Journal scan: A review of ten recent papers of immediate clinical significance, harvested from major international journals
By
From the desk of the Editor-in-Chief
(1). Blood-Brain barrier crossing renin-angiotensin drugs and cognition in the elderly: a meta-analysis. Hypertension 2021
Hypertension is an established risk factor for cognitive decline and dementia in older adults, highlighting the potential importance of antihypertensive treatments in prevention efforts. Work surrounding antihypertensive treatments has suggested possible salutary effects on cognition and neuropathology.
Several studies have specifically highlighted renin-angiotensin system drugs, including AT1-receptor blockers and angiotensin-converting-enzyme inhibitors, as potentially benefiting cognition in later life. A small number of studies have further suggested renin-angiotensin system drugs that cross the blood-brain barrier may be linked to lower dementia risk compared to their nonpenetrant counterparts.
The present meta-analysis sought to evaluate the potential cognitive benefits of blood-brain barrier crossing renin-angiotensin system drugs relative to their nonpenetrant counterparts.
We harmonized longitudinal participant data from 14 cohorts from 6 countries (Australia, Canada, Germany, Ireland, Japan, United States), for a total of 12 849 individuals at baseline, and assessed for blood-brain barrier crossing potential within antihypertensive medications used by cognitively normal participants.
We analyzed 7 cognitive domains (attention, executive function, language, verbal memory learning, recall, mental status, and processing speed) using ANCOVA (adjusted for age, sex, and education) and meta-analyses.
Older adults taking blood-brain barrier-crossing renin-angiotensin drugs exhibited better memory recall over up to 3 years of follow-up, relative to those taking nonpenetrant medications, despite their relatively higher vascular risk burden.
Findings suggest links between blood-brain barrier crossing renin-angiotensin drugs and less memory decline.
(2). Regenerative medicine for neurological diseases – will regenerative neurosurgery deliver. BMJ 2021;373.
Regenerative medicine aspires to transform the future practice of medicine by providing curative, rather than palliative, treatments.
Healing the central nervous system (CNS) remains among regenerative medicine’s most highly prized but formidable challenges. “Regenerative neurosurgery” provides access to the CNS or its surrounding structures to preserve or restore neurological function. Pioneering efforts over the past three decades have introduced cells, neurotrophins, and genes with putative regenerative capacity into the CNS to combat neurodegenerative, ischemic, and traumatic diseases.
In this review we critically evaluate the rationale, paradigms, and translational progress of regenerative neurosurgery, harnessing access to the CNS to protect, rejuvenate, or replace cell types otherwise irreversibly compromised by neurological disease. We discuss the evidence surrounding fetal, somatic, and pluripotent stem cell derived implants to replace endogenous neuronal and glial cell types and provide trophic support. Neurotrophin based strategies via infusions and gene therapy highlight the motivation to preserve neuronal circuits, the complex fidelity of which cannot be readily recreated. We specifically highlight ongoing translational efforts in Parkinson’s disease, amyotrophic lateral sclerosis, stroke, and spinal cord injury, using these to illustrate the principles, challenges, and opportunities of regenerative neurosurgery. Risks of associated procedures and novel neurosurgical trials are discussed, together with the ethical challenges they pose. After decades of efforts to develop and refine necessary tools and methodologies, regenerative neurosurgery is well positioned to advance treatments for refractory neurological diseases. Strategic multidisciplinary efforts will be critical to harness complementary technologies and maximize mechanistic feedback, accelerating iterative progress toward cures for neurological diseases.
(3). Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients. N Engl J Med. 2021
A weak immune response to two doses of vaccine against severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) has been observed in recipients of solid-organ transplants. Severe cases of coronavirus disease 2019 (Covid-19) have also been reported in transplant recipients who had received two doses of vaccine. These reports prompted the French National Authority for Health to recommend the use of a third dose in immunosuppressed patients.
Here, we report the humoral response in a group of 101 consecutive solid-organ transplant recipients (mean [±SD] age, 58 ± 2 years; 69% were men) who were given three doses of the messenger RNA vaccine BNT162b2 (Pfizer–BioNTech). The group included 78 kidney-transplant recipients, 12 liver-transplant recipients, 8 lung-transplant or heart-transplant recipients, and 3 pancreas-transplant recipients.
The first two doses were given 1 month apart, and the third dose was administered 61 ± 1 days after the second dose. The time between transplantation and the initiation of vaccination was 97 ± 8 months. Immunosuppression was due to the use of glucocorticoids (in 87% of patients), calcineurin inhibitors (in 79% of patients), mycophenolic acid (in 63% of patients), mammalian target of rapamycin inhibitors (in 30% of patients), and belatacept (in 12% of patients).
