Yaniv Dotan

Implanted upper airway stimulation device for obstructive sleep apnea

Previous feasibility studies have shown that electrical stimulation of the hypoglossal nerve can improve obstructive sleep apnea (OSA). The current study examined the safety and preliminary effectiveness of a second generation device, the Upper Airway Stimulation (UAS) system, and identified baseline predictors for therapy success.

A novel host-proteome signature for distinguishing between acute bacterial and viral infections.

Bacterial and viral infections are often clinically indistinguishable, leading to inappropriate patient management and antibiotic misuse. Bacterial-induced host proteins such as procalcitonin, C-reactive protein (CRP), and Interleukin-6, are routinely used to support diagnosis of infection. However, their performance is negatively affected by inter-patient variability, including time from symptom onset, clinical syndrome, and pathogens. Our aim was to identify novel viral-induced host proteins that can complement bacterial-induced proteins to increase diagnostic accuracy. Initially, we conducted a bioinformatic screen to identify putative circulating host immune response proteins. The resulting 600 candidates were then quantitatively screened for diagnostic potential using blood samples from 1002 prospectively recruited patients with suspected acute infectious disease and controls with no apparent infection. For each patient, three independent physicians assigned a diagnosis based on comprehensive clinical and laboratory investigation including PCR for 21 pathogens yielding 319 bacterial, 334 viral, 112 control and 98 indeterminate diagnoses; 139 patients were excluded based on predetermined criteria. The best performing host-protein was TNF-related apoptosis-inducing ligand (TRAIL) (area under the curve [AUC] of 0.89; 95% confidence interval [CI], 0.86 to 0.91), which was consistently up-regulated in viral infected patients. We further developed a multi-protein signature using logistic-regression on half of the patients and validated it on the remaining half. The signature with the highest precision included both viral- and bacterial-induced proteins: TRAIL, Interferon gamma-induced protein-10, and CRP (AUC of 0.94; 95% CI, 0.92 to 0.96). The signature was superior to any of the individual proteins (P<0.001), as well as routinely used clinical parameters and their combinations (P<0.001). It remained robust across different physiological systems, times from symptom onset, and pathogens (AUCs 0.87-1.0). The accurate differential diagnosis provided by this novel combination of viral- and bacterial-induced proteins has the potential to improve management of patients with acute infections and reduce antibiotic misuse.

Parameters affecting pharyngeal response to genioglossus stimulation in sleep apnoea

Chronic stimulation of the hypoglossus nerve may provide a new treatment modality for obstructive sleep apnoea (OSA). In previous studies we observed large differences in response to stimulation of the genioglossus (GG). We hypothesised that both individual patient characteristics and the area of the GG stimulated are responsible for these differences. In the present study, we compared the response to GG electrical stimulation at the anterior area (GGa-ES), which activates the whole GG and the posterior area (GGp-ES), which activates preferentially the longitudinal fibres. Studies were performed in 14 propofol-sedated OSA patients. The parameters evaluated included cephalometry, pressure–flow relationship and pharyngeal shape and compliance assessed by pharyngoscopy. Compared with GGa-ES, GGp-ES resulted in significantly larger decreases in the critical value of end-expiratory pressure (Pcrit) (from 3.8±2.2 to 2.9±3.3 and -2.0±3.9 cmH2O, respectively (p<0.001)). Both tongue size and velopharyngeal shape (anteroposterior to lateral ratio) correlated significantly with the decrease in Pcrit during GGp-ES (R = 0.53 and -0.66, respectively; p<0.05). In the patients with the larger tongue size (n = 7), the decrease in Pcrit reached 8.0±2.2 cmH2O during GGp-ES. We conclude that directing stimulation to longitudinal fibres of the GG improves the flow-mechanical effect. In addition, patients with large tongues and narrow pharynx tend to respond better to GGp-ES.

Dissociation of electromyogram and mechanical response in sleep apnoea during propofol anaesthesia

