This report, based on guidance from a panel of UK retina specialists, introduces a revised intravitreal aflibercept (IVT-AFL) treat-and-extend (T&E) pathway for the treatment of neovascular age-related macular degeneration (nAMD). The T&E pathway incorporates the updated IVT-AFL label (April 2021) allowing flexible treatment intervals of 4 weeks to 16 weeks, after three initiation doses and a further dose after 8 weeks. Practical guidance is provided on the clinical implementation of the revised pathway, with the aim of supporting clinical decision-making to benefit patients and addressing capacity issues in nAMD services.Three structured round-table meetings of UK retina specialists were held online on 19 May, 16 June and 13 October 2021. These meetings were organised and funded by Bayer.The authors revised the previously published consensus pathway to reflect the changes to the IVT-AFL label and developed guidelines for the implementation of the pathway in UK clinical practice. The guidelines include topics such as recommendations for extending patients with 2- or 4-week adjustments, extending patients to 16-week treatment intervals, managing fellow eye involvement, and reducing treatment intervals for patients with particularly active disease.The revised IVT-AFL T&E nAMD pathway offers guidance to clinicians seeking to increase the dosing flexibility of IVT-AFL, with 4- to 16-week treatment intervals, in line with the updated IVT-AFL label, to meet the continually evolving demands of nAMD service provision. Evidence from clinical trials and real-world studies demonstrate three main intravitreal anti-VEGF treatment regimens: proactive fixed regimens, reactive ountries , 2.Fixed treatment regimens provide predictability and can simplify decision-making, but may result in over- or undertreatment if the treatment interval is not optimal . PRN regKey data supporting intravitreal aflibercept (IVT-AFL) T&E for the treatment of nAMD are provided by the ALTAIR and ARIES studies , 8. In YAlthough many UK NHS medical retina services have expanded to meet the growing demand for anti-VEGF injections, it has been difficult, and nAMD case numbers are predicted to increase by 59–64% from 2015 to 2035 –13. AddiDespite the availability of data and the unprecedented pressures on services, treatment intervals of up to 16 weeks with IVT-AFL are not always used in clinical practice. This may be due to low awareness of the data supporting extension to 16-week intervals, and many clinicians may feel that the achievement of stable disease at 12-week intervals for 1 year is sufficient to discontinue treatment and commence monitoring.In April 2021, the IVT-AFL product licence in Europe for the treatment of patients with nAMD was extended to include the option of dosing at 4-week intervals in Year 1 of treatment, after the initiation phase (often referred to as the loading phase) of three initial monthly doses and an additional dose after 8 weeks . This upThe objectives of this publication are to introduce the revised T&E pathway and provide expert-led practical guidance on its clinical implementation. The publication will address how the revised pathway may help to support clinical decision-making and alleviate the capacity and resource issues that continue to strain nAMD services.Three structured round-table meetings of UK retina specialists were held online on 19 May, 16 June and 13 October 2021. These meetings were organised and funded by Bayer and were set up to develop a revised T&E pathway that reflects the updated IVT-AFL licence in nAMD and to explore the practical guidance required for its implementation within a standard UK clinic.Development of the T&E pathway was supported by a pre-meeting survey of current clinical practice and use of IVT-AFL. During the online meetings, further data on the use of T&E regimens were reviewed and the panel discussed predefined questions developed by Bayer to support pathway generation.The revised IVT-AFL T&E pathway is presented in Fig. The initiation phase consists of three consecutive IVT-AFL doses at 4-week intervals. Visual acuity (VA) assessment is optional during the initiation phase and at the discretion of the treating clinician.The fourth IVT-AFL dose is given 8 weeks after the third initiation dose. VA assessment and optical coherence tomography (OCT) imaging should be performed at this visit, and at all subsequent intravitreal injection (IVI) visits, to determine the succeeding treatment interval.After the fourth IVT-AFL dose, the treatment interval is either extended, maintained or reduced; criteria for each decision are shown in Fig. The licensed posology of IVT-AFL allows injection intervals to be increased by 2 or 4 weeks to maintain stable vision and/or anatomical outcomes .In the ARIES study, both patients randomised to early-start T&E and to late-start T&E showed improved visual outcomes from baseline to Week 104. The mean change in best corrected VA from Week 16 to Week 104 with the early-start T&E regimen was non-inferior