Postmarketing studies: can they provide a safety net for COVID-19 vaccines in the UK?

In the current era of the COVID-19 pandemic, the world has never been more interested in the process of vaccine development. While researchers across the globe race to find an effective yet safe vaccine to protect populations from the newly emergent SARS-CoV-2 virus, more than one-third of the world has been subjected to either full or partial lockdown measures. With communities having felt the burden of prolonged isolation, finding a safe and efficacious vaccine will yield direct beneficial effects on protecting against COVID-19 morbidity and mortality and help relieve the psychological and economic load on communities living with COVID-19. There is hope that with the extraordinary efforts of scientists a vaccine will become available. However, given the global public health crisis, development of a COVID-19 vaccine will need to be fast tracked through the usual prelicensing development stages and introduced with limited clinical trial data compared with those vaccines that are developed conventionally over more than a decade. In this scenario, surveillance of the vaccine in the real world becomes even more paramount. This responsibility falls to observational researchers who can provide an essential safety net by continuing to monitor the effectiveness and safety of a COVID-19 vaccine after licensing. Postauthorisation observational studies for safety and effectiveness are complementary to prelaunch clinical trials and not a replacement. In this paper, we highlight the importance of postmarketing studies for future newly licensed COVID-19 vaccines and the key epidemiological considerations.

Tele-Integrative Medicine to Support Rehabilitative Care.

Complementary and integrative health (CIH) modalities have therapeutic value in the multidisciplinary rehabilitation of chronic pain patients. Evidence of such has been seen with the Whole Health Model at the (Veterans Affairs) VA Healthcare system. CIH therapies, including yoga, tai chi, mindfulness meditation, hypnosis, self-massage, and acupressure, are significantly effective for managing chronic pain with little to no negative effects, and can be easily incorporated into telemedicine care with great potential benefit. The future of wellness in telemedicine is evolving with great potential, and needs further attention to addressing barriers of care.

Challenges for Drug Repurposing in the COVID-19 Pandemic Era.

The coronavirus disease (COVID-19) pandemic has affected an estimated 16 million persons and caused 0.6 million deaths worldwide by September 2020. The pandemic has led to a rush to repurpose existing drugs, although the underlying evidence base is of variable quality. The improving knowledge of the virology and clinical presentation of COVID-19 is leading to a broadening pool of potential pharmacological targets. The aim of this review is to describe regulatory and pharmacological aspects of drug repurposing and to identify drugs proposed for repurposing in COVID-19 based on registered clinical trials, discussing the evidence to support their use in the treatment of this disease. The challenges of the correct interpretation of existing pre-clinical/clinical evidence as well as the generation of new evidence concerning drug repurposing in COVID-19 will also be discussed. Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT04321174, NCT04342663, NCT04280705, NCT04244591, NCT04359329, NCT04348695, NCT04304313, NCT043505931.

Investigation assessing the publicly available evidence supporting postmarketing withdrawals, revocations and suspensions of marketing authorisations in the EU since 2012.

OBJECTIVES: To assess the sources of publicly available evidence supporting withdrawal, revocation or suspension of marketing authorisations ('regulatory actions') due to safety reasons in the EU since 2012 and to investigate the time taken since initial marketing authorisation to reach these regulatory decisions. SETTING: This investigation examined the sources of evidence supporting 18 identified prescription medicinal products which underwent regulatory action due to safety reasons within the EU in the period 1 July 2012 to 31 December 2016. RESULTS: Eighteen single or combined active substances ('medicinal products') withdrawn, revoked or suspended within the EU for safety reasons between 2012 and 2016 met the inclusion criteria. Case reports were most commonly cited, supporting 94.4% of regulatory actions (n=17), followed by randomised controlled trial, meta-analyses, animal and in vitro, ex vivo or in silico study designs, each cited in 72.2% of regulatory actions (n=13). Epidemiological study designs were least commonly cited (n=8, 44.4%). Multiple sources of evidence contributed to 94.4% of regulatory decisions (n=17). Death was the most common adverse drug reaction leading to regulatory action (n=5; 27.8%), with four of these related to medication error or overdose. Median (IQR) time taken to reach a decision from the start of regulatory review was found to be 204.5 days (143, 535 days) and decreased across the study period. Duration of marketing prior to regulatory action, from the medicinal product's authorisation date, increased across the period 2012-2016. CONCLUSIONS: The sources of evidence supporting pharmacovigilance regulatory activities appear to have changed since implementation of Directive 2010/84/EU and Regulation (EU) No. 1235/2010. This, together with a small improvement in regulatory efficiency, suggests progress towards more rapid regulatory decisions based on more robust evidence. Future research should continue to monitor sources of evidence supporting regulatory decisions and the time taken to reach these decisions over time.

