p53 mutations in deep tissues are more strongly associated with recurrence than mutation-positive mucosal margins.

PURPOSE: Application of ultrasensitive diagnostics has shown that small numbers of p53 mutation-positive cells may signify the presence of residual tumor in histologically normal tissues after resection of squamous cell carcinomas arising in the head and neck area. To date, most studies in this area have focused on analysis of tissues at the mucosal aspect of the resection and highlighted the importance of molecular changes in the field with respect to the risk of recurrence. EXPERIMENTAL DESIGN: In the present investigation, we analyzed normal tissues from mucosal and deep surgical margins, referred to as "molecular margins," for the presence of the signature p53 mutation identified for each tumor. RESULTS: The p53 mutation status of these carcinomas did not correlate with clinical or histopathologic variables, but these mutations provided an excellent target for ultrasensitive analysis of margin status. We found that 11 of 16 (68%) of cases with histologically tumor-free (including 9 without dysplasia), but with p53 mutation-positive molecular margins, developed recurrence. The probability of developing local recurrence was significantly higher for the group with p53 mutation-positive margins when compared with the group with clear margins (P = 0.048) and more strongly associated with p53 mutation-positive deep molecular margins than mutation-positive mucosal molecular margins or positivity at both sites (P = 0.009). CONCLUSIONS: This shows that although persistent mucosal fields may contribute to recurrence, clonal p53 mutations in deep tissues are an important cause of treatment failure, and molecular margins from both sites should be analyzed in future prospective series.     

Fluorescent tracking of nickel ions in human cultured cells

The carcinogenic activity of various nickel (Ni) compounds is likely dependent upon their ability to enter cells and elevate intracellular levels of Ni ions. Water-insoluble Ni compounds such as NiS and Ni(3)S(2) were shown in vitro to enter cells by phagocytosis and potently induce tumors in experimental animals at the site of exposure. These water-insoluble nickel compounds are generally considered to be more potent carcinogens than the water-soluble forms. However, recent in vitro studies have shown similar effects for insoluble and soluble Ni compounds. Using a dye that fluoresces when intracellular Ni ion binds to it, we showed that both soluble and insoluble Ni compounds were able to elevate the levels of Ni ions in the cytoplasmic and nuclear compartments. However, when the source of Ni ions was removed from the culture dish, the intracellular Ni ions derived from soluble Ni compound were lost from the cells at a significantly faster rate than those derived from the insoluble Ni compound. Within 10 h after NiCl(2) removal from the culture medium, Ni ions disappeared from the nucleus and were not detected in the cells by 16 h, while insoluble Ni(3)S(2) yielded Ni ions that persisted in the nucleus after 16 h and were detected in the cytoplasm even after 24 h following Ni removal. These effects are discussed in terms of whole body exposure to water-soluble and -insoluble Ni compounds and consistency with animal carcinogenicity studies.     

Impact of severe hypoglycaemia requiring hospitalization on mortality in people with type 1 diabetes: A national retrospective observational cohort study

Aims

To assess if the risk of all-cause mortality increases in people with type 1 diabetes (T1D) with increasing number of severe hypoglycaemia episodes requiring hospitalization.

Materials and methods

We conducted a national retrospective observational cohort study in people with T1D (diagnosed between 2000 and 2018). Clinical, comorbidity and demographic variables were assessed for impact on mortality for people with no, one, two and three or more episodes of severe hypoglycaemia requiring hospitalization. The time to death (all-cause mortality) from the timepoint of the last episode of severe hypoglycaemia was modelled using a parametric survival model.

Results

A total of 8224 people had a T1D diagnosis in Wales during the study period. The mortality rate (95% confidence interval [CI]) was 6.9 (6.1-7.8) deaths/ 1000 person-years (crude) and 15.31 (13.3-17.63) deaths/ 1000 person-years (age-adjusted) for those with no occurrence of severe hypoglycaemia requiring hospitalization. For those with one episode of severe hypoglycaemia requiring hospitalization the mortality rate (95% CI) was 24.9 (21.0-29.6; crude) and 53.8 (44.6-64.7) deaths/ 1000 person-years (age-adjusted), for those with two episodes of severe hypoglycaemia requiring hospitalization it was 28.0 (23.1-34.0; crude) and 72.8 (59.2-89.5) deaths/ 1000 person-years (age-adjusted), and for those with three or more episodes of severe hypoglycaemia requiring hospitalization it was 33.5 (30.0-37.3; crude) and 86.3 (71.7-103.9) deaths/ 1000 person years (age-adjusted; P < 0.001). A parametric survival model showed that having two episodes of severe hypoglycaemia requiring hospitalization was the strongest predictor for time to death (accelerated failure time coefficient 0.073 [95% CI 0.009-0.565]), followed by having one episode of severe hypoglycaemia requiring hospitalization (0.126 [0.036-0.438]) and age at most recent episode of severe hypoglycaemia requiring hospitalization (0.917 [0.885-0.951]).

Conclusions

The strongest predictor for time to death was having two or more episodes of severe hypoglycaemia requiring hospitalization.     

