The androgen receptor (AR) is a member of the family of ligand-activated transcription factors. Selective androgen receptor modulators (SARMs) exert their biological function through complex interactions with the AR. It has been speculated that overexertion of AR signaling cascades as a result of SARM abuse can be a risk factor for the development of various cardiovascular diseases. The present literature review explores the implications of the interaction between SARMs and the AR on cardiovascular health by focusing on the AR structure, function, and mechanisms of action, as well as the current clinical literature on various SARMs. It is shown that SARMs may increase the risk of cardiovascular diseases through implications on the renin–angiotensin system, smooth muscle cells, sympathetic nervous system, lipid profile, inflammation, platelet activity, and various other factors. More research on this topic is necessary as SARM abuse is becoming increasingly common. There is a noticeable lack of clinical trials and literature on the relationship between SARMs, cardiovascular diseases, and the AR. Future in vivo and in vitro studies within this field are vital to understand the mechanisms that underpin these complex interactions and risk factors. Selective androgen receptor modulators (SARMs) are a class of synthetic, orally bioavailable compounds that exert their biological function through the androgen receptor (AR) as either agonists or antagonists ,2,3. SARSARMs have raised concerns about the implications that abuse may have on the health of those who take them. In particular, it has been suggested that the recreational use and abuse of SARMs may have negative implications on cardiovascular health and the development of cardiovascular diseases (CVDs) . Recent Due to the significant lack of clinical trials regarding SARMs and CVDs, the exact pathophysiology of how SARMs may lead to various CVDs is unclear. Since SARMs exert their biological activity through interactions with the AR, it is speculated that SARMs may lead to the development of CVDs through interactions with the AR at supra-physiological doses. Supra-physiological doses of androgens refers to when doses of androgens are above physiological levels, which results in increased or ‘exaggerated’ levels of AR signaling cascades as a result of the abundance of ligands for the AR . This, fThe AR is a member of the steroid receptor family of ligand-activated transcription factors . The AR The primary endogenous androgens, such as testosterone and dihydrotestosterone (DHT), perform their function as ligands and exert their effects through complex interactions with the androgen receptor. The AR functions as a ligand-inducible transcription factor that mediates the expression of target genes ,18. As wN-terminal regulatory domain (NTD), a DNA-binding domain, a hinge region, and a ligand-binding domain (LBD) [The AR is a modular protein that is organized into various domains . These iin (LBD) . There ein (LBD) . As suchin (LBD) . AF1 is in (LBD) . AF2 is in (LBD) .N-terminal fragment that has very similar transcriptional activity to the activity of the full-length ligand-bound AR [Within the AR, the majority of the transcriptional activity is mediated by the NTD, which represents approximately half of the AR coding sequence . Deletiobound AR , suggestbound AR . The NTDbound AR . There abound AR . The NTDbound AR .C-terminal extension that forms part of the hinge, as well as two zinc finger motifs [The DBD contains a short r motifs . The twor motifs ,25. The r motifs . The secr motifs .The H region exists between the DBD and the LBD . It contThe LBD is responsible for the high binding affinity of the AR to androgenic ligands . The LBDWithout a bound ligand, the AR is located primarily in the cytoplasm where it binds with heat-shock proteins (HSPs) and cytoskeletal proteins . HSPs te2+ release from the endoplasmic reticulum and/or mitochondria (10). It has been suggested that intracellular Ca2+ ions stimulate the binding of AR ligands to the AR [Aside from the well-documented genomic signaling of the AR, evidence of a non-genomic AR signaling pathway has emerged within the last 20 years. Non-genomic AR signaling occurs within a case of seconds to minutes, implying a lack of transcription and translation from androgen-responsive genes . The proo the AR .As a result of these proposed mechanisms of AR non-genomic activity, it has been suggested that non-genomic signaling ultimately serves to influence the AR regarding its genomic activity (11), as well as other nuclear receptors . Thus, tThe AR most commonly interacts with endogenous agonistic ligands, such as T and DHT, in order to produce their biological effects . HoweverExogenous AR agonists are also often used in sport and bodybuilding and have gained popularity in recent decades . AndrogeSARMs are a novel class of tissue-selective AR ligands . SARMs aThe mechanism of action of SARM signaling is similar to other endogenous androgens. The mechanism of SARM action is shown in Companies such as Pfizer, Johnson and Johnson, Merck, and Glaxo began developing SARMs in the late 1990s due to preclinical evidence suggesting potent tissue selectivity and anabolic activity . The majSARMs were banned in professional sports in 2008 by the World Anti-Doping Agency, and in 2017, the FDA issued a public advisory statement that products containing SARMs posed a high risk for harmful side effects [Ostarine  is an orally bioavailable, nonsteroidal SARM that has been extensively studied for its potential in treating muscle-wasting conditions. It has shown positive effects on lean muscle mass and strength, as well as decreases in fat mass ,35. CommLigandrol is an orally bioavailable nonsteroidal SARM . LigandrAndarine is an orally bioavailable SARM, which has no human clinical trials. Anecdotally, it has been touted as a muscle-boosting and fat-loss supplement . AndarinTestolone is an orally bioavailable nonsteroidal SARM  developeCVDs are the highest leading cause of death worldwide. Risk factors for cardiovascular disease are well documented in the scientific literature, including smoking, diabetes, hyperlipidemia, and gender, among others . There i®) could be used to target CVDs without affecting androgen levels and resulting in unwanted side effects [Targeting the AR instead of using androgens as a therapy method for CVDs poses multiple benefits. Firstly, targeting the AR will result in far less side effects, as it will not affect whole-body androgen levels and will work much more locally . Secondl effects , but on  effects ,48 and t effects . The folHypertension is one of the most prevalent CVDs, affecting 25% of the US population . There aThere are multiple mechanisms by which AR activity can have implications on hypertension. Firstly, androgens have been shown to increase renin levels and expression of angiotensin-converting enzyme (ACE) and angiotensin II receptor type 1 (AT1R), while simultaneously decreasing angiotensin II receptor type 2 (AT2R) . AT1R haAng II-induced vascular constriction is seemingly important in the development of hypertension. In line with this, in various rat studies, androgen deficiency via castration decreases blood pressure through decreased Ang II activity , and conAs well as the implications of AR activity on the RAAS, there is also potential for AR activity to interact with the sympathetic nervous system (SNS). Androgens can increase neuropeptide Y release and increase norepinephrine synthesis , both ofSimilar to hypertension, gender differences exist regarding the prevalence of atherosclerotic development . AtherosAs well as an altered lipid profile, androgens and AR signaling can stimulate smooth-muscle-cell proliferation in the arterial walls . This prThe implications of high AR signaling under supra-physiological androgen levels on atherosclerosis are illustrated in Myocardial hypertrophy (MH) is defined by the augmentation of ventricular mass as a result of increased cardiomyocyte size  and is aOne mechanism by which androgens can promote MH is through the activation of the mammalian target of rapamycin (mTOR) signaling pathway . ActivatAndrogens have also been shown to have implications on calcium homeostasis in cardiac muscle cells . Here, aIn summary, men have increased hypertrophy compared to age-matched women, with androgens likely promoting cardiac hypertrophy. This is most likely due to exaggerated levels of AR signaling. The implications of high AR signaling under supra-physiological