to that with the late-start T&E regimen. The mean number of injections was comparable between groups  [The ALTAIR study demonstrated that visual outcomes were maintained in patients receiving IVT-AFL with either 2- or 4- week adjustments. From baseline to Week 96, mean gains in best corrected VA were 7.6 and 6.1 Early Treatment Diabetic Retinopathy Study letters for the 2- and 4-week extension groups, respectively. Furthermore, the mean number of injections was the same for both groups over 96 weeks (10.4 injections). The ALTAIR study also showed that patients extended with 2-week adjustments were more likely than patients receiving 4-week adjustments to maintain 16-week treatment intervals to Week 96. Up to 96.3% of patients in the 2-week extension group who were extended to 16-week treatment intervals during the study were maintained on 16-week intervals to Week 96, compared with 77.6% of patients in the 4-week extension group .The revised T&E pathway shown in Fig. Recommendation: We recommend that most patients should be extended with 2-week adjustments; however, 4-week adjustments can be considered for patients with stable or improved VA and a completely dry macula after the initiation phase. The response to the three initiation doses can be used to determine whether 2-week or 4-week adjustments can be made after the fourth dose has been received (8 weeks after the third initiation dose). A qualitative assessment of OCT can determine these adjustments along with clinical judgement.Treatment intervals with IVT-AFL for nAMD can be extended incrementally to a maximum of 16 weeks . By WeekThe effect of treatment delays with anti-VEGF agents due to the COVID-19 pandemic was explored by Stone et al. Patients with nAMD, diabetic macular oedema or retinal vein occlusion who received at least one anti-VEGF injection between 1 January 2020 and 23 March 2020 experienced a mean delay in requested review of 13.1 weeks. Despite this delay, 26.7% of eyes with nAMD remained dry and 61.9% of patients with nAMD maintained their VA (within 5 letters of their baseline) . Data frRecommendation: The clinical trial data support extending suitable patients to 16-week treatment intervals. The guidance in this report may be used when considering extension.Alongside the treatment of active disease, prevention of disease recurrence and/or worsening also defines the success of anti-VEGF agents . In our The recommended criteria for reducing treatment intervals are a loss of ≥5 letters due to disease activity, or OCT imaging showing increased disease activity, evidenced by new or increased fluid , macular haemorrhage or subretinal hyperreflective material.Recommendation: The revised T&E pathway Fig.  allows fAfter one failed extension, we advise that fixed dosing at the last effective treatment interval should recommence for 4–6 months prior to re-attempting extension, and for 1 year after two or more failed extensions, depending on recurrence severity.In accordance with the licensed IVT-AFL posology, there is no requirement for monitoring between injections, and the frequency of monitoring is to be determined by the treating clinician . The RoyRecommendation: For services constrained by capacity issues, we recommend that injection-only visits without diagnostics be considered for patients who are stable at planned treatment intervals. Injection-only visits can aid capacity planning; however, local policies should be followed because these visits are dependent on the set-up of individual clinics and clinical assessment by the treating clinician, including consideration of possible second eye involvement.The number of permitted injection-only visits should be determined by the patient’s current injection interval. The duration that the interval should be maintained prior to commencing injection-only visits is at the discretion of the treating clinician and is dependent on factors such as the number of previous failed treatment extensions and how recently interval extension has been attempted. For patients receiving IVI at a fixed treatment interval of 4 weeks, a maximum of three injection-only visits are recommended before performing diagnostics. For patients at a fixed treatment interval of 6 weeks, a maximum of two injection-only visits before performing diagnostics is preferred. For patients with a treatment interval of 8 weeks, one injection-only visit is recommended before performing diagnostics, whereas diagnostics are recommended at each clinic visit for patients at intervals over 8 weeks. Where suitable, outsourcing (or insourcing) imaging hubs managed by hospital medical retina teams, could potentially help with capacity restraints.Patients with nAMD in one eye have a high risk of developing nAMD in the fellow eye. In a study performed by Moorfields Eye Hospital, UK, the fellow eye involvement rate was 32% at Year 2, with a median interval to fellow eye involvement of 71 weeks .A high proportion of fellow eyes with nAMD are asymptomatic at diagnosis, with the disease detected