JOURNAL SCAN
Journal scan: A review of 10 recent papers of immediate clinical significance, harvested from major international journals
From the desk of the Editor-in-Chief
(1). Adekoya I et al. Comparison of antibiotics included in national essential medicines lists of 138 countries using the WHO Access, Watch, Reserve (AWaRe) classification: a cross-sectional study. Lancet 2021
Background
The WHO Model List of Essential Medicines classified antibiotics into Access, Watch, and Reserve (AWaRe) categories for the treatment of 31 priority bacterial infections as a tool to facilitate antibiotic stewardship and optimal use. We compared the listing of antibiotics on national essential medicines lists (NEMLs) to those in the 2019 WHO Model List and the AWaRe classification database to determine the degree to which NEMLs are in alignment with the AWaRe classification framework recommended by WHO.
Methods
In this cross-sectional study, we obtained up-to-date (data after 2017) NEMLs from our Global Essential Medicines (GEM) database, WHO online resources, and individual countries’ websites. From the 2019 WHO Model List we extracted, as a reference standard, a list of 37 antibiotics (44 unique antibiotics after accounting for combination drugs or therapeutically equivalent drugs as specified by WHO) that were considered essential in treating 31 of the most common and severe clinical infectious syndromes (priority infections). From the WHO AWaRe Classification Database, which contains commonly used antibiotics globally, we extracted a list of 122 AWaRe antibiotics listed by at least one country in the GEM database. We then assessed individual countries’ NEMLs for listing of the 44 essential and 122 commonly used antibiotics, overall and according to AWaRe classification group. We also evaluated and summarised the listing of both first-choice and second-choice treatments for the 31 priority infections. A total coverage score was calculated for each country by assigning a treatment score of 0-3 for each priority infection on the basis of whether first-choice and second-choice treatments, according to the 2019 WHO Model List, were included in the country’s NEML. Coverage scores were then compared against the score of the 2019 WHO Model List and across World Bank income groups and WHO regions.
Findings
As of July 7, 2020, we had up-to-date NEMLs for 138 countries. Of the 44 unique essential antibiotics, 24 were Access, 15 were Watch, and five were Reserve. The median number of total essential antibiotics listed across the 138 NEMLs was 26 (IQR 21-32). 102 (74%) countries listed at least 22 (50%) of the 44 essential antibiotics. The median number of total AWaRe antibiotics listed by the 138 countries was 35 (IQR 29-46), of Access antibiotics was 18 (16-21), of Watch antibiotics was 16 (11-22), and of Reserve antibiotics was one (0-2). 56 (41%) countries did not list any essential Reserve antibiotics. 131 (95%) countries had coverage scores of at least 60, equivalent to at least 75% of the score of the 2019 WHO Model List, which was 80. Nine (7%) countries listed fewer than 12 of 24 essential Access antibiotics, and seven (5%) did not list sufficient first-choice and second-choice treatments for priority infections (i.e., they had coverage scores lower than 60). Of the 31 priority infections, acute neonatal meningitis and high-risk febrile neutropenia did not have enough listed treatments, with 82 (59%) countries listing no treatment for acute neonatal meningitis and 84 (61%) countries listing only a first-choice treatment, only a second-choice treatment, or no treatment for high-risk febrile neutropenia. Coverage scores differed between countries on the basis of World Bank income groups (p = 0.025).
Interpretation
Our findings highlight potential changes to the antibiotics included in NEMLs that would increase adherence to international guidance aimed at effectively treating infectious diseases while addressing antimicrobial resistance.
(2). Dhairyawan R. The medical practice of silencing. Lancet. 2021;398(10298):382-383.
Shortly after I became an HIV consultant, I was admitted to hospital. I had severe pelvic and lower back pain, two days after egg retrieval, in my third cycle of in-vitro fertility treatment (IVF). Having suffered from endometriosis and adenomyosis for some years, I was accustomed to pain and managing it with a heat pad and ibuprofen. But that evening the pain intensity made me realize something quite different was happening. It felt like someone was using a heavy shovel to scrape away the lining of my abdomen. My husband realised something was seriously wrong and took me to the emergency department. I was seen quickly, given oral morphine, and then admitted to a gynecology ward. The team decided to keep me in for embryo transfer but the next night, despite regular oral morphine, the pain worsened dramatically. I requested more pain relief, but the nursing team said that I had reached the maximum dose of oral medication and would have to wait until the next dose was due. The pain got worse. The health-care staff gave me the impression that I was deliberately exaggerating my pain to access more morphine. They made me feel like a nuisance for using the buzzer to repeat my request for additional pain relief. Eventually, and after much pleading, I was seen by the on-call doctor, who prescribed intramuscular morphine, which finally relieved my symptoms.