androgen levels on myocardial hypertrophy are illustrated in Stroke refers to a rapid loss of brain function due to ischemia caused by a blockage or hemorrhage of blood vessels . The cerSome of the primary mechanisms that can lead to the development of stroke are other CVDs. Hypertension and atherosclerosis are known to cause stroke . A strokIn summary, the potential implications of high AR signaling on the risk of stroke are illustrated in While the relationship between the AR/androgens and cardiovascular disease is far from conclusive, the risks associated with androgens and CVD are of real concern regarding the prevention of a cardiac event. In the case of SARMs, the relationship between  androgens/AR and CVDs is of great importance since SARMs exert their physiological effects through the AR. Improving our understanding of the cells in cardiovascular systems that are influenced by AR agonists will help to develop SARMs that have beneficial effects on cardiovascular health . SARMs hFrom a molecular perspective, are well as the receptor interactions see , AR signRegarding the pre-receptor aspect of the AR signaling process, this refers to the interactions that occur before ligand binding to the AR. Androgens are synthesized by steroidogenic enzymes, which convert cholesterol into androgens . SteroidDetermining whether SARMs can interfere with any key enzymes in the steroidogenesis pathway may be critical for understanding whether SARM abuse may lead to indirect cardiovascular outcomes. This could include low endogenous androgen-related CVDs ,48, whicThe hypothalamic–pituitary–gonadal axis (HPGA) is a critical hormonal system that regulates the production and release of sex hormones, including testosterone and estrogen, in the body. It involves a series of interactions between the hypothalamus, pituitary gland, and gonads . The hypThere is evidence that SARM use can result in alterations of the plasma levels of anabolic hormones involved in the HPGA . The effThe implications of the relationship between SARM abuse and the HGPA on the development of CVDs lie within the increased likelihood of CVD development as a result of low endogenous androgen levels after ending an SARM cycle . ProlongThe development and use of SARMs is a double-edged sword. SARMs can be used to treat low-androgen-related diseases (such as hypogonadism or CVD induced by a lack of cardioprotective androgens), but if abused, it could contribute to an increased risk of certain CVDs. It is possible that SARM abuse can directly contribute to cardiac events, despite evidence being scarce. Padappayil et al. presented a case in 2022 of a healthy young male patient who presented with shortness of breath after self-medicating himself with the SARM testolone/RAD-140 for the purpose of performance enhancement and muscle hypertrophy . The resOverall, it is highly likely that SARMs contribute to the development of CVDs through interactions with AR. Whilst the exact mechanisms of how SARMs can lead to the development of CVDs is not known, the present literature review has provided some potential mechanisms through which SARMs may contribute to the development of various CVDs. It is also likely that the reason this occurs is as a result of an over-expression of AR signaling pathways. Similar to supra-physiological doses of androgens, a portion of the risk of cardiovascular health comes from the disruption of normal physiological homeostasis, with various signaling pathways being overexpressed, which can lead to the development of CVDs. More research is needed on how exactly this occurs in the case of SARMs and which specific AR-derived pathways can lead to worsened cardiovascular health, but it is highly likely that the risk of SARM abuse on CVDs is mediated by the AR and relevant gene cascades. In summary, this review finds that the following mechanisms that are potential contributing factors to the development of various CVDs are a result of exaggerated AR signaling. Regarding hypertension, high AR signaling may have implications on the RAAS, smooth muscle cells, and the SNS. Regarding atherosclerosis, high levels of AR signaling can lead to changes in blood lipid profiles in the body, increased inflammation in endothelial cells, increased muscle cell proliferation, and changes in platelet activity. Regarding MH, exaggerated AR signaling may lead to increased muscle cell proliferation and decreased breakdown, as well as increases in muscle protein synthesis pathways and changes in calcium homeostasis within cardiac muscle cells. Regarding the incidence of stroke, hypertension and atherosclerosis are the main factors that cause stroke, but there is also evidence that endothelial dysfunction can contribute to stroke development, with there being evidence that high levels of AR signaling can lead to endothelial dysfunction.Research within the field of SARMs in relation to (cardiovascular) health is essential for a reduction in SARM abuse in the future. This is of great societal relevance since SARM abuse has been increasing in recent years due to a multitude of factors, as mentioned within the body of the present review. Currently, rules and regulations regarding SARM use are very relaxed, with many loopholes being present, allowing people to purchase SARMs with very little difficulty. The looseness of terms such as ‘research chemicals’ allow these products to be sold for research purposes, but it is very clear that this is not the case in most situations, with SARMs often being used recreationally as anabolic agents. The lack of a need to prove intentions for the use of the SARMs (in most cases), the lack of regulations regarding the purity of compounds, and the ease at which people can buy them, in combination with the stigma that SARMs are a safer alternative to traditional AAS, are some of the reasons as to why abuse is increasing. SARMs have great potential to be used to treat various diseases within a clinical setting, and SARM development should continue with this idea at the forefront. It is probable that SARMs are less likely to result in the development of CVDs or other ailments, such as liver failure, when compared to other anabolic agents, such as T or AASs, because SARMs generally having lower potency and higher selectivity and specificity for the AR. However, it is important to consider the resulting physiological changes that derive from AR signaling pathways being over-expressed.It is very apparent that more in vivo and in vitro research is needed in order to better understand how individual SARMs may have implications on individual CVDs and to address the multitude of knowledge gaps within this field. More empirical research is critical for future development and knowledge expansion since the relationship between the AR, CVDs, and SARMs is still unclear. The AR response to compounds is pivotal to understanding their potency and, as such, is useful for understand the risks of using SARMs.


Prostate cancer (PCa) is the most common cancer in men worldwide. Despite better and more intensive treatment options in earlier disease stages, a large subset of patients still progress to metastatic castration-resistant PCa (mCRPC). Recently, poly-(ADP-ribose)-polymerase (PARP)-inhibitors have been introduced in this setting. The TALAPRO-2 and PROpel trials both showed a marked benefit of PARPi in combination with an androgen receptor signaling inhibitor (ARSI), compared with an ARSI alone in both the homologous recombination repair (HRR)-mutated, as well as in the HRR-non-mutated subgroup. In this review, we present a comprehensive overview of how maximal AR-blockade via an ARSI in combination with a PARPi has a synergistic effect at the molecular level, leading to synthetic lethality in both HRR-mutated and HRR-non-mutated PCa patients. PARP2 is known to be a cofactor of the AR complex, needed for decompacting the chromatin and start of transcription of AR target genes (including HRR genes). The inhibition of PARP thus reinforces the effect of an ARSI. The deep androgen deprivation caused by combining androgen deprivation therapy (ADT) with an ARSI, induces an HRR-like deficient state, often referred to as “BRCA-ness”. Further, PARPi will prevent the repair of single-strand DNA breaks, leading to the accumulation of DNA double-strand breaks (DSBs). Due to the induced HRR-deficient state, DSBs cannot be repaired, leading to apoptosis. Prostate cancer (PCa) represents the most prevalent cancer and the fifth most frequent cause of cancer-related