Volume 2 - Issue 12

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). Options for a global pandemic treaty: The world must act now to be prepared for future health emergencies. BMJ 2021;375.

An upcoming special session of the World Health Assembly, taking place from 29 November to 1 December 2021, will discuss the benefits of developing a new global agreement on pandemic preparedness and response. It offers a historic opportunity to protect current and future generations from health crises.

Covid-19 has affected each and every one of us. This is what sets it apart from other recent crises: no region or country has been spared. In less than two years, we have lost over five million lives to this virus, based only on official counts. It has infected more than 240 million people, so many of whom have been hospitalised in difficult circumstances. Long covid will trouble us for many years ahead. Our collective and individual mental health have been shaken. Children have missed out on education and socialisation, affecting their futures. Economies have suffered losses of trillions and dire effects on employment.

No one wants to see this happen again. Undeniably, individual countries and the global community were insufficiently prepared for this pandemic. Despite laudable ad hoc-initiatives, such as ACT-A and COVAX, the global community has so far failed to ensure equitable distribution of medical countermeasures.

At the same time, experts agree that this will likely not be the last pandemic. We live in the "Age of pandemics," in which pathogens of zoonotic origin, and the challenges posed by anti-microbial resistance, present a continued and growing risk.

While strengthening our prevention capacities, we must also build a system that will ensure a rapid, joint, effective, and equitable global response to future health crises that reaches every corner of the world.

We must learn the lessons from this crisis and make the necessary changes, both in terms of global collaboration to prevent a repeat of this pandemic and strengthening the global system to react better and faster.

This is why, in March this year, 25 heads of state and government issued a bold call for a new global agreement to use the pandemic as a watershed moment to prevent a global crisis of this kind occurring again. Piecemeal reforms and adjustments of the current system will not do the trick. We need fundamental reform.

A legally binding treaty, convention, or agreement, under the auspices of the World Health Organisation (WHO) has the potential to provide the world with an ambitious framework to better prevent, prepare for, and respond to future pandemics and epidemics. We see several benefits.

A new international instrument should break the cycle of "panic and neglect" and elevate high-level political attention for pandemic preparedness and response. Pandemic preparedness and response requires sustained political commitment and investment, even, or just, when a crisis subsides. A new treaty should systematically convene signatories, driving and supporting stronger compliance through a regular review process, and ensuring that pandemic preparedness and response remain a regular feature on world leaders' agendas.

Promoting cross-sectoral cooperation and coherence would be another benefit. The current crisis has shown that preventing, preparing for, and responding to pandemics is beyond the sole remit of health ministries; cooperation across sectors is required. Home affairs, civil protection, the environment, trade, transport, and finance policies are equally affected and equally important. What is missing in multilateral cooperation is a single forum that brings together all relevant organizations and actors under one umbrella. A treaty could provide this, closely involving other international organizations with a mandate linked to health threats.

In the past months we have witnessed an impressive, collective reflection process regarding the potential benefits and possible contents of a pandemic treaty. The indispensable substantive pillars of such a treaty are already emerging.

First, during the current pandemic we have seen a multitude of initiatives to address the pandemic and to do better in the future. While not denying their value, a treaty under the auspices of WHO would build coherence and avoid fragmentation. Currently, it is the only substantial proposal that would create a global, inclusive forum to discuss and improve pandemic preparedness and response.

Second, we need equitable access to safe and effective medical countermeasures, such as vaccines, therapeutics, and diagnostics. While some countries have enjoyed privileged access to high-quality medical countermeasures, others have faced extreme shortages. We must increase and globalise production, strengthen supply chains and regulatory systems, and put in place long term mechanisms to improve equitable access. This could include a framework for concrete measures to develop, manufacture, and scale up new countermeasures, and improve equitable access to existing countermeasures.

Third, we need to share data, samples, technologies, and benefits. In view of the cross-border nature of communicable diseases, it is necessary that all relevant knowledge is available worldwide as soon as possible. A new instrument could potentially include a multilateral framework for sharing surveillance and monitoring data, genetic data and pathogens. It could also include mechanisms to facilitate research and rapid sharing of technology and new insights.

Fourth, we must recognise the importance of One Health. Our health is a continuum across human, animal, plant, and planetary health. To reduce the risk of zoonotic diseases in the future, the human, anima and environmental health sectors must cooperate more closely. A new instrument could strengthen existing platforms and surveillance, further multisectoral partnerships, and promote specific countermeasures in line with the One Health approach, built on robust health systems at national level.