Levels of antibodies to SARS-CoV-2 spike protein were assessed in all the patients with the use of the Wantai enzyme-linked immunosorbent assay (Beijing Wantai Biological Pharmacy Enterprise). Antibody titers are expressed as the ratio of the sample signal to a calibrator-assigned cutoff signal (the signal-to-cutoff ratio). According to French law, because this was an anonymous retrospective study, institutional review board approval was not required.
Immunogenicity
The prevalence of anti–SARS-CoV-2 antibodies was 0% (95% confidence interval [CI], 0 to 4; 0 of 101 patients) before the first dose, 4% (95% CI, 1 to 10; 4 of 101 patients) before the second dose, 40% (95% CI, 31 to 51; 40 of 99 patients) before the third dose, and 68% (95% CI, 58 to 77; 67 of 99 patients) 4 weeks after the third dose. Among the 59 patients who had been seronegative before the third dose, 26 (44%) were seropositive at 4 weeks after the third dose (mean [±SD] signal-to-cutoff ratio, 690±293). All 40 patients who had been seropositive before the third dose were still seropositive 4 weeks later; their antibody titers increased from 36±12 before the third dose to 2676±350 1 month after the third dose (P < 0.001). Patients who did not have an antibody response were older, had a higher degree of immunosuppression, and had a lower estimated glomerular filtration rate than patients who had an antibody response.
As of this writing, Covid-19 had not developed in any of the patients after they received the three vaccine doses. No serious adverse events were reported after the administration of the third dose, and no acute rejection episodes occurred.
This study showed that administration of a third dose of the BNT162b2 vaccine to solid-organ transplant recipients significantly improved the immunogenicity of the vaccine, with no cases of Covid-19 reported in any of the patients. However, a large proportion of the patients remain at risk for Covid-19. Barrier measures should be maintained, and vaccination of the relatives of these patients should be encouraged.
(4). Venous thromboembolism. Lancet 2021;398(10294):64-77
Venous thromboembolism, comprising both deep vein thrombosis and pulmonary embolism, is a chronic illness that affects nearly 10 million people every year worldwide.
Strong provoking risk factors for venous thromboembolism include major surgery and active cancer, but most events are unprovoked.
Diagnosis requires a sequential work-up that combines assessment of clinical pretest probability for venous thromboembolism using a clinical score (e.g., Wells score), D-dimer testing, and imaging.
Venous thromboembolism can be considered excluded in patients with both a non-high clinical pretest probability and normal D-dimer concentrations. When required, ultrasonography should be done for a suspected deep vein thrombosis and CT or ventilation–perfusion scintigraphy for a suspected pulmonary embolism.
Direct oral anticoagulants (DOACs) are the first-line treatment for almost all patients with venous thromboembolism (including those with cancer). After completing 3–6 months of initial treatment, anticoagulation can be discontinued in patients with venous thromboembolism provoked by a major transient risk factor.
Patients whose long-term risk of recurrent venous thromboembolism outweighs the long-term risk of major bleeding, such as those with active cancer or men with unprovoked venous thromboembolism, should receive indefinite anticoagulant treatment.
Pharmacological venous thromboembolism prophylaxis is generally warranted in patients undergoing major orthopaedic or cancer surgery. Ongoing research is focused on improving diagnostic strategies for suspected deep vein thrombosis, comparing different DOACs, developing safer anticoagulants, and further individualising approaches for the prevention and management of venous thromboembolism.
(5). Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine ( Novavax). N Engl J Med. 2021
Background
Early clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population.
Methods
In this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-μg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline.
Results
A total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval [CI], 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups.
Conclusions
A two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant.
(6). Review: Sparks through the stubble: dying in a pandemic- a film on the pandemic. Lancet 2021;398(10294):18-9
Excerpts:
“For our time is the passing of a shadow
And our lives will run like
Sparks through the stubble.”
Since the start of the COVID-19 pandemic, dying has dominated the national consciousness. Everyone knows someone who has lost a loved one to COVID-19.
COVID-19 has radically disrupted modern medicine. For over a century, doctors have operated within a professional paradigm that places action—our ability to intervene—center stage. With every advance—for example, anesthetics, chemotherapy, mechanical ventilation, or organ transplantation—doctors have accrued more power with which to swoop in, take command, and save the day. Medicine, as practiced in wealthy countries, deploys a dizzying array of technologies aimed at deferring and defying death. Life expectancy has typically soared. Against the illnesses and accidents that would otherwise fell us, doctors are life-prolonging, death-cheating, weapon thrusting samurais with stethoscopes instead of capes, but superheroes all the same.
The health profession’s triumphs—for this is exactly how they are framed—have been particularly notable against infectious diseases.
But COVID-19 has shredded that narrative. Nature—in the form of a microbe too primitive even to count as life—has forced humanity, and its doctors, to our complacent knees.