Pharyngeal collapsibility during sleep is believed to increase due to a decline in dilator muscle activity. However, genioglossus electromyogram (EMG) often increases during apnoeas and hypopnoeas, often without mechanical effect. 17 patients with obstructive sleep apnoea were anaesthetised and evaluated from termination of propofol administration to awakening. Genioglossus EMG, flow and pharyngeal area (pharyngoscopy) were monitored. Prolonged hypopnoeas enabled evaluation of the relationships between genioglossus EMG and mechanical events, before and after awakening. Additional dilator muscle EMGs were recorded and compared to the genioglossus. Electrical stimulation of the genioglossus was used to evaluate possible mechanical dysfunction. Prolonged hypopnoeas during inspiration before arousal triggered an increase in genioglossus EMG, reaching mean±sd 62.2±32.7% of maximum. This augmented activity failed to increase flow and pharyngeal area. Awakening resulted in fast pharyngeal enlargement and restoration of unobstructed flow, with marked reduction in genioglossus EMG. Electrical stimulation of the genioglossus under propofol anaesthesia increased the inspiratory pharyngeal area (from 25.1±28 to 66.3±75.5 mm2; p<0.01) and flow (from 11.5±6.5 to 18.6±9.2 L·min−1; p<0.001), indicating adequate mechanical response. All additional dilators increased their inspiratory activity during hypopnoeas. During propofol anaesthesia, pharyngeal occlusion persists despite large increases in genioglossus EMG, in the presence of a preserved mechanical response to electrical stimulation.

Asynchrony of lingual muscle recruitment during sleep in obstructive sleep apnea

Pharyngeal collapsibility during sleep increases primarily due to decline in dilator muscle activity. However, genioglossus EMG is known to increase during apneas and hypopneas, usually without reversing upper airway obstruction or inspiratory flow limitation. The present study was undertaken to test the hypothesis that intense activation of the genioglossus fails to prevent pharyngeal obstruction during sleep, and to evaluate if sleep-induced changes in tongue muscle coordination may be responsible for this phenomenon. We compared genioglossus and tongue retractors EMG activity in 13 obstructive sleep apnea (OSA) patients during wakefulness, while breathing through inspiratory resistors, to the activity observed at the end of apneas and hypopneas after 25 mg of brotizolam, before arousal, at equal esophageal pressure. During wakefulness, resistive breathing triggered increases in both genioglossus and retractor EMG. Activation of agonist tongue muscles differed considerably from that of the arm, as both genioglossus and retractors were activated similarly during all tongue movements. During sleep, flow limitation triggered increases in genioglossal EMG that could reach more than twofold the level observed while awake. In contrast, EMGs of the retractors reached less than half the wakefulness level. In sleeping OSA patients, genioglossal activity may increase during obstructed breathing to levels that exceed substantially those required to prevent pharyngeal collapse during wakefulness. In contrast, coactivation of retractors is deficient during sleep. These findings suggest that sleep-induced alteration in tongue muscle coordination may be responsible for the failure of high genioglossal EMG activity to alleviate flow limitation.

A novel host-protein assay outperforms routine parameters for distinguishing between bacterial and viral lower respiratory tract infections

Bacterial and viral lower respiratory tract infections (LRTIs) are often clinically indistinguishable, leading to antibiotic overuse. We compared the diagnostic accuracy of a new assay that combines 3 host-biomarkers (TRAIL, IP-10, CRP) with parameters in routine use to distinguish bacterial from viral LRTIs. Study cohort included 184 potentially eligible pediatric and adult patients. Reference standard diagnosis was based on adjudication by an expert panel following comprehensive clinical and laboratory investigation (including respiratory PCRs). Experts were blinded to assay results and assay performers were blinded to reference standard outcomes. Evaluated cohort included 88 bacterial and 36 viral patients (23 did not fulfill inclusion criteria; 37 had indeterminate reference standard outcome). Assay distinguished bacterial from viral LRTI patients with sensitivity of 0.93±0.06 and specificity of 0.91±0.09, outperforming routine parameters, including WBC, CRP and chest x-ray signs. These findings support the assays potential to help clinicians avoid missing bacterial LRTIs or overusing antibiotics.

Alteration in upper airway dilator muscle coactivation during sleep: Comparison of patients with obstructive sleep apnea and healthy subjects