mortality among men worldwide . About 8The concept of using PARPi in men with prostate cancer is rapidly gaining popularity. Since two of the three large phase III trials showed a significantly better rPFS not only in the HRR-mutated, but also in the HRR-non-mutated population, many questions arise about the mechanism behind this possible synergistic effect.Like prostate epithelial cells, prostate cancer (PCa) cells are primarily driven by stimulation of the androgen receptor (AR). AR stimulation by androgens provides survival- and growth-promoting signals for PCa cells . AndrogeOn the other hand, AA, the only clinically used second-generation androgen synthesis inhibitor, is an irreversible inhibitor of both 17,20-lyase and 17-alpha hydroxylase. Inhibition of CYP17 enzymes result in an inability to synthesize progesterone and pregnenolone into testosterone . AdminisThe combination of ADT with an ARSI leads to increased suppression of the AR and decreased transcription of associated AR target genes. The most important of these associated effects is the emerging evidence of increased DNA damage and decreased DNA repair when treating PCa with an ARSI. The link between the AR and DNA damage repair (DDR) has been partially unraveled , 25–31. During the transition from mHSPC to mCRPC, there are numerous escape mechanisms that prostate cancer cells can develop to circumvent androgen or AR dependence. These escape mechanisms include, but are not limited to, AR splice variants, increased AR expression, and glucocorticoid receptor takeover , 17. MulDepending on the presence of single-strand breaks (SSBs) or double-strand breaks (DSBs), different DNA repair mechanisms are triggered. Each type of break initiates specific repair pathways, the most important of which are non-homologous end joining (NHEJ) and HRR for DSBs, and nucleotide excision repair (NER), base excision repair (BER) and mismatch repair (MMR) for SSBs . PARP1 iNormally, the PARP1-initiated cascade by will repair the SSBs and restore the DNA strand without further problems. However, in the absence of functional PARP1 (e.g. PARP inhibition), there are two major consequences, representing the dual function PARP. First, when SSBs are encountered during DNA replication and cannot be repaired, as discussed above, the replication fork stalls and DSBs accumulate. DSBs in combination with a stalled replication fork are normally repaired via HRR. Even though NHEJ is an alternative option for DSB repair, in these situations, there seems to be an exclusion of NHEJ in favor of HRR . Thus, wDSBs that accumulate and cannot be repaired before entering mitosis, drives the cancer cell in ‘mitotic catastrophe’, where these cell is prevented from proliferating and driven towards cell death or senescence . Hereby,Second, in addition to its role in DNA damage repair, PARP1 is also involved in transcriptional regulation as a potent modulator of AR function and inducer of AR activity, and thus is involved in tumor proliferation. Schiewer et al. showed that PARP enzymatic activity is required for AR function in hormone-sensitive prostate cancer cells. Targeting PARP with PARP-inhibitors decreases AR activity and suppresses AR target gene expression, enhancing the activity of an ARSI. This is believed to prolong tumor doubling time and suppress the transition to CRPC. In patients with CRPC, PARP-inhibition plus castration significantly reduces tumor volume . PARP1 aThus, PARPi exploits the dual function of PARP1 in DNA damage repair and AR regulation to suppress multiple pathways critical for prostate cancer cell survival and progression.As previously described, administration of a PARPi in a patient with a dysfunctional HRR pathway  will lead to accumulation of DSBs that cannot be repaired, leading to cell death. Drug-induced apoptosis, for example when the escape route is dysfunctional, is often referred to as ‘synthetic lethality’ , 52, 53.This combination effect of ARSI and PARPi in non-HRR-mutated patients can be explained by a synergistic effect of both drugs Figure 3We take a closer look at each synergistic effect.First, the combination will slow or stop the growth and progression of the tumor on multiple levels. The ARSI blocks the AR deeply and at three levels , resulting in elimination of growth stimuli for the PCa. This lack of AR stimulation (and thus growth inhibitory effect) is enhanced by the addition of PARPi, which suppresses AR function and activity.Second, DNA repair pathways are blocked, leading to cell death. This effect results directly from the strong inhibition of the AR. Since the AR activity is known to be a regulator of DNA repair genes, blockade of the AR will result in deficiency of the HRR pathway, inducing a ‘BRCAness’ situation. At this level, PARPi’s will do the job they are best known for: SSBs cannot be repaired, the replication fork stalls and DSBs accumulate, leading to apoptosis. It can be concluded that both agents reinforce each other’s mechanisms of action.The therapeutic potential of PARPi’s has been tested in an explant of primary human tumors, showing that inhibition of the PARP1 enzyme leads to a decrease in tumor proliferation, all the more so when simultaneous inhibition of DSB repair via maximal androgen deprivation is achieved .In addition, one of the escape mechanisms from AR-blockade using an ARSI, is deletion of the BRCA-gene (sometimes combined with co-loss of RB1). In this subgroup, the addition of a PARPi will act as in an HRR-mutated setting, leading to synthetic lethality .Understanding the molecular basis behind this synergistic effect is crucial for future research in selecting optimal non-HRR-mutated patients for combination therapy with PARPi and an ARSI.On paper, this combination therapy looks promising. The phase III trials investigating PARPi in combination with ARSI for mCRPC have not yet been able to confirm or refute this synergistic effect. In MAGNITUDE , patientThe question arises whether this combination therapy offers sufficient synergism to also benefit HRR-mutated patients, or whether sequencing these drugs in mCRPC patients is a valuable option (since no “BRCA-ness” needs to be created). A phase II trial, BRCAAWAY (NCT03012321) is currently investigating this question. In BRCAAWAY, eligible mCRPC patients with BRCA1, BRCA2 or ATM mutation were randomized in one of three arms: (i) AAP, (ii) Olaparib, (iii) AAP + Olaparib with PFS as primary endpoint. Crossover at progression was considered in the first two arms. While final results have not yet been published, an interim analysis presented at ASCO 2022, showed a strong benefit of the combination therapy over either agent alone .With the great results of using PARP-inhibition in a mCRPC setting, multiple new trials testing these PARP-inhibitors in a mHSPC population are starting. Currently, we are also waiting results of rucaparib together with enzalumatide in mCRPC patients .An overview of previous and registered studies using a combination of PARPi and an ARSI can be found in 50, investigation around these aberrations in clinical trials can be indicated.Published trials (except NCI 9102 ) used paNew treatment modalities are emerging for patients with metastatic castration-resistant prostate cancer (mCRPC). Recently, poly-(ADP-ribose)-polymerase (PARP)-inhibition has been introduced in mCRPC. Phase III trials  showed a clear benefit in radiographic progression-free survival (rPFS), time to first subsequent therapy or death (TFST), and a trend towards better overall survival (OS) in HRR-mutated patients. However, TALAPRO-2 and PROpel also demonstrated this benefit in rPFS in a non-HRR-mutated patient population. While lacking real-world confirmation, preclinical studies showed that maximal inhibition of the androgen receptor (AR) via an AR signaling inhibitor (ARSI) resulted in arresting tumor growth and progression while downregulating HRR gene expression. This results in a “BRCA-ness” situation, which can be exploited with concomitant PARPi. Well-designed proof-of-concept studies are needed to confirm this concept.AG: Conceptualization, Investigation, Methodology, Writing- original draft, Writing- review & editing. LB: Visualization, Writing- original draft. WD: Conceptualization, Data curation, Investigation, Writing- original draft. GD: Writing- review & editing, Conceptualization. HD: Supervision, Writing- review & editing. WE: Supervision, Writing- review & editing. FC: Supervision, Writing- review & editing. SJ: Supervision, Writing- review & editing.