Nearly 10 years later, I still remember how scared and helpless I felt. I was clearly not seen as a reliable narrator of my symptoms and was treated as an annoyance, an opioid seeker, someone not to be believed. I very much regret that I did not make a complaint about my care at the time. I felt ashamed and didn’t want to be regarded as a nuisance. But if it could happen to me, a physician with knowledge of the health-care system, what might happen to less informed patients in a similar situation or with a life-threatening condition?
I now understand I experienced an example of testimonial injustice. This is a type of epistemic injustice—a wrongdoing related to knowledge or the validation of knowledge, as conceptualised by the philosopher Miranda Fricker. Testimonial injustice can occur when a person’s voice or knowledge is discounted or dismissed due to bias from the listener about their social identity. It is often associated with the speaker’s gender, ethnicity, class, sexuality, or religion. Testimonial injustice is commonly reported by women, particularly women from racially minoritised groups. In a health-care setting, patients experience testimonial injustice if their account of their symptoms is not believed because they are not seen as a credible narrator. Testimonial injustice is at its most damaging when it is cumulative and systematic. In institutions, this can result in systematic discrimination against certain groups such as racially minoritised populations. My experience of having pain dismissed as a woman of colour resonates with past injustices in medicine. Women have had their pain ascribed to “hysteria”, resulting in the undertreatment of their symptoms. Racial bias in pain assessment and treatment has also been well documented in western medicine.
A recent example is a safety review in 2020 of pelvic mesh implants used to treat pelvic organ prolapse in the UK. Despite evidence showing the meshes were causing nerve damage and recurrent infections, women reported that they were often told by their doctors that their pain was due to the “normal consequences of childbirth or menopause”. For many women, this led to years of unnecessary suffering. Similarly, endometriosis takes an average of 8 years to diagnose in the UK. Patients frequently report that clinicians do not take their concerns seriously. This means that by the time they are given a diagnosis, they may have endured considerable physical or psychological harm.
Testimonial injustice also occurs in other conditions. Women often face delays in diagnosis of autoimmune conditions, and recent research into long COVID has found that some individuals are experiencing testimonial injustice when trying to access care. In short, due to societal prejudices ingrained in us as health-care professionals at an individual and institutional level, we expect a higher standard of evidence from some patient cohorts before we believe and value their testimonies.
What happens when an individual’s testimony is routinely dismissed? Philosopher Kristie Dotson suggests that it may cause a type of silencing called “testimonial smothering”. This is a form of self-censoring, where silence or withholding testimony is preferable to the psychological trauma of being dismissed and disbelieved. She describes this as “the truncating of one’s own testimony in order to ensure that the testimony only contains content for which the audience demonstrates testimonial competence”. In health-care settings, patients may self-censor their symptoms and concerns so as to remain a “good patient”. This could lead to ineffective treatment. Individuals from minoritised groups are more likely to be silenced in this way, which could exacerbate existing health inequalities.
An example of where individuals may be silenced in health care is medication adherence. In my own speciality I have seen how HIV is effectively suppressed by antiretroviral therapy, lives are saved, life expectancy is close to normal, and HIV cannot be transmitted sexually. It can therefore be difficult for a health professional to understand why some people do not take their antiretroviral therapy regularly. But HIV remains a highly stigmatised condition; taking tablets every day of your life can be difficult, particularly for people who face social and economic adversity, with HIV just one of many daily challenges. And patients do not always share with their clinician the real reasons why they have stopped taking their medication. The reasons for this are complex and could include concern about side-effects, the worry that their questions about treatment are not taken seriously and that they are not included when making treatment decisions, and mistrust of their service provider. In some consultations, I have known that blood tests show that a person is not adhering to their antiretroviral therapy but they tell me they are taking their tablets every day. Such patients may be labelled as unreliable, making it easier to disbelieve their testimony in future consultations. Yet such encounters should prompt clinicians to engage more fully with the patient and listen to their testimony.
One area where progress is being made in addressing testimonial injustice and testimonial smothering is in response to disclosure of domestic abuse in health-care settings. An integral part of the training for health professionals on responding to such a disclosure is to start by saying to the individual “I believe you”. If we are more ready as clinicians to say this in every area of health care, along with “I hear you”, we may begin to hear our patients’ true testimonies, a crucial step towards being able to identify the care they need.
Instead of blaming patients for not telling us what is really going on, we should focus our attention on why they feel unable to tell us this. Have they perhaps felt their testimony was rejected or dismissed in the past and, as a result, are purposefully self-censoring to protect themselves? They may not believe they will receive the help they need if they do tell the truth. In other words, they are anticipating our negligence. This understandably engenders mistrust, which may deter them from seeking health care in the future.
