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.

Early Enteral Nutrition in Aeromedically Evacuated Critically Ill/Injured Patients With a Resultant Validation Algorithm for the Theater Validating Flight Surgeon.

INTRODUCTION: Early enteral feeding in critically ill/injured patients promotes gut integrity and immunocompetence and reduces infections and intensive care unit/hospital stays. Aeromedical evacuation (AE) often takes place concurrently. As a result, AE and early enteral feeding should be inseparable. MATERIALS AND METHODS: This retrospective descriptive study employed AE enteral nutrition (EN) data (2007-2019) collected from patients who were U.S. citizens and mechanically ventilated. The dataset was created from the En Route Critical Care, Transportation Command Regulating and Command and Control Evacuation System, and Theater Medical Data Store databases. Comparisons were performed between patients extracted and patients not extracted, patients treated with EN and patients treated without EN, and within the EN group, between AE Fed and AE Withheld. The impact of the nutrition support in the Joint Trauma System Clinical Practice Guidelines (CPG) was assessed using the 'before' and 'after' methodology. RESULTS: An uptick in feeding rates was found after the 2010 CPG, 15% → 17%. With the next two CPG iterations, rates rose significantly, 17% → 48%. Concurrently, AE feeding holds rose significantly, 10% → 24%, later dropping to 17%. In addition, little difference was found between those patients not enterally fed preflight and those enterally fed across collected demographic, mission, and clinical parameters. Likewise, no difference was found between those enterally fed during AE and those withheld. Yet, 83% of the study's patients were not fed, and 18% of those that were fed had feeding withheld for AE. CONCLUSIONS: It appeared that the Clinical Practice Guidelines (CPGs) reinforced the value of feeding, but may well have sensitized to the threat of aspiration. It also appeared that early enteral feeding was underprescribed and AE feeding withholds were overprescribed. Consequently, an algorithm was devised for the Theater Validating Flight Surgeon, bearing in mind relevant preflight/inflight/clinical issues, with prescriptions designed to boost feeding, diminish AE withholding, and minimize complications.

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.

Muscle Atrophy Marker Expression Differs between Rotary Cell Culture System and Animal Studies.

Muscular atrophy, defined as the loss of muscle tissue, is a serious issue for immobilized patients on Earth and for humans during spaceflight, where microgravity prevents normal muscle loading. In vitro modeling is an important step in understanding atrophy mechanisms and testing countermeasures before animal trials. The most ideal environment for modeling must be empirically determined to best mimic known responses in vivo. To simulate microgravity conditions, murine C2C12 myoblasts were cultured in a rotary cell culture system (RCCS). Alginate encapsulation was compared against polystyrene microcarrier beads as a substrate for culturing these adherent muscle cells. Changes after culture under simulated microgravity were characterized by assessing mRNA expression of MuRF1, MAFbx, Caspase 3, Akt2, mTOR, Ankrd1, and Foxo3. Protein concentration of myosin heavy chain 4 (Myh4) was used as a differentiation marker. Cell morphology and substrate structure were evaluated with brightfield and fluorescent imaging. Differentiated C2C12 cells encapsulated in alginate had a significant increase in MuRF1 only following simulated microgravity culture and were morphologically dissimilar to normal cultured muscle tissue. On the other hand, C2C12 cells cultured on polystyrene microcarriers had significantly increased expression of MuRF1, Caspase 3, and Foxo3 and easily identifiable multinucleated myotubes. The extent of differentiation was higher in simulated microgravity and protein synthesis more active with increased Myh4, Akt2, and mTOR. The in vitro microcarrier model described herein significantly increases expression of several of the same atrophy markers as in vivo models. However, unlike animal models, MAFbx and Ankrd1 were not significantly increased and the fold change in MuRF1 and Foxo3 was lower than expected. Using a standard commercially available RCCS, the substrates and culture methods described only partially model changes in mRNAs associated with atrophy in vivo.

Investigation of Stethoscope Technology for En Route Care.

OBJECTIVE: Occupational challenges in air transport domains make auscultation with traditional stethoscopes difficult. This study aimed to investigate two commercial off-the-shelf stethoscopes for use in high noise military patient transport environments. The stethoscopes were assessed by Aeromedical Evacuation providers in a simulated C-130 trainer on live standardized mock patients. Device 1 was a dual-mode stethoscope developed for rotary wing military airframes. Device 2 was an electronic stethoscope developed for high noise civilian environments. Twenty clinicians performed cardiopulmonary auscultation using the devices on the same two standardized patients in a simulated C-130 then completed a subjective questionnaire on their ability to identify heart and lung sounds. Results indicated the dual-mode stethoscope had limited utility with clinician likeliness of use rated as low (median = 2; interquartile range = 1.75-3.25), whereas the electronic stethoscope had potential utility with likeliness of use rated as good (median = 4; interquartile range = 3.25-5). We conclude that further examination of devices capable of auscultation in high noise military environments is needed. In-flight testing of device 2 for use by end users has been completed and will be reported in a separate manuscript.