by OCT scanning or fundal examination during follow-up appointments of first-treated eyes. This highlights the importance of regular monitoring of fellow eyes, ensuring early detection to prevent treatment delay, which is crucial for maintaining vision and quality of life , 22.Recommendation: Unless the second eye is untreatable, we recommend monitoring both eyes with OCT. For certain patients, clinical circumstances may require OCT imaging even if the fellow eye is untreatable .To promote efficient implementation of services, increased patient convenience and improved patient compliance, synchronisation of treatment and monitoring of the more active eye should be considered where possible.For unaffected fellow eyes, OCT imaging should be performed every 12–16 weeks, during diagnostic visits for the affected eye. Additionally, patients  should be told to remain vigilant for evidence of disease activity and to report any symptoms as soon as they occur.Polypoidal choroidal vasculopathy is a subtype of nAMD. Indocyanine green imaging can be used to visualise the vasculature of the choroid and thereby add value when differentiating between polypoidal choroidal vasculopathy and typical nAMD , 24.Recommendation: We recommend considering fluorescein angiography and/or indocyanine green imaging to assess for polypoidal choroidal vasculopathy or other pathologies if the patient has a poor response to treatment, or there is no change or worsening on OCT imaging at Visit 4 . If disease activity remains unchanged by Visit 4, the treatment interval should be reduced as per the revised T&E pathway Fig.  and the There are limited data on the risk of disease recurrence after treatment cessation and on post-treatment recurrence outcomes. Disease recurrence rates in nAMD are high; a 2021 study showed that 52.9% of patients who were followed-up for 12 months after treatment cessation showed evidence of disease recurrence, with a mean time to recurrence after the last injection of 6.7 months . FurtherRecommendation: Treatment cessation should be discussed with long-term stable patients who have received at least three injections at a treatment interval of 16 weeks with no disease activity. Some UK clinics adopt a ‘monitor-and-extend’ regimen to monitor patients who have stopped treatment; this type of monitoring is most suitable for a virtual clinic approach. A monitor-and-extend regimen initially involves monitoring patients with VA and OCT assessments 4 weeks after the last missed dose. After this, if nAMD remains inactive, monitoring intervals can be incrementally increased at the discretion of the treating clinician. Even though long-term follow-up with OCT would be ideal, capacity constraints mean that in many units, patients who have been monitored for 2 years without disease recurrence are discharged with self-monitoring and annual sight tests with their local optometrist. However, some clinics discharge low-risk patients (with the exclusion of patients with only one treatable eye and vulnerable adults) after discussion, before completion of 2 years of monitoring.To capture patients who experience disease recurrence, we recommend that clinics have a fast-track referral system in place for patients who are monitored by optometrists or discharged.Treatment might not only be discontinued in those with stable disease who perform well. A subset of patients may wish to prematurely end treatment for reasons such as treatment fatigue or lack of perceived efficacy. Nursing staff and clinicians may also identify patients who are no longer benefiting from treatment at injection clinics. We recommend that clinics establish internal policies for periodic reviews with supervising consultants to discuss treatment cessation.Prior to discharge, we recommend that patients be reviewed face-to-face by a clinician to confirm discharge eligibility and exclude any ocular co-pathology requiring treatment.The severity of a disease relapse should be determined by the treating clinician.Recommendation: We recommend that, for stable patients who have been treatment-free  for 0–2 years presenting with disease relapse, a decision should be made on whether to restart the pathway or determine injection frequency based on disease severity and previous response to treatment.Further guidance on the implementation of the revised T&E pathway is shown in Table It is predicted that the nAMD disease burden will continue to rise over the next decade, leading to an increased demand for IVI and added pressures for services across the UK , 12.There are limited studies published showing real-world outcomes of anti-VEGF treatment over many years. A retrospective review, published in 2021, demonstrated that maintaining anti-VEGF treatment for nAMD sustains vision over a 10-year period, with 63.3% of eyes losing ≤ 15 letters of VA after 10 years of treatment . HoweverAdditionally, it is important to note that increased reliance on retinal imaging in the management of nAMD does not replace a holistic approach to eye