Overcoming bioethical, legal, and hereditary barriers to mitochondrial replacement therapy in the USA.

The purpose of the paper is to explore novel means to overcome the controversial ban in the USA against mitochondrial replacement therapy, a form of IVF, with the added step of replacing a woman's diseased mutated mitochondria with a donor's healthy mitochondria to prevent debilitating and often fatal mitochondrial diseases. Long proven effective in non-human species, MRT recently performed in Mexico resulted in the birth of a healthy baby boy. We explore the ethics of the ban, the concerns over hereditability of mitochondrial disease and its mathematical basis, the overlooked role of Mitochondrial Eve, the financial burden of mitochondrial diseases for taxpayers, and a woman's reproductive rights. We examine applicable court cases, particularly protection of autonomy within the reproductive rights assured by Roe v Wade. We examine the consequences of misinterpreting MRT as genetic engineering in the congressional funding prohibitions causing the MRT ban by the FDA. Allowing MRT to take place in the USA would ensure a high standard of reproductive medicine and safety for afflicted women wishing to have genetically related children, concurrently alleviating the significant financial burden of mitochondrial diseases on its taxpayers. Since MRT does not modify any genome, it falls outside the "heritable genetic modification" terminology of concern to Congress and the FDA. Correcting this terminology, the IOM's conclusion that MRT is ethical, the continuing normalcy of the first MRT recipient, and increasing public awareness of the promising benefits might be all that is required to modify the FDA's position on MRT.

Human temperatures for syndromic surveillance in the emergency department: data from the autumn wave of the 2009 swine flu (H1N1) pandemic and a seasonal influenza outbreak.

BACKGROUND: The emergency department (ED) increasingly acts as a gateway to the evaluation and treatment of acute illnesses. Consequently, it has also become a key testing ground for systems that monitor and identify outbreaks of disease. Here, we describe a new technology that automatically collects body temperatures during triage. The technology was tested in an ED as an approach to monitoring diseases that cause fever, such as seasonal flu and some pandemics. METHODS: Temporal artery thermometers that log temperature measurements were placed in a Boston ED and used for initial triage vital signs. Time-stamped measurements were collected from the thermometers to investigate the performance a real-time system would offer. The data were summarized in terms of rates of fever (temperatures ≥100.4 °F [≥38.0 °C]) and were qualitatively compared with regional disease surveillance programs in Massachusetts. RESULTS: From September 2009 through August 2011, 71,865 body temperatures were collected and included in our analysis, 2073 (2.6 %) of which were fevers. The period of study included the autumn-winter wave of the 2009-2010 H1N1 (swine flu) pandemic, during which the weekly incidence of fever reached a maximum of 5.6 %, as well as the 2010-2011 seasonal flu outbreak, during which the maximum weekly incidence of fever was 6.6 %. The periods of peak fever rates corresponded with the periods of regionally elevated flu activity. CONCLUSIONS: Temperature measurements were monitored at triage in the ED over a period of 2 years. The resulting data showed promise as a potential surveillance tool for febrile disease that could complement current disease surveillance systems. Because temperature can easily be measured by non-experts, it might also be suitable for monitoring febrile disease activity in schools, workplaces, and transportation hubs, where many traditional syndromic indicators are impractical. However, the system's validity and generalizability should be evaluated in additional years and settings.

Mortality rates among adult critical care patients with unusual or extreme values of vital signs and other physiological parameters: a retrospective study.

