Coronavirus seasonality, respiratory infections and weather.

BACKGROUND: The survival of coronaviruses are influenced by weather conditions and seasonal coronaviruses are more common in winter months. We examine the seasonality of respiratory infections in England and Wales and the associations between weather parameters and seasonal coronavirus cases. METHODS: Respiratory virus disease data for England and Wales between 1989 and 2019 was extracted from the Second-Generation Surveillance System (SGSS) database used for routine surveillance. Seasonal coronaviruses from 2012 to 2019 were compared to daily average weather parameters for the period before the patient's specimen date with a range of lag periods. RESULTS: The seasonal distribution of 985,524 viral infections in England and Wales (1989-2019) showed coronavirus infections had a similar seasonal distribution to influenza A and bocavirus, with a winter peak between weeks 2 to 8. Ninety percent of infections occurred where the daily mean ambient temperatures were below 10 °C; where daily average global radiation exceeded 500 kJ/m2/h; where sunshine was less than 5 h per day; or where relative humidity was above 80%. Coronavirus infections were significantly more common where daily average global radiation was under 300 kJ/m2/h (OR 4.3; CI 3.9-4.6; p < 0.001); where average relative humidity was over 84% (OR 1.9; CI 3.9-4.6; p < 0.001); where average air temperature was below 10 °C (OR 6.7; CI 6.1-7.3; p < 0.001) or where sunshine was below 4 h (OR 2.4; CI 2.2-2.6; p < 0.001) when compared to the distribution of weather values for the same time period. Seasonal coronavirus infections in children under 3 years old were more frequent at the start of an annual epidemic than at the end, suggesting that the size of the susceptible child population may be important in the annual cycle. CONCLUSIONS: The dynamics of seasonal coronaviruses reflect immunological, weather, social and travel drivers of infection. Evidence from studies on different coronaviruses suggest that low temperature and low radiation/sunlight favour survival. This implies a seasonal increase in SARS-CoV-2 may occur in the UK and countries with a similar climate as a result of an increase in the R0 associated with reduced temperatures and solar radiation. Increased measures to reduce transmission will need to be introduced in winter months for COVID-19.

Exploring Campylobacter seasonality across Europe using The European Surveillance System (TESSy), 2008 to 2016.

BackgroundCampylobacteriosis is the most commonly reported food-borne infection in the European Union, with an annual number of cases estimated at around 9 million. In many countries, campylobacteriosis has a striking seasonal peak during early/mid-summer. In the early 2000s, several publications reported on campylobacteriosis seasonality across Europe and associations with temperature and precipitation. Subsequently, many European countries have introduced new measures against this food-borne disease.AimTo examine how the seasonality of campylobacteriosis varied across Europe from 2008-16, to explore associations with temperature and precipitation, and to compare these results with previous studies. We also sought to assess the utility of the European Surveillance System TESSy for cross-European seasonal analysis of campylobacteriosis.MethodsWard's Minimum Variance Clustering was used to group countries with similar seasonal patterns of campylobacteriosis. A two-stage multivariate meta-analysis methodology was used to explore associations with temperature and precipitation.ResultsNordic countries had a pronounced seasonal campylobacteriosis peak in mid- to late summer (weeks 29-32), while most other European countries had a less pronounced peak earlier in the year. The United Kingdom, Ireland, Hungary and Slovakia had a slightly earlier peak (week 24). Campylobacteriosis cases were positively associated with temperature and, to a lesser degree, precipitation.ConclusionAcross Europe, the strength and timing of campylobacteriosis peaks have remained similar to those observed previously. In addition, TESSy is a useful resource for cross-European seasonal analysis of infectious diseases such as campylobacteriosis, but its utility depends upon each country's reporting infrastructure.

Impact on glycated haemoglobin of a biological response-based measure of medication adherence.