Patients take a risk when they share their testimonies with us and make themselves vulnerable. What can health professionals do to encourage them to talk honestly and to earn patients’ trust? On an individual level, we can become better listeners. We need to be humble, recognising the limitations of our knowledge, and be open to hearing something new that may challenge us, but that we can learn from. Patients know their bodies and conditions better than anyone else, and should be regarded as having this expertise. We should also be aware of how our learned biases may affect how we judge someone’s credibility, and how we may be susceptible to using stereotypes at times of stress or when we are tired. Systemic solutions are also needed to address individual and institutional bias. This should start at medical school and include teaching the historical origins of gender and racial stereotypes in medicine and how they affect health outcomes now. There should also be an emphasis on teaching structural competency to help health-care practitioners understand how patients’ health is affected by social and economic factors. Health-care services can use tools such as policies and proformas to overcome individual bias. An example of this comes from my speciality, where introducing opt-out testing for HIV in emergency departments has removed the need for health professionals to make a value judgment of whether someone may have HIV. There also needs to be considerable investment into making health-care services easier to access for people from minoritised communities, and they should be at the heart of designing and evaluating these services. Finally, it is sometimes suggested that patients should empower themselves to be more assertive with their health professional. But this can be a form of victim blaming, shifting the responsibility of addressing institutional discrimination to the person who is actually experiencing it. Indeed, it may be hard for people who have experienced testimonial injustice repeatedly and systematically to be assertive in health-care settings.
I am aware that my own personal experience of testimonial injustice silenced me for nearly a decade. I hope that sharing it will encourage other health professionals to reflect on the medical practice of silencing patients, its harmful effects, and why both individual and institutional solutions are needed to address it.
(3). Guimarães PO et al. Tofacitinib in patients hospitalized with COVID-19 pneumonia. N Engl J Med. 2021; 385:406-415
Background
The efficacy and safety of tofacitinib, a Janus kinase inhibitor, in patients who are hospitalized with coronavirus disease 2019 (COVID-19) pneumonia are unclear.
Methods
We randomly assigned, in a 1:1 ratio, hospitalized adults with COVID-19 pneumonia to receive either tofacitinib at a dose of 10 mg or placebo twice daily for up to 14 days or until hospital discharge. The primary outcome was the occurrence of death or respiratory failure through day 28 as assessed with the use of an eight-level ordinal scale (with scores ranging from 1 to 8 and higher scores indicating a worse condition). All-cause mortality and safety were also assessed.
Results
A total of 289 patients underwent randomization at 15 sites in Brazil. Overall, 89.3% of the patients received glucocorticoids during hospitalization. The cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group and 29.0% in the placebo group (risk ratio, 0.63; 95% confidence interval [CI], 0.41 to 0.97; P = 0.04). Death from any cause through day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the placebo group (hazard ratio, 0.49; 95% CI, 0.15 to 1.63). The proportional odds of having a worse score on the eight-level ordinal scale with tofacitinib, as compared with placebo, was 0.60 (95% CI, 0.36 to 1.00) at day 14 and 0.54 (95% CI, 0.27 to 1.06) at day 28. Serious adverse events occurred in 20 patients (14.1%) in the tofacitinib group and in 17 (12.0%) in the placebo group.
Conclusions
Among patients hospitalized with COVID-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo.
(4). Lund FE, Randall TD. Scent of a vaccine. Nasal Vaccines. Science 2021;373(6553):397-399.
The highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects the respiratory tract and is transmitted, in part, by respiratory droplets and aerosols. Consequently, unvaccinated people are encouraged to wear masks in public, self-quarantine if symptomatic, and practice social distancing. Despite these precautions, millions are dying. As the pandemic takes its toll, vaccines are once again headline news, notably for the speed of their development and the success of messenger RNA (mRNA) vaccines. Given the respiratory tropism of the virus, however, it seems surprising that only seven of the nearly 100 SARS-CoV-2 vaccines currently in clinical trials are delivered intranasally. Advantages of intranasal vaccines include needle-free administration, delivery of antigen to the site of infection, and the elicitation of mucosal immunity in the respiratory tract.
The idea that intranasal vaccination preferentially protects the respiratory tract is not new: Development of the US Food and Drug Administration (FDA)-approved live attenuated influenza vaccine (LAIV) began in the 1960s. Immunologists have long known that nasal infection or vaccination elicits an immunoglobulin A (IgA) response in both serum and respiratory fluids, whereas intramuscular vaccines primarily elicit serum IgG. IgA is particularly important in the upper airways and nasal passages, where it is actively transported across the epithelium and released into the airway lumen as a dimer bound to secretory component, a stabilizing configuration that allows it to more effectively neutralize viruses like SARS-CoV-2. By contrast, IgG enters and protects the lower lung through passive transudation across the thin alveolar epithelium. IgG is also found in the upper respiratory tract and nasal passages, perhaps carried from the lower lung by the mucociliary escalator. However, protection of the nasal passages by IgG is only achieved at high serum concentrations. Consequently, intramuscular vaccines that elicit high titers of serum IgG can reduce viral titers in the lungs and nasal passages.
