Journal scan: A review of 10 recent papers of immediate clinical significance, harvested from major international journals

“Human challenge trials” may help answer important questions quickly

If you are going to catch covid-19, jokes Jacob Hopkins, a university student, the safest place to do it is in a hospital. So, in March Mr. Hopkins lay down on a bed in the Royal Free Hospital in London while doctors placed droplets of liquid carrying the sars-cov-2 virus into his nose. Mr. Hopkins was one of 36 participants in the first “human challenge trial” (hct) for covid-19.

Human trials are a valuable part of medical research. Studying sick people in the controlled environment of a lab allows scientists to collect valuable information about how diseases work much more quickly than relying on messy and uncertain data from the real world. Since the second world war, around 40,000 volunteers have allowed themselves to be infected with everything from malaria and typhoid to dengue fever and cholera.

But although the idea of doing hcts for covid-19 has been discussed since the early days of the pandemic, it has proved controversial enough that only Britain has allowed them to go ahead (A second hct is under way at Oxford University). The results from the Royal Free trial, conducted with help from Imperial College London and a firm called hvivo, which specialises in hcts, are expected in the coming weeks. They will include details on the natural course of infection of covid-19, how well different tests do in detecting infections, how much exposure to sars-cov-2 is necessary to infect someone, and how useful masks are in preventing transmission.

Despite the safety worries, the trials have proceeded without incident, says Andrew Catchpole, hvivo’s chief scientific officer. Volunteers in the trials had only mild symptoms. And the data generated look like being very useful. Dr Catchpole says he and his team were “stunned” by how consistent the course of the disease was in different volunteers. The shedding of viral particles, for instance – which can then go on to infect others – usually starts within a few days of infection, typically up to day four, after which it increases very quickly.

Another strand of the trial aims to nail down just how long it takes, after an individual is infected, for covid-19 to be detected, both by cheap, widely used lateral-flow tests, and by more expensive, more accurate pcr ones. During the trial, researchers conducted frequent swabs of the rooms that volunteers were confined to. That allowed them to figure out exactly when infectious viral particles-as opposed to just passive blobs of genetic material-were present in the room. There will also be more to say on covid-19’s neurological symptoms, and on the immune response of infected individuals.

Despite this promised bounty of data, hcts for covid-19 remain controversial. Opponents point out that covid-19 is a potentially dangerous disease that is not well-understood or always treatable. “Long covid”, a mysterious condition in which symptoms persist for months, is a possibility, as is death. Jan Helge Solbakk, head of research at the Centre for Medical Ethics in Oslo, says there is no longer any good argument in favour of hcts now that vaccines have been developed and tested.

Proponents counter that the safety record of previous hcts is “outstanding”, and that risks can be minimised by giving young and healthy volunteers the smallest possible dose of the virus. Arthur Caplan, a professor of medical ethics at the Grossman School of Medicine at New York University, points out that drug trials also involve the risk of injury or death, yet are uncontroversial. He says opponents of hcts are not focusing on the research that is still needed, including into new vaccines, or the time it will take to obtain such data without hcts. He accuses them of “fuzzy moral thinking”.

The trial has infected participants with the original strain of sars-cov-2 that first emerged in China in 2019. That means not all the data will be generalisable to the Delta variant of the virus, which has become dominant in many countries. But Dr Catchpole says he expects at least some consistency in results concerning the minimum dose needed for infection.

And having conducted one set of hcts safely, it should be easier to undertake more in future. Further trials could allow quicker tests of vaccines against new variants of sars-cov-2, for instance, or tightly controlled comparisons of different jabs to see which is the most effective. (Such questions could take years to answer with real-world data.) They could also help obtain swift answers on how well new or existing drugs work against covid-19.

Adrian Hill, the director of the Jenner Institute, a vaccine-research body based in Oxford, says the risks of conducting hcts have been reduced by the availability of new treatments for covid-19, such as monoclonal antibodies. Yet even in gung-ho Britain, arguments about safety delayed the start of the trials by months. Covid-19 is unlikely to be the last novel disease the world faces, says Dr Hill. To help save lives in future, he would like to see the ethical questions around hcts settled before the next pandemic arrives.

(2). Mahase E. Covid-19: Booster dose reduces infections and severe illness in over 60s, Israeli study reports. BMJ 2021;374:n2297.

Rates of infection and of severe illness were substantially lower in people aged over 60 who received a booster (third) dose of the Pfizer-BioNTech covid-19 vaccine than in those who had only two doses, Israeli researchers have reported.

Using the Israeli Ministry of Health database (for 30 July to 31 August 2021), the researchers extracted data on more than 1.1 million people aged 60 or over who had been fully vaccinated at least five months earlier. They compared the incidence of confirmed covid-19 and severe illness in people who had received the booster dose at least 12 days earlier with the rates in people who had not received a booster.

In the paper, published in the New England Journal of Medicine, the researchers reported that at least 12 days after the booster dose the rate of confirmed infection was lower in the booster group than in the non-booster group by a factor of 11.3 (95% confidence interval 10.4 to 12.3).

The rate of severe illness was also lower in the booster group, by a factor of 19.5 (12.9 to 29.5). The absolute difference between the groups in the rate of severe illness was 7.5 cases per 100 000 person-days.