AIMS: The aim of this study was to examine the relationship between a specific glycated haemoglobin (HbA1c) measurement and a pharmaceutical dispensings-based measure of adherence calculated over the 90 days before each HbA1c measure among patients who have newly initiated metformin therapy. METHODS: We identified 3109 people with type 2 diabetes who initiated metformin as their first-ever antihyperglycaemic drug, analysing all 9918 HbA1c measurements that were taken over the next 2 years. We used an adaptation of the 'proportion of days covered' method for assessing medication adherence that corresponded to an ∼90-day interval preceding an HbA1c measurement, terming the adaptation the 'biological response-based proportion of days covered' (BRB-PDC). To account for multiple observations per patient, we analysed the association between HbA1c and BRB-PDC within the generalized estimating equation framework. Analyses were stratified by HbA1c level before metformin initiation using a threshold of 8% (64 mmol/mol). RESULTS: After multivariable adjustment using 0% adherence as the reference category, BRB-PDC in the range 50-79% was associated with HbA1c values lower by -0.113 [95% confidence interval (CI) -0.202, -0.025] among patients with pre-metformin HbA1c <8%, and by -0.247 (95% CI -0.390, -0.104) among those with HbA1c ≥8% at metformin initiation. Full adherence (≥80%) was associated with HbA1c values lower by -0.175% (95% CI -0.257, -0.093) and by -0.453% (95% CI -0.586, -0.320). CONCLUSIONS: Using this novel short-interval approach that more closely associates adherence with the expected biological response, the association between better adherence and HbA1c levels was considerably stronger than has been previously reported; however, the strength of the impact was dependent upon the HbA1c level before initiating metformin.

Food-borne diseases associated with frozen berries consumption: a historical perspective, European Union, 1983 to 2013.

Epidemiological investigations of outbreaks of hepatitis A virus (HAV) and norovirus (NoV) infections in the European Union/European Economic Area (EU/EEA) in the last five years have highlighted frozen berries as a vehicle of infection. Given the increasing berry consumption in the EU over the last decades, we undertook a review of the existing evidence to assess the potential scale of threat associated with this product. We searched the literature and four restricted-access online platforms for outbreak/contamination events associated with consumption of frozen berries. We performed an evaluation of the sources to identify areas for improvement. The review revealed 32 independent events (i.e. outbreak, food contamination) in the period 1983­2013, of which 26 were reported after 2004. The identified pathogens were NoV, HAV and Shigella sonnei. NoV was the most common and implicated in 27 events with over 15,000 cases reported. A capture­recapture analysis was performed including three overlapping sources for the period 2005­2013. The study estimated that the event-ascertainment was 62%. Consumption of frozen berries is associated with increasing reports of NoV and HAV outbreaks and contamination events, particularly after 2003. A review of the risks associated with this product is required to inform future prevention strategies. Better integration of the available communication platforms and databases should be sought at EU/EEA level to improve monitoring, prevention and control of food-borne-related events.

Waterborne outbreaks in the Nordic countries, 1998 to 2012.

A total of 175 waterborne outbreaks affecting 85,995 individuals were notified to the national outbreak surveillance systems in Denmark, Finland and Norway from 1998 to 2012, and in Sweden from 1998 to 2011. Between 4 and 18 outbreaks were reported each year during this period. Outbreaks occurred throughout the countries in all seasons, but were most common (n = 75/169, 44%) between June and August. Viruses belonging to the Caliciviridae family and Campylobacter were the pathogens most frequently involved, comprising n = 51 (41%) and n = 36 (29%) of all 123 outbreaks with known aetiology respectively. Although only a few outbreaks were caused by parasites (Giardia and/or Cryptosporidium), they accounted for the largest outbreaks reported during the study period, affecting up to 53,000 persons. Most outbreaks, 124 (76%) of those with a known water source (n = 163) were linked to groundwater. A large proportion of the outbreaks (n = 130/170, 76%) affected a small number of people (less than 100 per outbreak) and were linked to single-household water supplies. However, in 11 (6%) of the outbreaks, more than 1,000 people became ill. Although outbreaks of this size are rare, they highlight the need for increased awareness, particularly of parasites, correct water treatment regimens, and vigilant management and maintenance of the water supply and distribution systems.

