Journal scan: A review of twelve recent papers of immediate clinical significance, harvested from major international journals
by
From the desk of the Editor-in-Chief
(1). Help me trust you after my misdiagnosis, BMJ 2021;373 :n1175.
Debilitating daily life
For more than 12 years, I lived with undiagnosed chronic pain, spinal problems, pelvic floor dysfunction, gastrointestinal issues, bladder problems, bleeding tendency, and easy scarring, among other symptoms. I was exhausted. Living with all these problems in combination made my daily life debilitating and challenging on a practical level. But even more difficult was not being believed about my physical problems by health professionals.
While trying to find answers about my physical symptoms I had accrued a collection of psychiatric diagnoses, including emotionally unstable personality disorder and neurotic depression. These stigmatizing descriptors meant it was difficult to have my physical symptoms taken seriously, or even believed at all. I felt like the labels made my doctors invalidate any of my physical symptoms. They continually accredited the symptoms to my psychiatric labels and my history of sexual abuse.
Facing a misdiagnosis
As I had received several psychiatric diagnoses, the pain team wouldn’t help with my physical pain. The mental health team told me I had health anxiety. No one could appreciate the amount of physical pain I was in, or how it affected my daily life. I felt my credibility with health professionals being increasingly undermined as most of my doctors saw mental health problems as the only ones I had.
Over many years, my undiagnosed physical problems and mental health diagnoses had a devasting impact on me. I simply couldn’t stand the physical pain and bladder and bowel complications, and felt like my physical health problems were being invalidated. As my physical health deteriorated, the exhaustion from fighting to be believed and to get appropriate help made me feel like my life was too difficult. This even led to suicide attempts.
How to rebuild the trust
Eventually, a magnetic imaging scan showed features suggestive of hypermobility. This led to a diagnosis of hypermobile Ehlers-Danlos syndrome, a rare genetic disorder of the connective tissue. It was a huge relief. I finally had some answers, but I also felt I had wasted years of my life trying to convince health professionals of my physical symptoms.
Rebuilding trust with patients who have been previously misdiagnosed requires time, compassion, and empathy. Ensure you are really listening to patients. Consider what it must be like to live with the symptoms they are describing. Be open and honest if you feel you might not have the relevant knowledge or experience to help them. Help us feel heard and respected by acknowledging our perseverance in getting a diagnosis.
Finally getting answers
The usefulness of getting a diagnosis for Ehlers-Danlos syndrome is commonly questioned as there is no cure. However, with better management of physical symptoms and support, my life has dramatically improved just this past year. I have got back some aspects of my health and wellbeing that I thought I had lost forever. I am even back at university studying for a masters degree in neuropsychology. This simply would not have happened if I hadn’t fought so hard for a correct diagnosis.
What you need to know
Listen to your patient’s concerns and explore their ideas about diagnosis before deciding on your own
Compassion and empathy are even more important when a patient may appear defensive; try to consider their previous negative experience of healthcare
Being honest and transparent with patients can help rebuild the trust
(2). Targeting IL-6 in patients at high cardiovascular risk, Lancet 2021; 397(10289):P2025-7.
The understanding that atherosclerosis is a chronic inflammatory disorder mediated through both adaptive and innate immunity has led to the hypothesis that anti-cytokine therapies targeting interleukin signaling pathways could serve as adjuncts to lipid lowering in the prevention and treatment of cardiovascular disease. The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) showed that targeting interleukin (IL)-1β reduced cardiovascular event rates without lowering lipids or blood pressure. The magnitude of this effect was directly associated with the reduction in IL-6 and the downstream clinical biomarker high-sensitivity C-reactive protein (CRP). CANTOS included a subgroup of 1875 patients with chronic kidney disease (estimated glomerular filtration rate [eGFR] < 60 mL/min per 1•73 m2). In this subgroup at high cardiovascular risk, canakinumab significantly reduced major atherosclerotic cardiovascular events, particularly among those who had the greatest reduction in IL-6 and high-sensitivity CRP. Therefore, there is considerable interest in addressing the effect of IL-6 inhibition on markers of inflammation and thrombosis in patients at high cardiovascular risk, such as patients with chronic kidney disease.