Furthermore, in a secondary analysis the researchers found that the rate of confirmed infection at least 12 days after the booster vaccination was lower than the rate after 4-6 days by a factor of 5.4 (4.8 to 6.1).

The authors wrote, “Even under this conservative analysis, the demonstrated rate reduction highlights the important role that a booster dose could play in mitigating the effects of waning immunity and immune evasion, especially during the emergence of variants of concern, such as the delta variant.”

The study’s limitations included that it did not consider differences in coexisting illnesses or the time interval between the first two doses, and that the follow-up period was short.

Commenting on the research, Peter English, a retired consultant in communicable disease control and former editor of Vaccines in Practice, said, “These are spectacularly good results, which are likely to have a very significant effect on the direct risk to individuals who receive a booster dose.”

However, he added that because the UK generally used a longer dose interval between the first two doses (three months versus three weeks), which research indicated could result in increased efficacy, the UK may not see as big an improvement with booster doses as seen in Israel. “But even if the effect of giving a booster dose of vaccine is not as good as this paper found it to be in Israel, they could be extremely beneficial here in the UK,” English said.

In the UK 30 million people from the highest risk groups are set to be offered booster jabs, with the government’s vaccination advisory committee saying that the decision was “precautionary” and that on balance it was preferable to maintain a high level of protection among vulnerable adults throughout winter.

This was despite other experts, including the developers of the Oxford-AstraZeneca vaccine Sarah Gilbert and Andrew Pollard, saying that boosters were not needed because immunity was lasting well. They have called for these vaccine doses to go towards vaccinating people around the world who are yet to have a single dose. Currently, 43% of the world’s population has received at least one dose of a covid-19 vaccine.

The World Health Organization called for a moratorium on boosters until at least the end of September, to enable a minimum of 10% of the population of every country to be vaccinated. Its director general, Tedros Adhanom Ghebreyesus, said in a speech on 4 August, “We cannot accept countries that have already used most of the global supply of vaccines using even more of it, while the world’s most vulnerable people remain unprotected.”

(3). Sandhu S, et al. Prostate cancer. The Lancet. 2021;398:P1075-1090.

The management of prostate cancer continues to evolve rapidly, with substantial advances being made in understanding the genomic landscape and biology underpinning both primary and metastatic prostate cancer. Similarly, the emergence of more sensitive imaging methods has improved diagnostic and staging accuracy and refined surveillance strategies. These advances have introduced personalised therapeutics to clinical practice, with treatments targeting genomic alterations in DNA repair pathways now clinically validated. An important shift in the therapeutic framework for metastatic disease has taken place, with metastatic-directed therapies being evaluated for oligometastatic disease, aggressive management of the primary lesion shown to benefit patients with low-volume metastatic disease, and with several novel androgen pathway inhibitors significantly improving survival when used as a first-line therapy for metastatic disease. Research into the molecular characterisation of localised, recurrent, and progressive disease will undoubtedly have an impact on clinical management. Similarly, emerging research into novel therapeutics, such as targeted radioisotopes and immunotherapy, holds much promise for improving the lives of patients with prostate cancer.

(4). Bruce Neal, et al. Effect of Salt Substitution on Cardiovascular Events and Death. N Engl J Med. 2021;385:1067-1077.

Background

Salt substitutes with reduced sodium levels and increased potassium levels have been shown to lower blood pressure, but their effects on cardiovascular and safety outcomes are uncertain.

Methods

We conducted an open-label, cluster-randomized trial involving persons from 600 villages in rural China. The participants had a history of stroke or were 60 years of age or older and had high blood pressure. The villages were randomly assigned in a 1:1 ratio to the intervention group, in which the participants used a salt substitute (75% sodium chloride and 25% potassium chloride by mass), or to the control group, in which the participants continued to use regular salt (100% sodium chloride). The primary outcome was stroke, the secondary outcomes were major adverse cardiovascular events and death from any cause, and the safety outcome was clinical hyperkalemia.

Results

A total of 20,995 persons were enrolled in the trial. The mean age of the participants was 65.4 years, and 49.5% were female, 72.6% had a history of stroke, and 88.4% a history of hypertension. The mean duration of follow-up was 4.74 years. The rate of stroke was lower with the salt substitute than with regular salt (29.14 events vs. 33.65 events per 1000 person-years; rate ratio, 0.86; 95% confidence interval [CI], 0.77 to 0.96; P = 0.006), as were the rates of major cardiovascular events (49.09 events vs. 56.29 events per 1000 person-years; rate ratio, 0.87; 95% CI, 0.80 to 0.94; P < 0.001) and death (39.28 events vs. 44.61 events per 1000 person-years; rate ratio, 0.88; 95% CI, 0.82 to 0.95; P < 0.001). The rate of serious adverse events attributed to hyperkalemia was not significantly higher with the salt substitute than with regular salt (3.35 events vs. 3.30 events per 1000 person-years; rate ratio, 1.04; 95% CI, 0.80 to 1.37; P = 0.76).