An increase in the prevalence of allergic rhinitis (AR) worldwide presents a significant burden to the health care system. An initiative was started in Europe designated as Allergic Rhinitis and Its Impact on Asthma (ARIA) to develop internationally applicable guidelines by utilising an evidence-based approach to address this crucial issue. The efforts are directed at empowerment of patients for self-management, the use of digital mobile technology to complement and personalise treatment, and establishment of real-life integrated care pathways (ICPs). This guideline includes aspects of patients’ and health care providers’ management and covers the main areas of treatment for AR. The model provides better real-life health care than the previous traditional models. This review summarises the ARIA next-generation guideline in the context of the Malaysian health care system. Allergic rhinitis (AR) is a worldwide health problem that is particularly prevalent in Southeast Asia . AccordiAR is typically caused by perennial or seasonal allergies to the indoor and/or outdoor environment. House dust mites, pets, cockroaches, and mould are the primary causes of perennial AR, whereas grass, trees, and weeds are the primary causes of seasonal AR. House dust mites (HDMs), particularly Dermatophagoides pteronyssinus (Der p) and Dermatophagoides farina (Der f), are the most common indoor allergens for allergic diseases such as AR and asthma worldwide. Malaysia’s tropical climate, which is warm and humid all year, promotes the growth of dust mites and mould. The Allergic Rhinitis and Its Impact on Asthma (ARIA) next-generation recommendations and integrated care pathways (ICPs) for AR in reference to the Malaysian health care system are reviewed in the paper ,7. TheseIn Malaysia, both primary and secondary health care systems deal with AR patients, which are further separated into public and private  organisations ,9. In adCommunity pharmacists are frequently the first responders for AR patients’ needs because of the availability of over-the-counter oral antihistamines and patients’ reluctance to seek medical consultation . They sePatients with AR who do not respond to over-the-counter antihistamines frequently seek additional treatment from their general practitioners (GPs). GPs must be well-informed and knowledgeable in order to provide an accurate AR diagnosis and provide suitable treatment. It should be noted that not all health care practitioners are familiar with the proper administration of intranasal corticosteroid sprays. Incorrect administration can result in suboptimal effects, which can lead to patient frustration and poor compliance. Despite the fact that various international recommendations for AR have been published, their impact and effectiveness on GPs’ management of AR patients is unknown. ARIA Care Pathways 2019 is a useful practical guideline that assists frontline clinicians like GPs and pharmacists in identifying and managing patients with AR, as well as advising them on the necessity for referral in cases with refractory and complicated rhinitis.The goal of selecting medication for AR patients is to keep the patient’s condition under control. With the ongoing support of many organisations such as MASK (Mobile Airways Sentinel Network) and POLLAR  and in collaboration with professional and patient organisations in the field of allergy and respiratory diseases, a meeting on chronic disease care was held in Paris on 3 December 2018, where a new project (the ARIA guidelines) was launched ,12. It wICPs are interdisciplinary care plans that outline critical treatment milestones for patients. They promote the translation of guidelines, their incorporation into local health care systems, and their use in clinical practise. The formation of AIRWAYS ICPs was the initial step towards the development of ICPs for the multimorbidity of rhinitis and asthma . Figure Although the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) technique clearly considers all types of study designs, guideline developers usually prefer to confine guidelines to randomised controlled trials (RCTs). GRADE also considers evidence on values and preferences, as well as acceptability, feasibility, and directness of results. Real-world data (RWD) is increasingly being used to inform health care practise. Quintessentially, both GRADE and RWD can be combined to generate real-world evidence (RWE).During the Paris meeting, next-generation guidelines for the pharmacologic treatment of AR were developed, which were tested utilising RWD provided by mobile technology and chamber studies ,16,17,18The MASK algorithm, which is based on the visual analogue scale (VAS), was developed and digitalised to suggest step-up or step-down AR treatment that may be adjusted and altered using Malaysian medicinal products and resources .Although there have been few head-to-head drug comparisons utilising RCTs, AR medication comparisons have been advocated by reviews and guidelines ,15,16,19The ARIA revision 2016 and the US Practise Parameters 2017 were created independently, but both used the same GRADE-based methodological approach ,16. InteTo investigate the commencement of action of AR medications, traditional Phase III double-blind RCTs using both park setting and allergen exposure chamber (AEC) trials can be used ,22. AECsIn the Ontario and Vienna chambers, several oral and intranasal medications were tested. The Ontario Chamber studies indicated that azelastine and its combinations, including MPAzeFlu, have a rapid onset of efficacy. Other intranasal H1-antihistamines take longer to have an effect. Intranasal corticosteroids (INCS), either alone or in conjunction with oral H1-antihistamines, are ineffective within 2 h of administration. In Vienna chamber tests, azelastine and levocabastine with fluticasone responded faster than oral H1-antihistamines or INCS .The MASK algorithm as well as the next-generation ARIA guidelines were validated or refined by combining GRADE recommendations with RWD and data from mHealth technologies . DespiteBox 11. Patients did not follow guidelines and often self-medicate.2. Adherence to treatment was poor.3. Patients treat themselves as and when needed, depending on the control of their disease, and increase their treatment when they are unwell. However, co-medication does not improve the control.4. MPAzeFlu is superior to INCS, which are superior to oral H1-anti-histamines.Although direct verification of adherence is hard because MASK users may not input data every day and may not record all drugs consumed, secondary adherence was determined to be less than 5% using modified the Medication Possession Ratio (MPR) and Proportion of Days Covered (PDC) . PotentiAlthough a physician’s diagnosis of AR was not validated, the majority of users are likely to have rhinitis  . NonetheIn the next-generation ARIA-GRADE guidelines, the algorithm presented a stepwise approach for selecting AR medicine based on GRADE recommendations optimised using RWE and chamber studies ,27. The Box 21. Intranasal corticosteroids are potent medications but require a few hours to days to be effective.2. Intranasal H1-antihistamines are less effective than intranasal corticosteroids but have faster onset of action (within minutes).3. Though oral H1-antihistamines are less potent than intranasal corticosteroids, most patients prefer oral to intranasal medications. 4. There is no advantage of using combined oral H1-antihistamines and intranasal corticosteroids over intranasal corticosteroids alone.5. The combined efficacy of intranasal H1-antihistamines and intranasal corticosteroids is superior to intranasal corticosteroids alone with rapid onset of action (within minutes). MPAzeFlu, which combines intranasal fluticasone propionate and azelastine, is effective in severe allergic rhinitis following failure of intranasal corticosteroids and can be given to patients who want faster symptomatic relief.6. The effectiveness of intranasal corticosteroids is superior to leukotriene antagonists.7. The recommended pharmacotherapy is safe at the usual prescribed dose. 8. Avoid the use of the sedating first-generation oral H1-antihistamines and prolonged application of topical vasoconstrictors.9. Intramuscular corticosteroids have no role in the treatment of allergic rhinitis.Allergen-specific immunotherapy (AIT) is a well-known treatment for AR and/or asthma that can be given sublingually (SLIT) or subcutaneously (SCIT) ,31,32,33Prescription of AIT should be based on symptoms encountered during allergen exposure, evidence of sensitisation, and the availability of high-quality, standardised extracts. The use of AIT products must conform to regulatory requirements and be supported by proof of efficacy and safety. Extracted allergens should not be considered generics. There is no evidence that mixing different allergens has the same effect as delivering each allergen individually. This practise may result in a dilutional effect and allergen degradation. Only use combined allergen products represented by allergen sources from homogeneous groupings . PatientRedness and swelling at the injection site are usual  symptoms that occur quickly after or several hours after the injection. Systemic responses include sneezing, nasal congestion, and hives. Serious injection responses are exceedingly rare, but they must be treated right away. The majority of adverse reactions occur within 30 min of injection, underlining the importance of patients being monitored at their doctor’s office for at least 30 min following an injection.Oral allergen drops or pills provide a higher safety profile than SCIT. SLIT can be administered at home after the initial dose, which is done under the supervision of a physician. The majority of adverse effects are minimal  and go away on their own within a few days after starting therapy. The severity of local adverse effects is often determined by their duration and impact on quality of life . PatientTo enable shared decision making (SDM), the patient’s point of view should be taken into account at all times. There are numerous real-world studies that evaluate AIT knowledge, perceptions, expectations, and satisfaction. However, AR patients frequently lack information, and enhanced communication is required to improve patient knowledge and satisfaction.AIT patients must completely adhere to the treatment in order for it to be effective. Noncompliance with an AIT regimen, as well as premature termination, are common occurrences . The ratSDM should be used from a medico-legal standpoint, using current medical knowledge. It is the physician’s job to inform the patient about treatment alternatives, risks, and benefits in accordance with professional