(3a). Left atrial appendage occlusion during cardiac surgery to prevent stroke, N Engl J Med. 2021;384(22):2081-91.
Background
Surgical occlusion of the left atrial appendage has been hypothesized to prevent ischemic stroke in patients with atrial fibrillation, but this has not been proved. The procedure can be performed during cardiac surgery undertaken for other reasons.
Methods
We conducted a multicenter, randomized trial involving participants with atrial fibrillation and a CHA2DS2-VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating greater risk of stroke) who were scheduled to undergo cardiac surgery for another indication. The participants were randomly assigned to undergo or not undergo occlusion of the left atrial appendage during surgery; all the participants were expected to receive usual care, including oral anticoagulation, during follow-up. The primary outcome was the occurrence of ischemic stroke (including transient ischemic attack with positive neuroimaging) or systemic embolism. The participants, research personnel, and primary care physicians (other than the surgeons) were unaware of the trial-group assignments.
Results
The primary analysis population included 2379 participants in the occlusion group and 2391 in the no-occlusion group, with a mean age of 71 years and a mean CHA2DS2-VASc score of 4.2. The participants were followed for a mean of 3.8 years. A total of 92.1% of the participants received the assigned procedure, and at 3 years, 76.8% of the participants continued to receive oral anticoagulation. Stroke or systemic embolism occurred in 114 participants (4.8%) in the occlusion group and in 168 (7.0%) in the no-occlusion group (hazard ratio, 0.67; 95% confidence interval, 0.53 to 0.85; P = 0.001). The incidence of perioperative bleeding, heart failure, or death did not differ significantly between the trial groups.
Conclusions
Among participants with atrial fibrillation who had undergone cardiac surgery, most of whom continued to receive ongoing antithrombotic therapy, the risk of ischemic stroke or systemic embolism was lower with concomitant left atrial appendage occlusion performed during the surgery than without it.
(3b). The Closing Argument for Surgical Left Atrial Appendage Occlusion, N Engl J Med. 2021;384:2154-5.
It is widely accepted that the increased risk of stroke among patients with atrial fibrillation is substantially due to embolization of thrombi that develop in the left atrial appendage. On the basis of multiple randomized trials showing that the risk of stroke is reduced with oral anticoagulation therapy among high-risk patients with nonvalvular atrial fibrillation, clinical practice guidelines provide the strongest level of recommendation for oral anticoagulation in these patients, as guided by CHA2DS2-VASc1,2 or CHADS-653 risk scores.
In comparison with the robust data that underlie the recommendation for oral anticoagulation, the strategy of percutaneous occlusion of the left atrial appendage, instead of anticoagulation, to reduce the risk of stroke among patients with atrial fibrillation is not as well supported by data from randomized trials. For that reason, practice guidelines state that percutaneous occlusion may be “considered” in patients with increased risk of stroke and atrial fibrillation who have contraindications to long-term anticoagulation. The tempered enthusiasm and limited recommendation in the guidelines stand in contrast to the Food and Drug Administration (FDA)–approved indication that the device is advisable for patients with “an appropriate rationale to seek a nonpharmacologic alternative to anticoagulation therapy, taking into account the safety and effectiveness of the device compared to anticoagulation therapy.” Such language, implying equipoise with oral anticoagulant therapy, was of concern to members of the FDA Circulatory System Devices Panel, who noted complications and issues of efficacy with percutaneous occlusion when they rendered a split recommendation to approve this technology in 2014 at the third FDA panel review. In the time since approval, longer-term experience with the percutaneous procedure has been gained; at the same time, anticoagulant therapy has become safer and more effective with the adoption of direct oral anticoagulants. Accordingly, percutaneous occlusion should be an alternative treatment for patients with atrial fibrillation only when they are unable to receive long-term anticoagulant therapy.