BACKGROUND: We evaluated relationships of vital signs and laboratory-tested physiological parameters with in-hospital mortality, focusing on values that are unusual or extreme even in critical care settings. METHODS: We retrospectively studied Philips Healthcare-MIT eICU data (207 U.S. hospitals, 20142015), including 166,959 adult-patient critical care admissions. Analyzing most-deranged (worst) value measured in the first admission day, we investigated vital signs (body temperature, heart rate, mean arterial pressure, and respiratory rate) as well as albumin, bilirubin, blood pH via arterial blood gas (ABG), blood urea nitrogen, creatinine, FiO2 ABG, glucose, hematocrit, PaO2 ABG, PaCO2 ABG, sodium, 24-hour urine output, and white blood cell count (WBC). RESULTS: In-hospital mortality was ≥50% at extremes of low blood pH, low and high body temperature, low albumin, low glucose, and low heart rate. Near extremes of blood pH, temperature, glucose, heart rate, PaO2 , and WBC, relatively. Small changes in measured values correlated with several-fold mortality rate increases. However, high mortality rates and abrupt mortality increases were often hidden by the common practice of thresholding or binning physiological parameters. The best predictors of in-hospital mortality were blood pH, temperature, and FiO2 (scaled Brier scores: 0.084, 0.063, and 0.049, respectively). CONCLUSIONS: In-hospital mortality is high and sharply increasing at extremes of blood pH, body temperature, and other parameters. Common-practice thresholding obscures these associations. In practice, vital signs are sometimes treated more casually than laboratory-tested parameters. Yet, vitals are easier to obtain and we found they are often the best mortality predictors, supporting perspectives that vitals are undervalued.

Peak and decline in cancer incidence, mortality, and prevalence at old ages.

BACKGROUND: Cancer incidence and mortality increase with age through much of adulthood, but earlier work has found that these rates decline among the very elderly. To compare incidence and mortality at the oldest ages, the authors investigated both in the same large population, which comprised 9.5% of the United States in 2000. The authors also report age-specific prevalence among the elderly, which has received little attention. METHODS: Twenty-three cancer types were studied in men, and 24 cancer types were studied in women. Patient records were obtained from the SEER 9 cancer registries, and population figures were taken from the 2000 US Census. The authors explored the reliability of census data on the oldest old, which has been questioned. RESULTS: Age-specific incidence, prevalence, and mortality results are presented for the years 1998 to 2002. Incidence and mortality usually decreased or plateaued at very old ages. Prevalence usually decreased swiftly at ages >90 years. When there was statistical power, incidence normally peaked between ages 75 years and 90 years, dropping abruptly afterward. With several large exceptions, peak incidence and mortality coincided within ±5 years. Both rates often trended toward zero among centenarians, who may be asymptomatic or insusceptible. CONCLUSIONS: The current results were found to be consistent with autopsy and survival studies. Most age-specific models of carcinogenesis are based on cancer rate data for ages <85 years. The authors argue that these models could not fit the current results without fundamental modification and outline biologic mechanisms for such modification, mostly cellular and tissue senescence. They also recommend caution to researchers who use census data on the very elderly.

Dissociable functional connectivity changes during the Stroop task relating to risk, resilience and disease expression in bipolar disorder.

Reduced cognitive control is considered a core feature of bipolar disorder (BD). Abnormalities in ventrolateral prefrontal cortex (VLPFC) and other functionally linked regions that underpin cognitive control during the Stroop Colour Word Task (SCWT) have been reported in patients with BD and their relatives. In this functional magnetic resonance study we used psychophysiological interaction analysis to examine functional connectivity during the SCWT in 39 euthymic BD patients, 39 of their first-degree relatives (25 with no Axis I disorders and 14 with major depressive disorder) and 48 healthy controls. The aim of this study was to identify potential diagnosis-specific functional connectivity changes differentiating patients with BD from their relatives with MDD, as well as functional connectivity correlates of resilience in relatives of BD patients who remain well. Psychophysiological interactions in healthy controls revealed a negative functional connectivity between the VLPFC and the ventral anterior cingulate cortex and insula and a positive connectivity between the VLPFC and the caudate and parietal cortices. Abnormalities in fronto-insular connectivity emerged as a key correlate of predisposition and disease expression for BD. Reduced fronto-cingulate connectivity was also observed in association with predisposition to BD irrespective of clinical outcome. BD patients and their MDD relatives showed additional abnormalities in frontal-basal ganglia connectivity while increased coupling between the ventral and dorsal lateral PFC was observed in relatives without any Axis I disorder. These findings suggest that during the SCWT the VLPFC and subcortical regions are involved in a dynamic interplay. Breakdown in these interactions is associated with risk and disease expression for mood disorders while increased functional coupling between dorsal and ventral prefrontal regions may reflect adaptive functional changes associated with resilience.