From 29 November, the World Health Assembly will convene in a Special Session to consider the benefits of a pandemic treaty or other international instrument with a view to establishing an intergovernmental negotiation process.

The momentum is there. More than 70 WHO Member States are already in favour of a treaty, and we are observing growing support to start negotiations, alongside the proposal to strengthen the existing International Health Regulations as well as WHO's important technical work.

We need to save lives and prevent a repeat of covid-19, and the only way to do that is through collaboration, investing in national and global systems to prevent and respond to outbreaks, and equipping and empowering WHO, once and for all, to fulfill its role as the pivotal player in global public health.

We urge all WHO Member States to support the opening of negotiations towards a new instrument at the upcoming World Health Assembly. We must seize this historic opportunity to get global preparedness and response in order. We cannot wait for the next crisis before we act.

(2). Israel A et al. Elapsed time since BNT162b2 vaccine and risk of SARS-CoV-2 infection: test negative design study. BMJ 2021;375.

Objectives: To determine whether time elapsed since the second injection of the Pfizer-BioNTech BNT162b2 mRNA vaccine was significantly associated with the risk of covid-19 infection after vaccination in people who received two vaccine injections.

Design: Test negative design study.

Setting: Electronic health records of a large state mandated healthcare organisation, Israel.

Participants: Adults aged ≥18 years who had received a reverse transcription polymerase chain reaction (RT-PCR) test between 15 May 2021 and 17 September 2021, at least three weeks after their second vaccine injection, had not received a third vaccine injection, and had no history of covid-19 infection.

Main outcome measures: Positive result for the RT-PCR test. Individuals who tested positive for SARS-CoV-2 and controls were matched for week of testing, age category, and demographic group (ultra-orthodox Jews, individuals of Arab ancestry, and the general population). Conditional logistic regression was adjusted for age, sex, socioeconomic status, and comorbid conditions.

Results: 83 057 adults received an RT-PCR test for SARS-CoV-2 during the study period and 9.6% had a positive result. Time elapsed since the vaccine injection was significantly longer in individuals who tested positive (P<0.001). Adjusted odds ratio for infection at time intervals >90 days since vaccination were significantly increased compared with the reference of <90 days: 2.37 (95% confidence interval 1.67 to 3.36) for 90-119 days, 2.66 (1.94 to 3.66) for 120-149 days, 2.82 (2.07 to 3.84) for 150-179 days, and 2.82 (2.07 to 3.85) for ≥180 days (P<0.001 for each 30 day interval).

Conclusions: In this large population of adults tested for SARS-CoV-2 by RT-PCR after two doses of mRNA BNT162b2 vaccine, a gradual increase in the risk of infection was seen for individuals who received their second vaccine dose after at least 90 days.

Immunity to SARS-CoV-2 can be induced by SARS-CoV-2 infection or vaccination. Individuals who are immune have some protection against reinfection and a reduced risk of severe clinical consequences. Recovering seropositive adult individuals have about 90% protection from SARS-CoV-2 reinfection after 150 days, and distinguishing reinfection from the effects of the initial infection is challenging before 90 days. In contrast, vaccination has been reported to be 50-95% effective at various time points.456 Nevertheless, the memory B cell humoral response and spike specific CD4+ cellular immune responses to SARS-CoV-2 are predictably diminishing over time.78 Therefore, concerns have been raised about a possible reduction in SARS-CoV-2 immune protection in vaccinated populations and in those who have recovered from covid-19 disease.

Israel was among the first countries to initiate a large scale vaccination campaign on 20 December 2020. A large proportion of the population were quickly immunised, partly because of the centralised health services and the decision to use only one vaccine, achieving early control over the spread of the virus.101112 Up to 26 July 2021, more than 5.2 million Israelis were fully vaccinated with two doses of the Pfizer-BioNTech vaccine.13 Since June 2021, however, a resurgence of individuals with SARS-CoV-2 has been seen, which could be at least partially because of decreasing levels of anti-SARS-CoV-2 antibodies in vaccinated people.14 Here, we describe the results of a large scale study measuring the association between time elapsed since administration of the second dose of the Pfizer-BioNTech BNT162b2 vaccine and the risk of covid-19 disease.

(3). Beltrame JF, et al. State of the art review: Management of ischaemia with non-obstructive coronary arteries (INOCA). BMJ 2021;375.