CD8+ T cells are another important component of antiviral immunity and directly kill virus-infected cells, thereby reducing viral replication and accelerating viral clearance and recovery. Some activated CD8+ T cells develop into memory cells, which by themselves do not prevent infection, but are poised for rapid reactivation and effector function. Notably, B and T cells primed by mucosal vaccination or infection express receptors that promote homing to mucosal sites as long-lived antibody-secreting cells or as tissue-resident memory cells. Resident memory B and T cells in the lung and nasal passages act as nonredundant, first responders to challenge infection and are essential for rapid virus clearance. The placement of tissue-resident memory cells in the respiratory tract requires that they encounter antigen in the respiratory trac, meaning that vaccines designed to recruit resident memory cells to the respiratory tract should be administered intranasally.
Compared to intramuscular vaccines, intranasal vaccines provide two additional layers of protection: Vaccine-elicited IgA and resident memory B and T cells in the respiratory mucosa provide an effective barrier to infection at those sites; and, even if infection does occur, perhaps by a viral variant, cross-reactive, resident memory B and T cells, which encounter antigen earlier and respond more quickly than systemic memory cells, impede viral replication and reduce viral shedding and transmission
Of the seven SARS-CoV-2 vaccines being tested for intranasal delivery, six are live-attenuated viruses or virus-vectored vaccines and one is a protein subunit vaccine (see the table). Attenuated viruses and viral vectors that encode vaccine antigens are particularly useful for intranasal immunization because the infection process effectively breaches the epithelium and is intrinsically immunogenic. Because vaccine antigens are expressed by infected cells, antigen presentation occurs via the class I pathway and efficiently triggers CD8+ T cell responses-an advantage over protein subunit vaccines that poorly engage CD8+ T cells.
Preclinical studies of adenovirus-vectored vaccines expressing the SARS-CoV-2 spike host receptor protein or its receptor binding domain (RBD) demonstrate that intranasal delivery triggers long-lasting, virus-neutralizing serum IgG responses as well as antigen-specific IgA and CD8+ T cells in the respiratory tract. Moreover, both intranasal and intramuscular vaccination with adenovirus-vectored vaccines protect against pneumonia and weight loss after a challenge infection. However, animals vaccinated intramuscularly still shed virus from the nasal passages, whereas animals vaccinated intranasally have reduced viral replication and shedding in both the lungs and the nasal passages.
Adenoviruses are natural human pathogens, and many adults have been exposed to one or more strains, meaning that they may have antivector antibodies that impair vaccine efficacy (negative interference). However, Ad5-vectored intranasal influenza vaccine (NasoVAX), administered at high doses, works similarly in Ad5 seropositive and seronegative individuals (9), perhaps because the inoculating volume dilutes local antibody concentrations. Nevertheless, in an attempt to avoid any potential negative interference, some developers are using rare strains of human adenoviruses or chimp adenoviruses, to which most humans have not been exposed.
The influenza-vectored SARS-CoV-2 vaccine being developed by the University of Hong Kong may face related hurdles. The deletion of the influenza virus gene encoding nonstructural protein 1 (NS1) strongly attenuates the vector and allows developers to replace NS1 with the SARS-CoV-2 spike-RBD. Like adenovirus-vectored vaccines, this one should also elicit mucosal IgA against RBD and place resident memory cells in the respiratory tract. However, negative interference from preexisting antibodies against the influenza vector may impair its effectiveness. Similarly, Meissa Vaccines developed a live attenuated respiratory syncytial virus (RSV) vector in which it replaced the RSV F and G host receptor proteins with SARS-CoV-2 spike. Delivered intranasally, the chimeric virus should elicit mucosal immunity. Notably, the change in surface proteins will likely alter the cellular tropism of the virus and perhaps its immunogenicity. Preexisting antibodies against RSV should not interfere with vaccination, but preexisting antibodies against spike may neutralize it.
Intranasal SARS-CoV-2 vaccines in clinical trials
Live attenuated SARS-CoV-2 intranasal vaccines should also effectively elicit mucosal IgA responses and resident-memory cells in the respiratory tract. Unlike vectored vaccines that express only spike or RBD, live attenuated SARS-CoV-2 has the advantage of expressing (and potentially eliciting immune responses against) all viral proteins, thereby conferring broad-spectrum immunity that should cross-react with and provide some level of immunity against variant strains of SARS-CoV-2. Although modern molecular techniques minimize the risk of reversion, live attenuated viruses retain replicative capacity and are contraindicated for infants <2 years, people aged >49 years, or immune-compromised persons. Live attenuated SARS-CoV-2 and spike-expressing RSV may also face scrutiny over their potential to cause neuronal symptoms.
Past experience with LAIV will be relevant to these live attenuated vaccines. In children, intranasal LAIV is generally superior to intramuscular vaccination. This success likely reflects the immunological naí¯veté of children (most have not been exposed to influenza virus). As a result, there is no immune barrier to LAIV infection in the nasal passages and vaccine “take” is efficient, leading to robust mucosal IgA responses and the placement of tissue-resident memory cells in the airways. LAIV is also effective in adults, but not necessarily better than intramuscular vaccination, in part because prior influenza virus infection has established a baseline of immunity that impairs the infectivity of LAIV. Consequently, live attenuated SARS-CoV-2 vaccines may elicit robust protection in naí¯ve individuals, but preexposed individuals may have sufficient immunity to neutralize the vaccine, rendering it ineffective even as a booster.