Familial and disease specific abnormalities in the neural correlates of the Stroop Task in Bipolar Disorder.

Patients with Bipolar Disorder (BD) perform poorly on tasks of selective attention and inhibitory control. Although similar behavioural deficits have been noted in their relatives, it is yet unclear whether they reflect dysfunction in the same neural circuits. We used functional magnetic resonance imaging and the Stroop Colour Word Task to compare task related neural activity between 39 euthymic BD patients, 39 of their first-degree relatives (25 with no Axis I disorders and 14 with Major Depressive Disorder) and 48 healthy controls. Compared to controls, all individuals with familial predisposition to BD, irrespective of diagnosis, showed similar reductions in neural responsiveness in regions involved in selective attention within the posterior and inferior parietal lobules. In contrast, hypoactivation within fronto-striatal regions, implicated in inhibitory control, was observed only in BD patients and MDD relatives. Although striatal deficits were comparable between BD patients and their MDD relatives, right ventrolateral prefrontal dysfunction was uniquely associated with BD. Our findings suggest that while reduced parietal engagement relates to genetic risk, fronto-striatal dysfunction reflects processes underpinning disease expression for mood disorders.

Corrections to: ''Age distribution of cancer in mice''.

We found a crucial error in an earlier paper on cancer in elderly mice, Age distribution of cancer in mice: the incidence turnover at old age (Pompei et al., 2001). That paper's principal data set, the ED01 records, was scrambled when read and analyzed with a statistical software package. Having done our best to correct the error, and having subjected the data to a more exact extension of originally published methods, we arrive at conclusions significantly different from those proposed in the original article. What appeared to be a dramatic fall off of the cancer mortality rate in mice over 2 years of age is now found to be a continuation or flattening of approximately exponential growth. This new finding is entirely at odds with the old, and does not support our later work on humans. Two of this paper's authors, F Pompei and R Wilson, contributed to the original article. We are informing authors who have cited our paper in the past and apologize deeply for any wasted time or lost work. We should have subjected the ED01 records to more error checks. We thank Jennifer Blank for helping us discover and correct this error. The ED01 records and our earlier research are available http://physics.harvard.edu/∼wilson/cancer&chemicals/ED01.

In Vitro Effect of the Common Culinary Herb Winter Savory (Satureja montana) against the Infamous Food Pathogen Campylobacter jejuni.

The culinary herb Satureja montana, known as winter savory, is an ingredient of traditional dishes known in different parts of the world. As an ingredient of foods it has the potential to improve their safety. In this study, the herb's activity was investigated against Campylobacter jejuni, the leading cause of the most prevalent bacterial gastroenteritis worldwide. The ethanolic extract and essential oil of the herb were chemically characterized and six pure compounds-carvacrol, thymol, thymoquinone, p-cymene, γ-terpinene, and rosmarinic acid-were chosen for further analysis. The antimicrobial activity of the ethanolic extract (MIC 250 mg/L) was 4-fold higher compared to the essential oil. Carvacrol, thymol and thymoquinone had the strongest antimicrobial effect (MIC 31.25 mg/L) and a strong synergistic activity between carvacrol and thymol was determined (FICi 0.2). Strong inhibitory effect on C. jejuni efflux pumps (2-fold inhibition) and disruption of membrane integrity (> 80% disruption) of the herb were determined as modes of action. For resistance against the herb, C. jejuni need efflux pumps, although increased resistance against this herb does not co-occur with increased efflux pump activity, as for antibiotics. This study shows the potential of a common culinary herb for the reduction of the food pathogen C. jejuni without increasing resistance.