Up to half of patients undergoing elective coronary angiography for the investigation of chest pain do not present with evidence of obstructive coronary artery disease. These patients are often discharged with a diagnosis of non-cardiac chest pain, yet many could have an ischaemic basis for their symptoms. This type of ischaemic chest pain in the absence of obstructive coronary artery disease is referred to as INOCA (ischaemia with non-obstructive coronary arteries). This comprehensive review of INOCA management looks at why these patients require treatment, who requires treatment based on diagnostic evaluation, what clinical treatment targets should be considered, how to treat patients using a personalised medicine approach, when to initiate treatment, and where future research is progressing.

(4). Dancer SJ, et al. Editorials: Why don't we just open the windows? BMJ 2021;375.

It is time to accept the fact that most people acquire SARS-CoV-2 by breathing in contaminated air. Window opening is a start, but it is not a panacea for covid-19 or, for that matter, any other airborne viruses in the 21st century.

The evidence for preventing covid-19 is lost in translation

The world is finally coming to terms with the realisation that transmission of SARS-CoV-2 is airborne. First came the modelling studies, sizing up airborne particles, their trajectories, and viral load; and then came examples from the real world, completing the gaps in the models and confirming that the pandemic virus is chiefly spread through tiny aerosolised respiratory particles. Trying to validate this by detecting live virus, however, is fraught with technical difficulties. Hence, the frenetic attempts at measuring the quantity of infectious virus in breath as well as revisiting knowledge on ventilation sciences. While keeping your distance, wearing a mask, and getting vaccinated have provided much protection, one intervention that would have a significant impact is adequate indoor ventilation. Healthcare, homes, schools, and workplaces should have been encouraged to improve ventilation at the very beginning of the pandemic, but tardy recognition of the airborne route by leading authorities in 2020 stalled any progress that could have been made at that stage. This was compounded by controversies over the terms "droplet" and "aerosol," as the definition of these dictates different infection prevention strategies, including type of mask.

Inserting the term "ventilation" into a covid-19 policy document might appease readers, but ensuring people get enough fresh air in indoor environments seems to have fallen by the wayside. Why is this? Can we establish the reasons for this seemingly lethargic response to improving indoor air quality?

In order to answer, it is imperative to understand three fundamental principles of infection prevention and control. Firstly, most pathogens are invisible; secondly, you know the system has failed only when there is an outbreak; and, finally, you cannot always identify a specific cause, making it difficult to implement the most appropriate intervention. Infection control relies on a bundle of measures that are assumed to cover most transmission routes, explaining initial misguided emphasis on droplets and surface risk rather than unconstrained aerosol.

Common sense dictates so much of what is done for infection control, since most funding bodies consistently prioritise the most immediate, urgent, or commercially beneficial societal problems. Furthermore, current guidelines tend to focus on solid bodies, such as people; surfaces, both hard and soft; equipment; and water. Air is literally nebulous. Just as cleaning was the Cinderella of infection control during the past decade or so (and methicillin resistant Staphylococcus aureus sorted that out), we must now confront the neglected, but substantive, role of air in transmitting infection. It is fair to say that air could be the final medium to define and standardise within the infection control itinerary.

Another major compelling reason that air quality has been side lined is cost. Most buildings are neither designed nor well operated from the air quality aspect, with energy conservation and thermal comfort at the top of the list of requirements. Pumping in adequate amounts of fresh outside air, however engineered, will challenge running costs as well as carbon status. Outdoor air generally differs from indoor air in terms of temperature and humidity, and conditioning outdoor air needs significant energy. While evolving green technologies might be able to offset some of these increased energy requirements, any revision or upgrade of existing systems is a big undertaking and enormously expensive. Additionally, ventilation is usually controlled by building operators and owners, not necessarily individuals, and the former are not yet mandated by law to improve ventilation in public venues.

Ventilation and air cleaning systems are noisy, drafty, and require fine tuning and regular maintenance. Even simple window opening invites discussion over chill, airflow, and security. There are some standards for indoor air quality, notably through proffered air changes, but these chiefly concern specialist healthcare environments such as operating theatres. Indeed, existing ventilation standards hardly consider the risk of airborne infection in non-specialist public spaces at all.

So where are we now with indoor air quality? Clearly, better ventilation requires planning and investment, but who is going to ensure this and how should it be done? Upgrading internal air quality for billions of indoor environments in the world needs solid research, funding, and mandated standards. Those that we have are variable or are applied inconsistently. We have established public health strategies for foods and water and even pollution, but air quality inside most public venues in our communities resembles nothing more than miasmic uncertainty.