Only one of the intranasal vaccines in clinical trials is inert-Cuba’s CIBG-669, which consists of RBD linked to the hepatitis B virus core antigen, a potent stimulator of T cells. Because inert vaccines do not rely on infection or gene expression, they cannot be neutralized by preexisting antibodies. However, soluble proteins delivered to the nasal passages do not efficiently breach the epithelium. Instead, they must be transported across the epithelial barrier by specialized microfold (M) cell, which deliver antigens to immune cells underneath the epithelium.
Notably absent from the list of intranasal vaccines are those formulated as lipid-encapsulated mRNA. Delivered intramuscularly, mRNA vaccines elicit high titers of serum IgG against encoded antigens. Rodent studies suggest that mRNA vaccines are also efficacious when delivered intranasally. However, it is important to distinguish intranasal delivery and nasal vaccination. Rodents are often anesthetized for intranasal vaccination and infection, causing them to take slow, deep breaths that deliver the inoculum all the way into the lung. As a result, much of the literature (including some cited here) on intranasal vaccination in rodents actually refers to intrapulmonary vaccination, which may provide more complete protection than strictly nasal vaccination. Nevertheless, resident memory cells in the nasal passages can prevent virus dissemination to the lung. Given that vaccine delivery to the lower respiratory tract may directly cause inflammation or may exacerbate conditions such as asthma or chronic obstructive pulmonary disease (COPD), intranasal vaccines are typically administered to humans in a way that prevents antigen delivery to lungs.
Routes of vaccination
Immunoglobulin A (IgA) and resident memory B and T cells in the nasal passages and upper airways are elicited by intranasal vaccination and prevent infection and reduce virus shedding. Serum IgG elicited by intramuscular vaccination transudates into the lungs and prevents pulmonary infection but allows infection in the nasal passages and virus shedding.
Lipid formulation is critical for mRNA vaccine stability, for cell targeting, and for releasing mRNA to the cytosol. Thus, the future success of intranasal mRNA vaccines will likely hinge on developing lipid nanoparticles that target the appropriate cell types in the nasal passages. Unlike viruses and viral vectors, lipid nanoparticles lack proteins on their surface and should not be neutralized by antibodies, making the same formulation viable for repeated vaccination. However, adverse events such as fatigue and malaise are frequently linked to mRNA vaccination. Therefore, intranasal mRNA vaccines should be developed cautiously to avoid side effects and reactogenicity.
Ultimately, the goal of vaccination is to elicit long-lived protective immunity. However, the duration of serum antibody responses varies considerably, depending on poorly understood attributes of the initiating antigen. Mucosal antibody responses are often considered short-lived, but their actual duration may depend on how antigen is encountered. Similarly, recirculating central-memory T cells are self-renewing and persist for long periods, whereas lung-resident memory T cells wane relatively rapidly-more so for CD8+ T cells than for CD4+ T cells. Thus, intranasal vaccines may have to balance the goal of local immunity in the respiratory tract with the longevity of systemic immunity. However, effective vaccination strategies need not be restricted to a single route. Indeed, memory cells primed by intramuscular vaccination can be “pulled” into mucosal sites by subsequent mucosal vaccination. Thus, the ideal vaccination strategy may use an intramuscular vaccine to elicit a long-lived systemic IgG response and a broad repertoire of central memory B and T cells, followed by an intranasal booster that recruits memory B and T cells to the nasal passages and further guides their differentiation toward mucosal protection, including IgA secretion and tissue-resident memory cells in the respiratory tract.
(5). Benjamin Landré et al. Terminal decline in objective and self-reported measures of motor function before death: 10-year follow-up of Whitehall II cohort study. BMJ 2021;374: n1743
Objectives
To examine multiple objective and self-reported measures of motor function for their associations with mortality.
Design
Prospective cohort study.
Setting
UK based Whitehall II cohort study, which recruited participants aged 35-55 years in 1985-88; motor function component was added at the 2007-09 wave.
Participants
6194 participants with motor function measures in 2007-09 (mean age 65.6, SD 5.9), 2012-13, and 2015-16.
Main outcome measures
All-cause mortality between 2007 and 2019 in relation to objective measures (walking speed, grip strength, and timed chair rises) and self-reported measures (physical component summary score of the SF-36 and limitations in basic and instrumental activities of daily living (ADL)) of motor function.