Fever Incidence Is Much Lower in the Morning than the Evening: Boston and US National Triage Data.

INTRODUCTION: In this observational study, we evaluated time-of-day variation in the incidence of fever that is seen at triage. The observed incidence of fever could change greatly over the day because body temperatures generally rise and fall in a daily cycle, yet fever is identified using a temperature threshold that is unchanging, such as ≥38.0° Celsius (C) (≥100.4° Fahrenheit [F]). METHODS: We analyzed 93,225 triage temperature measurements from a Boston emergency department (ED) (2009-2012) and 264,617 triage temperature measurements from the National Hospital Ambulatory Medical Care Survey (NHAMCS, 2002-2010), making this the largest study of body temperature since the mid-1800s. Boston data were investigated exploratorily, while NHAMCS was used to corroborate Boston findings and check whether they generalized. NHAMCS results are nationally representative of United States EDs. Analyses focused on adults. RESULTS: In the Boston ED, the proportion of patients with triage temperatures in the fever range (≥38.0°C, ≥100.4°F) increased 2.5-fold from morning to evening (7:00-8:59 PM vs 7:00-8:59 AM: risk ratio [RR] 2.5, 95% confidence interval [CI], 2.0-3.3). Similar time-of-day changes were observed when investigating alternative definitions of fever: temperatures ≥39.0°C (≥102.2°F) and ≥40.0°C (≥104.0°F) increased 2.4- and 3.6-fold from morning to evening (7:00-8:59 PM vs 7:00-8:59 AM: RRs [95% CIs] 2.4 [1.5-4.3] and 3.6 [1.5-17.7], respectively). Analyses of adult NHAMCS patients provided confirmation, showing mostly similar increases for the same fever definitions and times of day (RRs [95% CIs] 1.8 [1.6-2.1], 1.9 [1.4-2.5], and 2.8 [0.8-9.3], respectively), including after adjusting for 12 potential confounders using multivariable regression (adjusted RRs [95% CIs] 1.8 [1.5-2.1], 1.8 [1.3-2.4], and 2.7 [0.8-9.2], respectively), in age-group analyses (18-64 vs 65+ years), and in several sensitivity analyses. The patterns observed for fever mirror the circadian rhythm of body temperature, which reaches its highest and lowest points at similar times. CONCLUSION: Fever incidence is lower at morning triages than at evening triages. High fevers are especially rare at morning triage and may warrant special consideration for this reason. Studies should examine whether fever-causing diseases are missed or underappreciated during mornings, especially for sepsis cases and during screenings for infectious disease outbreaks. The daily cycling of fever incidence may result from the circadian rhythm.

The daily, weekly, and seasonal cycles of body temperature analyzed at large scale.

We performed large-scale analyses of circadian and infradian cycles of human body temperature, focusing on changes over the day, week, and year. Temperatures (n= 93,225) were collected using temporal artery thermometers from a Boston emergency department during 2009-2012 and were statistically analyzed using regression with cyclic splines. The overall mean body temperature was 36.7°C (98.1°F), with a 95% confidence interval of 36.7-36.7°C (98.1-98.1°F) and a standard deviation of 0.6°C (1.1°F). Over the day, mean body temperature followed a steady cycle, reaching its minimum at 6:00-8:00 and its maximum at 18:00-20:00. Across days of the week, this diurnal cycle was essentially unchanged, even though activities and sleeping hours change substantially during the weekly cycles of human behavior. Over the year, body temperatures were slightly colder in winter than summer (~0.2°C difference), consistent with most prior studies. We propose these seasonal differences might be due to ambient effects on body temperature that are not eliminated because they fall within the tolerance range of the thermoregulatory system. Over the year, bathyphase (daily time of minimum temperature) appeared to parallel sunrise times, as expected from sunrise's zeitgeber role in circadian rhythms. However, orthophase (daily time of maximum temperature) and sunset times followed opposite seasonal patterns, with orthophase preceding nightfall in summer and following nightfall in winter. Throughout the year, bathyphase and orthophase remained separated by approximately 12 h, suggesting this interval might be conserved. Finally, although 37.0°C (98.6°F) is widely recognized as the mean or normal human body temperature, analysis showed mean temperature was <37.0°C during all times of day, days of the week, and seasons of the year, supporting prior arguments that the 37.0°C standard has no scientific basis. Overall, this large study showed robust and consistent behavior of the human circadian cycle at the population level, providing a strong example of circadian homeostasis.