As with all major shifts in scientific understanding, tackling the final medium requires courage, investment, and political support for scientists and policy makers. The same applies to business and industry, who are already producing a range of air cleaning technologies and equipment. We cannot ignore airborne transmission any longer, however difficult or costly it may be to control. It is time to accept the fact that most people acquire SARS-CoV-2 by breathing in contaminated air. Window opening is a start, but it is not a panacea for covid-19 or, for that matter, any other airborne viruses in the 21st century.

(5). Yamey G, et al. Preventing pandemics in the world's most vulnerable settings. BMJ 2021;375.

A global framework convention must include the needs of fragile and conflict affected settings

The covid-19 pandemic has exposed major gaps in national, regional, and global systems of pandemic preparedness and response, including underfunding, weak application of the International Health Regulations (IHR), and global inequities in access to covid-19 vaccines. Several global reports have made recommendations for closing these gaps. But these reports do not capture the unique context of fragile, conflict affected, and vulnerable (FCV) settings. From 29 November to 1 December 2021 a World Health Assembly special session will discuss the merits of developing a new international instrument (such as a "framework convention") on pandemic preparedness and response. We call on member states to ensure that the needs of FCV settings are included in these discussions.

These needs matter. There is no "global" preparedness without preparedness in FCV settings, where an estimated one in eight people currently live. Pandemics can amplify existing political tensions and worsen conflict in these settings, as seen in west Africa in the 2014-16 Ebola epidemic, and can have catastrophic health and economic effects on these already vulnerable places. Covid-19, for example, pushed an additional 20 million people into extreme poverty in FCV nations.6 And the underlying conditions in these settings-such as overcrowding and poor access to water, sanitation, and hygiene-can contribute to "spark risk (where a pandemic is likely to arise) and spread risk (how likely it is to diffuse broadly through human populations).

Preparedness is uniquely challenging in FCV settings. A deficit of trust between citizens and leaders, divided territories, and poor joint pandemic planning among many national and international actors all threaten the governance of preparedness. Policy planning and implementation is difficult when the security situation is volatile. Health services, information systems, and infrastructure may have been weakened or destroyed by conflict. Health professionals may have insufficient training or work in unsafe conditions. Sustainable financing from domestic and external sources is lacking, as is funding to purchase pandemic vaccines. Internally displaced people, refugees, migrants, and returnees face heightened risks, in part due to stigma, discrimination, and exclusion from health services.

How can these challenges be tackled? Based on published research, case studies of successful approaches, and field experience, we propose five key actions for consideration.

First, diplomacy should become a central plank of pandemic preparedness and response in FCV settings. Diplomacy to cease hostilities across divided territories has been fruitful in, for example, achieving "vaccination ceasefires" in Afghanistan, Lebanon, and Yemen, and in reaching communities that may be suspicious of outsiders or of pandemic control campaigns.

Second, we need dedicated, long term funding specifically for preparedness, including for core IHR capacities (those "required to detect, assess, notify and report events, and respond to public health risks and emergencies of national and international concern"). Such funding has fallen through the cracks between humanitarian and development donors. Funding should target strengthening and protection of the health workforce and improvement of epidemiological surveillance and laboratory capacities, including early warning and response systems (used in Iraq, Libya, Somalia, Syria, and Yemen8). National action plans for health security, drawn up following joint external evaluation of a country's capacity to meet international health regulations,9 must be fully funded. External financing should be channelled through public systems where possible, strengthening these systems in the process-the ultimate aim should be domestic ownership of pandemic preparedness financing.

Third, action should be taken to strengthen multisectoral governance at regional and community levels and to bolster the governance capacity of non-governmental organisations (NGOs). Experienced frontline NGOs often bring speed, scale, and community knowledge to pandemic preparedness efforts. Engaging communities underpins preparedness and response in FCV settings and has been critical during the covid-19 pandemic for raising awareness, linking local communities with central campaigns, and identifying high risk groups for shielding. Regional governance approaches should be bolstered-their value is clear from successful regional collaborations such as the East Africa Health Laboratory Networking Project for TB control, polio, meningitis, cholera, and yellow fever.

Fourth, while there is widespread interest in a pandemic framework convention, experts working in FCV settings are calling for technical guidance specific to particular types of settings and consistent with on-the-ground realities and available resources. Tailored guidance is needed particularly in settings without a functioning government, where a government or territory is divided, or where there are large numbers of displaced people. For example, where testing capacity for epidemic or pandemic infections is limited, resource stratified guidelines could prioritise targeted tests for at-risk populations and healthcare workers.