Variation in the limit-of-detection of the ProSpecT Campylobacter microplate enzyme immunoassay in stools spiked with emerging Campylobacter species.

Campylobacter enteritis in humans is primarily associated with C. jejuni/coli infection. The impact of other Campylobacter spp. is likely to be underestimated due to the bias of culture methods towards Campylobacter jejuni/coli diagnosis. Stool antigen tests are becoming increasingly popular and appear generally less species-specific. A review of independent studies of the ProSpecT® Campylobacter Microplate enzyme immunoassay (EIA) developed for C. jejuni/coli showed comparable diagnostic results to culture methods but the examination of non-jejuni/coli Campylobacter spp. was limited and the limit-of-detection (LOD), where reported, varied between studies. This study investigated LOD of EIA for Campylobacter upsaliensis, Campylobacter hyointestinalis and Campylobacter helveticus spiked in human stools. Multiple stools and Campylobacter isolates were used in three different concentrations (10(4)-10(9)CFU/ml) to reflect sample heterogeneity. All Campylobacter species evaluated were detectable by EIA. Multivariate analysis showed LOD varied between Campylobacter spp. and faecal consistency as fixed effects and individual faecal samples as random effects. EIA showed excellent performance in replicate testing for both within and between batches of reagents, in agreement between visual and spectrophotometric reading of results, and returned no discordance between the bacterial concentrations within independent dilution test runs (positive results with lower but not higher concentrations). This study shows how limitations in experimental procedures lead to an overestimation of consistency and uniformity of LOD for EIA that may not hold under routine use in diagnostic laboratories. Benefits and limitations for clinical practice and the influence on estimates of performance characteristics from detection of multiple Campylobacter spp. by EIA are discussed.

Safety of Intranasal Quadrivalent Live Attenuated Influenza Vaccine (QLAIV) in Children and Adolescents: A Pilot Prospective Cohort Study in England.

INTRODUCTION: Fluenz Tetra is an intranasal quadrivalent live attenuated influenza vaccine (QLAIV) and is recommended as the vaccine of choice for children in the 2014/2015 influenza season vaccination programme in the UK. OBJECTIVE: The primary objective of the study was to estimate the crude incidence rate of adverse events of interest (AEIs) following vaccination with the nasal QLAIV early in the 2014/2015 influenza season in children and adolescents in England. METHODS: A pilot non-interventional cohort post-authorisation safety study (PASS) was conducted during the 2014/2015 influenza season in England. Vaccinees were recruited via the mass vaccination programme in England. Participant outcomes, validated by a healthcare professional (general practitioner) where appropriate, were captured through questionnaires (surface mail, telephone, e-questionnaire). Data analysis comprised descriptive statistics and calculation of event risks and incidence rates, stratified by age group and selected co-morbidities. RESULTS: The final evaluable cohort consisted of 385 participants; the median (interquartile range) age was 4 (3-9) years with a range of 2-17 years, and 53.2 % were female. The most frequently reported AEI was nasal congestion (n = 167; 43.4 %; 312.3 per 1000 patient-weeks [95 % CI 267.3-364.8]). Further frequently reported AEIs were malaise (n = 87; 22.6 %; 123.4 per 1000 patient-weeks [95 % CI 98.9-154.1]) and cough (n = 80; 20.8 %; 118.5 per 1000 patient-weeks [95 % CI 95.1-147.8]). Five hypersensitivity-type reactions were reported, although on follow-up none were true hypersensitivity reactions or required hospitalisation. No serious adverse events (SAEs) were reported, with no hospitalisations or deaths. No significant change in reactogenicity or other apparent safety signals was detected as part of this study. CONCLUSION: The pilot study showed no significant change in reactogenicity or other apparent safety signals from the data collected. Continued enhanced surveillance of seasonal influenza vaccines will ensure their ongoing safety for the prevention of serious illness from seasonal influenza outbreaks.

Orexin Receptor Activation Generates Gamma Band Input to Cholinergic and Serotonergic Arousal System Neurons and Drives an Intrinsic Ca(2+)-Dependent Resonance in LDT and PPT Cholinergic Neurons.