Structurally diverse MDM2-p53 antagonists act as modulators of MDR-1 function in neuroblastoma.

BACKGROUND: A frequent mechanism of acquired multidrug resistance in human cancers is overexpression of ATP-binding cassette transporters such as the Multi-Drug Resistance Protein 1 (MDR-1). Nutlin-3, an MDM2-p53 antagonist, has previously been reported to be a competitive MDR-1 inhibitor. METHODS: This study assessed whether the structurally diverse MDM2-p53 antagonists, MI-63, NDD0005, and RG7388 are also able to modulate MDR-1 function, particularly in p53 mutant neuroblastoma cells, using XTT-based cell viability assays, western blotting, and liquid chromatography-mass spectrometry analysis. RESULTS: Verapamil and the MDM2-p53 antagonists potentiated vincristine-mediated growth inhibition in a concentration-dependent manner when used in combination with high MDR-1-expressing p53 mutant neuroblastoma cell lines at concentrations that did not affect the viability of cells when given alone. Liquid chromatography-mass spectrometry analyses showed that verapamil, Nutlin-3, MI-63 and NDD0005, but not RG7388, led to increased intracellular levels of vincristine in high MDR-1-expressing cell lines. CONCLUSIONS: These results show that in addition to Nutlin-3, other structurally unrelated MDM2-p53 antagonists can also act as MDR-1 inhibitors and reverse MDR-1-mediated multidrug resistance in neuroblastoma cell lines in a p53-independent manner. These findings are important for future clinical trial design with MDM2-p53 antagonists when used in combination with agents that are MDR-1 substrates.

Dolutegravir: clinical and laboratory safety in integrase inhibitor-naive patients.

BACKGROUND: The efficacy of dolutegravir (DTG) has been demonstrated in 5 randomized studies in integrase inhibitor (INI)-naive adult populations. To date, a detailed safety review of DTG has not been provided in the literature. OBJECTIVE: To describe the safety and tolerability profile of DTG in adults based on 5 randomized, controlled trials and comparison with drugs in 3 major antiretroviral (ARV) classes. METHODS: Safety data from phase IIb/III/IIIb trials in ART-naive and ART-experienced, INI-naive adults were integrated. RESULTS: In 4 ART-naive (SPRING-1, SPRING-2, SINGLE, FLAMINGO) and 1 ART-experienced, INI-naive study (SAILING), 1,579 individuals received a DTG-containing regimen. The proportion of individuals from DTG treatment arms who withdrew due to adverse events (AEs) was low (≤2%) compared to raltegravir (RAL; 2% SPRING-2, 4% SAILING), efavirenz (EFV)-containing comparator arm (10% SINGLE), and darunavir + ritonavir (DRV/r; 4% FLAMINGO). The most frequently observed AEs (diarrhea, nausea, headache), typically grade 1 or 2 in severity, did not lead to study discontinuation. Psychiatric and nervous system disorders with DTG were comparable to RAL- and DRV/r-containing regimens and favorable to EFV-containing regimens. In hepatitis B and/or C coinfected ART-naive individuals, the incidence of transaminase elevations was lower with DTG versus RAL and EFV comparators, but was similar to DRV/r. In SAILING, transaminase elevations were more commonly observed with DTG, particularly in the setting of inadequate hepatitis B therapy or immune reconstitution. On DTG treatment, mild creatinine elevations occurred and stabilized early. Few cases of hypersensitivity reaction and/or severe rash were seen. Rates of these events were comparable to or lower than with RAL-, EFV-, and DRV/r-containing regimens. CONCLUSIONS: The safety profile for DTG 50 mg once daily in INI-naive individuals was comparable to RAL- and DRV/r-containing regimens and generally favorable compared with EFV-containing regimens.