Results
One sex specific standard deviation poorer motor function in 2007-09 (cases/total, 610/5645) was associated with an increased mortality risk of 22% (95% confidence interval 12% to 33%) for walking speed, 15% (6% to 25%) for grip strength, 14% (7% to 23%) for timed chair rises, and 17% (8% to 26%) for physical component summary score over a mean 10.6 year follow-up. Having basic/instrumental ADL limitations was associated with a 30% (7% to 58%) increased mortality risk. These associations were progressively stronger when measures were drawn from 2012-13 (mean follow-up 6.8 years) and 2015-16 (mean follow-up 3.7 years). Analysis of trajectories showed poorer motor function in decedents (n=484) than survivors (n = 6194) up to 10 years before death for timed chair rises (standardised difference 0.35, 95% confidence interval 0.12 to 0.59; equivalent to a 1.2 (men) and 1.3 (women) second difference), nine years for walking speed (0.21, 0.05 to 0.36; 5.5 (men) and 5.3 (women) cm/s difference), six years for grip strength (0.10, 0.01 to 0.20; 0.9 (men) and 0.6 (women) kg difference), seven years for physical component summary score (0.15, 0.05 to 0.25; 1.2 (men) and 1.6 (women) score difference), and four years for basic/instrumental ADL limitations (prevalence difference 2%, 0% to 4%). These differences increased in the period leading to death for timed chair rises, physical component summary score, and ADL limitations.
Discussion
Ageing is characterised by a decline in cognitive and motor function over the adult life course, along with an increase in heterogeneity of individual trajectories, partly as a result of pathological processes of age-related chronic diseases. In the years immediately preceding death, an accelerated decline in functioning has been observed, referred to as “terminal decline. As described in a recent review, terminal decline is observed in multiple domains, although much of the research is confined to cognitive decline.
Better understanding of changes in functional status in the one or two years before death is useful for planning care, but it has minimal utility for identifying individuals who could benefit from clinical or behavioural interventions. Consideration of longer spans to study decline preceding death is also supported by findings showing decline in motor and cognitive function to be manifest starting in midlife. Furthermore, several studies have shown midlife poorer cognitive and motor function to be associated with higher mortality risk. The long-term change in trajectories of functioning before death is less well characterised in relation to motor function. For cognitive function, long term trajectories are known, and change-point studies show that differences in different measures emerge up to 15 years before death.
Change in motor function in the years before death is a dynamic process and may reflect changes over a longer period than at end of life examined in several studies. To date, few studies have considered a longer follow-up. An exception is a study showing decline in walking speed starting 10 years before death. Some studies have used composite measures of motor function, in which the role played by strength and upper and lower body function cannot be separated. A further limitation, apart from notable exceptions, is a lack of studies assessing both objective and self-reported measures of function. To overcome these limitations, the aim of this longitudinal cohort study was to examine multiple measures of motor function for their associations with mortality by using time-to-event analyses to capture the importance of between person differences in motor function and retrospective trajectory analyses to compare within person change in motor function over 10 years in survivors and deceased participants. Use of this twin analytical strategy allows both between person and within person differences in motor function to be examined in relation to mortality in the same study, with the second being reflected in the shape of the change in motor function leading to death.
Conclusion
Motor function in early old age has a robust association with mortality, with evidence of terminal decline emerging early in measures of overall motor function (timed chair rises and physical component summary score) and late in basic/instrumental ADL limitations.
(6). Mahase E. COVID-19: All 16 and 17-year olds in the UK to be offered first vaccine dose. BMJ 2021;374: n1958
All 16 and 17-year olds in the UK will be offered a first dose of the Pfizer BioNTech COVID-19 vaccine, the Joint Committee on Vaccination and Immunisation (JCVI) has announced.
The committee has not yet decided, however, when the second dose will be offered. Instead, it will continue to examine the emerging evidence over the next few weeks to determine the best dosing interval, which will probably be within 12 weeks of the first, it is understood.
Speaking at a televised press conference on 4 August, JCVI chair Wei Shen Lim said that the committee had considered the benefits and risks of vaccination to individuals rather than to wider society, and concluded that the benefits outweighed any risks in this age group. Previously, only 16 and 17-year olds considered at risk of severe COVID illness were able to get the vaccine.
He said, “We are now seeing young people who are unvaccinated being admitted to hospital with quite severe COVID. Many of them need oxygen support and, sadly, some of them also need a machine to help them to breathe. Much of that suffering can be prevented or reduced through vaccination”.
The JCVI has estimated that one vaccine dose will provide young people with at least 80% protection against hospital admission with COVID-19.
Last month the committee announced that children aged 12-15 who are at increased risk of serious illness from infection with SARS-CoV-2 will be offered the Pfizer BioNTech vaccine.
The updated advice from the JCVI comes as the Office for National Statistics has estimated that over or around 9 in 10 adults in all four UK nations would have tested positive for antibodies against SARS-CoV-2 on a blood test in the week beginning 12 July 2021, suggesting they had the infection in the past or have been vaccinated. The report said that “there is a clear pattern between vaccination and testing positive for COVID-19 antibodies”.