standards.The vast majority of patients manage their AR on their own, with few interactions with their doctors. Community pharmacists are the most accessible health care providers to the general public, and one of the most common conditions they treat is AR . AIT proIn many countries, allergic disorders are first identified and treated at the primary care level. Primary care’s ease of access, accessibility, and holistic role in AR treatment and patient-centred SDM are paramount. Despite this, only a small percentage of GPs receive formal allergy training at the undergraduate or postgraduate level. SCIT can be administered in primary care, and while there are risks, these can be reduced when performed in an ideal primary care setting by trained GPs who carefully choose patients and are capable of managing systemic allergic reactions.SDM plays a crucial role in AIT. AIT is an expensive therapy in Malaysia that should only be delivered to eligible individuals and must be prescribed by professionals. Furthermore, patients should understand whether AIT is covered by their health system or insurance company, and whether it will result in a partial or full out-of-pocket cost.The ARIA 2019 care pathways advocate employing precision medicine when selecting an AIT regimen  42]. In. In42]. Patients with severe and/or uncontrolled asthma should not utilise AIT . BiologiThe coexistence of numerous allergic disorders in the same patient, known as multimorbidity, is exceedingly common in allergic diseases, with over 85% of asthma patients also having AR. In comparison, only 20–30% of AR patients suffer asthma. AR multimorbidity worsens asthma severity . AIT canOlder allergy sufferers have different immunologic and allergic characteristics than middle-aged people. Based on the available data, AIT may be beneficial in this demographic group .Electronic diaries created by mobile phones or other mHealth tools can aid in patient identification ,54. PhysIn contrast to other parts of the world, Malaysia still has limited information on attitudes and practises related to the management of AR. Antihistamines, particularly the second-generation oral antihistamines, are still the mainstay of AR treatment in primary care, according to a recent survey done in Malaysia and other Southeast Asian (ASEAN) nations . NotablyMedication adherence is crucial in achieving positive outcomes in chronic airway disorders such as AR. Despite this, it has been found that treatment adherence in allergic airway ailments is inadequate . A recenThese shortcomings and related constraints must be addressed effectively. The Malaysian Society of Allergy and Immunology (MSAI), in collaboration with Malaysian experts, developed an expert consensus statement to rationalise the pharmacologic therapy of AR , based oAlthough pharmaceutical treatment is the primary mode of treatment for AR, surgical intervention may be a beneficial adjuvant for recalcitrant nasal obstruction and coexisting chronic rhinosinusitis . To treaThe World Health Organisation has recognised digital technologies as an important tool for strengthening health systems and achieving universal health coverage . InitialA patient-centred information and communication technology system, such as the MASK app, is available in the majority of European nations in an increasing assortment of languages ,69,70. IMobile technology improves treatment adherence by personalising treatment based on the condition and needs of patients. For example, the daily intake of medication can be monitored using a smartphone video camera system for direct or indirect verification by health experts. Using this monitoring system, any challenges to the adherence to the offered treatment can be spotted, allowing patients to be counselled and treatment changes to be made as needed.The ARIA strategy for AR based on RCTs, observational research RWE, and chamber studies has been deemed sufficient and useful in Malaysian health care practise. Patients’ understanding, knowledge, and compliance are improved as a result of ARIA’s efforts to empower them for self-management, mHealth, and health care system-ICP. Both pharmacotherapy and AIT are efficient options that can be used to treat patients with allergic disorders.


Allergic rhinitis (AR) formerly perceived to be a nuisance disease is of global health concern now, causing significant economic and social burden worldwide. It is a common inflammatory condition of the nasal mucosa characterized by four cardinal symptoms: nasal pruritus, sneezing, rhinorrhea, and nasal congestion. Poorly controlled AR can also lead to impairment in sleep and a decrease in school/work performance, thereby affecting the quality of life. In addition, AR can produce serious mental and psychological disorders such as depression and anxiety. Yoga can be used as an alternative therapy to treat AR as it has been proven to have beneficial effects in alleviating the symptoms of AR and can also have an overall relaxing effect on the body and mind. The aim of this case report is to share my first-hand experience of enduring endless suffering due to AR because of my negligent behavior. My chronic symptoms that did not resolve on medication led me to anxiety and depression, and I finally resorted to yoga and meditation to battle the disorder. Allergic rhinitis (AR), colloquially known as hay fever, is an atopic disorder affecting around 400 million people globally and is caused by an immunoglobulin E (IgE)-mediated reaction to inhaled allergens in sensitized individuals. The majority of its symptoms are seen before the age of 20, with a peak incidence between 20 and 40 years, and symptoms gradually subside after the age of 40. It shows a male predilection in childhood and a female predilection in adolescents . HistoriIn AR, the allergic response is seen as early- and late-phase reactions triggered by exposure to allergens such as pollen, dust mites, and/or animal dander. In the early phase, mast cells undergo degranulation, releasing a variety of mediators, such as histamine, which rapidly induces nasal symptoms such as sneezing and rhinorrhea and ocular symptoms such as itching, redness, and watering. Late-phase reaction develops hours after the initial response, with the arrival of cytokines, prostaglandins, and leukotrienes that promote the infiltration of eosinophils, neutrophils, basophils, lymphocytes, and monocytes into the nasal mucosa, producing nasal edema with resultant congestion. Bronchial hyperresponsiveness occurs as a result of mucosal inflammation, and the tissue now becomes primed and reacts more vigorously to even normal stimuli .Earlier, AR has been categorized as seasonal or perennial, but now, according to Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines, AR is classified as “intermittent” if symptoms are present less than four days per week or for less than four consecutive weeks and “persistent” if symptoms are present more than four days per week and for more than four consecutive weeks. Symptoms are classified as mild when there is no sleep impairment and the patient is able to perform normal activities and moderate/severe when sleep or daily activities are affected . AR, wheAR can also have a serious impact on mental health, leading to depression and anxiety that not only complicates the treatment but also affects the quality of life of patients, thus adding to the burden on families and society . The sevI am a 34-year-old dentist working as an associate professor at a university for the past five years. I have been experiencing severe sneezing for the past six years along with a runny nose and nasal congestion. I have no family history of allergies, and I do not suffer from any other medical illness, but I have undergone a lot of emotional stress on the personal front. My symptoms have been more severe on waking up early in the morning. Although I have no trouble falling asleep, I often wake up in the middle of the night due to an itchy nose that triggers my sneezing, following which I sneeze continuously that can last for several minutes, and it is usually accompanied by clear thick nasal discharge. I also face unilateral nasal congestion, especially while lying down flat on my back during bedtime. Cold temperatures such as sleeping in a closed air-conditioned room every day owing to the hot humid temperature outside exacerbated my symptoms. My sneezing was aggravated by the hair my pet dogs shed or whenever the house is dusty and unclean.Due to disturbed sleep at night, I experienced daytime drowsiness, leaving me feeling irritable and tired. Being a doctor, I was about to self-diagnose that I was suffering from AR, but I did not seek any professional help and continued to ignore my symptoms. Whenever my condition worsened, I opted for self-medication that provided me temporary relief but left me feeling groggy throughout the day. Steam inhalation and warm showers helped me with my nasal congestion but only to a certain extent.In due course, my symptoms started worsening, and I started sneezing all year round, almost every other day, and at times, it was so severe that I sneezed nearly 100 times a day. My condition became more noticeable among others, leaving me feeling embarrassed most of the time. I mostly experienced a feeling of heaviness as soon as I woke up and also had frequent headaches. My nasal congestion became so severe that I had difficulty breathing through my nose and started to mouth breath. Dark circles started forming around my eyes, and the skin around my nostrils became dry. I also experienced occasional epistaxis and ear blockage.There were several days when my sneezing and nasal congestion were at its extreme that I barely slept for a few hours. Since the quality of my sleep was affected, my energy and concentration levels started decreasing, my work efficiency was reduced, and I also failed to report to work most of the time. My persistent AR took a major toll on my mental health, and I started feeling stressed and depressed, started reducing all my social interactions, and isolated myself. As a doctor, I know that increased stress levels can trigger allergies and that allergies can further lead to more stress, thus forming a vicious cycle.At one point, I was forced by my family and friends to seek medical help, and I consulted an ENT specialist. After a thorough physical examination, he confirmed my self-diagnosis of AR and stated that my anterior nasal mucosa was ulcerated and prescribed a nasal cream for the same (morning and night inside both nostrils), which is a combination of chlorhexidine hydrochloride and neomycin sulfate. I was also prescribed a combination of montelukast and fexofenadine (one tablet at night after food) and a nasal