Conclusions

Among persons who had a history of stroke or were 60 years of age or older and had high blood pressure, the rates of stroke, major cardiovascular events, and death from any cause were lower with the salt substitute than with regular salt.

(5). Ingelfinger JR. Can Salt Substitution Save At-Risk Persons from Stroke? N Engl J Med 2021;385:1137-1138.

For decades, opinions about the degree to which sodium intake affects the blood pressure level and the risk of adverse effects such as stroke have been varied, even partisan. Much relevant data have shown an association between high dietary sodium intake – and also low dietary potassium intake – and increased blood pressure levels, as well as higher risks of cardiovascular disease, stroke, and death. In addition, multiple studies have reported that reducing dietary sodium intake while increasing potassium intake lowers blood pressure levels and decreases morbidity. Although many debate the extent of these effects, there is no doubt that salt intake in most parts of the world generally exceeds that needed for homeostasis.

Sodium intake in the form of sodium chloride does not affect everyone similarly. Most normotensive persons have a minimal change in mean arterial pressure when they ingest a high-salt diet, whereas many persons with elevated blood pressure have a measurable increase in the blood pressure, by approximately 4 mm Hg according to one study. Furthermore, persons with hypertension who are categorized as “salt sensitive” may respond to high salt intake with an increase in the blood pressure of 10 mm Hg or more. How such blood-pressure responses relate to the renal handling of salt and water and the responsiveness of the renin-angiotensin-aldosterone system is key. Recent data indicate that the availability of sodium in the body varies, because much is stored in bone and in the interstitium.6 However, identifying salt-sensitive persons is beyond clinical care in “real life” for large populations, and effecting major dietary change is difficult.

An appealing way to change both sodium and potassium intake concomitantly may be through the use of so-called salt substitutes, which are available as single products in which potassium chloride is substituted for a proportion of pure sodium chloride. Although a smaller, individually randomized trial of several months’ duration in India showed that a salt substitute could be effective,8 very-large-scale randomized trials that examine the effect of salt substitutes in at-risk persons at home in their communities have been elusive. The Salt Substitute and Stroke Study (SSaSS), the results of which are now reported in the Journal, may have provided some answers. The SSaSS, a trial involving 20,995 persons from 600 villages in rural China, aimed
“to define the overall balance of benefits and risks of salt substitute as compared with regular salt on stroke, cardiovascular events, death, and clinical hyperkalemia.” The trial compared the effect of regular salt (100% sodium chloride) with a salt substitute (75% sodium chloride and 25% potassium chloride by mass) in a high-risk population with respect to hard outcomes of stroke, cardiovascular disease, and death. Vital status was purportedly determined for all the participants.

The participants in the SSaSS were at high risk – 72.6% had a history of stroke, the mean age was 65.4 years, and 88.4% reported having received a diagnosis of hypertension. In a cluster-randomization design, the villages were randomly assigned in a 1:1 ratio to the intervention group, in which the participants used the salt substitute, or to the control group, in which the participants continued to use regular salt. The primary trial outcome was stroke, and the secondary outcomes were major adverse cardiovascular events and death from any cause. Predictably, given the population studied, the safety outcome was clinical hyperkalemia.

Use of the salt substitute led to a lower rate of stroke than the use of regular salt (29.14 events vs. 33.65 events per 1000 person-years; rate ratio, 0.86; 95% confidence interval, 0.77 to 0.96; P=0.006). The rate of major adverse cardiovascular events were also lower with the salt substitute, as was death from any cause. Hyperkalemia was not more common in the intervention group than in the control group, although serial potassium levels were not available.

How was the performance of this trial even feasible? In rural villages in China, where the SSaSS was carried out, processed food is not generally used; dietary sodium chloride is added during food preparation within each household. In contrast, in much of the world, commercial food preservation adds much sodium chloride to the diet, and the use of salt substitutes would not fully account for the majority of salt intake.

The results of the SSaSS appear impressive. If the strategy is feasible over time, the salt-substitute approach might have a major public health consequence in China, and possibly, elsewhere. Yet there remain a number of things we do not know. For example, serial monitoring of potassium levels was not performed in the trial, and it is possible that hyperkalemic episodes were not detected. Furthermore, persons with a history of medical conditions that may be associated with hyperkalemia (e.g., chronic kidney disease) were not studied. Because the salt substitute was distributed to families, it would have been instructive to have data on the household members without risk factors, but no such data were obtained. Finally, only one version of a salt substitute was used – 75% sodium chloride and 25% potassium chloride; no salt substitutes with higher or lower potassium chloride concentrations were evaluated. Overall, the SSaSS provides some intriguing hints, but wider effectiveness is hard to predict, given limited generalizability.

(6). Anonymous. Covid-19 makes it harder for GPs to offer the quiet listening that made all the difference to me. BMJ 2021;374:n1757

An anonymous patient explains how her GP used shared decision making to help her manage her distress. Quiet listening can empower patients to lead conversations about their own care, she says, but is threatened by the effects of covid-19, including more triage, remote care, and burnout among GPs

How are the kids doing? Did they go to school today? These were among the first things she asked me. This was the beginning of sustained, personalised care from a general practitioner whose talents were asking the right questions and quiet listening.