Fifth, context specific research evaluating preparedness policies, systems, and implementation is urgently needed. Few preparedness responses have been formally evaluated in FCV settings, hindering adaptation and improvement. Biomedical research also has a critical role, given the value of innovations such as low cost rapid diagnostic tests and single dose vaccines in FCV settings.

The forthcoming World Health Assembly provides an opportunity to amplify voices from fragile, conflict affected, and vulnerable settings in discussions of pandemic preparedness. Global preparedness measures that exclude these settings will not be fit for purpose.

(6). Keshri VR, et al. Burns in India: a call for health policy action. 22,2021.

Globally, burns are one of the major causes of disability, with more than 8 million disability-adjusted life-years (DALYs). The burden of burns falls disproportionately on low-income and middle-income countries (LMICs). A trend of increased incidence of burns is observed in south Asia during the festive season of Diwali, celebrated each year in the months of October or November. The situation in India is particularly worrying. In 2019, more than 23 000 fire-related deaths were estimated in India, which is about 20% of the global mortality burden. Additionally, 1·5 million DALYs were attributed to burns. Burn survivors can be financially distressed, vocationally challenged, and socially excluded. The burden of burns among women (aged 15-49 years) in India is three-times higher than that among men. Women have differential exposure to risk, often arising from unsafe cooking and kitchen practices, suicides, and homicides associated with domestic violence and dowry-related conflict. Prevention of burns requires attention to gender-based inequities and upstream social determinants of health. The surge in burn cases during Diwali sees an increased representation of children. In high-income countries, the incidence, severity, mortality, and disability due to burns have reduced significantly due to advancement in prevention, management, and rehabilitation; whereas in LMICs, and particularly in south-Asian countries and India, the burden continues to be high.

In 2010, in response to this burden, a National Programme for Prevention and Management of Burns Injury was launched in India. However, the scope of the programme remains limited. Burn services in India are delivered primarily through a network of specialised tertiary care burn centres. There are 67 burn centres, of which 30 are in the public sector and 37 in the private sector. The geographical distribution of these centres and service availability are uneven and heterogeneous. In the public sector, many burn centres are constrained in terms of infrastructure and human resource capacity, and concerns have been raised about the quality of care Another bottleneck in the public sector is out-of-pocket expenditures for dietary supplementation, medicine, transport, and rehabilitation services. Being a patient with burns and poor financial means can also lead to poor burn services and poor recovery outcomes.

Running a medical burn centre has a high cost, and thus the financial viability of running such services is a major challenge for the private sector. Besides, burn care in the private sector is mostly located in big cities. Patients with burns often require long treatment that can lead to very high out-of-pocket costs and catastrophic expenditure for the family.

In 2017, a new National Health Policy (NHP) was formulated with a stated aspiration to progressively move towards Universal Health Coverage (UHC). The NHP brought a major strategic shift in public health care, aligning the private sector for public health goals, and thus expanding the role of government from just being a provider to being the purchaser. The subsequent introduction of the Ayushman Bharat scheme in 2018 consolidated this approach by introducing a major public financed health insurance scheme, the Pradhan Mantri Jan Arogya Yojana (PMJAY). In this changing landscape of health-care delivery in India, there is an opportunity for renewed health policy action for burns management.

The PMJAY scheme includes burn treatment under its service package, but the extent of coverage is limited to about 40% of Indian families with low socioeconomic status. Burn service coverage under PMJAY is restricted mainly to acute and hospitalised care, and the cost of coverage is also limited. Available evidence suggests inadequacy of the publicly financed health insurance scheme in averting catastrophic expenditure for patients with burns in need of emergency care. This situation highlights the need to expand the coverage and ensure adequate financial risk protection for patients with burns. One such example is a dedicated scheme by the local government in Delhi, which mandates free and cashless treatment for burn cases in all facilities.Universal provision of such a scheme might enable equitable access to burn care in India, reducing death and disability from burns. Strong regulation and effective stewardship are needed to support the effective implementation of these reform initiatives.

We call for making burn service free at the point of care across the country. The scope for PMJAY needs to be expanded to cover all patients with burns and all associated costs. At the same time, there is an urgent need to reform and broaden the scope of the national programme to strengthen burn care in the public sector and to ensure better rehabilitation of burn survivors. Social reintegration of burn survivors needs a welfare and justice approach guided by effective policy. In pursuit of UHC in India, a strong policy statement backed by clear strategies for effective response to burns is urgently needed.