spray (two puffs to each nostril thrice daily) that contains sodium chloride as the active ingredient to alleviate my clinical symptoms of AR. I was asked to follow all this for a week and report back for review.During the time of treatment and for a brief period afterward, I felt better, but to my dismay, my happiness was short-lived as my allergy started cropping up again. I switched to Ayurvedic treatment, where I was recommended herbal oil massages and various kashyamas to balance my doshas, only to leave me feeling disappointed once again as my symptoms did not resolve. Frustrated as I was unable to find any cure and my anxiety is at its peak now, I finally resorted to yoga, which includes asanas, pranayama, or breathing exercises along with meditation. I routinely did vrikshasana (tree pose), veerabhadrasana (warrior pose), trikosana (triangle pose), salamba sarvangasana (shoulder-stand pose), and matsyasana (fish pose) along with surya namaskar under the guidance of a trained yoga practitioner. These asanas were highly recommended by my trainer to relieve AR. I also practiced pranayama, which basically involves voluntary inhalation, retention, and exhalation of breath that will help in clearing nasal passages and will also improve lung capacity. In addition to the above, I meditated for around 15 minutes every day, which helped immensely in calming my mind by easing my stress. I kept my bedroom clean and tidy and pet-free. I started sleeping with my head propped up on a high pillow as sinuses can drain more properly this way.Yoga not only helped keep my stress at bay but also slowly improved my condition, quality of sleep, focus, and concentration levels, and I was able to perform better at work. Although I was one of the unlucky many to suffer from AR, I learned to deal with it by choosing yoga as an alternative therapy, and this decision was purely autonomous, but what worked for me might not work for everyone else. Nosing around the different treatment options available helped my nose function smoothly, yet I have not completely got rid of this illness and occasionally experience symptoms, but over time, AR had a progressively less negative effect on my overall physical and mental status, and I am a stronger, happier person now.Although being highly prevalent, AR often goes undetected due to its long-standing nature and patients failing to recognize the impact of this illness on their daily lives. Hence, patients with unrecognized AR not seeking medical treatment or those receiving inappropriate treatment pose the greatest global burden of this illness. This case history describes many of the AR-related challenges mentioned in the literature that are discussed below.Individuals with persistent emotional stress have frequent allergy flares, and stress and anxiety can enhance and prolong allergy symptoms. Psychological stress is strongly associated with persistent AR, and when stress is kept under control by pharmacotherapy of imipramine and levocetirizine, AR symptoms improved, resulting in a better quality of life -9. PsychJaruvongvanich et al. , in theiShedden  reportedADCYAP1R1 gene in association with depression in AR. In AR, when an IgE-mediated immune response is triggered by allergens, peripheral inﬂammatory signals or cytokines such as interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor-alpha (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-5, IL-13, and IL-4 in the nose enters the central system through neural , cellular, and humoral pathways, causing neuroinﬂammation, oxidative stress, and neurotransmitter disturbances in the brain, which results in depression [Symptoms such as nasal itching/congestion and olfactory disturbances are attributed to the development of depression in AR. AR patients with comorbidities such as asthma and sinusitis are more prone to depression and suicidal behavior. Excessive fear regarding the side effects of the drugs and sometimes the medication itself can cause depression in AR. There is some correlation between maternal inheritance and the Medications for AR can only provide symptomatic relief, but the improvement is not long-lasting as in my case. Immunotherapy might show better efficacy but is very expensive, which adds to the economic burden of developing countries. Holistic approaches such as yoga are mind-body therapies that are cost-effective and have no side effects. Recent evidence has proven that yoga can be a potential alternative or complementary treatment for AR.Yoga reduces nasal congestion and improves lung capacity, nasal airflow, and symptom score in AR. It also reduces psychological stress and sleep difficulty. It may downregulate certain inflammatory and pro-inflammatory cytokines and upregulate anti-inflammatory interleukin in AR. Yoga might also reduce the hyperresponsiveness of the nasal airway by improving sympathovagal balance. Hatha yoga is a combination of postural exercise (asana), deep breathing (pranayama), and meditation (shavasana) . Chanta AR can either be a seasonal nuisance or a year-round hassle, but it should never be waived off as trivial with its symptoms being overlooked or undertreated. Patients often underestimate the severity of this debilitating condition and fail to seek medical therapy, which can turn out to be detrimental to physical and mental health. Unfortunately, there is no permanent cure for AR, but the effects of the disease can be lessened with accurate and timely diagnosis. Physicians should acknowledge the complexity of the condition in AR patients, and a multidisciplinary approach along with psychological support not only provides symptom relief and controls associated comorbidities but can also improve the quality of life of AR patients.


Editorial on the Research TopicEquity, diversity, and inclusion in rehabilitation sciencesEquity, Diversity, and Inclusion have become critical issues in the field of rehabilitation sciences . Like maWe are pleased to serve as guest associate editors for the Research Topic: Equity, Diversity, and Inclusion in Rehabilitation Sciences. While it is not possible to address all aspects of Equity, Diversity, and Inclusion in one issue, this Research Topic may be thought of as the beginning of the conversation. What is missing from the Research Topic is an examination of the impact of gender, sexual orientation, race and religion, and socioeconomic status on rehabilitation service delivery and outcomes. We hope that this Research Topic will inspire focus on these areas as they pertain to rehabilitation.Jiancaro et al., Sekome et al., Ibáñez-Carrasco et al., Chumo et al., Claus et al.), two are perspective articles , and two are brief research reports . From these nine articles, two main themes emerged. The first theme is the importance of knowledge transfer of Equity, Diversity, and Inclusion principles within the rehabilitation sciences professions. Lurch and colleagues provided an introduction to African philosophies and how these ways of thinking may challenge Western biomedical approaches to health care . The authors argue that the default physiotherapy identity, curricula, and practices are derived from Western epistemologies which have devalued other ways of knowing. Lurch et al. describe African philosophies that can benefit rehabilitation providers and their clients across the world. Fricke et al. provide an assessment of the impact of an anti-racism simulation workshop among rehabilitation providers as a strategy to address racial microaggressions toward Indigenous peoples in the workplace. As part of this study, the authors asked workshop participants to fill in a post-workshop survey. Four themes emerged from the participant surveys: so much to unlearn, remain humble, resist the silence, and discomfort is okay. Sekome et al. describe undergraduate physiotherapy training in South Africa aimed at providing equitable services for disadvantaged rural and urban communities. The study emphasizes the theoretical and classroom-based learning experiences of physiotherapy students and propose that students can become agents of change to expand access to rehabilitation services for equity-deserving communities. Ibáñez-Carrasco et al. describe the development, implementation, and evaluation of a community of practice (HIV in Motion) aimed at advancing rehabilitation interventions for people living with HIV. The community of practice consisting of people living with HIV, researchers, representatives from non-profit organizations, exercise personnel, trainees, and health professionals had a total of 451 participants and 72% reported connecting with another participant because of the 8 online sessions. Outcomes of this study included sharing the lived experiences of people living with HIV, the inclusion of diverse voices, and the mentorship of peer-researchers. These four articles highlighted ways in which knowledge transfer has begun in the area of equity, diversity, and inclusion in rehabilitation sciences and also identify opportunities for ongoing work.We are fortunate to have nine articles included in this Research Topic, five of which are original research articles , revealing that personalities that were more agreeable, extraverted, open-minded, intellectually complex, and less neurotic were associated with more positive attitudes to disability. Interestingly, the most negative attitudes were directed toward the character vignette with a bionic eye, suggesting that more work should be done to educate individuals about bionic devices. Jiancaro et al. investigated factors influencing implementation of a pilot online community-based exercise intervention for people living with HIV, identifying 55 factors influencing implementation spanning natural, societal, organizational, personal and human factors. Chumo et al. conducted interviews with employers, entrepreneurs, and officials in Kenya to find out how to socially support employed people with disabilities in informal settlements. Participants reported that inadequate or poorly administrated resources, work dissatisfaction, and workplace conflict that contributed to non-inclusion were challenges to social support for people with disabilities. Clearly there is much work to be done in empowering equity-deserving groups in the field of rehabilitation.The second theme that emerged from the articles was This Research Topic highlights the advances in our collective knowledge and advocacy that are already taking place in this field. Many of the articles offer strategies to change rehabilitation professions for the better, while others suggest priorities for further research. We hope that rehabilitation science practitioners, trainees, and researchers feel inspired to have brave conversations moving forward.


