Dear Editor,

We thank Dr Zuccheri for the comments. Indeed, Acanthamoeba keratitis is an important consideration as a causative microorganism for infective keratitis, which was the primary diagnosis of consideration in this patient. As rightfully pointed out, exposure to contaminated water sources is a significant risk factor (Lim et al., 2018). In arriving at a diagnosis, it is also crucial to consider the prevalence of organisms within the local context of the patient. The incidence of Acanthamoeba as a causative organism of contact lens related infective keratitis, where this case was identified and managed has been reported to be low (Lim et al., 2016).

The diagnosis of Acanthamoeba keratitis can be challenging to achieve due to an overlap of clinical signs with other causative organisms, and is often underdiagnosed, particularly in the early stages of disease. In view of this, the fastidious nature of Acanthamoeba, and need for specific culture media to isolate this microorganism, we agree that due consideration should be in place for a broad range of microorganisms. In this patient, routine clinical sampling and microbiological testing through microscopy and cultures was performed to identify possible bacterial, fungal, and protozoal aetiologies of infective keratitis, of which both microscopy and cultures confirmed the presence of Pseudomonas Aeruginosa. The rest of the microbiological results were negative. These details were excluded in the earlier version of the report to cater to the brevity of its format. It is also important to be cognizant that false negative results may be present with microbiological sampling and clinicians ought to be guided by clinical response to treatment in determining if repeat sampling or modification of treatment, or both are necessary. Given the significant and rapid improvement of this patient on topical fortified antibiotics, with subsequent complete resolution of infection, the presence of primary or co-infection with Acanthamoeba is unlikely.

In considering anti-amoebic therapy, there have been concerns around the ocular toxicity that may arise with use of agents such as biguanides and diamidines, which includes cataract formation and iris atrophy (Ehlers & Hjortdal, 2004). However, safety results from a recently reported phase 3 randomised, double-masked study comparing use of topical PHMB 0.02% with propamidine 0.1%, with PHMB 0.08% have been encouraging (Dart et al., 2024). Anti-amoebics and adjunctive therapies should be considered in patients with clinical signs and symptoms suggestive of Acanthamoeba keratitis, with positive identification and confirmation of the microorganism during sampling, confirmatory identification through clinical investigations such as in-vivo confocal microscopy, and in patients with poor clinical response to antibiotic therapy.

In response to Dr Zuccheri’s comment on the possibility of Pseudomonas Aeruginosa establishing dominance in the presence of co-infection with Acanthamoeba, this can only be speculated in this clinical scenario, although Pseudomonas Aeruginosa indeed has been reported to demonstrate anti-amoebic activity (Shteindel & Gerchman, 2021). Co-infection with both organisms has also been reported in the literature (Dini et al., 2000; Sharma et al., 2013). Acanthamoeba has also been reported to serve as an environmental host for microorganisms, such as Pseudomonas Aeruginosa. Acanthamoeba containing live intracellular Pseudomonas Aeruginosa has been associated with more severe keratitis compared to Acanthamoeba alone in murine models (Rayamajhee et al., 2024).

Therefore, while we agree that a high index of suspicion for Acanthamoeba Keratitis should exist, treatment of patients with infective keratitis ought to be individualised and guided by prevailing microbiota, the clinical scenario and response to treatment. Patients with infective keratitis should be monitored closely and due consideration given to the underlying the causative organism (or organisms) in patients with a suboptimal clinical response to therapy.

References
Dart, J. K., Papa, V., Rama, P., Knutsson, K. A., Ahmad, S., Hau, S., Sanchez, S., Franch, A., Birattari, F., & Leon, P. (2024). The orphan drug for acanthamoeba keratitis (ODAK) trial: PHMB 0.08% (polihexanide) and placebo versus PHMB 0.02% and propamidine 0.1%. Ophthalmology, 131(3), 277-287.
Rayamajhee, B., Willcox, M., Henriquez, F. L., Vijay, A. K., Petsoglou, C., Shrestha, G. S., Peguda, H. K., & Carnt, N. (2024). The role of naturally acquired intracellular Pseudomonas aeruginosa in the development of Acanthamoeba keratitis in an animal model. PLOS Neglected Tropical Diseases, 18(1), e0011878.
Dart, J. K., Papa, V., Rama, P., Knutsson, K. A., Ahmad, S., Hau, S., Sanchez, S., Franch, A., Birattari, F., & Leon, P. (2024). The orphan drug for acanthamoeba keratitis (ODAK) trial: PHMB 0.08%(polihexanide) and placebo versus PHMB 0.02% and propamidine 0.1%. Ophthalmology, 131(3), 277-287.
Dini, L., Cockinos, C., Frean, J., Niszl, I., & Markus, M. (2000). Unusual case of Acanthamoeba polyphaga and Pseudomonas aeruginosa keratitis in a contact lens wearer from Gauteng, South Africa. Journal of Clinical Microbiology, 38(2), 826-829.
Ehlers, N., & Hjortdal, J. (2004). Are cataract and iris atrophy toxic complications of medical treatment of acanthamoeba keratitis? Acta Ophthalmologica Scandinavica, 82(2), 228-231.
Lim, C., Carnt, N., Farook, M., Lam, J., Tan, D., Mehta, J., & Stapleton, F. (2016). Risk factors for contact lens-related microbial keratitis in Singapore. Eye, 30(3), 447-455.
Lim, C. H., Stapleton, F., & Mehta, J. S. (2018). Review of contact lens–related complications. Eye & contact lens, 44, S1-S10.
Sharma, R., Jhanji, V., Satpathy, G., Sharma, N., Khokhar, S., & Agarwal, T. (2013). Coinfection with Acanthamoeba and Pseudomonas in contact lens–associated keratitis. Optometry and Vision Science, 90(2), e53-e55.
Shteindel, N., & Gerchman, Y. (2021). Pseudomonas aeruginosa mobbing-like behavior against Acanthamoeba castellanii bacterivore and its rapid control by quorum sensing and environmental cues. Microbiology Spectrum, 9(3), e00642-00621.