(7). Nijssen EC, et al. A novel risk score for contrast-associated acute kidney injury: the heart of the matter. Lancet 2021;398(10315):P1941-3.

Given the hundreds of thousands of contrast medium doses that are injected every day, contrast-associated acute kidney injury is an important issue. However, it is fraught with controversy. The first reports of acute kidney injury after contrast administration date from the 1950s, but who is at risk and the risk itself are still being debated. Identifying kidney injury caused by contrast media is a challenge because it is not characterised by specific symptoms; contrast-associated acute kidney injury is an indirect, biochemical diagnosis based on absolute or relative increases in serum creatinine within a few days after contrast medium administration. Various thresholds of serum creatinine have been used and reported incidences vary widely. Interestingly, increases in serum creatinine akin to those in contrast-associated acute kidney injury definitions have been reported in patients who did not receive contrast at all. To further complicate matters, serum creatinine is directly affected by a large number of factors, many of which are encountered in the setting of contrast procedures, leading some to speculate that we are seeing signal where there is mostly noise.  Despite these uncertainties, reports of associations between contrast-associated acute kidney injury and increased morbidity, longer hospital stays, and mortality risk are consistent, especially in patients with cardiac disease.  Whether the relationship is causal or coincidental remains unclear, but the general assumption is that preventing contrast-associated acute kidney injury will prevent associated risks of adverse outcomes.

Background

Contrast-associated acute kidney injury can occur after percutaneous coronary intervention (PCI). Prediction of the contrast-associated acute kidney injury risk is important for a tailored prevention and mitigation strategy. We sought to develop a simple risk score to estimate contrast-associated acute kidney injury risk based on a large contemporary PCI cohort.

Methods

Consecutive patients undergoing PCI at a large tertiary care centre between Jan 1, 2012, and Dec 31, 2020, with available creatinine measurements both before and within 48 h after the procedure, were included; only patients on chronic dialysis were excluded. Patients treated between 2012 and 2017 comprised the derivation cohort and those treated between 2018 and 2020 formed the validation cohort. The primary endpoint was contrast-associated acute kidney injury, defined according to the Acute Kidney Injury Network. Independent predictors of contrast-associated acute kidney injury were derived from multivariate logistic regression analysis. Model 1 included only pre-procedural variables, whereas Model 2 also included procedural variables. A weighted integer score based on the effect estimate of each independent variable was used to calculate the final risk score for each patient. The impact of contrast-associated acute kidney injury on 1-year deaths was also evaluated.

Findings

32 378 PCI procedures were performed and screened for inclusion in the present analysis. After the exclusion of patients without paired creatinine measurements, patients on chronic dialysis, and multiple procedures, 14 616 patients were included in the derivation cohort (mean age 66·2 years, 29·2% female) and 5606 were included in the validation cohort (mean age 67·0 years, 26·4% female). Contrast-associated acute kidney injury occurred in 860 (4·3%) patients. Independent predictors of contrast-associated acute kidney injury included in Model 1 were: clinical presentation, estimated glomerular filtration rate, left ventricular ejection fraction, diabetes, haemoglobin, basal glucose, congestive heart failure, and age. Additional independent predictors in Model 2 were: contrast volume, peri-procedural bleeding, no flow or slow flow post procedure, and complex PCI anatomy. The occurrence of contrast-associated acute kidney injury in the derivation cohort increased gradually from the lowest to the highest of the four risk score groups in both models (2·3% to 34·9% in Model 1, and 2·0% to 38·8% in Model 2). Inclusion of procedural variables in the model only slightly improved the discrimination of the risk score (C-statistic in the derivation cohort: 0·72 for Model 1 and 0·74 for model 2; in the validation cohort: 0·84 for Model 1 and 0·86 for Model 2). The risk of 1-year deaths significantly increased in patients with contrast-associated acute kidney injury (10·2% vs 2·5%; adjusted hazard ratio 1·76, 95% CI 1·31-2·36; p=0·0002), which was mainly due to excess 30-day deaths.

Interpretation

A contemporary simple risk score based on readily available variables from patients undergoing PCI can accurately discriminate the risk of contrast-associated acute kidney injury, the occurrence of which is strongly associated with subsequent death.

(8). Neuman MD, et al. Spinal anesthesia or general anesthesia for hip surgery in older adults. N Engl J Med. 2021;385:2025-35.

Background

The effects of spinal anesthesia as compared with general anesthesia on the ability to walk in older adults undergoing surgery for hip fracture have not been well studied.