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.

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.

Substituent effects on spin state in a series of mononuclear manganese(III) complexes with hexadentate Schiff-Base ligands.

Eleven new mononuclear manganese(III) complexes prepared from two hexadentate ligands, L1 and L2, with different degrees of steric bulk in the substituents are reported. L1 and L2 are Schiff bases resulting from condensation of N,N'-bis(3-aminopropyl)ethylenediamine with 3-methoxy-2-hydroxybenzaldehyde and 3-ethoxy-2-hydroxybenzaldehyde respectively, and are members of a ligand series we have abbreviated as R-Sal2323 to indicate the 323 alkyl connectivity in the starting tetraamine and the substitution (R) on the phenolate ring. L1 hosts a methoxy substituent on both phenolate rings, while L2 bears a larger ethoxy group in the same position. Structural and magnetic properties are reported in comparison with those of a previously reported analogue with L1, namely, [MnL1]NO3, (1e). The BPh4(-) and PF6(-) complexes [MnL1]BPh4, (1a), [MnL2]BPh4, (2a), [MnL1]PF6, (1b'), and [MnL2]PF6, (2b), with both ligands L1 and L2, remain high-spin (HS) over the measured temperature range. However, the monohydrate of (1b') [MnL1]PF6·H2O, (1b), shows gradual spin-crossover (SCO), as do the ClO4(-), BF4(-), and NO3(-) complexes [MnL1]ClO4·H2O, (1c), [MnL2]ClO4, (2c), [MnL1]BF4·H2O, (1d), [MnL2]BF4·0.4H2O, (2d), [MnL1]NO3, (1e), and [MnL2]NO3·EtOH, (2e). The three complexes formed with ethoxy-substituted ligand L2 all show a higher T1/2 than the analogous complexes with methoxy-substituted ligand L1. Analysis of distortion parameters shows that complexes formed with the bulkier ligand L2 exhibit more deformation from perfect octahedral geometry, leading to a higher T1/2 in the SCO examples, where T1/2 is the temperature where the spin state is 50% high spin and 50% low spin. Spin state assignment in the solid state is shown to be solvate-dependent for complexes (1b) and (2e), and room temperature UV-visible and NMR spectra indicate a solution-state spin assignment intermediate between fully HS and fully low spin in 10 complexes, (1a)-(1e) and (2a)-(2e).

Co-crystallisation of competing structural modes in geometrically constrained Jahn-Teller manganese(III) complexes.

The combination of Jahn-Teller distortion and chelating ligands produces a fine balance between competing coordination modes in manganese(III) resulting in well-ordered co-crystallization of two distinct assemblies from one set of components under a single set of conditions.

Lattice effects on the spin-crossover profile of a mononuclear manganese(III) cation.

Six solvated salts of a mononuclear manganese(III) complex with a chelating hexadentate Schiff base ligand are reported. One member of the series, [MnL]PF(6)⋅0.5 CH(3)OH (1), shows a rare low-spin (LS) electronic configuration between 10-300 K. The remaining five salts, [MnL]NO(3)⋅C(2)H(5)OH(2), [MnL]BF(4)⋅C(2)H(5)OH(3), [MnL]CF(3)SO(3)⋅C(2)H(5)OH (4), [MnL]ClO(4)⋅C(2)H(5)OH (5) and [MnL]ClO(4)⋅0.5 CH(3)CN (6), all show gradual incomplete spin-crossover (SCO) behaviour. The structures of all were determined at 100 K, and also at 293 K in the case of 3-6. The LS salt [MnL]PF(6)⋅0.5 CH(3)OH is the only member of the series that does not exhibit strong hydrogen bonding. At 100 K two of the four SCO complexes (2 and 4) assemble into 1D hydrogen-bonded chains, which weaken or rupture on warming. The remaining SCO complexes 3, 5 and 6 do not form 1D hydrogen-bonded chains, but instead exhibit discrete hydrogen bonding between cation/counterion, cation/solvent or counterion/solvent and show no significant change on warming.

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.

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.