Although there has been an impressive research response to this pandemic with the remarkably rapid development of COVID-19 vaccines, therapeutics, and tests, this pandemic has also exposed the hubris of modern medicine.
COVID-19 has forced a triple reckoning.
- First, our species has been forced to confront its essential powerlessness and mortality.
- Second, COVID-19 has exposed the inherent power of entrenched racial, socioeconomic, and other inequalities in exacerbating the gulf between poor and good health.
- Third, COVID-19 has framed in the starkest terms the harms of failing to consider how we wish to die.
Urgent appeals for more advance care planning—the means through which a person aims to curate the manner of their dying—are common enough in medicine these days.
But COVID-19 has polarized the issue, particularly in high-income countries. Here, on the one hand, you may be able to die at home surrounded by your ungloved, unmasked loved ones. On the other hand, infection control measures aimed at reducing SARS-CoV-2 transmission have drastically dehumanized our hospitals and care homes. Wards have been almost entirely emptied of in-person visiting by loved ones, while staff are forced to barricade themselves behind swathes of personal protective equipment. During this pandemic, anyone dying hospital, for example, has been destined, from the moment of admission, never to set eyes on an unmasked human face again.
The horror of these new conditions of dying—cleaving patients so brutally from those they love, at the one time they need them the most—is well documented.
Writing with colleagues, Lucy Selman, sociologist and founding director of the UK’s Good Grief Festival, summarized the public narrative on dying during the COVID-19:
“The act of ‘saying goodbye’ (before, during and after death) was central to media representations of COVID bereavement, represented as inherently important and profoundly disrupted. Bedside access was portrayed as restricted, variable and uncertain, with families begging or bargaining for contact. Video-link goodbyes were described with ambivalence. Patients were portrayed as ‘dying alone’ regardless of clinician presence. Funerals were portrayed as travesties and grieving alone as unnatural. Articles focused on what was forbidden and offered little practical guidance”.
The writer and teacher Kate Clanchy’s article for The Guardian about trying to help her parents avoid heroic interventions in their dying days touched a deep chord with the public.
Despite her advance care plan stipulating no hospital, no ventilators, and no active treatment in the event of catching COVID-19, Clanchy’s mother died alone, of COVID-19, in hospital.
Clanchy described what happened to them: “My parents did not want to combat death: they were trying to let it in, to find a human way to go”.
The pandemic has highlighted how challenging genuinely patient-centered advance care planning can be.
Yet too often in UK medical schools and training curriculums, it is taught as something of an add-on extra, an annoying hoop to jump through, an afterthought. The COVID-19 pandemic has thrust death center stage.
But we have a post-pandemic opportunity. Health professionals should strive to embed teaching about death, dying, listening, respecting, and—above all—choosing when not to act at the heart of medical education.
Expecting young doctors to skillfully traverse this most delicate terrain with only cursory training fails them as well as their patients. From day one of medical school, then, let us reshape this aspect of medical education. Because increasingly, one of the defining questions of medicine is no longer can we, but should we?
(7). Lumbar spinal stenosis. BMJ 2021;373:n1581
What you need to know
Suspect lumbar spinal stenosis in people over 50 who describe leg pain or paraesthesia on walking or prolonged standing, and who are walking reduced distances as a result
Imaging is not required during initial assessment as the correlation between imaging findings and symptoms is poor
Conservative treatment, which includes supervised exercise and manual therapy, is advised as first line treatment; about 30-50% of patients with mild to moderate symptoms experience spontaneous improvement in pain and ability to walk greater distances
Prescribe pain medication only for a short period and after careful consideration, taking into account the important side effects, especially in older people, and the absence of good evidence for efficacy
Refer patients with severe symptoms, neurological deficits, or no improvement after 3-6 months of conservative treatment to a spine specialist for imaging and further intervention or surgery
Lumbar spinal stenosis (LSS) affects about 11% of the population,1 and primarily affects older adults.1 Pain in legs and difficulty walking can limit function and participation in daily activities, which can have negative psychological effects.2
Diagnosis can be challenging because of the overlap of symptoms with other conditions that cause leg or low back pain in older adults. Lumbar spinal stenosis can usually be diagnosed clinically and managed conservatively in primary care. Patients with severe symptoms may require referral for imaging and intervention. The evidence for most treatment options is limited.345 Shared decision making with patients must consider the severity of symptoms and their impact on the person’s life, risks and benefits of treatments, and individual preferences
(8). Covid-19: Regeneron’s antibody combination cuts deaths in seronegative patients, Recovery trial finds. BMJ 2021;373:n1570
Regeneron’s antibody combination treatment cut deaths in seronegative patients—meaning those who had not mounted their own antibody response to covid-19—by one fifth, the Recovery trial has found.