Less frequently investigated is the surgical approach to left atrial appendage occlusion performed at the time of other cardiac surgery. In this clinical setting, the procedural risk of surgical occlusion seems likely to be limited, in contrast to the potential risk of the percutaneous procedure in patients not undergoing surgery. On the basis of the results of nonrandomized studies, the current guidelines provide a tepid recommendation for surgical left atrial appendage occlusion at the time of cardiac surgery in patients with atrial fibrillation (a class IIb recommendation and a “weak” recommendation).
The Left Atrial Appendage Occlusion Study (LAAOS III), the results of which are now reported in the Journal, provides new and compelling data to guide clinical decisions regarding surgical occlusion. In this multicenter trial, 4811 patients with atrial fibrillation and a CHA2DS2-VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating a greater risk of stroke) were randomly assigned to receive standard care or undergo concomitant occlusion of the left atrial appendage at the time of cardiac surgery; oral anticoagulant therapy was recommended to be continued in all the patients. The risk of ischemic stroke or systemic thromboembolism (primary end point) was 33% lower with surgical occlusion than with standard care after 3.8 years (7.0% vs. 4.8%; hazard ratio, 0.67). At three years of follow-up, 77% of the patients in the trial continued to receive oral anticoagulants. The procedure caused minimal prolongation of bypass time and cross-clamp time and did not have a significant effect on death, hospitalization for heart failure, myocardial infarction, or bleeding. It is unknown what proportion of patients were screened and excluded from the trial on the basis of a CHA2DS2-VASc score of 0 or 1 or how these patients fared over the time the trial was conducted, because no registry was maintained.
This trial provides important answers, even as it raises questions. On the basis of the demonstrated benefit with no discernible risk, surgical left atrial appendage occlusion should be performed at the time of other cardiac surgery in patients with atrial fibrillation and a CHA2DS2-VASc score of at least 2, with anticoagulation continued thereafter. The major clinical practice guidelines will probably include these new data and the conclusion they imply, perhaps with a class I recommendation for the population studied. The trial provides no insight as to the possible benefit of surgical occlusion in patients who are unable to receive oral anticoagulants after the procedure, although in light of the data for percutaneous occlusion, some benefit is likely. Moreover, there are no data for patients with atrial fibrillation and a CHA2DS2-VASc score lower than 2 or for patients without a history of atrial fibrillation but with high CHA2DS2-VASc scores; any consideration of extending the indications for surgical occlusion to such patients would require new data from randomized trials.
Finally, the results showing the added benefit of surgical left atrial appendage occlusion in combination with anticoagulant therapy raise the question of whether percutaneous occlusion, when added to ongoing oral anticoagulation, might provide benefit over anticoagulation alone in high-risk patients with atrial fibrillation. This intriguing question would require careful study, given the added cost and risk of that invasive procedure.
(4). Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia, N Engl J Med. 2021
The modern era of fetal surgical interventions began in the 1980s, when improved ultrasonographic imaging enabled prenatal detection of life-limiting birth defects. However, the rarity of many severe fetal anomalies, maternal complications associated with open fetal interventions, and the availability of effective, if imperfect, strategies for postnatal infant care restricted the performance of informative clinical trials.1 The Management of Myelomeningocele Study (MOMS), the results of which were reported in 2011, served as an early example of the importance of randomized clinical trials in assessing the benefits and risks of fetal interventions that had previously been performed largely on the basis.
Background
Observational studies have shown that fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data from randomized trials are lacking.
Methods
In this open-label trial conducted at centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with severe isolated congenital diaphragmatic hernia on the left side to FETO at 27 to 29 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcome was infant survival to discharge from the neonatal intensive care unit. We used a group-sequential design with five prespecified interim analyses for superiority, with a maximum sample size of 116 women.