care. Significant ocular comorbidities, such as cataract and glaucoma, can be overlooked in practice when the major focus is on nAMD and treatment pathways; therefore, it is important that patients are encouraged to seek help should they experience any symptoms or require urgent advice.Moreover, it is important for patients to understand that treatment for nAMD is a long-term undertaking; this should be made clear at treatment initiation and as therapy continues. Patients who are considering anti-VEGF discontinuation because of treatment fatigue should be reminded of this need for long-term therapy and the potential for disease recurrence .To offer increased patient support and to reduce the number of follow-up appointments, it is also recommended that patients have access to an optometrist trained in low visual aid and an eye clinic liaison officer, including during discharge consultations , 27.The revised IVT-AFL T&E pathway for the treatment of nAMD outlined in this publication is based on our clinical experience as UK medical retina specialists. The revised pathway provides clear guidance and demonstrates how the updated IVT-AFL label can be followed in clinical practice. The aim of implementing the revised pathway is to help services to efficiently address and alleviate capacity issues while improving patient experience and clinical care and treatment outcomes.T&E regimens have become the mainstay for the treatment of nAMD in many countries, which may decrease the treatment burden for patients and healthcare systems while maintaining good visual outcomes.In April 2021, the product licence in Europe for IVT-AFL was extended for the treatment of patients with nAMD, allowing the option of dosing at 4-week intervals in Year 1 of treatment, after the initiation phase of three monthly doses and a further dose after 8 weeks.A revised proactive T&E pathway for the treatment of nAMD with IVT-AFL, allowing treatment intervals of 4 weeks to 16 weeks, after three initial monthly doses and a further dose after 8 weeks, with guidance for treatment extension, reduction and maintenance.Expert-led practical recommendations from UK retina specialists on the clinical implementation of the extended IVT-AFL label, addressing how the revised T&E pathway may help to support clinical decision-making and address the capacity and resource issues that strain nAMD services.


Pseudo-arthrosis of the proximal humerus is an uncommon condition that is difficult to treat. Humoral hypercalcemia from a benign tumour is a rare clinical entity and pleomorphic adenoma as its source has never been reported in the literature. We present the case of a 53-year-old gentleman with a pleomorphic parotid gland adenoma and pseudoarthrosis non-union of the proximal humerus exacerbated by symptomatic parathormone-independent hypercalcemia. The non-union is fixed using a novel technique of placing an ipsilateral cortico-cancellous iliac strut graft as a medial buttress and stabilized with a fixed-angle plate over the lateral side. Following the surgical resection of the tumour, hypercalcemia resolved and the patient improved clinically. This case is a good example of a rare endocrine disease managed by a multidisciplinary approach. Pseudo-arthrosis of the proximal humerus is an uncommon condition that is difficult to treat . VariousA 53-year-old gentleman sustained a right proximal humerus two-part fracture Figure  followinAfter an initial evaluation from the endocrinology department, the patient was planned for surgery. The patient was operated on under general anaesthesia using the deltopectoral approach, and the non-union site of the fracture was freshened. Using Ethibond 2 suture bites were taken from the cuff as well as a proximal head fragment and the head was reduced onto the top of the shaft correcting the varus orientation of the head. Dissection was extended on the medial aspect of the fracture below the head and a space was created in the region of the humeral calcar. A 3-5 cm tricortical ipsilateral iliac crest graft was harvested and placed in this space closely abutting the humeral head. The reduction was checked on an image intensifier and temporarily stabilized using wires. A 3-5 cm tricortical ipsilateral iliac crest graft was harvested for bone grafting. A fixed-angle fixation anatomically contoured PHILOS  plate was used to fix the fracture and bone graft constructs  secretion, the cause of symptomatic hypercalcemia was probably assumed to be the parotid pleomorphic adenoma. An otolaryngologist consultation was sought and a surgical superficial parotidectomy was done. A specimen of the size of 5 × 4 × 2 cm was resected and sent to confirm the histopathological diagnosis.In the immediate post-operative period, patients' calcium levels dropped to 6.6 mg/dL (8.6-10 mg/dL), mimicking a hungry bone syndrome, like a scenario that occurs following parathyroidectomy in cases of hyperparathyroidism . The patDuring the follow-up period, patients’ calcium levels were normalized, and serum ALP was