N-acetyltransferase polymorphisms and colorectal cancer: a HuGE review

The two expressed genes coding for N-acetyltransferase (NAT) activity, NAT1 and NAT2, are located on chromosome 8 at 8p21.3-23.1 and are polymorphic. Both enzymes are capable of N-acetylation, O-acetylation, and N,O-acetylation and are implicated in the activation and detoxification of known carcinogens. Single base-pair substitutions in NAT2 tend to occur in combination with other substitutions within the gene. As yet, less work has been done to characterize NAT1 allelic variants. Various methods for the detection of the reported polymorphisms exist. It is important to select a method that is appropriate to the population being studied. The functional significance of many NAT allelic variants has not been determined. Geographic and ethnic variation in the frequency of NAT2 genotypes associated with fast or intermediate acetylation has been observed. Insufficient data for NAT1 genotypes are available to reveal a clear geographic pattern. No consistent association has been found between acetylator phenotype or genotype and colorectal cancer. The lack of consistency can in part be accounted for by methodological factors, including limited statistical power. Possible interactions between the NAT genes and either environmental exposures or other polymorphic genes encoding xenobiotic metabolizing enzymes have been investigated in only a minority of these studies, and these studies have lacked statistical power to detect interactions.     

Ethonomics: the ethics of the unaffordable

The most familiar basis for medical ethics since the 1950s has been principle-based ethics. The 4 basic principles are known as the "Georgetown mantra" of beneficence, nonmaleficence, respect for autonomy, and justice. These principles have served us well since their enunciation in the wake of the activities of the Nazi doctors in the concentration and extermination camps of World War II. In the past 15 years, however, they have begun to serve less well. In the era of resource constraints, however, the clinical relationship has become more complex. It now involves many more stakeholders, who control funds, make policy, and effectively ration services. Lawyers are also involved in important ways. All these people take part with varying directness in the processes of consultation and treatment. The consulting room has become a crowded office. For these reasons, the old ethics will no longer serve us. We need a new ethics that recognizes the involvement of the new stakeholders, and recognizes that resource constraints influence clinical practice.     

Asymptomatic spondylodiscitis an unusual feature of ankylosing spondylitis

Six patients with ankylosing spondylitis were found to have asymptomatic spondylodiscitis. They have been followed for a mean of 17 years and have been free of symptoms or complications from this lesion. This benign asymptomatic course has not been stressed by previous authors.     

Papers Please - Predictive Factors of National and International Attitudes Toward Immunity and Vaccination Passports: Online Representative Surveys

BackgroundIn response to the COVID-19 pandemic, countries are introducing digital passports that allow citizens to return to normal activities if they were previously infected with (immunity passport) or vaccinated against (vaccination passport) SARS-CoV-2. To be effective, policy decision-makers must know whether these passports will be widely accepted by the public and under what conditions. This study focuses attention on immunity passports, as these may prove useful in countries both with and without an existing COVID-19 vaccination program; however, our general findings also extend to vaccination passports.ObjectiveWe aimed to assess attitudes toward the introduction of immunity passports in six countries, and determine what social, personal, and contextual factors predicted their support.MethodsWe collected 13,678 participants through online representative sampling across six countries—Australia, Japan, Taiwan, Germany, Spain, and the United Kingdom—during April to May of the 2020 COVID-19 pandemic, and assessed attitudes and support for the introduction of immunity passports.ResultsImmunity passport support was moderate to low, being the highest in Germany (775/1507 participants, 51.43%) and the United Kingdom (759/1484, 51.15%); followed by Taiwan (2841/5989, 47.44%), Australia (963/2086, 46.16%), and Spain (693/1491, 46.48%); and was the lowest in Japan (241/1081, 22.94%). Bayesian generalized linear mixed effects modeling was used to assess predictive factors for immunity passport support across countries. International results showed neoliberal worldviews (odds ratio [OR] 1.17, 95% CI 1.13-1.22), personal concern (OR 1.07, 95% CI 1.00-1.16), perceived virus severity (OR 1.07, 95% CI 1.01-1.14), the fairness of immunity passports (OR 2.51, 95% CI 2.36-2.66), liking immunity passports (OR 2.77, 95% CI 2.61-2.94), and a willingness to become infected to gain an immunity passport (OR 1.6, 95% CI 1.51-1.68) were all predictive factors of immunity passport support. By contrast, gender (woman; OR 0.9, 95% CI 0.82-0.98), immunity passport concern (OR 0.61, 95% CI 0.57-0.65), and risk of harm to society (OR 0.71, 95% CI 0.67-0.76) predicted a decrease in support for immunity passports. Minor differences in predictive factors were found between countries and results were modeled separately to provide national accounts of these data.ConclusionsOur research suggests that support for immunity passports is predicted by the personal benefits and societal risks they confer. These findings generalized across six countries and may also prove informative for the introduction of vaccination passports, helping policymakers to introduce effective COVID-19 passport policies in these six countries and around the world.     

