COVID-19 therapeutics: Challenges and directions for the future

The emergence of SARS-CoV-2 triggering the COVID-19 pandemic ranks as arguably the greatest medical emergency of the last century. COVID-19 has highlighted health disparities both within and between countries and will leave a lasting impact on global society. Nonetheless, substantial investment in life sciences over recent decades has facilitated a rapid scientific response with innovations in viral characterization, testing, and sequencing. Perhaps most remarkably, this permitted the development of highly effective vaccines, which are being distributed globally at unprecedented speed. In contrast, drug treatments for the established disease have delivered limited benefits so far. Innovative and rapid approaches in the design and execution of large-scale clinical trials and repurposing of existing drugs have saved many lives; however, many more remain at risk. In this review we describe challenges and unmet needs, discuss existing therapeutics, and address future opportunities. Consideration is given to factors that have hindered drug development in order to support planning for the next pandemic challenge and to allow rapid and cost-effective development of new therapeutics with equitable delivery.     

Ethylcholine mustard aziridinium ion (AF64A) impairs cholinergic neuromuscular transmission in the guinea-pig ileum and urinary bladder, and cholinergic neuromodulation in the enteric nervous system of the guinea-pig distal colon

AF64A was examined for its ability to impair cholinergic neurotransmission in the autonomic nervous system. In the guinea-pig ileum AF64A impaired cholinergic neuromuscular transmission. In the guinea-pig urinary bladder AF64A selectivity impaired the cholinergic but not the purinergic component of neuromuscular transmission. In the guinea-pig colon circular muscle AF64A impaired cholinergic neuromodulation of the inhibitory transmission but not the inhibitory transmission itself. The nature of impairment of cholinergic transmission by AF64A is discussed.     

Effects of Peroxide and Catalase on Near Ultraviolet Radiation Sensitivity in Escherichia Coli Strains

Summary

The role of peroxide and catalase on NUV radiation sensitivity was examined in two repair competent E. coli strains, AB1157 and B/r. Exponential phase B/r is considerably more sensitive to NUV radiation than exponential phase AB1157. However, resistance to 5 mmol dm^?3 H₂O₂ was induced in both AB1157 and B/r by pretreating growing cells with 30 μmol dm^?3 H₂O₂. Pretreatment also induced resistance to broad-band NUV radiation in these strains. The addition of catalase to the post-irradiation plating medium increased survival to the same extent as that provided by pretreatment with 30 μmol dm^?3 H₂O₂, in both strains. The NUV radiation sensitivity seen in B/r does not appear to be due to a deficiency in enzymes that scavenge H₂O₂, as a catalase deficient mutant, E. coli UM1, is more resistant to NUV radiation than B/r. Also, assays for H₂O₂ scavenging ability show little difference between AB1157 and B/r in this respect. Two hypotheses are put forward to account for the sensitivity of exponential phase B/r. Whilst it is apparent that peroxides and catalase do have a role in NUV radiation damage, it is clear that other factors also influence survival under certain conditions.     

Ultrasensitive profiling of UV-induced mutations identifies thousands of subclinical facial tumors in tuberous sclerosis complex

BackgroundTuberous sclerosis complex (TSC) is a neurogenetic syndrome due to loss-of-function mutations in TSC2 or TSC1, characterized by tumors at multiple body sites, including facial angiofibroma (FAF). Here, an ultrasensitive assessment of the extent and range of UV-induced mutations in TSC facial skin was performed.MethodsA multiplex high-sensitivity PCR assay (MHPA) was developed, enabling mutation detection at extremely low (<0.1%) variant allele frequencies (VAFs).ResultsMHPA assays were developed for both TSC2 and TP53, and applied to 81 samples, including 66 skin biopsies. UV-induced second-hit mutation causing inactivation of TSC2 was pervasive in TSC facial skin with an average of 4.8 mutations per 2-mm biopsy at median VAF 0.08%, generating more than 150,000 incipient facial tumors (subclinical “micro-FAFs”) in the average TSC subject. The MHPA analysis also led to the identification of a refined UV-related indel signature and a recurrent complex mutation pattern, consisting of both a single-nucleotide or dinucleotide variant and a 1- to 9-nucleotide deletion, in cis.ConclusionTSC facial skin can be viewed as harboring a patchwork of clonal fibroblast proliferations (micro-FAFs) with indolent growth, a small proportion of which develop into clinically observable FAF. Our observations also expand the spectrum of UV-related mutation signatures.FundingThis work was supported by the TSC Alliance; the Engles Family Fund for Research in TSC and LAM; and the NIH, National Heart, Lung, and Blood Institute (U01HL131022-04 and Intramural Research Program).     