Dear Editor

Tessa Richards’ opinion piece (BMJ 2024;385:q1210) highlights the challenges faced by people with medically unexplained symptoms (MUS)/persistent physical symptoms (PPS). These were discussed at a recent multidisciplinary hybrid conference in London. The event was chaired by Dr Jay Verma and Jeshni Amblum-Almer from the GP and Primary Care section of RSM, and Dr Adrian Tookman, a retired palliative care physician and chair of ‘Forgotten Patients, Overlooked Diseases. The latter multidisciplinary charity was set up in 2021 as a response to the significant number of undiagnozed patients with complex symptoms referred to Adrian’s clinic.

Over 20 healthcare professionals and patient representatives addressed a range of topics. Attendees came from varied backgrounds and global locations. All agreed that this is a major, but often overlooked health problem. Without a diagnosis, those affected are often unable to access appropriate help. Not knowing what is wrong can have a huge impact on individuals’ quality of life and mental health.[1] Furthermore, it is a public health issue with significant financial and resource implications. [2] It has been suggested that over £3 billion is wasted by the NHS annually. Recent contact with several hospitals in Europe, academia and volunteer organisations including EURORDIS and the Witte Raven confirms that others are not only taking an interest but are looking for solutions.

While some may perceive the issue as psychological, a recurrent theme among our speakers was the premature dismissal or labeling of individuals as having 'functional' symptoms early in their diagnostic journey. During the consultations, several contributory factors were identified, including a lack of knowledge among some healthcare professionals, rarely seeing the same doctor, limitations of current testing, and the constraints of siloed, super-specialized healthcare. Several comments posted on X (formerly Twitter) since the article appeared remind us that MUS can be due to prescribed drugs, where the doctors were unaware of a connection. All the above suggest a pressing need for a more effective organisational system to identify patients with unmet needs. Defining those with MUS/PPS can be challenging: some will likely be frequent users of the service, while others may have given up and remain hidden.

On a more positive note, it was suggested that genetic testing, a deeper understanding of biochemical processes, and the application of AI could benefit individuals with MUS/PPS. However, caution is advised, as factors such as epigenetics, family history, and iatrogenic influences must also be considered.

As Dr Richards notes, getting a diagnosis, even if there are no effective treatments, can be a relief and opens the door to future research and organisational support. To illustrate this, a GP participant described how given time and clinical doubt, she was eventually able to reach a diagnosis in a frequent attender who then made no further visits over the next 12-months.

How do we move forward? A good starting point would be greater application of funnelling and systematically working through a list of differential diagnoses. Next, we need research and evidence-based resources such as test and referral guidelines and signposting to sources of information and interested clinicians. Participants discussed the possible benefits of some novel therapeutic and supportive approaches. These need objective evaluation. A recurrent theme, however, was the potential benefit of properly resourced specialist clinics as are starting to emerge in other countries.

The meeting identified two initial ambitions for the future; for some doctors to be open-minded, listen better, believe what their patients are saying, be prepared to explore doubt, and for the health system to acknowledging the problem and collectively find solutions.

We would value any support and advice to help us turn these ambitions to reality.

References
1. Noble BTAS, C. Stephens, R. Oesterling, C. Jani, K. Speck, P. Diehl-Wiesenecker, E. Chrysostomou, K. Walker, S. The challenge of medically unexplained symptoms, overlooked diseases and forgotten patients. . BJGP Life. 2022 12 August 2022.

2. Jadhakhan F, Romeu D, Lindner O, Blakemore A, Guthrie E. Prevalence of medically unexplained symptoms in adults who are high users of healthcare services and magnitude of associated costs: a systematic review. BMJ Open. 2022 Oct 5;12(10):e059971. doi: 10.1136/bmjopen-2021-059971. PMID: 36198445; PMCID: PMC9535167.