Results
The trial was stopped early for efficacy after the third interim analysis. In an intention-to-treat analysis that included 80 women, 40% of infants (16 of 40) in the FETO group survived to discharge, as compared with 15% (6 of 40) in the expectant care group (relative risk, 2.67; 95% confidence interval [CI], 1.22 to 6.11; twosided P=0.009). Survival to 6 months of age was identical to the survival to discharge (relative risk, 2.67; 95% CI, 1.22 to 6.11). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (47% vs. 11%; relative risk, 4.51; 95% CI, 1.83 to 11.9), as was the incidence of preterm birth (75% vs. 29%; relative risk, 2.59; 95% CI, 1.59 to 4.52). One neonatal death occurred after emergency delivery for placental laceration from fetoscopic balloon removal, and one neonatal death occurred because of failed balloon removal. In an analysis that included 11 additional participants with data that were available after the trial was stopped, survival to discharge was 36% among infants in the FETO group and 14% among those in the expectant care group (relative risk, 2.65; 95% CI, 1.21 to 6.09).
Conclusions
In fetuses with isolated severe congenital diaphragmatic hernia on the left side, FETO performed at 27 to 29 weeks of gestation resulted in a significant benefit over expectant care with respect to survival to discharge, and this benefit was sustained to 6 months of age. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth.
(5). Mask related acne (“maskne”) and other facial dermatoses, BMJ 2021;373 :n1304.
What you need to know
- Not all facial dermatoses related to personal protective equipment are “maskne”
- Irritant contact dermatitis is the most common cause
- Maintenance of the skin barrier and regular “mask breaks” are important aspects of management, in addition to standard medical treatment of the skin condition
The COVID-19 pandemic has led to a marked increase in the use of personal protective equipment (PPE) both in and out of healthcare settings. The term “maskne” has become increasingly popular during the pandemic, particularly in the media, where it is used to describe several facial dermatoses. Individuals often buy expensive but potentially ineffective treatments for these conditions.
In this practice pointer we summarize the most common causes of facial eruptions associated with wearing facial PPE, and highlight the key areas to cover when assessing someone with new orworsening pre-existing facial dermatoses that they attribute to the use of facial PPE.
(6). Imposter syndrome is no cause for shame, BMJ 2021;373:n1387.
How much of a problem for doctors is imposter syndrome? Is it just a term used by those who struggle to fit in? Is it a manifestation of totally natural self-doubt? Over the years we’ve lived with the rhetoric that successful people “don’t show weakness” or “don’t cry.” When interacting virtually in the online world, it’s far easier to make such judgments about others without knowing them as individuals. In doing so we may be reinforcing false beliefs or perhaps even forcing someone to conform to a set opinion or view.
In the past decade or so—helped by the work of some amazing people such as Stephen Fry and Dwayne Johnson—far more of us have realized the importance of talking about self-doubt and about mental health issues such as depression. These subjects have become less taboo, less something we only speak about coyly. Here, I want to dispel the notion that there can’t be any self-doubt in people occupying leadership roles, as well as reflecting on the old rhetoric around strength and whether it always has to be on show.
By luck or default, I’ve ended up in a position in the NHS where sometimes, in some areas, my voice is listened to. I’ve seen my personality evoke, in similar measure, anger and inspiration, disdain and admiration, hate and affection. Yet behind all of that, behind what can seem like bulletproof confidence, sits a shy boy who cried when made to feel like a loser by some in school; a teenager who struggled to talk and hated public speaking; and a man who has been racked with self-doubt, wondering whether he was good enough and whether he’d convinced others of his worth. Imposter syndrome is a constant Sword of Damocles—the constant querying of one’s worth and value.
Time has taught me many things—most importantly that, when you’re fighting to choke back those hot tears, few people will put their arm around you. But it’s taught me that feeling low, or not worthy or not good enough, is actually natural. It’s also taught me that it’s OK to talk about these things, that you’re not being weak when you feel sad or want a hug—it’s simply human. Success and failure are just parameters by which others judge you, and the highs and lows of our careers and lives are just a part of who we are.
