Return to work after COVID-19 infection - A Danish nationwide registry study.

OBJECTIVES: This study aimed to explore return to work after COVID-19 and how disease severity affects this. STUDY DESIGN: This is a Nationwide Danish registry-based cohort study using a retrospective follow-up design. METHODS: Patients with a first-time positive SARS-CoV-2 polymerase chain reaction test between 1 January 2020 and 30 May 2020, including 18-64 years old, 30-day survivors, and available to the workforce at the time of the first positive test were included. Admission types (i.e. no admission, admission to non-intensive care unit [ICU] department and admission to ICU) and return to work was investigated using Cox regression standardised to the age, sex, comorbidity and education-level distribution of all included subjects with estimates at 3 months from positive test displayed. RESULTS: Among the 7466 patients included in the study, 81.9% (6119/7466) and 98.4% (7344/7466) returned to work within 4 weeks and 6 months, respectively, with 1.5% (109/7466) not returning. Of the patients admitted, 72.1% (627/870) and 92.6% (805/870) returned 1 month and 6 months after admission to the hospital, with 6.6% (58/870) not returning within 6 months. Of patients admitted to the ICU, 36% (9/25) did not return within 6 months. Patients with an admission had a lower chance of return to work 3 months from positive test (relative risk [RR] 0.95, 95% confidence interval [CI] 0.94-0.96), with the lowest chance in patients admitted to an ICU department (RR 0.54, 95% CI 0.35-0.72). Female sex, older age, and comorbidity were associated with a lower chance of returning to work. CONCLUSION: Hospitalised patients with COVID-19 infection have a lower chance of returning to work with potential implications for postinfection follow-up and rehabilitation.

The use of a tablet-based app for investigating the influence of autistic and ADHD traits on performance in a complex drawing task.

This paper describes a smart tablet-based drawing app to digitally record participants' engagement with the Rey-Osterrieth complex figure (ROCF) task, a well-characterised perceptual memory task that assesses local and global memory. Digitisation of the tasks allows for improved ecological validity, especially in children attracted to tablet devices. Further, digital translation of the tasks affords new measures, including accuracy and computation of the fine motor control kinematics employed to carry out the drawing Here, we report a feasibility study to test the relationship between two neurodevelopmental conditions: autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). The smart tablet app was employed with 39 adult participants (18-35) characterised for autistic and ADHD traits, and scored using the ROCF perceptual and organisational scoring systems. Trait scores and conditions were predictor variables in linear regression models. Positive correlations were found between the attention-to-detail, attention-switching and communication subscales of the autistic trait questionnaire and organisational scores on the ROCF task. These findings suggest that autistic traits might be linked to differential performance on the ROCF task. Novelty and future applications of the app are discussed.

Increased long-term risk of heart failure and other adverse cardiac outcomes in dermatomyositis and polymyositis: Insights from a nationwide cohort.

BACKGROUND: Mounting evidence suggests that dermatomyositis/polymyositis (DM/PM) are associated with increased risk of atherosclerotic events and venous thromboembolism. However, data on the association between DM/PM and other cardiac outcomes, especially heart failure (HF), are scarce. OBJECTIVES: To examine the long-term risk and prognosis associated with adverse cardiac outcomes in patients with DM/PM. METHODS: Using Danish administrative registries, we included all patients ≥18 years with newly diagnosed DM/PM (1996-2018). Risks of incident outcomes were compared with non-DM/PM controls from the background population (matched 1:4 by age, sex, and comorbidity). In a secondary analysis, we compared mortality following HF diagnosis between DM/PM patients with HF and non-DM/PM patients with HF (matched 1:4 by age and sex). RESULTS: The study population included 936 DM/PM patients (median age 58.5 years, 59.0% women) and 3744 matched non-DM/PM controls. The median follow-up was 6.9 years. Absolute 10-year risks of incident outcomes for DM/PM patients vs matched controls were as follows: HF, 6.98% (CI, 5.16-9.16%) vs 4.58% (3.79-5.47%) (P = 0.002); atrial fibrillation, 10.17% (7.94-12.71%) vs 7.07% (6.09-8.15%) (P = 0.005); the composite of ICD implantation/ventricular arrhythmias/cardiac arrest, 1.99% (1.12-3.27%) vs 0.64% (0.40-0.98%) (P = 0.02); and all-cause mortality, 35.42% (31.64-39.21%) vs 16.57% (15.10-18.10%) (P < 0.0001). DM/PM with subsequent HF was associated with higher mortality compared with HF without DM/PM (adjusted hazard ratio 1.58 [CI, 1.01-2.47]). CONCLUSION: Patients with DM/PM had a higher associated risk of HF and other adverse cardiac outcomes compared with matched controls. Among patients developing HF, a history of DM/PM was associated with higher mortality.