Breast Cancer Screening, Incidence, and Mortality Across US Counties.

IMPORTANCE: Screening mammography rates vary considerably by location in the United States, providing a natural opportunity to investigate the associations of screening with breast cancer incidence and mortality, which are subjects of debate. OBJECTIVE: To examine the associations between rates of modern screening mammography and the incidence of breast cancer, mortality from breast cancer, and tumor size. DESIGN, SETTING, AND PARTICIPANTS: An ecological study of 16 million women 40 years or older who resided in 547 counties reporting to the Surveillance, Epidemiology, and End Results cancer registries during the year 2000. Of these women, 53,207 were diagnosed with breast cancer that year and followed up for the next 10 years. The study covered the period January 1, 2000, to December 31, 2010, and the analysis was performed between April 2013 and March 2015. EXPOSURES: Extent of screening in each county, assessed as the percentage of included women who received a screening mammogram in the prior 2 years. MAIN OUTCOMES AND MEASURES: Breast cancer incidence in 2000 and incidence-based breast cancer mortality during the 10-year follow-up. Incidence and mortality were calculated for each county and age adjusted to the US population. RESULTS: Across US counties, there was a positive correlation between the extent of screening and breast cancer incidence (weighted r = 0.54; P < .001) but not with breast cancer mortality (weighted r = 0.00; P = .98). An absolute increase of 10 percentage points in the extent of screening was accompanied by 16% more breast cancer diagnoses (relative rate [RR], 1.16; 95% CI, 1.13-1.19) but no significant change in breast cancer deaths (RR, 1.01; 95% CI, 0.96-1.06). In an analysis stratified by tumor size, we found that more screening was strongly associated with an increased incidence of small breast cancers (≤2 cm) but not with a decreased incidence of larger breast cancers (>2 cm). An increase of 10 percentage points in screening was associated with a 25% increase in the incidence of small breast cancers (RR, 1.25; 95% CI, 1.18-1.32) and a 7% increase in the incidence of larger breast cancers (RR, 1.07; 95% CI, 1.02-1.12). CONCLUSIONS AND RELEVANCE: When analyzed at the county level, the clearest result of mammography screening is the diagnosis of additional small cancers. Furthermore, there is no concomitant decline in the detection of larger cancers, which might explain the absence of any significant difference in the overall rate of death from the disease. Together, these findings suggest widespread overdiagnosis.

Bupropion perceived as a stimulant by two patients with a previous history of cocaine misuse.

BACKGROUND AND OBJECTIVE: Despite animal studies having shown a generalisation of the bupropion cue to cocaine, this drug has been used in cocaine abuse with mixed results. We here aimed at describing two cases which contradict current knowledge. CASE REPORTS: We describe two cases of former cocaine abusers who reported a cocaine-like sensation upon taking bupropion. Bupropion improved patients' depression without any increase in cocaine craving. One of the patients increased without doctor consultation his dose on an as needed basis. CONCLUSIONS: The issue of bupropion cue generalisation to cocaine needs further elucidation. People with past cocaine addiction need to be informed on the potential of bupropion to elicit cocaine-like cues and be invited to adhere to medical prescription, because bupropion has been associated with fatalities in some cases.