At this phase of my career, as well as saying no to racism, misogyny, and sexism, it’s time to say that it’s OK to feel low, OK to feel alone, OK to struggle and ask for help. If you see me or anyone else who appears to rarely crack under pressure and is laced with confidence, be aware that this is, to an extent, a front. I struggle as much as anyone else. It’s only natural to be hurt or to want to say, “Give me a moment to myself.” It’s also fine to feel like an imposter. My tip is to have a few trusted friends and loved ones to lean on when you need to. It’s OK not to fit the image of what society wants you to be.
I hope that this column helps someone somewhere who may be looking at others and thinking, “Wow, I could never be like that.” If you showed my 12-year-old self a glimpse of the 47-year-old me, it would seem to him totally unimaginable. If there are days when you feel like an imposter, don’t worry—we all do.
(7). Dying at home during the pandemic, BMJ 2021;373:n1437.
Should GPs look after patients who choose to stay at home with COVID-19?
Increase in home deaths could be because of preference or pressure
Data from the Office for National Statistics show that COVID-19 was responsible for most of the 76 000 excess deaths during 2020 in England and Wales, with only around 2000 attributable to other causes.1 The number of deaths from all causes in private homes increased by about one third to 167 000 in 2020, compared with an average of 125 000 between 2015 and 2019.
Around 41000 more people died in private homes than in a normal year (which is more than half of the total number of excess deaths) but only a small number (just over 3000 or 7%) were recorded as being due to COVID-19. Most of these deaths at home were from underlying causes seen every year: dementias (which increased by 65%), heart and lung diseases, cancers, and neurological diseases. Some COVID-19 deaths that occurred at home may have been wrongly attributed to these conditions, especially early in the pandemic when symptoms were poorly understood and testing scarce. Nevertheless, this is still likely to represent a significant shift of people dying of causes other than COVID-19 from hospital to home.
Many people prefer home over hospital for their end-of-life care, and, although some people do not have preferences regarding place of care,4 the mismatch between preferences and reality is well documented. In one survey of 138 older adults in England, Ireland, and the US, 56% of respondents said they would prefer to die at home, and one quarter specifically did not want to die in hospital. Despite this, most participants subsequently died in hospital. Only 25% achieved their first preference.
Preferences are influenced by trade-offs between competing priorities, expected outcomes, levels of engagement, and abilities to form and express preferences. Was the increase in home deaths during 2020 evidence of improved achievement of peoples’ preferences or the result of pandemic related displacement from healthcare facilities?
Hospitals and community services worked hard to free up beds for increasing numbers of COVID-19 admissions. This may have facilitated discharge of patients at the end of life, helping some to achieve their preference for home care. Alternatively, the pandemic may have influenced peoples’ preferences outside hospitals—through concerns about restricted visiting, fear of infection, and motivation to reduce pressure on stretched hospital services.
Unfortunately, we have no systematic evidence about the quality of home care given to people towards the end of life during the pandemic. Such information is vital if we are to understand whether the increase in deaths in private homes is a reflection of preference or of poor-quality alternatives because of pressured hospital services.
Care at home can be of high quality, particularly when home services are available at all times, symptoms are well controlled, and communication is timely and skillful. Rapid innovations to anticipatory prescribing by general practitioners observed during the pandemic may have aided symptom management for patients at home. However, the Marie Curie report on dying during the pandemic and other research present a mixed picture. For people needing palliative care during the pandemic, research is urgently need to find out how well symptoms were controlled; how families, preferences, and priorities were supported; and how easily services were accessed, including by remote consultation.
Sustaining the shift
Any shift towards more deaths at home needs to consider the size of the community palliative care workforce. In 2018, researchers predicted that as the annual numbers of deaths increased over the coming two decades, community capacity would need to double unless hospital capacity increased substantially. During 2020, pressure on community palliative and end-of-life care surged, reaching levels of need not expected until 2040. Combined with existing gaps in the workforce, this suggests an urgent need to grow and train community clinicians skilled in palliative care.