My husband was in an operating theatre, my head was spinning, and I hadn’t slept in days. He needed a biopsy of lymph nodes close to his aorta. We knew that he was really sick. We didn’t know what kind of cancer he had. I was terrified that he was dying (he was) and that there would be no cure (there wasn’t).

Asking if the kids had gone to school was the right question. In the context of a late diagnosis of incurable cancer, it’s a litmus test of how bad things are at home. In the following months, I became what can only be described as a walking waterfall. I was frightened of losing my husband. I was also frightened of losing the roof over our heads: the financial impact of cancer is something that too few people talk about.

The stress became unbearable. My husband exhausted NHS treatment and was negotiating access to clinical trials. He was in hospital for months at a time. My life was at an all-time low. Navigating this patch of my life was like walking on quicksand.

Hanging on to my mental health

I didn’t have flattened affect: I could still see joy and laugh. But I cried at night, as my husband groaned, sweating, startling, and waking with the pain that followed him everywhere. For months, I was hanging on to my mental health by a thread.

Discussing this with my GP was difficult. Her quiet listening was crucial. What followed was not a prescription for antidepressant drugs or an inpatient admission to a psychiatric ward, though both were very possible outcomes.

Instead, with my GP, I planned. You could call it a care plan, but it was instigated by the patient, not the health professional. A key feature was the joint decision to demedicalise my experience of distress. Together we agreed that I wouldn’t start taking antidepressants: I chose to live with the distress and to find resilience. These discussions were very personal and practical and included where to get advice on managing financial pressures, balancing the demands of work and being a carer, and psychological support.

If things got really bad, I’d avoid going to the emergency department: she suggested other options for an acute mental health crisis that in her experience tended to work out better for patients, such as attending the charity Mind’s sanctuary service. Avoiding unnecessary treatment saved the NHS money. My GP probably also helped me to avoid a psychiatric admission to hospital. None of this would have been possible without a GP who knew, and practised, the art of quiet listening.

No algorithmically programmed chatbot could do what she did in conveying humanity and allowing me to lead a clinical conversation. Entering “thoughts of suicide and self-harm” into an online triage tool or virtual symptom checker could not have produced the same outcome as I experienced through face-to-face care, or the same efficiency and value for the NHS.

Truly personalised and demedicalised care

Our conversation was about tailoring care to the individual: finding the right solution for me. This was personalised care in action. It speaks to the sharp end of conversations about the limits of the biomedical and clinical sciences to medical practice.

The BMJ’s Too Much Medicine campaign has focused on changing clinicians’ behaviour by identifying diagnostic practice and treatments that are unlikely to benefit most patients (www.bmj.com/too-much-medicine). What may be missing is a concurrent emphasis on empowering patients. How can clinical practice develop to enable patients jointly with clinicians to hold risk and manage uncertainty? How can practice develop to allow patients to lead conversations in which they can demedicalise their experiences of living with poor health or of dying?

I saw my GP a couple of times each month. The care I received was a masterclass in the highly skilled work of managing uncertainty and holding clinical risk in the community rather than referring to others. This helps create positive patient outcomes that avoid the harms of over-investigation and over-treatment, and it manages demand for health services. This is primary care’s hugely valuable but often under-recognised contribution to the efficiency of the whole system.

How to practise quiet listening

My GP’s willingness to play a supporting role was key. She elected that we jointly manage risk. By listening, rather than leading the conversation, she allowed me to make choices that were empowering while enabling me to demedicalise my experience of distress. She took her lead from me. I opened the conversation about whether I was depressed. I gave her my view of the evidence; I asked for her view. After a careful pause, she said, “I think you are not depressed.”

He took it together from there. We talked about treatment options. Cognitive behavioural therapy works best when reframing can help adjust a patient’s perspective on a problem. My GP and I agreed that this was not the right approach for my situation, where the problem itself was causing distress. Instead, we brainstormed together about who might locally offer psychological support based around acceptance and commitment therapy. The cancer charity Maggie’s, as it turns out.

My GP’s approach fits with newer thinking, exemplified in the SHERPA (sharing evidence routine for a person-centred plan for action) framework, for example, which values practical conversations that start by co-constructing with patients the nature of the problem. The focus is on simpler, more natural conversations about care that are appropriate for, and agreed with, individual patients.

Creating quiet spaces

How might quiet listening fit with active listening, often taught to students in medical school? Instead of an emphasis on listening with fascination, quiet listening is more about empathy in practice, about quiet spaces in conversations.

I am both a carer and a patient. Often my GP and I discussed both in the same consultation. Moving between the two conversations can be jarring for me-“How is your husband?” “Ah, it’s been an interesting few weeks. He’s broken his arm, his leg, and been hospitalised for two major internal bleeds.” “Shall I examine that lump under your arm now?” This was a single conversation, but my GP paused after discussing my husband and watched me. My head was down, my eyes at the floor. When my body language told her I was ready-when I lifted my head, and looked at her-she smiled and asked if I was ready to be examined. It’s subtle, but important, this ability to create quiet spaces within a consultation.