Epstein-Barr virus infection after adolescence and human herpesvirus 6A as risk factors for multiple sclerosis.

BACKGROUND AND PURPOSE: Infections with human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS. METHODS: In this nested case-control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. RESULTS: Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20-29 and 30-39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6-2.7). CONCLUSIONS: This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS.

Time trends and patient selection in the use of continuous electrocardiography for detecting atrial fibrillation after stroke: a nationwide cohort study.

BACKGROUND AND PURPOSE: Clinical use of continuous electrocardiography (cECG) for detecting atrial fibrillation (AF) after stroke is unclear. In a Danish nationwide cohort, we described post-stroke time trends in outpatient cECG usage and AF incidence and characterized factors associated with cECG use. METHODS: Patients without AF discharged after their first ischaemic stroke between 2010 and 2016 were identified from Danish nationwide registries. cECG included Holter or event recording within 120 days from discharge. Cumulative incidence analysis and multivariable adjusted logistic regression were used to assess time trends and factors associated with cECG usage and AF. RESULTS: The study population comprised 39 641 patients. Cumulative use of cECG increased threefold from 3.3% [95% confidence intervals (CI), 2.8-3.8] in 2010 to 10.5% (95% CI, 9.7-11.3) in 2016. Correspondingly, cumulative incidence of post-stroke AF increased from 1.9% (95% CI, 1.5-2.3) to 2.8% (95% CI, 2.4-3.2). Of all cECG-evaluated patients, 6.3% received an AF diagnosis versus 2.2% of the unevaluated. Receiving cECG was associated with increased odds of AF (odds ratio, 3.4; 95% CI, 2.8-4.0). Lower age, milder strokes and less comorbidity were associated with increased odds of receiving cECG. In contrast, risk factors for AF were increasing age and more comorbidity. CONCLUSIONS: Post-stroke outpatient cECG use and AF incidence have increased over time, but screening rates were low. cECG use was associated with tripled odds of detecting AF. There was a disparity between factors associated with cECG use and risk factors of AF. This raise questions as to the appropriateness of the current clinical approach to post-stoke AF detection.

The effect of bariatric surgery on breast cancer incidence and characteristics: A meta-analysis and systematic review.

BACKGROUND: Obesity is a major risk factor for breast cancer. This study examines whether bariatric surgery affects breast cancer incidence in women with obesity compared to BMI-matched controls. METHODS: EMBASE, MEDLINE, Web of Science, and CINAHL were searched. Primary studies on female breast cancer incidence after bariatric surgery were eligible. RESULTS: 11 studies were included (n = 1,106,939). The rate of cancer diagnosis was lower in the surgical group (0.54%) compared to control (0.84%; risk ratio (RR) 0.50, 95%CI 0.37-0.67, I2 = 88%). The results were robust to sensitivity analyses for patient age and study size. Bariatric surgery was associated with increased risk of stage I cancer (RR 1.23, 95%CI 1.06-1.44) and reduced risk of stage III or IV cancer (RR 0.50, 95%CI 0.28-0.88). Hormone receptor characteristics were not affected. CONCLUSIONS: Bariatric surgery is associated with reduced incidence and earlier stage at diagnosis of breast cancer in women with obesity compared to BMI-matched controls.

Outreach obstetrics training in Western Australia improves neonatal outcome and decreases caesarean sections.

