Compound mortality impacts from extreme temperatures and the COVID-19 pandemic.

Extreme weather and coronavirus-type pandemics are both leading global health concerns. Until now, no study has quantified the compound health consequences of the co-occurrence of them. We estimate the mortality attributable to extreme heat and cold events, which dominate the UK health burden from weather hazards, in England and Wales in the period 2020-2022, during which the COVID-19 pandemic peaked in terms of mortality. We show that temperature-related mortality exceeded COVID-19 mortality by 8% in South West England. Combined, extreme temperatures and COVID-19 led to 19 (95% confidence interval: 16-22 in North West England) to 24 (95% confidence interval: 20-29 in Wales) excess deaths per 100,000 population during heatwaves, and 80 (95% confidence interval: 75-86 in Yorkshire and the Humber) to 127 (95% confidence interval: 123-132 in East of England) excess deaths per 100,000 population during cold snaps. These numbers are at least ~2 times higher than the previous decade. Society must increase preparedness for compound health crises such as extreme weather coinciding with pandemics.

Heatwave attribution based on reliable operational weather forecasts.

The 2021 Pacific Northwest heatwave was so extreme as to challenge conventional statistical and climate-model-based approaches to extreme weather attribution. However, state-of-the-art operational weather prediction systems are demonstrably able to simulate the detailed physics of the heatwave. Here, we leverage these systems to show that human influence on the climate made this event at least 8 [2-50] times more likely. At the current rate of global warming, the likelihood of such an event is doubling every 20 [10-50] years. Given the multi-decade lower-bound return-time implied by the length of the historical record, this rate of change in likelihood is highly relevant for decision makers. Further, forecast-based attribution can synthesise the conditional event-specific storyline and unconditional event-class probabilistic approaches to attribution. If developed as a routine service in forecasting centres, it could provide reliable estimates of human influence on extreme weather risk, which is critical to supporting effective adaptation planning.

Optimal heat stress metric for modelling heat-related mortality varies from country to country.

Combined heat and humidity is frequently described as the main driver of human heat-related mortality, more so than dry-bulb temperature alone. While based on physiological thinking, this assumption has not been robustly supported by epidemiological evidence. By performing the first systematic comparison of eight heat stress metrics (i.e., temperature combined with humidity and other climate variables) with warm-season mortality, in 604 locations over 39 countries, we find that the optimal metric for modelling mortality varies from country to country. Temperature metrics with no or little humidity modification associates best with mortality in ~40% of the studied countries. Apparent temperature (combined temperature, humidity and wind speed) dominates in another 40% of countries. There is no obvious climate grouping in these results. We recommend, where possible, that researchers use the optimal metric for each country. However, dry-bulb temperature performs similarly to humidity-based heat stress metrics in estimating heat-related mortality in present-day climate.

Estimating heat-related mortality in near real time for national heatwave plans.

Heatwaves are a serious threat to human life. Public health agencies that are responsible for delivering heat-health action plans need to assess and reduce the mortality impacts of heat. Statistical models developed in epidemiology have previously been used to attribute past observed deaths to high temperatures and project future heat-related deaths. Here, we investigate the novel use of summer temperature-mortality associations established by these models for monitoring heat-related deaths in regions in England in near real time. For four summers in the period 2011-2020, we find that coupling these associations with observed daily mean temperatures results in England-wide heatwave mortality estimates that are consistent with the excess deaths estimated by UK Health Security Agency. However, our results for 2013, 2018 and 2020 highlight that the lagged effects of heat and characteristics of individual summers contribute to disagreement between the two methods. We suggest that our method can be used for heatwave mortality monitoring in England because it has the advantages of including lagged effects and controlling for other risk factors. It could also be employed by health agencies elsewhere for reliably estimating the health burden of heat in near real time and near-term forecasts.

Lessons from the Ebola Outbreak: Action Items for Emerging Infectious Disease Preparedness and Response.

As the Ebola outbreak in West Africa wanes, it is time for the international scientific community to reflect on how to improve the detection of and coordinated response to future epidemics. Our interdisciplinary team identified key lessons learned from the Ebola outbreak that can be clustered into three areas: environmental conditions related to early warning systems, host characteristics related to public health, and agent issues that can be addressed through the laboratory sciences. In particular, we need to increase zoonotic surveillance activities, implement more effective ecological health interventions, expand prediction modeling, support medical and public health systems in order to improve local and international responses to epidemics, improve risk communication, better understand the role of social media in outbreak awareness and response, produce better diagnostic tools, create better therapeutic medications, and design better vaccines. This list highlights research priorities and policy actions the global community can take now to be better prepared for future emerging infectious disease outbreaks that threaten global public health and security.

Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function.

The development of the first standardized "scratch 'n sniff" olfactory test is described. Over 1600 subjects participated in five experiments. In Experiment 1, 50 microencapsulated odorants were rated as to their intensity, pleasantness, irritation, coolness, and familiarity, and two procedures for releasing them were compared. In Experiment 2, the results of the first experiment and other data were used in the development of the test, which was administered to a large number of subjects. Using multiple regression analysis, scores on this test were shown to be significantly related to the subjects' gender, ethnic background, and smoking behavior. Average test scores decreased as a function of age, with the greatest decline occurring between the sixth and tenth decades of life. These age-related changes were not correlated with scores on the Wechsler Memory Scale. Women performed better than men within all age categories. In Experiment 3, the test was shown to differentiate between subjects with known olfactory disorders (e.g., Kallmann's syndrome; Korsakoff's syndrome) and normal controls, and to reliably detect persons instructed to feign total anosmia. In Experiment 4, the test-retest reliability was established (6-month interval; r = 0.918, p less than 0.001), and in Experiment 5 the test was shown to correlate thresholds with odor detection (r = -0.794, p less than 0.001). This self-administratered test now makes it possible to rapidly and accurately assess general olfactory function in the laboratory, clinic, or through the mail without complex equipment or space-consuming stores of chemicals.

University of Pennsylvania Smell Identification Test: a rapid quantitative olfactory function test for the clinic.

Despite the fact that clinical otolaryngologists are often presented with complaints of olfactory dysfunction, they have limited means to diagnose these problems. A major reason has been the lack of a clinically-useful and reliable quantitative test of olfactory function. Recent work at our Clinical Research Center has resulted in the development of such a test. This test--the University of Pennsylvania Smell Identification Test (UPSIT)--can be self-administered and uses microencapsulated odorants which are released by scratching standardized odor-impregnated test booklets. As indicated in this paper, studies have demonstrated that the UPSIT can identify most malingerers and is sensitive to age, gender, smoking habits, and a wide variety of olfactory disorders. A description of this new test, along with some of its applications, is presented.

Glycocinnamoylspermidines, a new class of antibiotics. II. Isolation, physiocochemical and biological properties of LL-BM123beta, gamma1 and gamma2.

LL-BM123beta, gamma1 and gamma2 are three new antibiotics produced by fermentation of an unidentified species of Nocardia. These strongly basic, water soluble compounds were isolated from the culture filtrate by CM-Sephadex ion-exchange and carbon chromatography. All three antibiotics are active against both gram-positive and gram-negative bacteria. A mixture of LL-BM123 gamma1 and gamma2 is more active than the beta component but generally less active than gentamicin.

Characterization of the Activation of Membrane-Bound and Soluble CF(1) by Thioredoxin.

The activation of spinach (Spinacia oleracea) chloroplast coupling factor 1 (CF(1)) by thioredoxin (ThR) was characterized using membrane-bound and soluble CF(1). Light generates an electrochemical proton gradient across the thylakoid membrane, which increases the accessibility of the disulfide bond on the gamma-subunit of CF(1) to reduced ThR. The proton gradient substantially accelerates the activation of CF(1) compared with thylakoids incubated in the dark with similar concentrations of dithiothreitol and ThR. The interaction of soluble CF(1) with ThR was studied using fluorescent probes. CF(1) in solution, with and without its associated epsilon-subunit, was labeled at Cys-322 of the gamma-subunit with fluoresceinyl maleimide. ThR from Escherichia coli was labeled with eosin isothiocyanate. Labeled ThR and CF(1) showed normal activities. Fluorescence energy transfer between donor fluoresceinyl maleimide and acceptor eosin isothiocyanate, manifested by a quenching of the donor fluorescence, was detected, suggesting that ThR and CF(1) form an intermolecular complex. When the epsilon-subunit was absent, quenching of donor fluorescence was approximately doubled, indicating that labeled ThR could approach more closely to the gamma-subunit of CF(1). The distance between the fluorescent probes on CF(1) and ThR was calculated to be approximately 65 A when epsilon-subunit was present and 52 A when epsilon was absent. These values are consistent with other distance measurements and energy transfer values reported previously for fluorescent probes on CF(1). Whereas the extent of quenching increased by removal of the epsilon-subunit, the apparent dissociation constant was unchanged. The quenching effect was reversed when the epsilon-subunit was added back to the titration mixture. Similarly, the addition of unlabeled ThR decreased donor quenching.