Contextual factors and perceived self-reported sleepiness: a preliminary report

OBJECTIVES: The purpose of the present study was to determine whether contextual factors affect self-reported sleepiness. Specifically, when a reference situation is held constant (e.g. watching television), does the respondent's position, location, or interest in the activity alter sleepiness rating. We also evaluated interactions between an individual's level of sleepiness and the effect of these contextual factors. METHOD: This is a prospective survey conducted at a teaching hospital. Samples were drawn from four populations: a general non-patient population (n=53), a geriatric population (n=22), a medical resident population (n=18), and patients referred for sleep evaluation (n=53). We developed and administered a questionnaire that included a list of activities varied according to respondent's position, location, or interest in the activity. This questionnaire, along with the Epworth Sleepiness Scale (ESS), was administered to 146 individuals. RESULTS: Overall, we found significant differences (P<0.01) in self-reported sleepiness when contextual factors were varied. However, the influence of contextual factors declined as a function of increasing sleepiness (estimated using ESS scores). CONCLUSIONS: The results of this preliminary study indicate that contextual factors can influence self-reported sleepiness rating; however, this influence diminishes as sleepiness increases. Thus, clarifying context may improve test sensitivity in more alert individuals but does not appear to add incremental value to self-reported sleepiness in sleepy patients.     

Sustainability of remission of pediatric primary nocturnal enuresis--comparison of remission using Try for Dry vs. non-Try for Dry treatment plans

This study examined the sustainability of remission of primary nocturnal enuresis (PNE) using an algorithm-based multimodal treatment plan, Try for Dry. Remission of PNE using the Try for Dry treatment method was retained longer and more often than using a non-Try for Dry plan.     

Partial pressure of end-tidal carbon dioxide predicts successful cardiopulmonary resuscitation in the field

Kolar and colleagues contribute an additional and important incentive for rescuers to utilize end-tidal carbon dioxide tensions as a routine monitor to guide management and decision-making during cardiopulmonary resuscitation. They conclude that below-threshold levels of 14 mmHg (1.5 kPa) measured after 20 minutes of cardiopulmonary resuscitation reliably predict that spontaneous circulation cannot be restored.In their report on 737 patients who sustained out-of-hospital cardiac arrest, collected over an interval of 9 years in a well-organized emergency medical system, Kolar and colleagues confirmed that the measurement of end-tidal carbon dioxide tension (PetCO₂) is predictive of the outcomes of cardiopulmonary resuscitation [1]. The authors provide impressive data supporting the conclusion that, in their population, failure to increase PetCO₂ to levels exceeding 14 mmHg (1.5 kPa) after 20 minutes of attempted resuscitation served as a reliable guide for terminating unsuccessful cardiopulmonary resuscitation. The population studied, however, differed in some respects from the majority of earlier demographic reports that the authors cited with hospital survival <3%. More than 53% survived. The majority of instances of cardiac arrest reported by them was witnessed, and as many as one-third of victims received bystander cardiopulmonary resuscitation – favoring improved outcomes. Fatal outcomes, as anticipated, were associated with a doubling of the response time of professional rescuers, presumably in the absence of bystander utilization of automated external defibrillators, especially since a majority of survivors had shockable ventricular fibrillation or ventricular tachycardia.As the authors pinpoint, PetCO₂ has evolved into a technically facile and singularly useful monitor to guide cardiopulmonary resuscitation. PetCO₂ provides an indirect measurement of the cardiac output generated by chest compression and thereby guides the effectiveness of the procedure, including chest compression, to achieve better outcomes. It also allows uninterrupted chest compression because it promptly signals the return of spontaneous circulation [2]. PetCO₂ is likely to promptly identify asphyxia, in contrast to primary cardiac causes of arrest as previously reported by one of the present authors [3]. PetCO₂ measurement during cardiopulmonary resuscitation may not require routine endotracheal intubation, which usually interrupts chest compression and under crisis conditions has a high failure rate and disproportionate airway injury. The alternatives of a laryngeal mask airway or even a facial mask incorporating a mainstream carbon dioxide sensor may be utilized. Because injection of bolus epinephrine produces a sharp although transient reduction in PetCO₂ when injected intravenously [4], clinicians would best be alerted to this potential error.These considerations notwithstanding, Kolar and colleagues contribute an additional and important incentive for rescuers to utilize PetCO₂ as a routine monitor to guide management and decision-making during cardiopulmonary resuscitation.     

Exclusion of a patient assessment interval and extension of the CPR interval both mitigate post-resuscitation myocardial dysfunction in a swine model of cardiac arrest

AIM OF STUDY: Interruptions in cardiopulmonary resuscitation (CPR), particularly as guided by automated external defibrillators, have been implicated in poor survival from cardiac arrest. Interruptions of CPR may be reduced by eliminating repetition of shocks between periods of CPR, elimination of the interval for patient assessment before CPR, and extension of the periods of CPR. MATERIALS AND METHODS: The effects of exclusion of a 30s post-shock assessment interval prior to CPR and use of a longer interval (180s versus 90s) of CPR on resuscitation and post-resuscitation function were assessed in a factorial design using an established swine model of cardiac arrest. Repetitive shocks were excluded. Ventricular fibrillation was induced ischemically and maintained untreated for 5min. RESULTS: All subjects were resuscitated, 95% survived 3 days, and 97% of survivors had full neurological recovery. Exclusion of the assessment interval reduced the delay to first return of spontaneous circulation by 33.1s (P=0.004) and the delay to sustained resuscitation by 99.2s (P=0.004), reduced post-resuscitation ECG ST elevation by 0.12mV (P=0.03), and alleviated transient post-resuscitation ejection fraction reduction (P<0.0001). Extension of the CPR interval reduced transient post-resuscitation fractional area change impairment (P=0.003). CONCLUSIONS: Exclusion of an interval for assessment of airway, breathing and signs of circulation mitigates post-resuscitation dysfunction in a swine model of cardiac arrest. Extension of the period of CPR independently provides measurable, though less comprehensive, mitigation as well.