The researchers found that for every 100 seronegative patients treated with the combination of Casirivimab and imdevimab, there were six fewer deaths. They said patients admitted to hospital should now be routinely tested for antibodies to determine whether the treatment could benefit them.
The two virus neutralising antibodies work by binding non-competitively to the critical receptor binding domain of SARS-CoV-2’s spike protein, thereby stopping the virus from binding to and entering human cells.
Recovery, which is being carried out in 177 UK hospitals, has been evaluating potential covid-19 treatments for patients admitted to hospital. As part of the trial, 9785 covid-19 patients admitted to hospital were randomised to receive either usual care plus the antibody combination treatment or usual care alone between September 2020 and May 2021. Of these, about one third were seronegative at baseline, half were seropositive (they had developed natural antibodies), and one sixth had unknown serostatus. Among patients who received usual care alone, 28-day mortality was twice as high in those who were seronegative (30%) compared with those who were seropositive (15%) at study entry. For those who were seronegative at baseline, however, the antibody combination reduced deaths by 25% (from 30% in the usual care group to 24% in the antibody combination group; rate ratio 0.80; 95% confidence interval 0.70 to 0.91; P=0.001). The treatment also reduced the duration of hospital stay by four days in this group (median 13 days v 17 days with usual care only.) The treatment did not have an effect on those who were seropositive at baseline.
Belt and braces approach
In the preprint of the study researchers said that while they did not specifically look at variants, the major variants circulating in the UK throughout the trial, such as α, remained sensitive to the treatment. They added that although spike glycoprotein mutations in the β and delta variants have been associated with a reduction of neutralisation activity of casivirimab, the treatment remains potent because of the inhibitory activity of imdevimab. The researchers described the treatment as having a “belt and braces approach” so that if one fails the other should still work.
Convalescent plasma
One question raised in light of the positive results is why this antibody treatment works while convalescent plasma—which contains antibodies to covid-19 from people who’ve recovered from the virus—does not. Speaking at the Science Media Centre briefing, Recovery trial chief investigator Peter Hornby, professor of emerging infectious diseases and global health at the University of Oxford, said it omes down to the dose and quality of antibodies.
“The monoclonal antibodies are selected to be highly potent—the best they can find. And we give a very high dose. Whereas with convalescent plasma you’ve got a mix of high quality and low quality antibodies and much lower quantities. It’s just a much less potent product, I think,” he said
(9). Virtual and in-person cardiac rehabilitation. BMJ 2021;373:n1270
What we need to know
- Most eligible patients with coronary heart disease and heart failure do not participate in cardiac rehabilitation. Covid-19 has exacerbated this, with a substantial drop in the number of patients participating.
- Home and telehealth-based interventions are increasingly being used as alternatives to traditional centre-based rehabilitation programmes.
- Outcomes for patients participating in home-based rehabilitation compare favourably with centre-based programmes in terms of hospitalisations, quality of life, and cost.
- Telehealth based interventions are promising, but some patients may find these interventions challenging.
- Novel ways of delivering rehabilitation have been employed during the covid-19 pandemic, including hybrid models that are likely to be offered as alternatives to centre based rehabilitation in future, enabling greater patient choice and greater uptake of cardiac rehabilitation.
(10). Digital medicine, cardiac rehabilitation in the digital era. Lancet 2021;397:2038
Cardiac rehabilitation (CR) after a heart attack or open-heart surgery acclimatises patients to increased physical activity.
CR is not universally available and where it is available the requirement for multiple visits to a clinic can limit participation. Only about 20–30% of people who meet the criteria take part in CR for structured physical activity, education, and behavioural counselling on modifiable risk factors.
There is a potential path to mobilise mobile technology to make CR more widely accessible and tailored to individual needs.
Smartphones and fitness trackers could be used to provide detailed instruction and monitoring of CR structured exercise. These data can be shared with physicians and CR staff to optimise therapy. Additionally, education relating to behavioural determinants and interventions can be implemented with app-based approaches, setting goals for patients to achieve while completing educational aspects of CR.
Digital CR would also enable patients to design their own activity schedules. Several existing technologies could even upgrade the next iteration of CR. Smartwatch sensors already track heart rate, activity, and oxygen saturation, and electrocardiogram (ECG) data can be used by physicians to monitor remote CR. Smartwatch ECG technology could potentially provide monitoring during exercise, thereby adding data not collected currently in traditional CR. Sensor data from realworld activities could also be used for CR assessment.
For many patients who need CR, overcoming the apprehension of day-to-day activities has greater psychological benefits than the exercise itself. Use of sensors to monitor patients in their home environments could reassure patients that they are able to complete activities safely.
This approach might spur patients to perform higher intensity exercise and to continue exercise beyond CR.