Help from family members and informal careers is a critical and often overlooked component of care at home. The furlough scheme and increase in working from home may have made it easier for some people to provide the flexible care needed to support those important to them at the end of life. In research done before the pandemic, for example, support from family members significantly increased the odds (range 1.78 to 7.85) of patients with cancer dying at home. For others, however, pandemic restrictions such as shielding and travel bans may have prevented them from providing support.
A detailed plan for better palliative care, you matter because you are you, recently published by Cicely Saunders International, gives a comprehensive approach to filling the gaps in palliative and end-of-life care. Providing expertise in places where people are cared for, joining up care, empowering patients to access palliative care, and increasing community support, training, and research are all essential to ensure that patients receive high quality end-of-life care in the place of their choosing—often at home.
(8). Delirium and long-term cognition in critically ill patients, BMJ 2021;373:n1007.
Delirium, a form of acute brain dysfunction, is very common in the critically ill adult patient population. Although its pathophysiology is poorly understood, multiple factors associated with delirium have been identified, many of which are coincident with critical illness. To date, no drug or non-drug treatments have been shown to improve outcomes in patients with delirium. Clinical trials have provided a limited understanding of the contributions of multiple triggers and processes of intensive care unit (ICU) acquired delirium, making identification of therapies difficult. Delirium is independently associated with poor long-term outcomes, including persistent cognitive impairment. A longer duration of delirium is associated with worse long-term cognition after adjustment for age, education, pre-existing cognitive function, severity of illness, and exposure to sedatives. Interestingly, differences in prevalence are seen between ICU survivor populations, with survivors of acute respiratory distress syndrome experiencing higher rates of cognitive impairment at early follow-up compared with mixed ICU survivor populations. Although cognitive performance improves over time for some ICU survivors, impairment is persistent in others. Studies have so far been unable to identify patients at higher risk of long-term cognitive impairment; this is an active area of scientific investigation.
(9). COVID-19: Aspirin does not improve survival for patients admitted to hospital, trial reports, BMJ 2021;373:n1475.
Aspirin does not improve survival for patients in hospital with COVID-19, the UK Recovery trial reported.
The randomised trial, which is testing a range of possible treatments for people admitted to hospital with COVID-19, studied the effect of aspirin in nearly 15 000 patients between November 2020 and March 2021. Some 7351 patients were randomised to aspirin 150 mg once daily and compared with 7541 patients randomised to usual care alone.
The results—released through a press release—showed no evidence that aspirin treatment reduced mortality. The team reported no significant difference in the primary endpoint of 28-day mortality (17% aspirin v 17% usual care; rate ratio 0.96 (95% confidence interval 0.89 to 1.04); P = 0.35). The results were also consistent in all prespecified subgroups of patients.
Patients who were allocated to aspirin had a slightly shorter length of stay in hospital (median 8 days v 9 days), and a higher proportion were discharged from hospital alive within 28 days (75% v 74%; rate ratio 1.06; 95% CI 1.02 to 1.10; P = 0.0062). Among patients who were not on invasive mechanical ventilation at baseline, the trial reported no significant difference in the proportion who progressed to invasive mechanical ventilation or death (21% v 22%; risk ratio 0.96; 95% CI 0.90 to 1.03; P = 0.23).
For every 1000 patients treated with aspirin, approximately six more patients experienced a major bleeding event and around six fewer experienced a thromboembolic (clotting) event, the study team reported.
The findings will shortly be published as a preprint and have been submitted for peer review.
Peter Horby, Professor of Emerging Infectious Diseases in the Nuffield Department of Medicine, University of Oxford, and joint chief investigator for the Recovery trial, said, “The data show that in patients admitted to hospital with COVID-19, aspirin was not associated with reductions in 28-day mortality or in the risk of progressing to invasive mechanical ventilation or death. Although aspirin was associated with a small increase in the likelihood of being discharged alive this does not seem to be sufficient to justify its widespread use for patients admitted to hospital with COVID-19”.