With an emphasis on patient activation, which focuses on what you can do, it can be hard to find space for conversations about what you can’t do. Quiet listening makes space to speak about worrying you can’t feed your children properly, not being able to buy their shoes, not having money to pay for a funeral. These are some of the things that distressed me the most. The Dutch anthropologist Annemarie Mol points out that care ‘makes space for what is not possible.” Quiet listening is an important part of this.

Continuity of care

A doctor who I trust and who knows me well is crucial in enabling quiet listening and to leading conversations about my own care. Seeing the same doctor over time also means that I don’t have to repeat my story to multiple different doctors. Once is enough: some things are not fun to talk about. Seeing the same GP over time has a survival advantage similar to many drugs and complex interventions, evidence shows. High relational continuity is associated with lower mortality, better self-management of long-term conditions, and fewer admissions to hospital.

The same GP can notice changes that would not be obvious to a doctor who doesn’t know me. I’m prone to ironic humour and making inappropriate jokes, for example, even about what was happening to me then. If I stop doing this, I’m in trouble. Losing my sense of humour indicates seriously deteriorating mental health. A GP who didn’t know me well couldn’t read that.

Since the pandemic, quiet listening and relationship-based care have arguably become even more important, particularly for more than a million people in the UK with long covid and those whose conditions have deteriorated while they have been unable to get treatment and care-including five million patients stuck on long waiting lists for hospital treatment in England.

Remote care and the future of quiet listening

At the same time, covid-19 could have long term effects on the ability of GPs to offer quiet listening and face-to-face care to patients. In the acute phase of the pandemic, NHS England was right to instate remote “total triage” and a shift towards remote consulting to protect patients and NHS staff. But what might be lost with this model, and with what unintended costs?

With so much recent concern about rising numbers of appointments and demand on general practices, have we thought carefully enough about the risk of telephone triage adding to clinicians’ workload through duplication, for which there is good evidence?

We cannot assume remote care is the best option for most patients in the long term. Early evaluation of “remote by default’ care finds over-protocolised general practice can come with risk. Case based judgment is needed to decide if remote consultation is best for a particular patient at a particular time. Complexity in primary care consultations include, for example, “doorknob disclosures,” when patients mention something crucial as they are leaving, and early detection of cancer through clinical intuition and timely investigation. In lung cancer, for example, clinicians believe face-to-face appointments are the best option for most purposes, especially breaking bad news.

Positioning remote care as the norm from which the traditional face-to-face consultation would deviate sits uncomfortably. Decisions should be guided by evidence on the benefits as well as possible unintended harms.

Alongside this, we should be careful not to take for granted the benefits of care that might be deemed “old fashioned” by some. I never set out to find a GP whose talent was quiet listening and relationship-based care. I didn’t know I’d need her. It was pure luck that, when I needed a GP who offered this kind of care, I had one. In an age of machine learning and techno-optimism, the artful skill of quiet listening can easily be undervalued. But it makes a crucial difference to the quality of patient care and to value for the NHS.

The challenge ahead for general practice

General practice is now at a crossroads. Demand for appointments is rising, as is concern about the harms to GPs through the “moral injury” that comes from being unable to provide the kind of care they believe that patients need.

We previously sought to find practical ways to provide continuity alongside better access to primary care. Now we need thinking that allows general practice to harness the benefits of remote consultations while holding on to the value to patients and to clinicians inherent in relationship-based care and quiet listening. One starting point may be the realisation of National Voices’ vision for inclusive and personalised care.

(7). Law MR. Low-dose combination of blood pressure-lowering medicines. BMJ. 2003;326(7404):1427.

There is strong evidence for an association between blood pressure and incident cardiovascular complications, and interventional studies have shown antihypertensive treatment to reduce cardiovascular events and all-cause mortality. However, many patients treated for hypertension do not reach current recommended target blood pressure values, with several possible explanations.

Care providers might think side-effects with treatment are a problem, or consider the evidence for current recommended target values insufficient. Inertia might result in medicines being prescribed in inadequate doses or inappropriate combinations, or cause insufficient procedures for follow-up and appropriate adjustment of treatment. Patient adherence to prescribed therapy might be low due to lack of motivation among prescribers or patients, or both. Additionally, knowledge and views among patients about hypertension and drugs might also affect treatment adherence.

Most of the effect on blood pressure reduction and the lowest risk for side-effects is achieved with low doses for most antihypertensive drug classes, suggesting that starting treatment with a combination of blood pressure-lowering medicines at low doses might improve blood pressure control.

In The Lancet, Clara Chow and colleagues report the results of a randomised, controlled, parallel-group, multicentre, phase 3 study in Australia comprising 591 people with hypertension. Participants had an untreated standard office blood pressure of 140-179 mm Hg systolic blood pressure or 90-109 mm Hg diastolic blood pressure, or both (or daytime average ambulatory blood pressure of 135 mm Hg or 85 mm Hg or above), or were receiving monotherapy with a treated standard office blood pressure of 130-179 mm Hg systolic blood pressure or 85-109 mm Hg diastolic blood pressure, or both (or daytime average ambulatory blood pressure of 125 mm Hg or 80 mm Hg or above). The mean age of the participants was 59 years (SD 12); 356 (60%) were male and 235 (40%) were female; and 483 (82%) were White, 70 (12%) were Asian, and 38 (6%) reported as other ethnicity. Baseline standard office blood pressure was 153/89 mm Hg, and a half of the participants were previously untreated.