Multi-population generalizability of a deep learning-based chest radiograph severity score for COVID-19

To tune and test the generalizability of a deep learning-based model for assessment of COVID-19 lung disease severity on chest radiographs (CXRs) from different patient populations.A published convolutional Siamese neural network-based model previously trained on hospitalized patients with COVID-19 was tuned using 250 outpatient CXRs. This model produces a quantitative measure of COVID-19 lung disease severity (pulmonary x-ray severity (PXS) score). The model was evaluated on CXRs from 4 test sets, including 3 from the United States (patients hospitalized at an academic medical center (N = 154), patients hospitalized at a community hospital (N = 113), and outpatients (N = 108)) and 1 from Brazil (patients at an academic medical center emergency department (N = 303)). Radiologists from both countries independently assigned reference standard CXR severity scores, which were correlated with the PXS scores as a measure of model performance (Pearson R). The Uniform Manifold Approximation and Projection (UMAP) technique was used to visualize the neural network results.Tuning the deep learning model with outpatient data showed high model performance in 2 United States hospitalized patient datasets (R = 0.88 and R = 0.90, compared to baseline R = 0.86). Model performance was similar, though slightly lower, when tested on the United States outpatient and Brazil emergency department datasets (R = 0.86 and R = 0.85, respectively). UMAP showed that the model learned disease severity information that generalized across test sets.A deep learning model that extracts a COVID-19 severity score on CXRs showed generalizable performance across multiple populations from 2 continents, including outpatients and hospitalized patients.     

Structure and function of delta-atracotoxins: lethal neurotoxins targeting the voltage-gated sodium channel.

Delta-atracotoxins (delta-ACTX), isolated from the venom of Australian funnel-web spiders, are responsible for the potentially lethal envenomation syndrome seen following funnel-web spider envenomation. They are 42-residue polypeptides with four disulfides and an "inhibitor cystine-knot" motif with structural but not sequence homology to a variety of other spider and marine snail toxins. Delta-atracotoxins induce spontaneous repetitive firing and prolongation of action potentials resulting in neurotransmitter release from somatic and autonomic nerve endings. This results from a slowing of voltage-gated sodium channel inactivation and a hyperpolarizing shift of the voltage-dependence of activation. This action is due to voltage-dependent binding to neurotoxin receptor site-3 in a similar, but not identical, fashion to scorpion alpha-toxins and sea anemone toxins. Unlike other site-3 neurotoxins, however, delta-ACTX bind with high affinity to both cockroach and mammalian sodium channels but low affinity to locust sodium channels. At present the pharmacophore of delta-ACTX is unknown but is believed to involve a number of basic residues distributed in a topologically similar manner to scorpion alpha-toxins and sea anemone toxins despite distinctly different protein scaffolds. As such, delta-ACTX provide us with specific tools with which to study sodium channel structure and function and determinants for phyla- and tissue-specific actions of neurotoxins interacting with site-3.     