Methods

We conducted a pragmatic, randomized superiority trial to evaluate spinal anesthesia as compared with general anesthesia in previously ambulatory patients 50 years of age or older who were undergoing surgery for hip fracture at 46 U.S. and Canadian hospitals. Patients were randomly assigned in a 1:1 ratio to receive spinal or general anesthesia. The primary outcome was a composite of death or an inability to walk approximately 10 ft (3 m) independently or with a walker or cane at 60 days after randomization. Secondary outcomes included death within 60 days, delirium, time to discharge, and ambulation at 60 days.

Results

A total of 1600 patients were enrolled; 795 were assigned to receive spinal anesthesia and 805 to receive general anesthesia. The mean age was 78 years, and 67.0% of the patients were women. A total of 666 patients (83.8%) assigned to spinal anesthesia and 769 patients (95.5%) assigned to general anesthesia received their assigned anesthesia. Among patients in the modified intention-to-treat population for whom data were available, the composite primary outcome occurred in 132 of 712 patients (18.5%) in the spinal anesthesia group and 132 of 733 (18.0%) in the general anesthesia group (relative risk, 1.03; 95% confidence interval [CI], 0.84 to 1.27; P = 0.83). An inability to walk independently at 60 days was reported in 104 of 684 patients (15.2%) and 101 of 702 patients (14.4%), respectively (relative risk, 1.06; 95% CI, 0.82 to 1.36), and death within 60 days occurred in 30 of 768 (3.9%) and 32 of 784 (4.1%), respectively (relative risk, 0.97; 95% CI, 0.59 to 1.57). Delirium occurred in 130 of 633 patients (20.5%) in the spinal anesthesia group and in 124 of 629 (19.7%) in the general anesthesia group (relative risk, 1.04; 95% CI, 0.84 to 1.30).

Conclusions

Spinal anesthesia for hip-fracture surgery in older adults was not superior to general anesthesia with respect to survival and recovery of ambulation at 60 days. The incidence of postoperative delirium was similar with the two types of anesthesia

(9). Murphy WJ, Longo DL. A Possible Role for Anti-idiotype Antibodies in SARS-CoV-2 Infection and Vaccination. N Engl J Med. 2021

The Clinical Implications of Basic Research series has focused on highlighting laboratory research that could lead to advances in clinical therapeutics. However, the path between the laboratory and the bedside runs both ways: clinical observations often pose new questions for laboratory investigations that then lead back to the clinic. 

One of a series of occasional articles drawing attention to the bedside-to-bench flow of information is presented here, under the Basic Implications of Clinical Observations rubric. We hope our readers will enjoy these stories of discovery, and we invite them to submit their own examples of clinical findings that have led to insights in basic science.

The pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is incompletely understood, with its effects on multiple organ systems1 and the syndrome of "long Covid" occurring long after the resolution of infection. The development of multiple efficacious vaccines has been critical in the control of the pandemic, but their efficacy has been limited by the appearance of viral variants, and the vaccines can be associated with rare off-target or toxic effects, including allergic reactions, myocarditis, and immune-mediated thrombosis and thrombocytopenia in some healthy adults. Many of these phenomena are likely to be immune-mediated.3 How can we understand this diversity in immune responses in different persons?

Anti-idiotype Antibodies and SARS-CoV-2

One way of thinking about the complexity of the immune response is through the lens of anti-idiotype immune responses. The Network Hypothesis, formulated in 1974 by Niels Jerne, described a mechanism by which the antibody responses to an antigen themselves induced downstream antibody responses against the antigen-specific antibody.4 Every antibody that is induced and specific for an antigen (termed "Ab1" antibody) has immunogenic regions, particularly in their variable-region antigen-binding domains, that are unique as a result of genetic recombination of immunoglobulin variable, diversity, and joining (VDJ) genes; VDJ recombination results in new and therefore immunogenic amino acid sequences called idiotopes, which are then capable of inducing specific antibodies against Ab1 antibodies as a form of down-regulation. A similar paradigm has been proposed for T cells. However, these regulatory immune responses are also capable of doing much more. The paratopes, or antigen-binding domains, of some of the resulting anti-idiotype (or "Ab2") antibodies that are specific for Ab1 can structurally resemble that of the original antigens themselves. Thus, the Ab2 antigen-binding region can potentially represent an exact mirror image of the initial targeted antigen in the Ab1 response, and Ab2 antibodies have even been examined for potential use as a surrogate for the antigen in vaccine studies. However, as a result of this mimicry, Ab2 antibodies also have the potential to bind the same receptor that the original antigen was targeting (Figure 1). Ab2 antibodies binding to the original receptor on normal cells therefore have the potential to mediate profound effects on the cell that could result in pathologic changes, particularly in the long term - long after the original antigen itself has disappeared.