A hallmark of the waking state is a shift in EEG power to higher frequencies with epochs of synchronized intracortical gamma activity (30-60 Hz) - a process associated with high-level cognitive functions. The ascending arousal system, including cholinergic laterodorsal (LDT) and pedunculopontine (PPT) tegmental neurons and serotonergic dorsal raphe (DR) neurons, promotes this state. Recently, this system has been proposed as a gamma wave generator, in part, because some neurons produce high-threshold, Ca(2+)-dependent oscillations at gamma frequencies. However, it is not known whether arousal-related inputs to these neurons generate such oscillations, or whether such oscillations are ever transmitted to neuronal targets. Since key arousal input arises from hypothalamic orexin (hypocretin) neurons, we investigated whether the unusually noisy, depolarizing orexin current could provide significant gamma input to cholinergic and serotonergic neurons, and whether such input could drive Ca(2+)-dependent oscillations. Whole-cell recordings in brain slices were obtained from mice expressing Cre-induced fluorescence in cholinergic LDT and PPT, and serotonergic DR neurons. After first quantifying reporter expression accuracy in cholinergic and serotonergic neurons, we found that the orexin current produced significant high frequency, including gamma, input to both cholinergic and serotonergic neurons. Then, by using a dynamic clamp, we found that adding a noisy orexin conductance to cholinergic neurons induced a Ca(2+)-dependent resonance that peaked in the theta and alpha frequency range (4-14 Hz) and extended up to 100 Hz. We propose that this orexin current noise and the Ca(2+) dependent resonance work synergistically to boost the encoding of high-frequency synaptic inputs into action potentials and to help ensure cholinergic neurons fire during EEG activation. This activity could reinforce thalamocortical states supporting arousal, REM sleep, and intracortical gamma.

Surgical repair of ileovesical fistulas: long-term complications, quality of life, and patient satisfaction.

Ileovesical fistulas (IVFs) are an uncommon complication of Crohn's disease. The aim of this study is to compare long-term surgical outcomes, assess quality of life, and quantify patient satisfaction after IVF repair. A retrospective chart review followed by a prospective survey was carried out. Survey questions focused on patient satisfaction and quality of life after repair of IVF. Fifty-one patients were identified from an administrative database. Mean follow-up was 4.3 years with a response rate of 51 per cent. At the time of the study, 0 per cent mortality and 16 per cent morbidity were recorded. No recurrence was noted. There was no statistical significance in incidence of complications between laparoscopic and open surgery. Statistically significant differences in single-stage versus multistage operations were found in postoperative day of discharge (P < 0.001) and patient satisfaction (P = 0.049). Ninety-eight per cent of patients reported extreme satisfaction with their surgery and an improvement in quality of life. A low incidence of morbidity and recurrence supports early surgical intervention in IVFs.

Radiographic findings of anastomotic leaks.

Although computed tomography (CT) scans play an important role in the diagnosis and management of anastomotic leaks (AL), there is no consensus on what radiographic findings are associated with AL. The purpose of this study is to identify the most common CT scan findings associated with AL and whether the amount of extraluminal air or the density of extraluminal fluid can be correlated with the presence of an AL. A retrospective chart review of 210 patients with anastomotic leaks from 2003 to 2010 at Mount Sinai Medical Center was performed. Eighty-six patients fit our criteria and were included. All CT scans were reread by an independent radiologist not involved with patient care. Our study included 59 per cent men and 41 per cent women with a mean age of 51 years. Diagnoses included inflammatory bowel disease (53%), malignancy (21%), and diverticulitis (12%). One hundred per cent of the patients had one of three findings: extraluminal air (92%), extraluminal fluid (88%), or extravasation of contrast (32%). Eighty-one per cent (70/86) had both fluid and air simultaneously. Extraluminal air was seen in 79 patients. The estimated amounts of extraluminal air were as follows: 0 to 25 mL (49%), 26 to 500 mL (41%), 500 to 1000 mL (5%), and more than 1000 mL (5%). The Hounsfield unit (HU) measurements of the fluid ranged from 3 to 633 HUs. The most common CT findings associated with AL are pneumoperitoneum and extraluminal fluid, including extravasation of contrast, which can be seen in up to 100 per cent of patients. The amount of estimated extraluminal air and density of fluid collection have no prognostic value in predicting AL.

Suture versus tack fixation of mesh in laparoscopic umbilical hernia repair.