In patients with obstructive sleep apnea (OSA), substantial increases in genioglossus (GG) activity during hypopneas/apneas usually fail to restore normal airflow. We have previously suggested that sleep-induced alteration in tongue muscle coordination may explain this finding, as retractor muscle coactivation was reduced during sleep compared with wakefulness. The present study was undertaken to evaluate whether these alterations in dilator muscle activation during sleep play a role in the pathogenesis of OSA and whether coactivation of additional peripharyngeal muscles (non-GG muscles: styloglossus, geniohyoid, sternohyoid, and sternocleidomastoid) is also impaired during sleep. We compared GG and non-GG muscle electromyographic (EMG) activity in 8 patients with OSA and 12 healthy subjects during wakefulness while breathing through inspiratory resistors with the activity observed during sleep toward the end of flow limitation, before arousal, at equivalent esophageal pressures. During wakefulness, resistive breathing triggered increases in both GG and non-GG muscle activity. During sleep, flow limitation was associated with increases in GG-EMG that reached, on average, >2-fold the level observed while awake. In contrast, EMGs of the non-GG muscles, recorded simultaneously, reached, on average, only ~2/3 the wakefulness level. We conclude that during sleep GG activity may increase to levels that substantially exceed those sufficient to prevent pharyngeal collapse during wakefulness, whereas other peripharyngeal muscles do not coactivate during sleep in both patients with OSA and healthy subjects. We speculate that upper airway muscle dyssynchrony during sleep may explain why GG-EMG activation fails to alleviate flow limitation and stabilize airway patency during sleep. NEW & NOTEWORTHY Pharyngeal obstruction during sleep may trigger genioglossus activity to levels substantially exceeding those observed during wakefulness, without ameliorating flow limitation. In contrast, other peripharyngeal muscles exhibit a much lower activity during sleep in both patients with obstructive sleep apnea and healthy subjects. Coordinated muscular synergy stabilizes the pharynx despite relatively low activity while awake, yet even higher genioglossal activity allows the pharynx to obstruct when simultaneous activity of other dilator muscles is inadequate during sleep.

Differential effects of respiratory and electrical stimulation-induced dilator muscle contraction on mechanical properties of the pharynx in the pig

Respiratory stimulation (RS) during sleep often fails to discontinue flow limitation, whereas electrical stimulation (ES) of the hypoglossus (HG) nerve frequently prevents obstruction. The present work compares the effects of RS and HG-ES on pharyngeal mechanics and the relative contribution of tongue muscles and thoracic forces to pharyngeal patency. We determined the pressure-area relationship of the collapsible segment of the pharynx in anesthetized pigs under the following three conditions: baseline (BL), RS induced by partial obstruction of the tracheostomy tube, and HG-ES. Parameters were obtained also after transection of the neck muscles and the trachea (NMT) and after additional bilateral HG transection (HGT). In addition, we measured the force produced by in situ isolated geniohyoid (GH) during RS and HG-ES. Intense RS was recognized by large negative intrathoracic pressures and triggered high phasic genioglossus and GH EMG activity. GH contraction produced during maximal RS less than a quarter of the force obtained during HG-ES. The major finding of the study was that RS and ES differed in the mechanism by which they stabilized the pharynx: RS lowered the pressure-area slope, i.e., reduced pharyngeal compliance (14.1 ± 2.9 to 9.2 ± 1.9 mm(2)/cmH2O, P < 0.01). HG-ES shifted the slope toward lower pressures, i.e., lowered the calculated extraluminal pressure (17.4 ± 5.8 to 9.2 ± 7.4 cmH2O, P < 0.01). Changes during RS and HG-ES were not affected by NMT, but the effect of RS decreased significantly after HGT. In conclusion, HG-ES and RS affect the pharyngeal site of collapse differently. Tongue muscle contraction contributes to pharyngeal stiffening during RS.

Delayed Bleeding after Percutaneous Liver Biopsy

Percutaneous liver biopsy (PLB) is a common procedure in patients with liver disease. Bleeding after PLB is rare, with an incidence of 0.35%. Most bleeding complications present within 24 h after biopsy. A 56-year-old woman was admitted to our hospital due to severe and sudden right upper quadrant (RUQ) abdominal pain 10 days after ultrasound (US)-guided PLB. CT study revealed both intrahepatic and intraperitoneal bleeding, and Hb levels decreased by 3.2 g/dl within a few hours. Such a prolonged delay in PLB-related bleeding has not been previously described in the medical literature. LEARNING POINTS Bleeding after liver biopsy is very rare, with an incidence of 0.35%. Approximately 95% of bleeding complications occur within 24 h. Physicians should be aware of rare delayed presentation in the days following liver biopsy.

Widespread osteoblastic metastases and marked elevation of CA19-9 as a presentation of signet ring cell gastric carcinoma

Widespread osteoblastic metastases, as well as marked elevations of CA19-9 and carcino-embryonic antigen (CEA), are the initial manifestations of gastric signet ring cell carcinoma. CT Imaging revealed diffuse sclerotic metastases in the axial skeleton. It was only following gastric biopsy that the primary site of metastatic bone tumor was identified. Recent studies suggest that early diagnosis of cancer origin, including tumor molecular profiling, may dictate specific therapy, improve prognosis and increase patient survival rates.