Martin Landray, Professor of Medicine and Epidemiology at the Nuffield Department of Population Health, University of Oxford, and joint chief investigator, said, “There has been a strong suggestion that blood clotting may be responsible for deteriorating lung function and death in patients with severe COVID-19. Aspirin is inexpensive and widely used in other diseases to reduce the risk of blood clots, so it is disappointing that it did not have a major impact for these patients. This is why large randomised trials are so important—to establish which treatments work and which do not”.
Anthony Gordon, Professor of Anaesthesia and Critical Care, and NIHR research professor, Imperial College London, who was not involved in the trial, said the findings were “disappointing” but “important to know”.
“Importantly there were no major safety concerns and so the Remap-Cap trial continues to evaluate aspirin and other similar drugs to prevent blood clots, in combination with other treatments in the sickest patients with COVID-19 in intensive care,” he said.
(10). Role of C reactive protein and procalcitonin in the diagnosis of lower respiratory tract infection in children in the outpatient setting, BMJ 2021;373:n1409.
What you need to know
The difficulty of discriminating between viral and bacterial lower respiratory tract infection (LRTI) in children using clinical features alone often leads to over prescription of antibiotics
Biomarkers such as C reactive protein (CRP) and procalcitonin (PCT) have a limited capacity to rule in bacterial pneumonia in children in ambulatory settings where the prevalence of bacterial pneumonia is low. (CRP and PCT have limited diagnostic value in severely ill children who meet criteria for pneumonia or sepsis and who are candidates for broad spectrum antibiotic therapy)
There is growing evidence that antibiotic therapy can be safely withheld in children who are not severely ill with equivocal clinical presentation and low CRP (<20 mg/L) and PCT (<0.5 μg/L) levels
(11). Efficacy of Wolbachia-Infected Mosquito Deployments for the Control of Dengue, N Engl J Med. 2021;384:2177-86.
Dengue is a mosquito-borne, acute viral syndrome caused by any of the four serotypes of dengue virus (DENV). In 2019, the World Health Organization designated dengue as one of the top 10 global health threats. An estimated 50 million to 100 million symptomatic cases occur globally each year. Dengue epidemics occur annually or at multiyear intervals, and the surge in case numbers places considerable pressure on health services.
Aedes aegypti mosquitoes are the primary vectors of dengue. Efforts to control A. aegypti populations with the use of insecticides or environmental management methods have not been effective in controlling dengue as a public health problem in most countries. Few randomized trials of A. aegypti–control methods have been conducted, and none have used the end point of virologically confirmed dengue (VCD). A trial of community mobilization to reduce the A. aegypti population in Nicaragua and Mexico showed modest efficacy (29.5%) against dengue seroconversion in the saliva of residents.
Wolbachia pipientis — a common, maternally inherited, obligate intracellular type of bacteria — infects many species of insects but does not occur naturally in A. aegypti. Stable transinfection of A. aegypti with some strains of Wolbachia confers resistance to disseminated infection by DENV and other arboviruses. Thus, the introgression of “virus-blocking” strains of Wolbachia into field populations of A. aegypti is an emerging dengue-control method. The approach involves regular releases of Wolbachia-infected mosquitoes into a wild mosquito population over a period of several months. Wolbachia facilitates its own population introgression by manipulating reproductive outcomes between wild-type and Wolbachia-infected mosquitoes: the only viable mating outcomes are those in which the progeny is infected with Wolbachia.
Here, we report the results of a cluster-randomized trial that assessed the efficacy of deployments of A. aegypti mosquitoes infected with the wMel strain of Wolbachia in reducing the incidence of VCD in Yogyakarta, Indonesia. The trial builds on earlier entomologic and epidemiologic pilot studies in this geographic setting
Background
Aedes aegypti mosquitoes infected with the wMel strain of Wolbachia pipientis are less susceptible than wild-type A. aegypti to dengue virus infection.