Effectiveness of Cardiac Resynchronization Therapy in Diabetic Patients with Ischemic and Nonischemic Cardiomyopathy

Background: Diabetes mellitus (DM) increases the risk for the development of both ischemic and nonischemic cardiomyopathy. We aimed to identify differences in response to cardiac resynchronization therapy with a defibrillator (CRT‐D) among DM patients with ischemic or nonischemic cardiomyopathy. Methods: Cox proportional hazards regression modeling was used to assess clinical response to CRT‐D (defined as CRT‐D vs. defibrillator‐only reduction in the risk of heart failure [HF] or death) and echocardiographic response (defined as percent reduction in left ventricular end diastolic and systolic volume [LVEDV and LVESV, respectively] at 12 month of follow‐up compared with baseline values) among 552 diabetic patients with ischemic (n = 367) or nonischemic (n = 185) cardiomyopathy enrolled in MADIT‐CRT. Results: The clinical benefit of CRT‐D was more pronounced among nonischemic patients (HR = 0.30 [P < 0.001] than among ischemic patients (HR = 0.59 [P = 0.004]; P for interaction = 0.10). Nonischemic patients also experienced significantly greater reductions in LVESV and LVEDV at 12 months with CRT‐D compared with ischemic patients (P < 0.001 for both). Subgroup analysis showed that the most pronounced reduction in HF or death with CRT‐D therapy occurred in nonischemic patients who were women (83% risk‐reduction [P < 0.001]), had a lower BMI (<30/kg/m²: 79% risk‐reduction [P < 0.001]), or had left bundle branch block at enrollment (82% risk‐reduction [P < 0.001]). Conclusions: The present study shows that treatment with CRT‐D in at‐risk cardiac patients with DM is associated with substantial reductions in the risk of HF or death and improvement in cardiac remodeling in those with ischemic and nonischemic cardiomyopathy, with a more pronounced benefit in patients with nonischemic disease. Ann Noninvasive Electrocardiol 2012;17(1):14–21     

Two-way television: An experiment in interactive programming for the elderly

This study was conducted to 1) assess the effectiveness of an experimental two-way cable TV system in reaching the older people for whom it was designed, and 2) assess the attraction of this locally-based age-targeted system for its viewers. The study evaluates the system's effectiveness in reaching its target audience by examining information about the types of viewers—both younger and older—who have been attracted to the system. In addition, differences in factors that predict viewing frequency for younger and older people are used to illuminate life stage differences in people's attraction to locally-based TV programming. Findings show that the system had successfully reached its target audience within two years of inception. Watching the interactive TV programs because of the system's provision of information about local events and because of the senior citizens' focus strongly predicted viewing frequency for both older and younger respondents. The ability of locally-based interactive TV programming to serve social and informational needs of older people which are unmet by traditional broadcast television is discussed.     

DAS181 treatment of severe parainfluenza type 3 pneumonia in a lung transplant recipient

Parainfluenza virus (PIV) may cause life‐threatening pneumonia in lung transplant patients and there are no proven effective therapies. We report the use of inhaled DAS181, a novel sialidase fusion protein, to treat severe PIV type 3 pneumonia in a lung transplant patient. Treatment was well tolerated and associated with improvement in oxygenation and symptoms, along with rapid clearance of PIV. DAS181 should be systematically evaluated for treatment of PIV infection in transplant recipients.     

Addressing Environmental Health Concerns near Trecatti Landfill Site,United Kingdom

Residents near the Trecatti landfill site located in South Wales, United Kingdom, expressed concern about odors and health effects they attributed to site emissions. The authors compared routinely collected, population-based, health data from potentially exposed electoral wards (i.e., United Kingdom electoral tracts) with data from both wards nearby, matched for socioeconomic deprivation scores, and with wards where residents were likely to attend the same hospital. Mortality rates were higher for all causes and neoplastic diseases (but not respiratory disease) in the exposed wards, but there was no change in rates after the site opened. Hospital data revealed a transient increase in admissions for asthma during the 3 yr that preceded the peak in odor complaints. The birth prevalence of congenital malformations was raised in the exposed wards, but the authors could not exclude a possible artifact resulting from differences in reporting practices between hospitals. The absence of environmental monitoring in the community during the period of public concern was a significant weakness of this study.     

A forced hypnoprojective fantasy used in the resolution of pseudoepileptic seizures

A highly detailed account of the psychotherapy of one female hysterioa treatment failureis the stimulant for discussion of the genetics and dynamics of this nosology. The patient's symptomatology includes feelings of unreality, seizures, an embryo dual personality, and frigidity. Hypnosis revealed the experimental basis for these symptoms and associated adjustment di5iculties. The dynamics bear a remarkable resemblance to those advanced by Freud and Breuer, though issue is taken with several fundamental psychoanalytic concepts. The Discussion deals largely with the phenomenology of the female hysteric. It is concluded that the seemingly favorable prognosis of the hysteric is illusionary if the goal is characterologic change.