Unacceptable delay
Deepti Gurdasani, a clinical epidemiologist and senior lecturer in machine learning at Queen Mary University of London, welcomed the JCVI’s decision but said the delay has been “unacceptable, given the Pfizer vaccine was approved by the Medicines and Healthcare Products Regulatory Agency for those 16 years old and over in December, and the benefit versus risk has been clear for a while”.
Gurdasani is one of 18 scientists who has authored a risk benefit analysis paper on vaccinating teenagers – made available as a preprint while it is being reviewed for publication – which has argued that the “benefits of offering vaccination to all 12 to 17-year olds clearly outweigh the risks”.
Using a US Centers for Disease Control and Prevention analysis as a template, the group examined the potential benefits and risks of offering vaccines to England’s 3.9 million 12 to 17-year olds ahead of school reopening in September. They used extracted data on the number of young people in this age group in England diagnosed with COVID-19 and the related hospital admissions and deaths between July 2020 and March 2021.
Looking at various infection rate scenarios, they reported that vaccination could avert between 4570 hospital admissions (based on late July 2021 infection rates continuing for 16 weeks) and 70 hospital admissions (based on a low incidence scenario of 50 infections per 100 000 per week) – even after assuming that all cases of vaccine induced myocarditis are admitted to hospital.
For long COVID, vaccination could avert 31 000 (assuming 8% incidence) or 16 000 (assuming 4% incidence) cases in 12 to 17-year olds, based on the July 2021 infection rates.
The researchers said that the risk of hospital admission with vaccination only exceeds the risk of hospital admission with COVID-19 when the case incidence is below 30 per 100 000 per week-a level not seen in adolescents in the UK in 2021.
(7). The REMAP-CAP, ACTIV-4a, and ATTACC Investigators. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with COVID-19.
August 4, 2021, DOI: 10.1056/NEJMoa21034172021
Background
Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (COVID-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with COVID-19.
Methods
In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe COVID-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.
Results
The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, −1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, −1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis.
Conclusion
In critically ill patients with COVID-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov
(8). O’Brien MP et al. Subcutaneous REGEN-COV antibody combination to prevent COVID-19. N Engl J Med. 2021
Background
REGEN-COV (previously known as REGN-COV2), a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to markedly reduce the risk of hospitalization or death among high-risk persons with coronavirus disease 2019 (COVID-19). Whether subcutaneous REGEN-COV prevents severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent COVID-19 in persons at high risk for infection because of household exposure to a person with SARS-CoV-2 infection is unknown.
Methods
We randomly assigned, in a 1:1 ratio, participants (>=12 years of age) who were enrolled within 96 h after a household contact received a diagnosis of SARS-CoV-2 infection to receive a total dose of 1200 mg of REGEN-COV or matching placebo administered by means of subcutaneous injection. At the time of randomization, participants were stratified according to the results of the local diagnostic assay for SARS-CoV-2 and according to age. The primary efficacy end point was the development of symptomatic SARS-CoV-2 infection through day 28 in participants who did not have SARS-COV-2 infection (as measured by reverse-transcriptase-quantitative polymerase-chain-reaction assay) or previous immunity (seronegativity).
Results
Symptomatic SARS-CoV-2 infection developed in 11 of 753 participants in the REGEN-COV group (1.5%) and in 59 of 752 participants in the placebo group (7.8%) (relative risk reduction [1 minus the relative risk], 81.4%; P < 0.001). In weeks 2 to 4, a total of 2 of 753 participants in the REGEN-COV group (0.3%) and 27 of 752 participants in the placebo group (3.6%) had symptomatic SARS-CoV-2 infection (relative risk reduction, 92.6%). REGEN-COV also prevented symptomatic and asymptomatic infections overall (relative risk reduction, 66.4%). Among symptomatic infected participants, the median time to resolution of symptoms was two weeks shorter with REGEN-COV than with placebo (1.2 weeks and 3.2 weeks, respectively), and the duration of a high viral load (>104 copies per milliliter) was shorter (0.4 weeks and 1.3 weeks, respectively). No dose-limiting toxic effects of REGEN-COV were noted.
Conclusion
Subcutaneous REGEN-COV prevented symptomatic COVID-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons. Among the participants who became infected, REGEN-COV reduced the duration of symptomatic disease and the duration of a high viral load. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04452318. opens in new tab.)
(9). Mathew R et al. Milrinone as compared with dobutamine in the treatment of cardiogenic shock. N Engl J Med. 2021;385:516-525
Cardiogenic shock is associated with substantial morbidity and mortality. Although inotropic support is a mainstay of medical therapy for cardiogenic shock, little evidence exists to guide the selection of inotropic agents in clinical practice.
Methods
We randomly assigned patients with cardiogenic shock to receive milrinone or dobutamine in a double-blind fashion. The primary outcome was a composite of in-hospital death from any cause, resuscitated cardiac arrest, receipt of a cardiac transplant or mechanical circulatory support, nonfatal myocardial infarction, transient ischemic attack or stroke diagnosed by a neurologist, or initiation of renal replacement therapy. Secondary outcomes included the individual components of the primary composite outcome.