Up to date, there has been a lack of software infrastructure to connect 3D Slicer to any augmented reality (AR) device. This work describes a novel connection approach using Microsoft HoloLens 2 and OpenIGTLink, with a demonstration in pedicle screw placement planning.We developed an AR application in Unity that is wirelessly rendered onto Microsoft HoloLens 2 using Holographic Remoting. Simultaneously, Unity connects to 3D Slicer using the OpenIGTLink communication protocol. Geometrical transform and image messages are transferred between both platforms in real time. Through the AR glasses, a user visualizes a patient’s computed tomography overlaid onto virtual 3D models showing anatomical structures. We technically evaluated the system by measuring message transference latency between the platforms. Its functionality was assessed in pedicle screw placement planning. Six volunteers planned pedicle screws' position and orientation with the AR system and on a 2D desktop planner. We compared the placement accuracy of each screw with both methods. Finally, we administered a questionnaire to all participants to assess their experience with the AR system.The latency in message exchange is sufficiently low to enable real-time communication between the platforms. The AR method was non-inferior to the 2D desktop planner, with a mean error of 2.1 ± 1.4 mm. Moreover, 98% of the screw placements performed with the AR system were successful, according to the Gertzbein–Robbins scale. The average questionnaire outcomes were 4.5/5.Real-time communication between Microsoft HoloLens 2 and 3D Slicer is feasible and supports accurate planning for pedicle screw placement.The online version contains supplementary material available at 10.1007/s11548-023-02977-0. Effective preoperative planning is crucial to the success of surgical procedures. Various simulation and visualization techniques have been developed in recent years to help surgeons better prepare for interventions. While medical images provide information about patient anatomy, their 2D nature limits depth perception . To addr3D Slicer is widely used for medical image visualization and analysis , 5. Its Alternative 3D techniques, such as virtual reality (VR) and augmented reality (AR), have been successfully adopted in various clinical applications . When usOne of the primary drawbacks of HDM-AR is their limited processing power, which restricts the complexity of applications that can be run on these devices . A soluthttps://github.com/BSEL-UC3M/HoloLens2and3DSlicer-PedicleScrewPlacementPlanning.git.Our approach demonstrates the potential of AR to improve surgical planning by providing an immersive and interactive visualization of medical image data. Our project is based on the work presented in . They diThe current section is organized into subsections that correspond to the two main objectives of this work: “Our AR system includes three main components: A Microsoft HoloLens 2 device, the Unity platform, and the 3D Slicer software Figure . The lathttps://github.com/franklinwk/OpenIGTLink-Unity. This code creates a TCP/IP socket that finds the server through a known hostname and port. Our pedicle screw planning application uses this communication bridge to transfer geometrical transforms and images. Whenever the user moves any model in the 3D world from Microsoft HoloLens 2, the updated pose information is received in Unity. The geometric transforms corresponding to the spine, CT plane, and pedicle screws are automatically sent to 3D Slicer. In Microsoft HoloLens 2, the origin of coordinates is established at the center of the user’s head when the Holographic Remoting app is initialized. All the geometrical transform information sent is in that local reference frame, considering the relative displacements of the models.Unity and 3D Slicer are connected using OpenIGTLink communication protocol. We created an OpenIGTLink server in 3D Slicer using the OpenIGTLinkIF module. Unity has no library supporting this protocol, so we developed a custom-made client-side extending the code provided at Once 3D Slicer receives this information, it loads analogous 3D models of the spine and each screw and applies the corresponding transforms on its local frame (irrelevant to our task). The information required to load the models of interest from the local storage of the PC is included in the message’s metadata. 3D Slicer reslices the patient’s CT (preloaded) according to the CT image plane pose with respect to the spine model. The resulting 2D image is sent back to Unity and Microsoft HoloLens 2 through the same communication channel.These features allow users to seamlessly manipulate the CT plane along the patient’s spine to view the corresponding resliced CT image in real-time. The main advantage of planning with no registration with real elements is that 3D models can be scaled and rotated freely to find the best perspective for inserting each screw. The final appearance of the application is shown in Fig. We developed two personalized modules on 3D Slicer version 5.0.3. The first one complements the AR system. It processes any CT volume to create a resliced 2D image of 100 × 100 uint8 pixels. The 2D slice can be freely moved within the CT volume and the module interpolates the 2D image corresponding to the intersection of the image plane and the 3D volume. This module also creates an OpenIGTLink server and sends the 2D slice to any potential client .The second 3D Slicer module simulates a traditional desktop planner for pedicle screw placement . Apart from the virtual 3D models of the spine, the CT image plane, and the screws, the application includes a control panel  library .Most spinal deformities caused by scoliosis, fractures, tumors, and many degenerative diseases, are treated with pedicle screws. This procedure involves fixing the spine with screws that provide strength and scaffolding for a bony fusion . PedicleSome criteria have been established to ensure proper placement . First, https://github.com/anjany/verse) [We retrieved the CT scans of two healthy human spines from the fully open-access VerSe  dataset (y/verse) . The datWe focused on vertebrae from L4 to L1 because lumbar segment pedicles are the largest in the spine. This results in a higher success rate , 25. ConSix users with diverse backgrounds volunteered to participate in our data acquisition process. This group included three undergraduate students actively engaged in surgical navigation research, one first-year medical student, and two highly experienced clinicians with over ten years of expertise in orthopedic surgery. The selection of such a varied group was intended to test the impact of experience on our technology while also gathering feedback from users with a range of different perspectives.Each participant virtually instrumented two spines with eight screws (two in each vertebra from L4 to L1), yielding a total of 96 virtual trajectory plans. One plan was completed using the AR system (AR method), and the other using the 2D desktop planner (desktop method). The order of the methods and the spines instrumented with each technique were randomized for each user. With this, we tried to minimize the influence of any learning curve or patient-specific factors in the results. This experiment is designed based on the work published by Ungi et. al. in 2013 .To enhance the realism of the planning process, the screws utilized in this study were available in three widths  and seven lengths . Nevertheless, the selection of screw dimensions was not evaluated in this study, as this criterion highly depends on the surgeon's preferences .complete transmission). This process entailed receiving the new transform in 3D Slicer, reslicing the CT volume, and sending the image back to HL2. Second, we paid closer attention to the latency between the reslicing of the CT volume in 3D Slicer and its display in the glasses (image reception). This second analysis, which aligns with [To ensure effective communication across platforms, it is crucial that the exchange of information is seamless and allows for real-time perception. In line with the approach taken by , we measgns with , allowedRegarding functional evaluation, we analyzed our system under three criteria. First, we compared the overall pedicle screw placement accuracy obtained with the AR method to the accuracy achieved with the 2D desktop planner. We measured accuracy by calculating the distance between the longitudinal axis of each screw and the centerline of the pedicles. To define the centerlines of the pedicles, we identified in the CT scans the coronal cross section of the pedicles where they had the minimum diameter. This is the most critical point to avoid breaches in the cortical bone. We extracted the center point of these cross sections by drawing a line in the largest transverse and longitudinal dimensions of the pedicle cross section. We considered the intersection of these lines to be the optimal point for the screw centerline.Our second assessment method used the patient’s CT scans to grade each screw with the Gertzbein-Robbins classification . PlanninOnline SupplementaryMaterial_Questionnaire. To determine statistically significant differences among patients or methods, we conducted a Mann–Whitney U Test. Additionally, we used Kruskal–Wallis tests to assess whether diverse pedicles and participants produced significantly distinct outcomes. Finally, we conducted a non-inferiority analysis of all the data to compare the results obtained with the AR and desktop methods. The non-inferiority margin was established at The third evaluation method involved administering an experience questionnaire to all study participants. It asked participants to rate the AR application from 1 (terrible) to 5 (perfect) in different aspects. Those include comfort and fatigue after