Online Bayesian optimization of vagus nerve stimulation.

Objective.In bioelectronic medicine, neuromodulation therapies induce neural signals to the brain or organs, modifying their function. Stimulation devices capable of triggering exogenous neural signals using electrical waveforms require a complex and multi-dimensional parameter space to control such waveforms. Determining the best combination of parameters (waveform optimization or dosing) for treating a particular patient's illness is therefore challenging. Comprehensive parameter searching for an optimal stimulation effect is often infeasible in a clinical setting due to the size of the parameter space. Restricting this space, however, may lead to suboptimal therapeutic results, reduced responder rates, and adverse effects.Approach. As an alternative to a full parameter search, we present a flexible machine learning, data acquisition, and processing framework for optimizing neural stimulation parameters, requiring as few steps as possible using Bayesian optimization. This optimization builds a model of the neural and physiological responses to stimulations, enabling it to optimize stimulation parameters and provide estimates of the accuracy of the response model. The vagus nerve (VN) innervates, among other thoracic and visceral organs, the heart, thus controlling heart rate (HR), making it an ideal candidate for demonstrating the effectiveness of our approach.Main results.The efficacy of our optimization approach was first evaluated on simulated neural responses, then applied to VN stimulation intraoperatively in porcine subjects. Optimization converged quickly on parameters achieving target HRs and optimizing neural B-fiber activations despite high intersubject variability.Significance.An optimized stimulation waveform was achieved in real time with far fewer stimulations than required by alternative optimization strategies, thus minimizing exposure to side effects. Uncertainty estimates helped avoiding stimulations outside a safe range. Our approach shows that a complex set of neural stimulation parameters can be optimized in real-time for a patient to achieve a personalized precision dosing.

Smoking cessation outcomes of referral to a specialist hospital outpatient clinic.

BACKGROUND AND OBJECTIVES: Hospital visits are an opportunity to engage smokers in tobacco treatment. However, little is known about engagement in follow-up referrals. The purpose of this study is to report the rates of program engagement and smoking cessation outcomes of patients referred to a specialist outpatient tobacco treatment program after a hospital visit or other referral. METHODS: A retrospective chart review was used to examine the outcomes of 486 participants referred to a hospital-based smoking cessation clinic provided by tobacco treatment specialists. Referral sources, demographics and smoking, medical, psychiatric, and substance use history were obtained. The main outcomes of interest were engagement in the program and 7-day point-prevalence of smoking abstinence. RESULTS: Sixty-eight percent of participants who were referred to the program were considered "engaged," of which 70% were from hospitals, 4% from community programs, 11% were from general practitioners, and 16% were self-referrals. Thirty-percent (98/331) of engagers were abstinent by time of chart review (30% from the hospital, 8% from community programs, 19% from general practitioners, and 39% of self-referrals). Having quit for 1 month or longer at the past quit attempt, greater confidence in quitting smoking, lower expired carbon monoxide levels at baseline, and greater duration in the program were significant predictors of successful smoking cessation. DISCUSSION AND CONCLUSION: Providing tobacco treatment follow-up and referral for smokers after a hospital visit is important to enhance smoking cessation efforts. SCIENTIFIC SIGNIFICANCE: Referral to evidence-based tobacco treatment after hospital visits is effective. Models of tobacco treatment based on sources of referral should further be explored.

Melanopsin and rod-cone photoreceptors play different roles in mediating pupillary light responses during exposure to continuous light in humans.

In mammals, the pupillary light reflex is mediated by intrinsically photosensitive melanopsin-containing retinal ganglion cells that also receive input from rod-cone photoreceptors. To assess the relative contribution of melanopsin and rod-cone photoreceptors to the pupillary light reflex in humans, we compared pupillary light responses in normally sighted individuals (n = 24) with a blind individual lacking rod-cone function. Here, we show that visual photoreceptors are required for normal pupillary responses to continuous light exposure at low irradiance levels, and for sustained pupillary constriction during exposure to light in the long-wavelength portion of the visual spectrum. In the absence of rod-cone function, pupillomotor responses are slow and sustained, and cannot track intermittent light stimuli, suggesting that rods/cones are required for encoding fast modulations in light intensity. In sighted individuals, pupillary constriction decreased monotonically for at least 30 min during exposure to continuous low-irradiance light, indicating that steady-state pupillary responses are an order of magnitude slower than previously reported. Exposure to low-irradiance intermittent green light (543 nm; 0.1-4 Hz) for 30 min, which was given to activate cone photoreceptors repeatedly, elicited sustained pupillary constriction responses that were more than twice as great compared with exposure to continuous green light. Our findings demonstrate nonredundant roles for rod-cone photoreceptors and melanopsin in mediating pupillary responses to continuous light. Moreover, our results suggest that it might be possible to enhance nonvisual light responses to low-irradiance exposures by using intermittent light to activate cone photoreceptors repeatedly in humans.