The objective of this study was to determine the effect of a multi-professional outreach obstetric training programme on perinatal and neonatal outcomes. This was a retrospective comparison of 5-min low Apgar scores, stillbirth, perinatal death and moderate/severe hypoxic ischaemic encephalopathy rates in 127,753 infants born in Western Australia before and after the introduction of training in rural and remote areas. Following the introduction of the training programme, there was a highly significant (p = 0.003) decrease in the rate of infants born with low 5-min Apgar scores (from 20.4 to 15.4/1,000 live births). While the changes in the other three outcomes were not significant, all three demonstrated a trend for improvement in the intervention area. This is the second study of an educational intervention in obstetrics to demonstrate improvement in neonatal outcome and the first to be associated with a decrease in caesarean sections.

Incidence of acute myocardial infarction-related cardiogenic shock during corona virus disease 19 (COVID-19) pandemic.

AIMS: The hospitalization of patients with MI has decreased during global lockdown due to the COVID-19 pandemic. Whether this decrease is associated with more severe MI, e.g. MI-CS, is unknown. We aimed to examine the association of Corona virus disease (COVID-19) pandemic and incidence of acute myocardial infarction with cardiogenic shock (MI-CS). METHODS: On March 11, 2020, the Danish government announced national lock-down. Using Danish nationwide registries, we identified patients hospitalized with MI-CS. Incidence rates (IR) and incidence rate ratios (IRR) were used to compare MI-CS before and after March 11 in 2015-2019 and in 2020. RESULTS: We identified 11,769 patients with MI of whom 696 (5.9%) had cardiogenic shock in 2015-2019. In 2020, 2132 MI patients were identified of whom 119 had cardiogenic shock (5.6%). The IR per 100,000 person years before March 11 in 2015-2019 was 9.2 (95% CI: 8.3-10.2) and after 8.9 (95% CI: 8.0-9.9). In 2020, the IR was 7.5 (95% CI: 5.8-9.7) before March 11 and 7.7 (95% CI: 6.0-9.9) after. The IRRs comparing the 2020-period with the 2015-2019 period before and after March 11 (lockdown) were 0.81 (95% CI: 0.59-1.12) and 0.87 (95% CI: 0.57-1.32), respectively. The IRR comparing the 2020-period during and before lockdown was 1.02 (95% CI: 0.74-1.41). No difference in 7-day mortality or in-hospital management was observed between study periods. CONCLUSION: We could not identify a significant association of the national lockdown on the incidence of MI-CS, along with similar in-hospital management and mortality in patients with MI-CS.

Incidental finding of a persistent median artery (palmar type) during a routine carpal tunnel decompression: a case report.

Carpal tunnel syndrome is characterised by compression of the median nerve. The mainstay of treatment is surgical decompression. This case report highlights the occurrence of a persistent median artery, which could complicate surgery. A 55-year-old woman underwent carpal tunnel decompression. An incidental finding of a large-calibre persistent median artery, which was superficial to the flexor sheath, could have been damaged. This was carefully retracted and the procedure was completed, without any complications. Several studies have shown the prevalence of persistent median artery to range from 1.1-27.1%. It is usually found deep to the flexor retinaculum but in this case it was found to be just beneath the palmar fascia. There is increased chance of iatrogenic injury with this particular variant. Surgeons performing the procedure should be mindful of this variation, because accidental damage could result in devastating consequences to the hand.

Vulvar cancer is not a disease of the elderly: Treatment and outcome at a tertiary referral centre in South Africa.