FURTHER STUDIES ON THE ETIOLOGICAL R?LE OF VIBRIO FETUS

The data bearing on these three cases are quite sufficient to rule out Bacillus abortus as the agent. Not only the cultures and guinea pig tests of fetal tissues and contents of the digestive tract, but also the agglutination and guinea pig tests of the milk, were negative. The same is true of the agglutination tests of the blood serum. Only in one case was the placenta obtained in part. The stained films and the sections from various regions showed no abortion bacilli. Guinea pig tests of placental tissue were negative for Bacillus abortus. On the other hand) minute organisms resembling vibrios were detected in the cytoplasm of endothelial cells within capillaries in the edematous subchorionic tissue. Subsequently the agglutination titer of the blood serum of one of these cases rose to a level indicating infection with Bacillus abortus during the second pregnancy. The peculiar distribution of abortions due to Vibrio fetus among older cows and heifers in this herd, resulting at first in cases among older cows and latterly passing to young stock, may be explained by certain occurrences in the herd itself. It may be assumed that the infection was originally brought in by purchased cows. The young stock is kept segregated from these in a special barn, and when 6 months old it is pastured on outlying farms until returned in an advanced stage of pregnancy. The heifers during the first pregnancy were thus kept away from vibrio carriers until after the first calf was born. In June and July, 1919, 55 older cows, purchased and native, were placed on the young stock pasture. The three cases of abortion in heifers due to Vibrio fetus occurred October 24, November 9, and December 2, 1919. The age and condition of the fetuses accord very well with the assumption that Vibrio fetus was introduced among the young stock in June or July of the same year. The information gathered thus far concerning vibrionic abortion in this herd enables us to formulate a tentative hypothesis subject to modification with increasing knowledge of this type of infectious abortion. The infectious agent was probably introduced by purchased cows in 1917 or earlier. It gained a certain headway up to 1919, then the number of cases declined so that between May, 1919, and May, 1920, only the above three cases in heifers, and one case of mixed infection with Bacillus abortus in an older cow, were detected. During the same period cases due to Bacillus abortus continued undiminished. The greater resistance of Bacillus abortus manifested in cultures as compared with Vibrio fetus is thus reflected in its behavior in nature. The temporary dying out of the infection indicates that natural immunization of a herd to Vibrio fetus proceeds quite rapidly. Another outbreak may be expected when the immunity of the herd has declined in the absence of the infecting agent and the latter is reintroduced from without, or it may reappear at any time when a vibrio of higher virulence is brought in.     

AN OUTBREAK OF PNEUMONIA IN DAIRY COWS ATTRIBUTED TO BACILLUS BOVISEPTICUS

All outbreak of pneumonia in dairy cows attributed to Bacillus bovisepticus is described. About twenty cows and two calves were affected. The first cases were noted in cows purchased in Michigan. The disease next appeared in another lot of cows from Pennsylvania and subsequently attacked native stock. Of the ten cases which came under our observation, five apparently recovered, two died, and two severely affected cows were killed. The other case developed multiple abscesses of the lung and was finally killed. The more characteristic symptoms observed were high temperature, rapid respiration, dyspnea, cough, dullness on percussion, bronchial breathing, and albuminuria. The pneumonia was diffuse but first affected the cephalic and more dependent lobes. The process varied from hyperemia and hemorrhage to exudation of fibrin and leucocytes within the air spaces. The plugging of the interlobular lymph channels and blood vessels with fibrin was frequent. Bacillus bovisepticus was isolated in pure cultures from all involved portions of lung at autopsy. It was not found in blood cultures during the height of the disease, nor could it be obtained from the spleen and kidney after death.     

Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: Consensus recommendations of the NCI Multiple Myeloma Steering Committee

A wide variety of new therapeutic options for Multiple Myeloma (MM) have recently become available, extending progression-free and overall survival for patients in meaningful ways. However, these treatments are not curative, and patients eventually relapse, necessitating decisions on the appropriate choice of treatment(s) for the next phase of the disease. Additionally, an important subset of MM patients will prove to be refractory to the majority of the available treatments, requiring selection of effective therapies from the remaining options. Immunomodulatory agents (IMiDs), proteasome inhibitors, monoclonal antibodies, and alkylating agents are the major classes of MM therapies, with several options in each class. Patients who are refractory to one agent in a class may be responsive to a related compound or to a drug from a different class. However, rules for selection of alternative treatments in these situations are somewhat empirical and later phase clinical trials to inform those choices are ongoing. To address these issues the NCI Multiple Myeloma Steering Committee formed a relapsed/refractory working group to review optimal treatment choices, timing, and sequencing and provide recommendations. Additional issues considered include the role of salvage autologous stem cell transplantation, risk stratification, targeted approaches for genetic subsets of MM, appropriate clinical trial endpoints, and promising investigational agents. This report summarizes the deliberations of the working group and suggests potential avenues of research to improve the precision, timing, and durability of treatments for Myeloma.Subject terms: Combination drug therapy, Cancer therapeutic resistance, Targeted therapies