Simultaneous increase of Cryptosporidium infections in the Netherlands, the United Kingdom and Germany in late summer season, 2012.

Starting August 2012, an increase in Cryptosporidium infections was reported in the Netherlands, the United Kingdom and Germany. It represented a 1.8 to 4.9-fold increase compared to previous years. Most samples were C. hominis IbA10G2. A case­control study was performed in the Netherlands but did not identify an endemic source. A case­case study in the north of England found travel abroad to be the most common risk factor.

Cardiovascular disease, heart failure, chronic kidney disease and depression independently increase the risk of incident diabetes.

AIMS/HYPOTHESIS: Diabetes increases the risk of cardiovascular disease (CVD) and heart failure, as well as other serious complications, such as renal disease and depression. However, these conditions are often present prior to diabetes diagnosis. We sought to determine whether they increase the risk of developing diabetes independent of other risk factors. METHODS: We identified 58,056 non-diabetic adults aged ≥30 years with no evidence of diabetes. Using electronic medical records, we identified the presence of four conditions at baseline (CVD, heart failure, renal disease and depression) and then estimated diabetes incidence over 5 years separately for patients with and without each of these conditions. Each incidence estimate was adjusted for baseline values of age, sex, fasting glucose, body mass index, systolic blood pressure, triacylglycerol, HDL-cholesterol, smoking and the presence of the other three conditions. RESULTS: Patients with CVD were 35% (95% CI 23-48%) more likely to develop diabetes after controlling for other risk factors. Heart failure was independently associated with an increase in diabetes incidence of 48% (95% CI 27-73%), and depression was associated with a 10% (95% CI 2-20%) increase. Chronic kidney disease was associated with a non-significant risk increase of 10% (95% CI -2-25%). CONCLUSIONS/INTERPRETATION: Complications of diabetes are more prevalent among patients who will ultimately develop diabetes, and increase the risk of diabetes independently of other known risk factors. The apparent bidirectional relationships suggest that primary prevention of CVD may also help prevent diabetes.

Phospholipid-calcium phosphate complex: enhanced calcium migration in the presence of phosphate.

In the presence of acidic phospholipids, inorganic phosphate greatly enhances the net migration of calcium ions from the aqueous phase to the organic phase, an effect that does not occur at less than the physiological pH. The calcium complex in the organic phase is shown by electron microscopy to consist of spherules, composed of stoichiometric amount of calcium, inorganic phosphate, and phospholipid. The demonstration of complex formation between calcium phosphate and acidic phospholipids adds Support to the concept that phospholipids are involved in biological mineralization.

Cosmic-ray tracks in plastics: the apollo helmet dosimetry experiment.

Counts of tracks from heavy cosmic-ray nuclei in helmets from Apollo missions 8 and 12 show variations caused by solar modulation of the galactic cosmic-ray flux. Specific estimates of the biological damage to certain nonreplaceable cells by track-forming particles during these space missions indicate that the fraction of deactivated cells could range from a lower limit of 3 x 10(-7) to an upper limit of 1.4 x 10(-4).

A re-evaluation of the impact of temperature and climate change on foodborne illness.

The effects of temperature on reported cases of a number of foodborne illnesses in England and Wales were investigated. We also explored whether the impact of temperature had changed over time. Food poisoning, campylobacteriosis, salmonellosis, Salmonella Typhimurium infections and Salmonella Enteritidis infections were positively associated (P<0.01) with temperature in the current and previous week. Only food poisoning, salmonellosis and S. Typhimurium infections were associated with temperature 2-5 weeks previously (P<0.01). There were significant reductions also in the impact of temperature on foodborne illnesses over time. This applies to temperature in the current and previous week for all illness types (P<0.01) except S. Enteritidis infection (P=0.079). Temperature 2-5 weeks previously diminished in importance for food poisoning and S. Typhimurium infection (P<0.001). The results are consistent with reduced pathogen concentrations in food and improved food hygiene over time. These adaptations to temperature imply that current estimates of how climate change may alter foodborne illness burden are overly pessimistic.