Decline of activity and quantity of ribulose bisphosphate carboxylase/oxygenase and net photosynthesis in ozone-treated potato foliage.

The effect of ozone (O(3)) on ribulose bisphosphate carboxylase/oxygenase (Rubisco) activity and quantity and net photosynthesis in greenhouse-grown Solanum tuberosum L. cv ;Norland' foliage was studied in relation to oxidant-induced premature senescence. Plants, 26 days old, were exposed to 0.06 to 0.08 microliters per liter O(3) from 1000 to 1600 hours for 4 days in a controlled environment chamber. On day 5, plants were exposed to a 6-hour simulated inversion in which O(3) peaked at 0.12 microliters per liter. Net photosynthesis declined in response to O(3) but recovered to near control levels 3 days after the exposure ended. Rubisco activity and quantity in control potato foliage increased and then decreased during the 12-day interval of the study. In some experiments foliage studied was physiologically mature and Rubisco activity had peaked when O(3) exposure commenced. In those cases, O(3) accelerated the decline in Rubisco activity. When less mature foliage was treated with O(3), the leaves never achieved the maximal level of Rubisco activity observed in control foliage and also exhibited more rapid decline in initial and total activity. Percent activation of Rubisco (initial/total activity) was not affected significantly by treatment. Quantity of Rubisco decreased in concert with activity. The decrease in activities is most likely due to a decrease in available protein rather than a decrease in the percentage of Rubisco activated in vivo. The reduction in the quantity of Rubisco, an important foliar storage protein, could contribute to premature senescence associated with toxicity of this air pollutant.

The specificity of the S1' subsite of papain.

The specificity of the S(1)' subsite of the proteolytic enzyme papain was investigated by studying the effect of l-alpha-amino acid amides on the enzyme-catalysed hydrolysis of N-benzyloxycarbonylglycine p-nitrophenyl ester and by determining the kinetic parameters for the enzyme-catalysed hydrolysis of some N-benzyloxycarbonylglycyl-l-amino acid amides. These studies showed that the S(1)' subsite has a predilection for hydrophobic residues, in particular l-leucine and l-tryptophan. The specificity for these residues is manifest in both the binding and acylation steps. N-Benzyloxycarbonylglycine amide is not hydrolysed under comparable conditions, indicating that the amide group adjacent to and on the C-terminal side of the peptide bond about to be cleaved makes an important contribution to the rate of the papain-catalysed hydrolysis of peptides.

Molecular dissection of the epsilon subunit of the chloroplast ATP synthase of spinach.

The gene encoding the epsilon subunit (atpE) of the chloroplast ATP synthase of Spinacia oleracea has been overexpressed in Escherichia coli. The recombinant protein can be solubilized in 8 M urea and directly diluted into buffer containing ethanol and glycerol to obtain epsilon that is as biologically active as epsilon purified from chloroplast-coupling factor 1 (CF1). Recombinant epsilon folded in this manner inhibits the ATPase activity of soluble and membrane-bound CF1 deficient in epsilon and restores proton impermeability to thylakoid membranes reconstituted with CF1 deficient in epsilon. Site-directed mutagenesis was used to generate truncations and single amino acid substitutions in the primary structure of epsilon. In the five mutants tested, alterations that weaken ATPase inhibition by recombinant epsilon affect its ability to restore proton impermeability to a similar extent, with one exception. Substitution of histidine-37 with arginine appears to uncouple ATPase inhibition and the restoration of proton impermeability. As in the case of E. coli, it appears that N-terminal truncations of the epsilon subunit have more profound effects than C-terminal deletions on the function of epsilon. Recombinant epsilon with six amino acids deleted from the C terminus, which is the only region of significant mismatch between the epsilon of spinach and the epsilon of Pisum sativum, inhibits ATPase activity with a reduced potency similar to that of purified pea epsilon. Four of the six amino acids are serine or threonine. These hydroxylated amino acids may be important in epsilon-CF1 interactions.