The participants were randomly assigned (double blind) to a single-pill, low-dose combination (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg; n=300) or initial monotherapy (irbesartan 150 mg; n=291). To achieve a standard office blood pressure below 140/90 mm Hg, amlodipine 5 mg was added at 6 weeks, with additional further drugs, if required. The primary outcome was the change in unattended office systolic blood pressure at 12 weeks (measured with an OMRON HEM907 device). Secondary outcomes included standard office blood pressure, ambulatory blood pressure, safety, and tolerability. Most patients were invited to an extended 52-week follow-up with maintained blinded therapy.

The results show a greater reduction in unattended office blood pressure using the single-pill, low-dose combination (142/86 mm Hg to 120/71 mm Hg) than by initial monotherapy (140/83 mm Hg to 127/78 mm Hg), with a reduction in unattended systolic blood pressure (primary outcome) of 6.9 mm Hg (95% CI 4.9 to 8.9; p<0.001). Additional therapy was less common in the single-pill, low-dose combination group than in the initial monotherapy group (15% vs 40%). The results were consistent across subgroups, for ambulatory and standard office blood pressure measurements as well, and for systolic and diastolic blood pressures.

The reduction in unattended systolic blood pressure in the 417 participants with a 52-week follow-up was maintained in favour of the single-pill, low-dose combination (-7.7 mm Hg, -5.2 to -10.3; p<0.001). Reports of hypotension (p<0.01), bradycardia (p<0.01), and dizziness (p=0.07) were more common in the single-pill, low-dose combination, but there were no major differences in safety or tolerability between the two study groups.

Most patients with hypertension will require two or more medicines to achieve the current recommended target blood pressure. Previous studies have shown that initiation of antihypertensive treatment with two or more medicines, as compared with monotherapy, improves drug and treatment adherence and persistence, reduces care provider inertia, improves blood pressure control, and reduces cardiovascular events; and single-pill combinations appear to offer additional advantage. Accordingly, current guidelines recommend initiating antihypertensive therapy with two medicines in most patients. The study by Chow and colleagues extends these findings by showing that a single-pill, low-dose combination will achieve target blood pressure quicker and maintain blood pressure control more effectively than the prevailing practice to start with a single medicine, without major impairment of safety or tolerability. However, further studies are warranted to show the optimal number of antihypertensive agents needed to include in a single-pill, low-dose combination for best performance. Also, the optimal dosing of the different components might be different with race. Antihypertensive drug classes might have different effects on cardiovascular pathophysiology beyond the effects of blood pressure reduction, with possible prognostic implications. Thus, we look forward to subsequent studies to show the transition of blood pressure reduction with single-pill, low-dose combinations to a superior reduction in cardiovascular events. This might eventually change the management of patients on antihypertensives.

(8). Editorial. Understanding long COVID: a modern medical challenge. Lancet 2021;398(10302):725.

As the COVID-19 pandemic continues, the need to understand and respond to long COVID is increasingly pressing. Symptoms such as persistent fatigue, breathlessness, brain fog, and depression could debilitate many millions of people globally. Yet very little is known about the condition. The term “long COVID” is commonly used to describe signs and symptoms that continue or develop after acute COVID-19. A NICE guideline, for example, includes both ongoing symptomatic COVID-19 (from 4 to 12 weeks) and post-COVID-19 syndrome (≥ 12 weeks), but there is no agreed upon definition. How distinct is long COVID from other postviral syndromes? No clear biochemical or radiological features exist to aid diagnosis, and there are potentially several phenotypes with different presentations, prognosis, and outcomes. With no proven treatments or even rehabilitation guidance, long COVID affects people’s ability to resume normal life and their capacity to work. The effect on society, from the increased health-care burden and economic and productivity losses, is substantial. Long COVID is a modern medical challenge of the first order.

Clearly, the condition is of public health concern. In the UK, for example, an estimated 945000 people (1.5% of the population) had self-reported long COVID on July 4, 2021, according to the UK Office for National Statistics, including 34000 children aged 2-16 years. Prevalence was greatest in people aged 35-69 years, girls and women, people living in the most deprived areas, those working in health or social care, and those with another activity-limiting health condition or disability.

Most evidence about long COVID has been limited and based on small cohorts with short follow-up. However, in The Lancet, Lixue Huang and colleagues report 12-month outcomes from the largest longitudinal cohort of hospitalised adult survivors of COVID-19 so far. Including adults (median age 59 years) discharged from Jin Yin-tan Hospital in Wuhan, China, this study advances our understanding of the nature and extent of long COVID. At 1 year, COVID-19 survivors had more mobility problems, pain or discomfort, and anxiety or depression than control participants (matched community-dwelling adults without SARS-CoV-2 infection). Fatigue or muscle weakness was the most frequently reported symptom at both 6 months and 12 months, while almost half of patients reported having at least one symptom, such as sleep difficulties, palpitations, joint pain, or chest pain, at 12 months. The study shows that for many patients, full recovery from COVID-19 will take more than 1 year, and raises important issues for health services and research.