Preparedness for the prevention and control of influenza outbreaks on passenger ships in the EU: the SHIPSAN TRAINET project communication.

Passenger ships carry a large number of people in confined spaces. A case of the new influenza A (H1N1) virus aboard a passenger ship is an expected event and would lead to rapid spread of the virus, if preventive measures are not in place. However, many cruise lines have detailed policies and procedures to deal with cases of influenza like illness (ILI). The EU SHIPSAN and SHIPSAN TRAINET projects include in their objectives guidelines for the prevention and control of communicable diseases aboard passenger ships. A literature review showed that from 1997 to 2005, nine confirmed outbreaks of influenza were linked to passenger ships, with attack rates up to 37%. It is important to establish and maintain a surveillance system for ILI aboard passenger ships, in order to systematically collect data that can help to determine the baseline illness levels. Monitoring these will enable early identification of outbreaks and allow timely implementation of control measures.

Risk of chronic kidney disease in hypertensive patients with other metabolic conditions.

Using a retrospective cohort design and electronic medical records, we examined chronic kidney disease (CKD) risk over a 6-year period among hypertensive patients in relation to the presence of diabetes, hyperlipidaemia and/or high body mass index. After adjusting for age, sex, smoking status and baseline glomerular filtration rate (GFR), hypertensive patients without other metabolic risk factors had a relative risk of CKD (versus normotensive patients) of 2.0 (95% CI 1.8-2.2); hypertensive patients with other metabolic conditions had adjusted relative risks ranging from 2.4 to 2.6 for those without comorbid diabetes, and from 3.3 to 5.5 for those with comorbid diabetes. Our study thus confirms prior research demonstrating elevated CKD risk in hypertensive patients, and suggests that this risk varies substantially in relation to other metabolic conditions, especially diabetes.

The microbiological quality of potable water on board ships docking in the UK and the Channel Islands: an association of Port Health Authorities and Health Protection Agency Study.

Providing safe potable water onboard vessels presents particular challenges and contamination can occur directly from source waters as well as during loading, storage and distribution. Between May and October 2005, 950 potable water samples were collected from 342 ships docking at ports. Comparison with Guidelines found 9% of samples contained coliforms, Escherichia coli or enterococci and 2.8% had faecal indicators (E. coli or enterococci). Action levels of aerobic colony count (ACC) bacteria were detected in 20% (22 degrees C) and 21.5% (37 degrees C) of samples. ACC results from one-off sampling are not informative as this does not enable port health authorities to monitor ACC trends. They should be removed as a routine criterion for remedial action and vessels should adopt the WHO Water Safety Plan approach, whilst continuing to monitor water quality with public health-based indicators (e.g. chlorine residual, coliforms, E. coli and enterococci). Logistic regression analyses identified practices associated with water quality. Practices protective against coliforms, E. coli or enterococci in potable supplies were: good hose hygiene, processing water onboard, maintaining free chlorine residual at >or=0.2 mg/L. This emphasizes the importance of good hygiene during potable water loading and maintaining adequate disinfection of supplies onboard.

Bone matrix turnover and balance in vitro. I. The effects of parathyroid hormone and thyrocalcitonin.

Labeled proline from incubation media has been shown to be incorporated into living bone matrix collagen in vitro. Hydroxyproline is released from fresh bone slices in similar systems in a characteristic curve against time. This hydroxyproline is derived from three distinct sources, each of which may be separately quantitated. Part of the total represents passive solubilization of matrix collagen, part is derived from new synthesis of soluble collagen occurring in vitro, and the remainder is released by cell-mediated resorptive action. The latter two processes are linear with time up to 8 hr; the former decays to zero at about 2 hr. Consequently, rates of collagen synthesis and of new collagen deposition and resorption can be quantitated simultaneously in the same system. The ability to measure these parameters of bone collagen metabolism provides methods both for the accurate evaluation of organic matrix resorption in vitro and for the accurate measurement of rates of collagen synthesis and collagen deposition. The application of the method is illustrated using parathyroid hormone and thyrocalcitonin. Parathyroid hormone diminishes collagen synthesis and stimulates collagen resorption. It reduces slightly the deposition of newly formed collagen in stable matrix. The net effect of these changes is to produce a marked negative balance. It does not significantly affect the solubility of matrix collagen.Thyrocalcitonin does not affect collagen synthesis or its deposition. It causes a marked fall in resorption rate. It has no effect on matrix collagen solubility. The net effect is to produce a marked positive balance of matrix collagen.