BACKGROUND: An increase in vulvar cancer in young women is attributed to infection with oncogenic human papillomavirus (HPV). South Africa (SA) has a high prevalence of HPV, and it was therefore hypothesised that women with vulvar cancer here would be younger than in high-income countries (HICs). OBJECTIVE: To describe age, cancer stage, treatment and outcome of patients with vulvar cancer at a tertiary referral centre in SA. METHODS: In a retrospective observational study, patient records of women diagnosed with vulvar cancer between 2001 and 2014 were reviewed and demographic and surgical details captured. Histology results of vulvar biopsies and resected specimens were checked for HPV changes, koilocytes and usual-type vulval intraepithelial neoplasia. Patients were restaged using the International Federation of Gynecology and Obstetrics (FIGO) 2009 staging system to allow for comparison of outcomes. Five-year disease-specific survival probability curves were generated using Kaplan-Meier analysis. RESULTS: The mean age of the 180 patients in the study was 52.5 years. Those who had documented HPV changes on histological specimens had a mean age of 50.4 years. More than 50% of the patients had advanced-stage disease, and 62.7% were treated with primary surgery. Five-year disease-specific survival probabilities were similar to those reported in the literature. CONCLUSIONS: Vulvar cancer should not be regarded as a disease of the elderly in SA, as women with vulvar cancer are 10 - 15 years younger than in HICs. A large proportion of patients present with advanced-stage disease. Health professionals should be alert to vulvar lesions, especially in women with abnormal Pap smears, to reduce the morbidity and mortality of this disease.

Management of spontaneous rupture of the oesophagus (Boerhaave's syndrome): single centre experience of 18 cases.

BACKGROUND: Spontaneous oesophageal rupture (Boerhaave's syndrome) is rare, and carries a high attendant risk of mortality. METHODS: A retrospective eight-year review from a tertiary unit. RESULTS: Eighteen patients were managed, with a mean age of 57 (39 - 88 years). Eight patients presented early and underwent surgery, seven with primary closure and one with exclusion and diversion. There was one death in this group. Ten patients were managed conservatively. In this group, two underwent an oesophagectomy because of failed conservative measures, and four had an endoprosthesis inserted. One patient died in this group on the first admission, but two patients with stents in situ died from massive bleeding relating to an aorto-oesophageal fistula at 39 days and 189 days respectively following presentation. CONCLUSIONS: Surgical intervention remains the gold standard when the diagnosis is made early. For late diagnoses, this series suggests caution in the use of endoprostheses.

Mechanisms of Bacterial Extracellular Electron Exchange.

The biochemical mechanisms by which microbes interact with extracellular soluble metal ions and insoluble redox-active minerals have been the focus of intense research over the last three decades. The process presents two challenges to the microorganism. Firstly, electrons have to be transported at the cell surface, which in Gram-negative bacteria presents an additional problem of electron transfer across the ~6nm of the outer membrane. Secondly, the electrons must be transferred to or from the terminal electron acceptors or donors. This review covers the known mechanisms that bacteria use to transport electrons across the cell envelope to external electron donors/acceptors. In Gram-negative bacteria, electron transfer across the outer membrane involves the use of an outer membrane ß-barrel and cytochrome. These can be in the form of a porin-cytochrome protein, such as Cyc2 of Acidithiobacillus ferrooxidans, or a multiprotein porin-cytochrome complex like MtrCAB of Shewanella oneidensis MR-1. For mineral-respiring organisms, there is the additional challenge of transferring the electrons from the cell to mineral surface. For the strict anaerobe Geobacter sulfurreducens this requires electron transfer through conductive pili to associated cytochrome OmcS that directly reduces Fe(III)oxides, while the facultative anaerobe S. oneidensis MR-1 accomplishes mineral reduction through direct membrane contact, contact through filamentous extensions and soluble flavin shuttles, all of which require the outer membrane cytochromes MtrC and OmcA in addition to secreted flavin.

Clinical spectrum of the upper gastrointestinal effects of nonsteroidal anti-inflammatory drugs. Natural history, symptomatology, and significance.

Nonsteroidal anti-inflammatory drugs (NSAIDs) relieve rheumatic pain and are in extensive use. Symptomatic complications of NSAIDs requiring the discontinuation of their use occur in 2 to 10 percent of patients with rheumatic diseases in sharp contrast to the common asymptomatic problems of gastroduodenal erosions, ulcerations, and bleeding, with resulting anemia in more than 40 percent of these patients. Opinions concerning the clinical significance of these complications are not uniform. The natural history of the effects of NSAIDs on the gastroduodenal mucosa reveals a sequence of initial subepithelial hemorrhage over a 24-hour period followed by gastroduodenal erosions and ulcerations in the next two weeks. From one week to three months, gastroduodenal erosions and ulcerations disappear in about half of the patients as an adaptation to continuing NSAID ingestion occurs. Hemorrhage may occur at any time in most patients and in a small minority (1 percent) it is massive. Non-aspirin NSAIDs (NANSAIDs) exhibit significantly fewer complications than do aspirin. These complications, however, demand considerable clinical attention and are ordered in a constant hierarchy, suggesting variable risks of complications among agents. NSAIDs are a blessing for those who have chronic pain, but that blessing does not prevent significant asymptomatic complications in the same patients. Prophylaxis for high-risk groups, such as women over the age of 65 years, should be subjected to study.