First, only 0.4% of patients with COVID-19 said that they had participated in a professional rehabilitation programme. The reason for such low use of rehabilitation services is unclear, but poor recognition of long COVID and lack of clear referral pathways have been common problems worldwide. Second, the effect of long COVID on mental health warrants further and longer-term investigation. The proportion of COVID-19 survivors who had anxiety or depression slightly increased between 6 months and 12 months, and the proportion was much greater in COVID-19 survivors than in controls. Third, the outcomes from this cohort cannot be generalised to other populations-eg, patients not admitted to hospital, younger people, and those from racially minoritized and other disadvantaged groups who have been disproportionately affected by the pandemic. Research in these populations needs to be prioritised urgently.

Tedros Adhanom Ghebreyesus, WHO’s Director General, has called on countries to prioritise recognition, rehabilitation, and research for the long-term consequences of COVID-19, as well as collection of data for long COVID. A cohesive research agenda is needed to prevent research waste and improve outcomes for patients. The scientific and medical communities must collaborate to explore the mechanism and pathogenesis of long COVID, estimate the global and regional disease burdens, better delineate who is most at risk, understand how vaccines might affect the condition, and find effective treatments via randomised controlled trials. At the same time, health-care providers must acknowledge and validate the toll of the persistent symptoms of long COVID on patients, and health systems need to be prepared to meet individualised, patient-oriented goals, with an appropriately trained workforce involving physical, cognitive, social, and occupational elements. Answering these research questions while providing compassionate and multidisciplinary care will require the full breadth of scientific and medical ingenuity. It is a challenge to which the whole health community must rise upto.

(9). Linton E. Patient perspectives: Story from a survivor of tuberculosis. Lancet Respir Med. 2021.

Mohammed Azam is a patient registered at Page Hall Medical Centre, a Deep End General Practice in one of the most deprived areas of Sheffield. He was diagnosed with pulmonary tuberculosis 2 years ago-this is his story.

Mohammed was 44 years old when he was admitted to an intensive care unit with complications of pulmonary tuberculosis. His story illustrates the profound consequences tuberculosis can have on an individual and their family. Mohammed describes unexpected positives amidst the challenges of tuberculosis treatment, including how this disease might provide an opportunity to change a person’s health trajectory.

Early life wasn’t always easy for Mohammed. At the age of 2 years his family moved from Pakistan to Sheffield, UK. He was the eldest of 12 siblings and life was busy. Mohammed interacted with health services during childhood. He graphically recalls an accident in the home with a pan of boiling water that resulted in a prolonged stay in the paediatric burns unit. He fondly reflects on his time spent in hospital: “Obviously I have scars, but I can just remember the best bits about it, being in hospital, playing with toys.” His subsequent diagnosis with hyperlipidaemia entailed regular trips to lipid clinics: “I used to be happy going, people would pay attention to you and ask questions you wouldn’t get asked at home or school.”

Religion was a significant part of Mohammed’s childhood. “I’m from a Muslim family’, he explains. “My dad was an orthodox Muslim, never missed a prayer.” “I used to leave school every day then go to the Mosque for an hour and a half to learn the Quran.” All his peers within the community did the same.

Mohammed snatched time to indulge his passion for football and cricket. ‘It was hard to fit school in-I left with hardly any O levels.’ College provided an opportunity to break from his Orthodox upbringing. ‘It was the freedom, meeting people, knowing what other people and other cultures are doing… I started going out, drinking and smoking weed.”

Mohammed moved on several occasions over the next two decades, spending time in both London and Manchester. Alcohol and substance use disorder crept in alongside a hectic working life, with disengagement from health service follow-up. During this time, he married, separated, and then reunited with his wife, who is also of Pakistani origin; together they had three children. Mohammed was regularly hospitalised with chronic pancreatitis, developing pancreatic insufficiency and diabetes.

Mohammed finally returned to Sheffield to his closely knit immediate and extended family. He rejoined weekly gatherings of upwards of 30 relatives at his parents’ house, or ‘HQ’ as it was colloquially known.

The family were stunned when one of their members was diagnosed with tuberculosis, resulting in all other members being contacted by health officials to assess their risk of exposure. ‘It was a shocking phone call”, Mohammed remembers, wondering how he had been exposed. ‘After my…[family member] was diagnosed, our only contact was wearing masks so there was no contamination.” As contact tracing identified active and latent cases within the family, Mohammed recalls his relatives’ disbelief. “Tuberculosis is a common thing in Pakistan…but people thought that as they hadn’t been abroad it wouldn’t affect them in the UK.’ Disbelief soon turned to mistrust. ‘Different family members were given different numbers of tablets’, he says, “sometimes two, sometimes eight, sometimes 18; they didn’t trust it… [they thought the nurses were] making it up.” The tuberculosis clinic was distanced from the hospital, causing speculation that “the nurses were coming out on their own behest.’ The index case in the family was slow to respond to treatment, further fuelling scepticism.