Quality of diagnosis and surgical management of breast lesions in a community hospital: room for improvement?

BACKGROUND: We aimed to examine both the diagnostic modalities used to identify breast lesions and their surgical management in an Ontario community hospital. METHODS: We conducted a retrospective chart review of the preoperative diagnostic tools used by 6 general surgeons for palpable and nonpalpable breast lesions and considered the types of surgical procedures performed. Patients who underwent noncosmetic breast surgery in the year 2000 were included in the study (n = 180). RESULTS: Of the 182 breast lesions, 89 (49%) were malignant. Of the 100 palpable lesions removed, fine needle aspiration biopsy (FNAB) was performed on 48. Positive FNABs in this study were highly predictive of malignancy (100%). Only 1 core needle biopsy was performed on a palpable lesion. Of the 78 mammograms obtained for nonpalpable lesions, the PPV (positive predictive value) of malignancy for "suggestive" lesions was 100%, 75% for "suspicious" lesions, 40% for "probably benign" lesions, 0% for "benign" lesions and 37% for lesions categorized as "needs additional imaging." Other preoperative diagnostic tools used were ultrasonography (n = 44) and stereotactic biopsies (n = 3). Of the initial operations performed, 76 were lumpectomies and 88 were needle-localized biopsies. Only 15 patients underwent initial definitive procedures, and of these 5 had positive margins and 8 had close (< or = 1-mm) margins. Positive margins were found in 35% of the needle-localized lumpectomies (61% had a close margin), in 60% of lumpectomies (75% had a close margin) and in 2 of the 5 lumpectomies with axillary node dissections done as first operations. Six frozen sections were obtained. Only 11% of surgical specimens were oriented for pathology. Reoperations were performed on 91% of women with malignancies (or 67% with a close margin). CONCLUSIONS: Considerable variation existed between surgeons with regard to the types of preoperative diagnostic procedure used and operations performed. The rate of positive margins was high, which resulted in many reoperations.

Isolated sulfite oxidase deficiency: a case report with a novel mutation and review of the literature.

Isolated sulfite oxidase deficiency is a rare but devastating neurologic disease that usually presents in early infancy with seizures and alterations in muscle tone. Only 21 cases have been reported in the literature. We report a case of a newborn infant boy with isolated sulfite oxidase deficiency who presented with generalized seizures on his fourth day of life. Plasma total homocysteine was not detectable. Urinary sulfite, thiosulfate, and S-sulfocysteine levels were elevated. The patient began a low-methionine and low-cysteine diet and was treated with thiamine and dextromethorphan. However, he became increasingly microcephalic and was severely developmentally delayed. Mutation analysis of the sulfite oxidase gene revealed that the patient was homozygous for a novel 4-base pair deletion, and both of his parents were found to be heterozygous carriers of the same deletion. We reviewed the clinical, biochemical, neuroradiologic, and neuropathologic features in all published cases of isolated sulfite oxidase deficiency. Seizures or abnormal movements were prominent features in all cases. Developmental delays were reported in 17 cases. Ectopia lentis was detected in 9 cases. Clinical improvement with dietary therapy was seen in only 2 patients, both of whom presented after the age of 6 months and had relatively mild developmental delays. Plasma or urinary S-sulfocysteine levels were elevated in all cases. Urinary sulfite was detected in all except 1 case. Cerebral atrophy and cystic encephalomalacia were observed with neuroradiologic imaging and were noted in all 3 postmortem reports of isolated sulfite oxidase deficiency. The main alternative in the differential diagnosis of isolated sulfite oxidase deficiency is molybdenum cofactor deficiency.