NSAIDs: a clinical approach to the problems of gastrointestinal side-effects.

Despite the fact that non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs in medicine today, 2-10% of patients must discontinue their use primarily due to gastrointestinal (GI) side-effects. While the development of non-aspirin NSAIDs (NA-NSAIDs) has significantly reduced GI side-effects, major problems persist. A practical clinical approach to these problems includes informing the patient about the risks and benefits of NSAIDs, risk management during treatment with NSAIDs and investigation of symptomatic side-effects during treatment. Prophylaxis of GI side-effects is feasible in selected populations, but it has not been studied widely and may not be cost-effective. At present, costs of prophylaxis in all but selected populations with multiple risks probably outweight the benefits.

Fatal myxedema pericarditis in a Christian Scientist.

A case of fatal cardiac tamponade due to myxedema pericarditis is reported. The woman, a 54-year-old Christian Scientist, had never sought medical care and died at home. The pericardial sac occupied most of the thorax and contained 2,270 mL of fluid. A thick, shaggy, fibrinous exudate on the pericardium contained abundant cholesterol clefts typical of chronic effusion and myxedema. Thyroid function tests on postmortem blood revealed profound hypothyroidism, and the thyroid was atrophied, with the histologic appearance of primary atrophic thyroiditis. Pericardial effusion is common in myxedema, but cardiac tamponade is rare, only 13 cases being previously reported, none of which was fatal.

Genome and MIC stability in Mycobacterium tuberculosis and indications for continuation of use of isoniazid in multidrug-resistant tuberculosis.

Mycobacterium tuberculosis strains resistant to two or more of the first line antituberculosis drugs (MDR) are a serious threat to successful tuberculosis control programmes. For this retrospective study, 85 follow-up drug resistant isolates from 23 patients residing in a community with a high incidence of tuberculosis were collected and the level of in-vitro resistance to antibiotics determined quantitatively. PCR-SSCP and sequencing techniques were used to screen for gene mutations associated with resistance in 31 follow-up samples from a smaller group of eight patients. DNA fingerprint analysis was done on sequential isolates to confirm identity. Although treatment had a profound effect on changes in drug resistance patterns, the MIC for a particular agent remained constant in follow-up isolates. DNA fingerprinting and mutational analysis (14 different loci) showed that the genome of MDR strains of M. tuberculosis is relatively stable during the course of therapy. The rpoB gene was the most frequently mutated structural gene involved in drug resistance and a novel C to T mutation upstream of open reading frame (ORF)1 of the inhA operon was detected. No evidence was found of the presence of strain W (New York) in this group of MDR strains. The results stress the importance of confirming individuality of strains for the accurate calculation of frequencies of particular mutations associated with drug resistance, particularly in a high incidence area. Approximately one-half (47.8%) of the patients had isolates resistant to concentrations just above the critical concentration for isoniazid (MICs of 0.2-5 mg/L). Therefore, these patients and their contacts who develop primary drug-resistant tuberculosis may respond to higher dosages of treatment which could have a considerable impact on the cost and the ease of management of resistant tuberculosis.

Iron-sulphur clusters with labile metal ions.