“The thought of tuberculosis didn’t occur to me’, says Mohammed, recalling the insidious development of breathlessness and fatigue that he had attributed to his other health conditions. “I was at a stage where I wasn’t too bothered.” Eventually, Mohammed collapsed at home and was diagnosed with tuberculosis. Mohammed spent time in intensive care before being moved to a ward to complete his quarantine. The words of a ward nurse have remained with him: “no matter what you do, don’t leave until you have completed treatment… even if you have a stable family at home, you need to be mentally and physically right.” With hindsight, Mohammed reflects, “I feel I came out too early because of my underlying issues.”

The physical manifestations of tuberculosis were very apparent to those around him: “It bulldozed me… I lost two and a half stone.” Mohammed felt overlooked; that people were ignoring him. ‘When people can see you are weak, they don’t pay attention to you”, he explains.

“Thoughts come into their head, for example, that you are taking heroin.” Such external perceptions undermined Mohammed’s self-esteem. Financial imperatives did not disappear, either. “I had to go to work”, he explains. “You can’t survive on £50 a week.” Work became increasingly difficult as treatment progressed.
“I dropped down to 6 h and changed shifts [from night today]”, but it wasn’t enough. “[tuberculosis] led to sick notes, and the sick notes ran out after 28 weeks.” Mohammed is now in receipt of universal credit. This financial hardship increased Mohammed’s psychological burden. “It stops you doing things and getting the bus to go places…you just can’t afford it.”

There were positive experiences during his months of treatment. Mohammed describes daily visits from tuberculosis nurses as wonderful. They would attend his home or workplace to give him his medication and they formed a very important part of his tuberculosis journey.

“It was the biggest joy”, he says. “They knew what was happening in my life and about my other issues; they looked after my diabetes.” With their support, Mohammed began to feel more in control of his health. “They treated me like a human being and helped me take my illnesses on.”

Mohammed’s treatment was deemed a success. This success, however, proved to be a double-edged sword.

The regular health-care support he had come to enjoy and depend on stopped. “I felt completely dropped”, he says. “Tuberculosis causes a grey patch on your chest x-ray, and it causes you to cough up grey [phlegm]. Once that disappears you are told you are better, but it doesn’t finish there.”

Unemployed, physically weakened, and increasingly disempowered, Mohammed’s mental and physical health suffered in the time following his treatment completion. 9 months on, feeling very low, Mohammed made an urgent appointment with his general practitioner. Regular contact with health care then resumed in the form of telephone consultations. ‘This changed my outlook on life, it changed everything”, Mohammed says. “Talking alleviates issues mentally and physically… feeling someone cares about you. It encourages you to take care of your health.” Mohammed undoubtedly had complex health needs before developing tuberculosis. His story is not an unusual one in this sense. Tuberculosis disproportionately affects lower socio-economic groups, those with underlying health conditions, and people with substance use disorder. Mohammed’s plight reflects the considerable morbidity experienced by tuberculosis survivors despite successful drug treatment.

It was estimated that there were 155 million tuberculosis survivors alive globally in 2020. Tuberculosis survivors have been shown to have nearly three times greater mortality than the general population and matched controls, with higher rates of recurrent tuberculosis, chronic lung disease, and socioeconomic deprivation. In light of this research, a diagnosis of tuberculosis in a high-income setting should act as a red flag. The intensive support necessitated by its treatment could be a springboard to address patient’s other comorbidities and issues. For Mohammed, tuberculosis survivorship is a daily struggle. These days it is one that he is winning, with a little help from his primary care team: “I want to carry on going up the ladders and not hitting any more snakes-I’m getting there now.” By sharing his story, he hopes to help others do the same.

(10). Hippisley-Cox J. Risk prediction of covid-19 related death and hospital admission in adults after covid-19 vaccination: national prospective cohort study. BMJ 2021;374:n2244.

Predictor variables for vaccinated cohort

Candidate predictor variables likely to be associated with increased risk of covid-19 death or hospital admission were identified from the original QCovid protocol and from previous studies. The variables were vaccine dose (first or second), age, sex, ethnic origin, Townsend deprivation score (an area level score based on postcode where higher scores indicate higher levels of deprivation), body mass index, domicile (care home, homeless, neither), chronic kidney disease, chemotherapy in previous 12 months, type 1 or type 2 diabetes (with glycated haemoglobin (HbA1c) levels < 59 or ≥ 59 mmol/mol), blood cancer, bone marrow transplantation in past six months, respiratory cancer, radiotherapy in past six months, solid organ transplantation, chronic obstructive pulmonary disease, asthma, rare lung diseases (cystic fibrosis, bronchiectasis, or alveolitis), pulmonary hypertension or pulmonary fibrosis, coronary heart disease, stroke, atrial fibrillation, heart failure, venous thromboembolism, peripheral vascular disease, congenital heart disease, dementia, Parkinson’s disease, epilepsy, rare neurological conditions (motor neurone disease, multiple sclerosis, myasthenia gravis, or Huntington’s chorea), cerebral palsy, osteoporotic fracture, rheumatoid arthritis or systemic lupus erythematosus, liver cirrhosis, bipolar disorder or schizophrenia, inflammatory bowel disease, sickle cell disease, HIV/AIDS, severe combined immunodeficiency, and record of a SARS-CoV-2 positive test result before cohort entry.