BACKGROUND AND OBJECTIVES: Mesh fixation in laparoscopic umbilical hernia repair is poorly studied. We compared postoperative outcomes of laparoscopic umbilical hernia repair in suture versus tack mesh fixation. METHODS: Patients who underwent laparoscopic umbilical hernia repair were separated by method of mesh fixation: sutures versus primarily tacks. Medical history and follow-up data were collected through medical records. The primary outcome of this study was the recurrence rates of hernias. Postoperative major and minor complications, such as surgical site infection, small-bowel obstruction, and seroma formation, were regarded as secondary outcomes. Additionally, a telephone interview was conducted to assess postoperative pain, recovery time, and overall patient satisfaction. RESULTS: Eighty-six patients were identified: 33 in the suture group and 53 in the tacks group. The number of emergent cases was increased in the tacks group (6 vs 0; P = .022). Mean follow-up time was 2.7 years for both groups. Documented postoperative follow-up was obtained in 29 (90%) suture group and 31 (58%) tacks group patients. Hernia recurrence occurred in 3 and 2 patients in the sutures and tacks groups, respectively (P was not significant). No differences were found in secondary outcomes, including subjective outcomes from telephone interviews, between groups. CONCLUSIONS: There are no differences in postoperative complication rates in suture versus tack mesh fixation in laparoscopic umbilical hernia repair.

Management and outcomes of colovesical fistula repair.

This large retrospective study presents the largest colovesical fistula (CVF) series to date. We report on recurrence risk factors and patient satisfaction based on quality of life after CVF repair. Approval was obtained from The Mount Sinai School of Medicine Institutional Review Board, and a retrospective review was performed from 2003 to 2010 involving 72 consecutive patients who underwent a colovesical fistula repair. The CVF recurrence rate was 11 per cent. Ten percent of our patients who had a history of radiation therapy were at a significantly higher risk of developing a recurrence. Noted recurrence rates were significantly higher in advanced bladder repairs compared with simple repair (P = 0.022). The modified (Gastrointestinal Quality of Life Index) surveys showed overall patient satisfaction score was 3.6, out of a maximum score of 4, regardless of the type of repair or any postoperative complications. Our study found the CVF recurrence rate to be 11 per cent. Patients at higher risk of recurrence include those needing advanced bladder repair, those with "complex" CVF, and those whose fistulas involve the urethra. Patient satisfaction was found to be more closely linked to the resolution of CVF symptoms, irrespective of the type of repair performed or development of postoperative complications.

Identification of gene expression elements in Histomonas meleagridis using splinkerette PCR, a variation of ligated adaptor PCR.

Histomonas meleagridis is the causative agent of blackhead disease in gallinaceous birds. Limited genetic information exists for this organism, with the majority of sequence information coming from the coding regions of genes. No information is available for intergenic regions that contain DNA elements required for the regulation of gene expression. In this study, we demonstrate that splinkerette PCR, a variation of ligated adaptor PCR, can be used to identify regions of unknown sequence that lie upstream and downstream of known genomic sequences. Using this technique, we identified upstream sequences of 2 ß-tubulin genes. Sequence analysis identified the 5' coding portions of the ß-tubulin genes, the intergenic regions, and 2 different open reading frames encoding for a putative serine/threonine phosphatase and a putative ras-related protein, racG. We predict that these intergenic regions contain polyadenylation and cleavage signals for the 2 open reading frames and initiator elements for the ß-tubulin genes. Our research demonstrates the use of splinkerette PCR as a valuable tool to identify unknown DNA sequences. In addition, the identification of the regulatory elements necessary for gene transcription in H. meleagridis will provide tools for future studies on its gene expression.

Postoperative antibiotics correlate with worse outcomes after appendectomy for nonperforated appendicitis.

