable" target for inhibiting CGRP release and for potential relevance for treatment of migraine pain. CRMP2 has been demonstrated to regulate N-type voltage gated Ca2+ channel (CaV2.2) activity and Ca2+-dependent CGRP release in sensory neurons. The co-expression of CRMP2 with CaV2.2 and CGRP in trigeminal ganglia (TG) sensory neurons suggested the possibility of a novel approach to regulate CGRP release in the trigeminal system. Screening protocols surprisingly revealed that (S)-Lacosamide ((S)-LCM), an inactive analog of the clinically-approved small molecule anti-epileptic drug (R)-Lacosamide (Vimpat®), inhibited CRMP2 phosphorylation by cyclin dependent kinase 5 (Cdk5) in rat TG slices and decreased depolarization-evoked Ca2+ influx in TG cells in culture. (S)-LCM significantly blocked capsaicin-evoked CGRP release from dural nerve terminals in the rat an ex vivo cranial cup preparation. Additionally, cephalic and extracephalic cutaneous allodynia (CA) induced in rats by activation of dural nociceptors with a cocktail of inflammatory mediators, was inhibited by oral administration of (S)-LCM. The confirmation of CRMP2 as an upstream mediator of CGRP release together with the brain penetrance of this molecule suggest (S)-LCM as a potential therapy for acute migraine.

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Chronic pain affects the life of millions of people. Current treatments have deleterious side effects. We have advanced a strategy for targeting protein interactions which regulate the N-type voltage-gated calcium (CaV2.2) channel as an alternative to direct channel block. Peptides uncoupling CaV2.2 interactions with the axonal collapsin response mediator protein 2 (CRMP2) were antinociceptive without effects on memory, depression, and reward/addiction. A search for small molecules that could recapitulate uncoupling of the CaV2.2-CRMP2 interaction identified (S)-lacosamide [(S)-LCM], the inactive enantiomer of the Food and Drug Administration-approved antiepileptic drug (R)-lacosamide [(R)-LCM, Vimpat]. We show that (S)-LCM, but not (R)-LCM, inhibits CRMP2 phosphorylation by cyclin dependent kinase 5, a step necessary for driving CaV2.2 activity, in sensory neurons. (S)-lacosamide inhibited depolarization-induced Ca influx with a low micromolar IC50. Voltage-clamp electrophysiology experiments demonstrated a commensurate reduction in Ca currents in sensory neurons after an acute application of (S)-LCM. Using constellation pharmacology, a recently described high content phenotypic screening platform for functional fingerprinting of neurons that uses subtype-selective pharmacological agents to elucidate cell-specific combinations (constellations) of key signaling proteins that define specific cell types, we investigated if (S)-LCM preferentially acts on certain types of neurons. (S)-lacosamide decreased the dorsal root ganglion neurons responding to mustard oil, and increased the number of cells responding to menthol. Finally, (S)-LCM reversed thermal hypersensitivity and mechanical allodynia in a model of postoperative pain, and 2 models of neuropathic pain. Thus, using (S)-LCM to inhibit CRMP2 phosphorylation is a novel and efficient strategy to treat pain, which works by targeting specific sensory neuron populations.

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