This aspect of regulation of immune-cell responses was postulated by Plotz in 1983 as a possible cause of autoimmunity arising after viral infection and has since been supported experimentally by direct transfer of anti-idiotype antibodies. Ab2 antibodies generated against the enterovirus coxsackievirus B3 in mice can bind myocyte antigens, resulting in autoimmune myocarditis, and anti-idiotype responses can act as acetylcholine receptor agonists, leading to myasthenia gravis symptoms in rabbits. In addition, by displaying the mirror image of the viral antigen, Ab2 alone can even mimic the deleterious effects of the virus particle itself, as has been shown with bovine viral diarrhea virus antigen.

For SARS-CoV-2 infection, attention centers on the spike (S) protein and its critical use of the angiotensin-converting-enzyme 2 (ACE2) receptor to gain entry into the cell. Given its critical role in regulating angiotensin responses, many physiological effects can be influenced by ACE2 engagement.9 The S protein itself has a direct effect on suppressing ACE2 signaling by a variety of mechanisms and can also directly trigger toll-like receptors and induce inflammatory cytokines.10 Anti-idiotype responses may affect ACE2 function, resulting in similar effects. However, preclinical and clinical assessments of antibody responses to SARS-CoV-2 vaccines have focused solely on Ab1 responses and virus-neutralizing efficacy. The delineation of potential anti-idiotype responses has inherent difficulties because of the polyclonal nature of responses, dynamic kinetics, and the concurrent presence of both Ab1 and Ab2 antibodies. Furthermore, ACE2 expression within cells and tissues can be variable. The different vaccine constructs (RNA, DNA, adenoviral, and protein) are also likely to have differential effects on Ab2 induction or in the mediation of vaccine effects that differ from responses to infection. Some off-target effects may not be directly linked to Ab2 responses. The association of thrombotic events with some SARS-CoV-2 vaccines in young women and the etiologic role of anti-platelet factor 4-polyanion antibodies may be the result of the adenoviral vector. However, the reported occurrence of myocarditis after vaccine administration bears striking similarities to the myocarditis associated with Ab2 antibodies induced after some viral infections.6 Ab2 antibodies could also mediate neurologic effects of SARS-CoV-2 infection or vaccines, given the expression of ACE2 on neuronal tissues, the specific neuropathologic effects of SARS-CoV-2 infection,11 and the similarity of these effects to Ab2-mediated neurologic effects observed in other viral models.It would therefore be prudent to fully characterize all antibody and T-cell responses to the virus and the vaccines, including Ab2 responses over time. Using huACE2 transgenic mice and crossing them with strains that are predisposed to autoimmunity or other human pathologic conditions can also provide important insights. An understanding of potential Ab2 responses may also provide insights into Ab1 maintenance and efficacy and into the application of antibody-based therapeutic agents. However, much more basic science research is needed to determine the potential role idiotype-based immunoregulation of both humoral and cell-mediated responses may play both in antiviral efficacy and in unwanted side effects of both SARS-CoV-2 infection and the vaccines that protect us from it.

(10). Clarke SLN. Tofacitinib in juvenile idiopathic arthritis. Lancet. 2021;398(10315): P1943-5.

Biological therapies have made a huge contribution to treatment of juvenile idiopathic arthritis (JIA) over the past two decades. However, their use does pose challenges in paediatric practice as they are exclusively injectable formulations. Therefore, an urgent unmet need for efficacious oral treatments for children with JIA who do not respond adequately to methotrexate remains. Tofacitinib was the first JAK inhibitor to be licensed for rheumatoid arthritis in 2012, and since then JAK inhibitors have been increasingly used for immune-mediated disorders in adults.  Their once or twice daily oral formulation makes them an attractive prospect for use in children. Furthermore, whereas the cost of biologics has reduced with the advent of biosimilars, small molecule JAK inhibitors still confer considerable price advantage, and therefore market accessibility, over biologics, particularly in low-income and middle-income countries. The annual cost of generic tofacitinib for a 40 kg child in India currently costs approximately INR 26760 (equivalent to £260, €300, or US$365) compared with thousands of pounds for a biologic (eg, adalimumab still costs approximately INR 250 000 [equivalent to £2420, €2810, or $3410] through patient assistance programmes). 

 


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