Bone matrix turnover and balance in vitro. II. The effects of aging.

The rates of both formation and resorption of bone collagen may be accurately quantitated by kinetic analysis of hydroxyproline metabolism in vitro. Using this approach we have studied the changes in bone collagen turnover with age in the rat. The rates of synthesis and resorption of collagen decline with age although the resorptive activity per cell increases up to 6 months of age. The solubility of collagen declines with age. The fraction of the newly synthesized collagen which is deposited as matrix declines dramatically with age revealing a new and hitherto unsuspected aspect of the osteoporotic process. The collagen balance becomes progressively more negative over the 1st 6 months of life. These results indicate that even in an animal who is not subject to clinical osteoporosis, biochemical measurement reveals that such a trend exists. The application of this approach to human subjects is feasible and has important implications.

The spectrum of myelodysplastic syndromes post-solid organ transplantation: a single institutional experience.

An increased incidence of acute myeloid leukemia (AML) has recently been documented in patients post-solid organ transplantation but the incidence and types of myelodysplastic syndromes (MDS) occurring in this patient population are not known. We identified 5 patients (3M, 2F, age 48-64 years) who developed MDS ranging from 1.8 to 25 years (median 4.2 years) post-solid organ transplantation, only 2 patients had received azathioprine. The cumulative incidence of MDS in heart and lung transplant recipients at 15 years was 0.5% and 1.8%, respectively, which is markedly higher compared to the general population. Low-risk types of MDS predominated, 3 of 5 patients are alive (median 3.9 years) since diagnosis. Deletions of chromosome 20q, which have not been previously reported in post-transplant MDS/AML, were identified in 3 cases. Our findings expand the morphologic and cytogenetic spectrum of MDS occurring post-solid organ transplantation and suggest that mechanisms beside azathioprine toxicity might be important in disease pathogenesis.

Randomized trial of low-dose interleukin-2 vs cyclosporine A and interferon-gamma after high-dose chemotherapy with peripheral blood progenitor support in women with high-risk primary breast cancer.

High-risk primary breast cancer patients treated with high-dose chemotherapy (HDC) and stem cell support (SCS) have shown prolonged disease-free survival (DFS) in many studies; however, only one trial has demonstrated an overall survival benefit (OS). We hypothesize that the period following myeloablative therapy is ideal for immunologic manipulation and studied the effects of two different methods of immunotherapy following HDC with SCS aimed at the window of immune reconstitution. Seventy-two women with high-risk stage II or III breast cancer were randomized following HDC to receive either interleukin 2 (IL-2) at 1 million units/m(2) SQ daily for 28 days or combined cyclosporine A (CsA) at 1.25 mg/kg intravenously daily from day 0 to +28 and interferon gamma (IFN-gamma) 0.025 mg/m(2) SQ every 2 days from day +7 to +28. At a median follow-up of 67 months, no significant difference was observed in DFS or OS between the two treatment groups. The IL-2 arm had a 59% DFS (95% CI (0.45, 0.78)) and a 72% OS (95% CI (0.58, 0.88)) at 5 years. The CsA/INF-gamma arm had a similar outcome with a 55% DFS (95% CI (0.40, 0.76)) and a 78% OS (95% CI (0.65, 0.94)) at 5 years. Treatment was well tolerated, without increased toxicity.