Results
A total of 192 participants (96 in each group) were enrolled. The treatment groups did not differ significantly with respect to the primary outcome; a primary outcome event occurred in 47 participants (49%) in the milrinone group and in 52 participants (54%) in the dobutamine group (relative risk, 0.90; 95% confidence interval [CI], 0.69 to 1.19; P = 0.47). There were also no significant differences between the groups with respect to secondary outcomes, including in-hospital death (37% and 43% of the participants, respectively; relative risk, 0.85; 95% CI, 0.60 to 1.21), resuscitated cardiac arrest (7% and 9%; hazard ratio, 0.78; 95% CI, 0.29 to 2.07), receipt of mechanical circulatory support (12% and 15%; hazard ratio, 0.78; 95% CI, 0.36 to 1.71), or initiation of renal replacement therapy (22% and 17%; hazard ratio, 1.39; 95% CI, 0.73 to 2.67).
Conclusions
In patients with cardiogenic shock, no significant difference between milrinone and dobutamine was found with respect to the primary composite outcome or important secondary outcomes.
(10). Frías JP et al. Efficacy and safety of once-weekly semaglutide 2.0 mg versus 1.0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial. 2021;9(9):P563-574
Background
Semaglutide is an effective treatment for type 2 diabetes; however, 20-30% of patients given semaglutide 1 mg do not reach glycaemic treatment goals. We aimed to investigate the efficacy and safety of once-weekly semaglutide 2 mg versus 1 mg in adults with inadequately controlled type 2 diabetes on a stable dose of metformin with or without a sulfonylurea.
Methods
We did a 40-week, randomised, active-controlled, parallel-group, double-blind, phase 3B trial (SUSTAIN FORTE) at 125 outpatient clinics in ten countries. Participants (≥18 years) with inadequately controlled type 2 diabetes (HbA1c 8·0-10·0%) with metformin and with or without sulfonylurea were randomly assigned (1:1) by an interactive web-response system to 2 or 1 mg once-weekly semaglutide. Participants, site personnel, the clinical study group, and investigators were masked to the randomised treatment. Outcomes included change from baseline at week 40 in HbA1c (primary outcome) and bodyweight (secondary confirmatory outcome), evaluated through trial product estimand (no treatment discontinuation or without rescue medication) and treatment policy estimand (regardless of treatment discontinuation or rescue medication) strategies. This study is registered with ClinicalTrials.gov, NCT03989232; EudraCT, 2018-004529-96; and WHO, U1111-1224-5162.
Findings
Between June 19 and Nov 28, 2019, of 1515 adults assessed for eligibility, 961 participants (mean age 58 years [SD 10·0]; 398 [41%] women) were included. Participants were randomly assigned to once-weekly semaglutide 2 mg (n = 480 [50%]) or 1 mg (n = 481 [50%]); 462 (96%) patients in the semaglutide 2 mg group and 471 (98%) in the semaglutide 1 mg group completed the trial. Mean baseline HbA1c was 8.9% (SD 0.6; 73.3 mmol/mol [SD 6.9]) and BMI was 34.6 kg/m2 (SD 7.0). Mean change in HbA1c from baseline at week 40 was -2.2 percentage points with semaglutide 2 mg and -1.9 percentage points with semaglutide 1.0 mg (estimated treatment difference [ETD] -0·23 percentage points [95% CI -0.36 to -0.11]; p = 0.0003; trial product estimand) and -2.1 percentage points with semaglutide 2.0 mg and -1.9 percentage points with semaglutide 1.0 mg (ETD -0.18 percentage points [-0.31 to −0.04]; p = 0.0098; treatment policy estimand). Mean change in bodyweight from baseline at week 40 was −6.9 kg with semaglutide 2.0 mg and -6.0 kg with semaglutide 1.0 mg (ETD -0.93 kg [95% CI -1.68 to −0.18]; p = 0.015; trial product estimand) and -6.4 kg with semaglutide 2.0 mg and -5.6 kg with semaglutide 1.0 mg (ETD -0.77 kg [-1.55 to 0.01]; p = 0.054; treatment policy estimand). Gastrointestinal disorders were the most commonly reported adverse events (163 [34%] in the 2.0 mg group and 148 [31%] in the 1.0 mg group). Serious adverse events were similar between treatment groups, reported for 21 (4%) participants given semaglutide 2.0 mg and 25 (5%) participants given semaglutide 1.0 mg. Three deaths were reported during the trial (one in the semaglutide 1.0 mg group and two in the semaglutide 2.0 mg group).
Interpretation
Semaglutide 2.0 mg was superior to 1.0 mg in reducing HbA1c, with additional body weight loss and a similar safety profile. This higher dose provides a treatment intensification option for patients with type 2 diabetes treated with semaglutide in need of additional glycaemic control.