Dear Editor
It is both puzzling and concerning that Tara Moriarty, of the Canadian covid-19 data tracking service, has reported increased death rates in Canadians in the past four years, including increased rates of deaths from diabetes, kidney disease, and cardiovascular disease.

This phenomenon is not unique to Canada.

Although Carolyn Brown’s news feature correctly points out that rates of death in England and Wales have decreased slightly over the past two years, this disguises the fact that in the United Kingdom, and in many other countries, death rates have been far greater than predicted for each of the past three years (1).

Mostert et al's recent publication (in one of your sister journals) (1) points out in a supplementary file (2) that while there were 43,833 excess deaths in Canada between 2020 and 2022, in the same period there were 182,533 excess deaths in the United Kingdom.

The authors concluded that “excess mortality has remained high in the Western World for three consecutive years, despite the implementation of covid-19 containment measures and covid-19 vaccines” and that “Government leaders and policymakers need to thoroughly investigate underlying causes of persistent excess mortality”

1) Mostert S, Hoogland M, Huibers M, et al. Excess mortality across countries in the Western World since the COVID-19 pandemic: ‘Our World in Data’ estimates of January 2020 to December 2022 BMJ Public Health 2024. doi.org/10.1136/bmjph-2023-000282

2) Supplementary PDF 1 https://bmjpublichealth.bmj.com/content/bmjph/2/1/e000282/DC1/embed/inli...

Dear Editor
I am responding promptly to the published thoughtful article entitled “Antiplatelet Therapy After Coronary Artery Bypass Surgery: Five-Year Follow-Up of the Randomised DACAB Trial”. The results obtained in this quality study make a significant contribution to the development of an understanding of aspects related to the long-term use of antiplatelet therapy after coronary artery bypass grafting.

The main result of the DACAB trial showed that dual antiplatelet therapy significantly reduced patency loss compared to aspirin therapy. This shows that long-term use of antiplatelet therapy has a high clinical effect (1). Furthermore, the study's large sample size and prolonged observation contribute to the results' high validity. Interestingly, the reduction in MACE in the DAPT group was about 25%, indicating that these medications not only reduce the rate of graft patency loss but also provide a decrease in adverse cardiac events (2).

Despite the positive results of the study, some points require special consideration. First of all, the fact that there were 2.5 times more major bleeding events against the backdrop of dual therapy can be a significant limitation. It is necessary to carefully evaluate the advantage of using DAPT, considering the risk of serious bleeding, especially in elderly patients or patients with thromboembolism using anticoagulants. In addition, the study once again shows that it is necessary to consider multi-variant therapy for patients with a large variety of prognoses(3). The secondary results of the study suggest that different groups of patients may respond differently to dual therapy. Lastly, it is important to mention the cost of the medication required for this therapy and the treatment of hemorrhage. However, there are many questions about whether the long-term benefits and risks remain stable throughout the entire period.

The main findings of the published study raise the question of changing antiplatelet therapy timeframes according to current guidelines. For example, the guidelines now recommend taking a course of short-term DAPT (4, 5). However, it would be premature to alter the policies based solely on the findings of these studies. These results lead to different trends, and in order to make amendments to the guidelines, we must base them on the obtained results, which ensures an optimal balance between advantages and risks.

Therefore, the DACAB trial results strongly suggest that DAPT can miraculously stop cardiac events. However, we should carefully weigh this strong effect against the risk of increased bleeding, the need for individualized treatment plans, the costs, the long-term effects, and the outcome of the decision. Continuing research assessment and prudent judgement will provide the opportunity to develop a better long-term post-CABG antiplatelet therapy approach.

References
1. Qu J, Zhang H, Rao C, Chen S, Zhao Y, Sun H, et al. Dual antiplatelet therapy with clopidogrel and aspirin versus aspirin monotherapy in patients undergoing coronary artery bypass graft surgery. Journal of the American Heart Association. 2021;10(11):e020413.
2. Sousa-Uva M, Storey R, Huber K, Falk V, Leite-Moreira AF, Amour J, et al. Expert position paper on the management of antiplatelet therapy in patients undergoing coronary artery bypass graft surgery. European heart journal. 2014;35(23):1510-4.
3. Zhao Q, Zhu Y, Xu Z, Cheng Z, Mei J, Chen X, Wang X. Effect of ticagrelor plus aspirin, ticagrelor alone, or aspirin alone on saphenous vein graft patency 1 year after coronary artery bypass grafting: a randomized clinical trial. Jama. 2018;319(16):1677-86.
4. Wang H-Y, Dou K-F, Guan C, Xie L, Huang Y, Zhang R, et al. New insights into long-versus short-term dual antiplatelet therapy duration in patients after stenting for left main coronary artery disease: findings from a prospective observational study. Circulation: Cardiovascular Interventions. 2022;15(6):e011536.
5. Cardoso R, Knijnik L, Whelton SP, Rivera M, Gluckman TJ, Metkus TS, et al. Dual versus single antiplatelet therapy after coronary artery bypass graft surgery: an updated meta-analysis. International journal of cardiology. 2018;269:80-8.