A study has been carried out of the redox-linked metal ion uptake processes of the iron-sulphur cluster [3Fe-4S] in the bacterial ferredoxin, Fd III from Desulphovibrio africanus using a combination of electron paramagnetic resonance (EPR) and low-temperature magnetic circular dichroism (MCD) spectroscopy and direct, unmediated electrochemistry of the Fd in a film deposited at a pyrolytic graphite electrode. Reduction of the three-iron cluster is required before a divalent metal ion becomes bound as in the reaction sequence [formula: see text] The redox potentials of these processes and the metal binding constants have been determined. The affinities of the [3Fe-4S]0 cluster for divalent ions lie in the sequence Cd greater than Zn much greater than Fe. In addition, specific binding of a monovalent ion, Thallium(I), is detected for [3Fe-4S]1+ as well as for [3Fe-4S]0. The results provide a clear and quantitative demonstration of the capability of the open triangular tri-mu 2-sulphido face of a [3Fe-4S] cluster to bind a variety of metal ions if the protein environment permits. In each case the entering metal ion is coordinated by at least one additional ligand which may be from solvent (H2O or OH-) or from a protein side chain (e.g., carboxylate from aspartic acid). Hence the [3Fe-4S] core can be a redox-linked sensor of divalent metal ions, Fe(II) or Zn(II), that may trigger conformational change.

Ramp test objects for slice sensitivity profile measurement in spiral CT.

Spiral CT is increasingly becoming a routine imaging technique in the UK. The ability to scan whole organs within a single breath-hold often demands that the scan pitch (ratio of the patient translation distance per tube rotation (d) to the collimated slice thickness) be increased within technically acceptable limits. It is known that the full width at half maximum height (FWHM) of the slice sensitivity profile (SSP), degrades with increasing scan pitch and also varies with interpolation algorithm. Published literature frequently reports values for FWHM of the SSP for spiral acquisitions which have been measured with a ramp test tool. However, it has previously been shown that a ramp is inappropriate for SSP measurements in spiral CT. This is because of the physical basis of the premise for this measurement and the large artefacts generated by the application of the interpolation algorithm to the ramp spiral projection data. We present experimental evidence confirming the unsuitability of the ramp test tool in spiral CT. A cyclical variation (d/2) of the data is demonstrated; the magnitude of the measured SSP being dependent upon scan pitch and the interpolation algorithm used, as well as on the longitudinal position of the reconstruction plane.

Solitary asymptomatic plaque of demyelination in the medulla oblongata.

Clinically benign and clinically silent multiple sclerosis is now recognized. The corresponding plaques of demyelination in such cases are usually located in silent areas of the brain. We report a case where a solitary 3 x 3 mm plaque of demyelination was incidentally found in the medulla oblongata at autopsy. Although the plaque should have produced sensory symptoms by virtue of its location, no such history was obtainable even after direct questioning of the spouse of the deceased. The case illustrates that a single episode of demyelination may take place within the CNS without recurrence, and that a demyelinating plaque may be asymptomatic due to a functionally benign local effect, and not only by location in a silent area of the brain.

Factors that influence emergency department visits for asthma.

BACKGROUND: Asthma can usually be controlled through allergen avoidance and/or appropriate medication. An emergency department visit for an acute exacerbation of asthma often represents a breakdown in asthma management. Emergency department treatment results in significant health care expenditures and reflects a compromised quality of life. OBJECTIVES: To identify risk factors associated with an emergency department visit for asthma. METHODS: This case-control study compared 299 people (76% of 390 cases contacted) who attended one of two emergency departments in Alberta in 1992 and 1993 for an acute exacerbation of asthma (cases) with 212 unmatched community controls with asthma who were located by random digit dialing. Cases and controls were asked to complete a mailed questionnaire to obtain data regarding severity, visits to doctors and emergency departments, medication use, allergies and other triggers, and smoking history. Data analysis included bivariate analysis of risk factors and multivariate model development using logistic regression. RESULTS: The response rate was similar between cases and controls. Cases were younger than controls (odds ratio [OR] 2.16, 95% CI 1.34 to 3.48) and more often reported their asthma to be severe (OR 4.25, 95% CI 2.24 to 8.06), and had experienced nocturnal symptoms (stratified OR range 1.36 to 6.82). Cases used more health care services in the previous year, had been admitted to hospital at some time for asthma (OR 1.62, 95% CI 1.10 to 2.38) and used more medication than controls. CONCLUSIONS: Physicians and other health care workers should be sensitive to the risk factors and target interventions to high risk individuals.