Methods
We conducted a cluster-randomized trial involving releases of wMel-infected A. aegypti mosquitoes for the control of dengue in Yogyakarta, Indonesia. We randomly assigned 12 geographic clusters to receive deployments of wMel-infected A. aegypti (intervention clusters) and 12 clusters to receive no deployments (control clusters). All clusters practiced local mosquito-control measures as usual. A test-negative design was used to assess the efficacy of the intervention. Patients with acute undifferentiated fever who presented to local primary care clinics and were 3 to 45 years of age were recruited. Laboratory testing was used to identify participants who had virologically confirmed dengue (VCD) and those who were test-negative controls. The primary end point was symptomatic VCD of any severity caused by any dengue virus serotype.
Results
After successful introgression of wMel into the intervention clusters, 8144 participants were enrolled; 3721 lived in intervention clusters, and 4423 lived in control clusters. In the intention-to-treat analysis, VCD occurred in 67 of 2905 participants (2.3%) in the intervention clusters and in 318 of 3401 (9.4%) in the control clusters (aggregate odds ratio for VCD, 0.23; 95% confidence interval [CI], 0.15 to 0.35; P = 0.004). The protective efficacy of the intervention was 77.1% (95% CI, 65.3 to 84.9) and was similar against the four dengue virus serotypes. The incidence of hospitalization for VCD was lower among participants who lived in intervention clusters (13 of 2905 participants [0.4%]) than among those who lived in control clusters (102 of 3401 [3.0%]) (protective efficacy, 86.2%; 95% CI, 66.2 to 94.3).
Conclusions
Introgression of wMel into A. aegypti populations was effective in reducing the incidence of symptomatic dengue and resulted in fewer hospitalizations for dengue among the participants.
(12). Brain imaging before and after COVID-19 in UK Biobank, MedRxiv 2021.
There is strong evidence for brain-related pathologies in COVID-19, some of which could be a consequence of viral neurotropism. The vast majority of brain imaging studies so far have focused on qualitative, gross pathology of moderate to severe cases, often carried out on hospitalised patients. It remains unknown however whether the impact of COVID-19 can be detected in milder cases, in a quantitative and automated manner, and whether this can reveal a possible mechanism for the spread of the disease. UK Biobank scanned over 40,000 participants before the start of the COVID-19 pandemic, making it possible to invite back in 2021 hundreds of previously-imaged participants for a second imaging visit. Here, we studied the effects of the disease in the brain using multimodal data from 782 participants from the UK Biobank COVID-19 re-imaging study, with 394 participants having tested positive for SARSCoV-2 infection between their two scans. We used structural and functional brain scans from before and after infection, to compare longitudinal brain changes between these 394 COVID19 patients and 388 controls who were matched for age, sex, ethnicity and interval between scans. We identified significant effects of COVID-19 in the brain with a loss of grey matter in the left parahippocampal gyrus, the left lateral orbitofrontal cortex and the left insula. When looking over the entire cortical surface, these results extended to the anterior cingulate cortex, supramarginal gyrus and temporal pole. We further compared COVID-19 patients who had been hospitalised (n = 15) with those who had not (n = 379), and while results were not significant, we found comparatively similar findings to the COVID-19 vs control group comparison, with, in addition, a greater loss of grey matter in the cingulate cortex, central nucleus of the amygdala and hippocampal cornu ammonis (all |Z|>3). Our findings thus consistently relate to loss of grey matter in limbic cortical areas directly linked to the primary olfactory and gustatory system. Unlike in post hoc disease studies, the availability of pre-infection imaging data helps avoid the danger of pre-existing risk factors or clinical conditions being mis-interpreted as disease effects. Since a possible entry point of the virus to the central nervous system might be via the olfactory mucosa and the olfactory bulb, these brain imaging results might be the in vivo hallmark of the spread of the disease (or the virus itself) via olfactory and gustatory pathways.