BACKGROUND: Acute appendicitis remains the most common cause of acute abdominal pain necessitating operative intervention. Although postoperative antibiotics are universally used for perforated appendicitis, no consensus exists on whether postoperative antibiotics are beneficial for preventing surgical site infections (SSIs) in nonperforated cases. We set out to determine how postoperative antibiotic therapy affects outcomes after appendectomy for nonperforated appendicitis. STUDY DESIGN: The medical records of 1,000 patients undergoing appendectomy for nonperforated appendicitis at The Mount Sinai Medical Center from January 2005 through July 2010 were retrospectively reviewed. RESULTS: In total, 728 cases contained sufficient follow-up data for analysis; 334 of these patients received postoperative antibiotics and 394 did not. There were no significant differences in patient demographics, medical comorbidities, American Society of Anesthesiologists (ASA) class, admission temperature, preoperative antibiotic treatment, operating room time, estimated blood loss, appendiceal diameter, or intraoperative transfusion between the two groups, although WBC was higher for patients receiving postoperative antibiotics (12.3 vs 14 cells/mm(3), p = 0.001). Postoperative antibiotics did not alter the incidence of superficial SSIs, deep SSIs, or organ space SSIs (all p = 0.1), but did correlate with higher rates of Clostridium difficile infection (p = 0.02), urinary tract infection (p = 0.05), postoperative diarrhea (p < 0.001), and longer length of stay (LOS) (1.1 vs 2.4 days, p < 0.001). Patients receiving postoperative antibiotics also showed trends toward higher readmission and reoperation rates (both p = 0.06). CONCLUSIONS: Postoperative antibiotic treatment for nonperforated appendicitis did not reduce infectious complications and prolonged LOS while increasing postoperative morbidity. Therefore, postoperative antibiotics likely increase the treatment cost for nonperforated appendicitis while not adding an appreciable clinical benefit and, in some cases, actually worsening outcomes.

Appendectomy during pregnancy: follow-up of progeny.

BACKGROUND: The incidence of appendicitis in pregnant patients is 0.04% to 0.20%, making it the most common nonobstetric surgical procedure in pregnancy. This study examines whether an appendectomy during any stage of pregnancy affects future development of motor, sensory, and social skills of the progeny. STUDY DESIGN: A prospective survey was administered to women who underwent an appendectomy during pregnancy at Mount Sinai Hospital from 2000 to 2009. The survey, which ranged from 1 to 9 years postpartum, consisted of questions about motor, sensory, and social development of their progeny, based on established pediatric milestones. Data were collected from the medical records of mother and child. Additional follow-up was gathered from outpatient and emergency room records. RESULTS: Fifty-two pregnant patients underwent an appendectomy during our study period. All pregnancies continued to full term with the exception of one fetal death due to extreme prematurity. Twenty-nine patients completed the follow-up survey, making the yield response rate 55.8%. There were 7 (26.9%), 14 (48.3%), and 8 (27.6%) appendectomies in the first, second, and third trimesters, respectively. Mean follow-up time was 47.2 months (range 13 to 117 months) after delivery. None of the children exhibited any developmental delay by their third year of life. Timing of the surgery (trimester) had no effect on child development. CONCLUSIONS: Appendectomy during pregnancy is not associated with developmental delays in children, regardless of which trimester the procedure was performed. All children in this study had normal motor, sensory, and social development by 3 years of age.

New postgraduate qualifications in pharmacovigilance from the Drug Safety Research Unit in the UK.

The Drug Safety Research Unit in the UK has recently launched new postgraduate certificate, diploma and masters courses in pharmacovigilance, in association with the University of Portsmouth. These courses have been developed to address the continuing demand for quality accredited education in pharmacovigilance and are aimed particularly at drug safety staff working in the pharmaceutical industry, regulatory bodies or academia. Flexibility is ensured by the availability of a wide choice of units, the use of online facilities for learning and assessment, and the possibility that previous relevant training or experience may be counted towards the awards.

Public computing options for individuals with cognitive impairments: survey outcomes.

PURPOSE: To examine availability and accessibility of public computing for individuals with cognitive impairment (CI) who reside in the USA. METHOD: A telephone survey was administered as a semi-structured interview to 145 informants representing seven types of public facilities across three geographically distinct regions using a snowball sampling technique. An Internet search of wireless (Wi-Fi) hotspots supplemented the survey. RESULTS: Survey results showed the availability of public computer terminals and Internet hotspots was greatest in the urban sample, followed by the mid-sized and rural cities. Across seven facility types surveyed, libraries had the highest percentage of access barriers, including complex queue procedures, login and password requirements, and limited technical support. University assistive technology centres and facilities with a restricted user policy, such as brain injury centres, had the lowest incidence of access barriers. CONCLUSION: Findings suggest optimal outcomes for people with CI will result from a careful match of technology and the user that takes into account potential barriers and opportunities to computing in an individual's preferred public environments. Trends in public computing, including the emergence of widespread Wi-Fi and limited access to terminals that permit auto-launch applications, should guide development of technology designed for use in public computing environments.