extended use, interpretability, virtual models’ quality and interaction, and the future of AR in this context. Additionally, it had questions about the specific tools and features of the app, such as CT slice visualization and voice commands. The complete questionnaire is included in t}δ=-10% .Online SupplementaryMaterial_Video.A demo video showing the functioning of the application is provided in Five of the six volunteers had prior experience with AR in head-mounted displays and did not report any fatigue with the glasses during the entire experiment. The one who had never used AR before needed more time to adjust to the technology. Nevertheless, he performed the experiments seamlessly after 10 min of training. Figure image reception timeframe, which includes the number of frames from the creation of the CT volume reslice in 3D Slicer to the display of the new image in HL2, was completed in 2 or fewer frames in 80% of the 30 analyzed events. On the other hand, the complete transmission, which incorporates the selection of the plane in the glasses, concluded in 6 or fewer frames also in 80% of the cases. This translates to a maximum of 50 ms for the complete exchange of information between the platforms, dedicating a maximum of 17 ms to image reception.The The results obtained with AR and desktop methods are depicted in Table In addition, we graded each screw placement following the Gertzbein-–Robbins classification Table . ConsideFigure good—perfect for pedicle screw placement planning. All participants reported that Microsoft HoloLens 2 glasses are comfortable to wear during the planning process. They also agreed that the application was easy to understand, and the virtual models’ quality was sufficient to complete the task. The most highly regarded feature was the clipping tool that used the CT plane to trim the spine. They all reported that physically moving the plane along the spine and seeing the corresponding CT slice was very useful in improving their perception of the problem. There were no ratings of “terrible” for any of the questions on the survey.Figure One limitation of 3D Slicer-based solutions is the lack of software infrastructure for AR visualization. In this work, we developed a solution that communicates Microsoft HoloLens 2 and 3D Slicer through an OpenIGTLink client in Unity. This enables the use of the widely popular image analysis software with the famous AR device. Our objective was to exploit the 3D capabilities of the AR glasses in conjunction with image processing tools available in 3D Slicer. Our system exchanges geometrical transform and image messages between the platforms with no perceptible delay. Latency analysis revealed a close-to-real-time transference of images, with a delay of only 17 ms. This value is lower than the 80 ms reported in  and compTo evaluate our system’s performance in a clinical context, we tailored it for pedicle screw placement planning. Thanks to the Unity—3D Slicer communication, the application displays a virtual 2D image resliced from the CT volume in the plane selected by the user with Microsoft HoloLens 2. This allows for a more accurate visualization of the ideal screw trajectory from multiple perspectives. There is no registration of virtual models in the real world. Consequently, the models can be scaled for an enhanced understanding of the anatomy, improving confidence and spatial perception. The lack of a physical model to align with also permits clipping the spine with the selected 2D plane, enhancing the pedicle visibility from any perspective.In parallel, we developed a more traditional desktop planner in 3D Slicer to compare with the AR application. Our results demonstrate that utilizing our AR method as a tool for pedicle screw placement planning is not only technically feasible but also accurate, with a mean error of 2.1 ± 1.4 mm. Furthermore, our system consistently yields comparable outcomes, irrespective of the user’s familiarity with AR technology or level of clinical expertise. Statistical analyses demonstrated that the accuracy achieved with our AR method was non-inferior to the one obtained with the desktop method (mean error of 1.3 ± 0.8 mm), although the outcomes of the second method were systematically better. In both cases, the results are comparable to the 1.28 ± 1.37 mm reported in . In thatParticipants’ perspectives were also very positive on the remaining aspects of the AR system. Yet, they pondered that the best technique should combine both methods. Specifically, they would employ the AR glasses for an initial rough placement of the screws in 3D, to then fine-tune the final position with desktop controllers. Since our system sends all positions in real time from Microsoft HoloLens 2 to 3D Slicer, it is currently possible to use it following this mixed approach. Once the virtual plan has been defined, it could also be displayed alongside the patient during surgery, serving as a reference during the procedure.Novarad OpenSight application and overlay it to a silicone phantom. However, this requires uploading one heavy CT volume into the AR glasses for each patient. Moreover, it is specific to Microsoft HoloLens and cannot be easily transferred to other AR devices.One of the main limitations of the pedicle screw placement implementation is the low number of subjects validating the system. Even though the results obtained are promising, further examinations with more users could determine if previous AR experience is required to plan correctly. In addition, this proof-of-concept research did not fully explore the placement of screws in cervical or thoracic vertebrae. Future studies could expand upon this work by including planning for the complete spine in a larger group of patients. Finally, our work lacks the placement of actual screws. The reason is that we mainly focused on testing the feasibility of our system in a clinical scenario, as well as comparing its convenience to traditional planning platforms. Nevertheless, the full impact of planning errors could be better assessed in a future study with actual screw placements in phantom models, animals, or human subjects, similar to . In thatIn turn, our system is designed to send and receive all necessary information in real time from the computer. This approach reduces the computational load on the AR device. Besides, any device compatible with Holographic Remoting or a similar toolkit integrated with Unity would work with our approach, enabling the transfer of the technology to other HMDs. This allows for a quick adjustment to technological advances in the future. Furthermore, since everything is developed for the computer, new patient information can be rapidly loaded anytime. It would only be necessary to import the desired 3D models into Unity and the corresponding CT volume into 3D Slicer. There is no need to build any application into the AR glasses.After evaluating both participant feedback and accuracy outcomes, we can conclude that our AR system may not be the optimal solution for enhancing pedicle screw placement procedures, as existing technologies are equally or more accurate. However, it was not originally developed with the specific goal of enhancing pedicle screw placement procedures. Instead, we designed the experiments to test the applicability of our framework in the clinical setting. Having demonstrated its ease of use and portability to a medical context, we believe that the true value of our system lies in its potential to benefit a broad range of medical applications. By utilizing AR as the 3D visualization technology, we can expand the possibilities beyond what is achievable with other 3D techniques such as VR. This unlocks new opportunities to enhance medical procedures, including surgical interventions. As such, we are eager to explore additional use cases with our AR solution and discover new ways to enhance medical care beyond our initial focus on pedicle screw placement planning.An example of our system's potential for future expansion is its integration with other devices compatible with OpenIGTLink, such as tracking systems. By utilizing the PLUS toolkit and this communication protocol, it is already possible to easily connect most external tools to 3D Slicer. The same channel could be employed to send information between all platforms, allowing for real-time display of tracking information directly in Microsoft HoloLens 2. This workflow could also facilitate the connection of multiple HMDs to 3D Slicer from various Unity projects. Information could be exchanged between the headsets to observe how a user manipulates a virtual model from another user’s glasses. To finish, some of the previous works did not share the data and code used for their evaluation , 20, 21.In this work, we used OpenIGTLink to communicate Microsoft HoloLens 2 and 3D Slicer with real-time perception. The function of the system was demonstrated for pedicle screw placement planning. The final application allows to move a virtual plane along a virtual 3D model of a patient’s spine and visualize the corresponding resliced 2D image from the CT scan. This dynamic visualization, coupled with the ability to manipulate the virtual models, enables users to easily develop surgical plans. The accuracy tests, statistical analyses, and user feedback results are very promising and comparable to the state-of-the-art in pedicle screw planning, although our main contribution is the easy transferability of our system to other clinical applications in the future. Combining AR and 3D Slicer can transform how we approach medical procedures. We hope this work is a foundation for future studies integrating AR visualization and powerful image analysis software in the medical field.Supplementary file1 (DOCX 32 kb)Supplementary file2 (MP4 323574 kb)Below is the link to the electronic supplementary material.