in a decreasing trend Table . ShouldeThe patient presented with a non-union of the proximal humerus with hypercalcemia, probably secondary to humoral hypercalcemia of benignancy from a parotid pleomorphic adenoma.This is a unique case with a chimaera of entities:a) pseudoarthrosis of the proximal humerus;b) humoral hypercalcemia of benignancy; andc) a benign parotid pleomorphic adenoma as a probable source of secondary hypercalcemia.The majority of proximal humerus fractures are managed non-surgically (89.1%), with an incidence of 1% to 7% progressing to delayed union or non-union .Non-union originates from either instability or a failure of fracture-healing biology secondary to an infection, inadequate vascularity, bone loss, or a metabolic cause. Elevated parathyroid hormone due to adenoma, hyperplasia, or rarely carcinoma and high calcium levels secondary to increased bone resorption is a known aetiological factor for non-union .Pseudarthrosis has a deranged pathoanatomy and a mortar-and-pestle-like effect which causes cavitation of the head with a shell of bone leading to persistent mobility and making the fixation a challenging task. Medial buttressing, particularly in those with pseudoarthrosis and Boileau type 3 fracture sequelae, is important in achieving a stable construct . OsteosyIn our case, the patient initially had high normal calcium levels, elevated ALP, low normal phosphate levels, low vitamin D levels, and low PTH levels. In 1979, Stewart et al.  first usPTHrP binds to the common PTH/PTHrP receptors in bone and kidney via its N-terminal domain and mimics PTH action, causing an increase in bone resorption and renal calcium reabsorption, resulting in hypercalcemia . This reRarely, benign tumours may secrete PTHrP, resulting in symptomatic hypercalcemia presenting with a clinical and biochemical scenario indistinguishable from the HHM, called the humoral hypercalcemia of benignancy . It has Pleomorphic adenoma is the most commonly occurring benign salivary gland tumour, constituting two-thirds of all salivary gland neoplasms (85%), which occur mostly in parotid glands. In our case, the pleomorphic adenoma was the only suspected cause of hypercalcemia after ruling out all the other differential diagnoses. Based on the clinicopathological assumption, PTH immunostain was sought as a surrogate marker of PTHrP secretion from parotid adenoma and it turned out to be positive. In normal salivary glands, PTHrP is found mainly in the ductal basal and dark cells but not in myoepithelial cells. In pleomorphic adenoma, PTHrP was found in the inner layer of tubuloductal, cyst-like, single-layer ducts, scattered cells, and clusters of squamous metaplasia in pleomorphic adenoma . Thus, PAlthough PTHrP is the most commonly detected humoral mediator of hypercalcemia in malignancy, several other mediators have also been implicated such as tumour necrosis factor-alpha, interleukins 1 and 2, transforming growth factor-beta, prostaglandin E2, and granulocyte-macrophage colony-stimulating factor.To our knowledge, this rare presentation of non-union pseudoarthrosis of the proximal humerus with probable hypercalcemia of benignancy from a parotid pleomorphic adenoma has not been reported in the literature till now. Although we conclude that the PTHrP from the parotid pleomorphic adenoma may be the cause of hypercalcemia of benignancy in our patient, the complexity of humoral mediators of hypercalcemia prevents us from excluding co-involvement of possible other secreted factors which are to be kept in mind during the management. Hypercalcemia of benignancy is a rare cause to be borne as a differential and a proper whole-body screening is required. This is also an excellent example of a rare endocrine disease managed by a multidisciplinary approach.


However, to translate these studies into large-scale industrial processes, careful considerations of catalyst loading, cost, and removal are required. This work presents organic solvent nanofiltration (OSN) as an answer to reduce TBADT consumption, increase its turnover number and lower its concentration in the product solution, thus enabling large-scale photocatalytic HAT-based transformations. The operating parameters for a suitable membrane for TBADT recovery in acetonitrile were optimized. Continuous photocatalytic C(sp3)-H alkylation and amination reactions were carried out with in-line TBADT recovery via two OSN steps. Promisingly, the observed product yields for the reactions with in-line catalyst recycling are comparable to those of reactions performed with pristine TBADT, therefore highlighting that not only catalyst recovery  is a possibility, but also that it does not happen at the expense of reaction performance.Photocatalytic hydrogen atom transfer (HAT) processes have been the object of numerous studies showcasing the potential of the homogeneous photocatalyst tetrabutylammonium decatungstate (TBADT) for the functionalization of C(sp Decatungstate-enabled Hydrogen Atom Transfer (HAT) photocatalysis of hydrocarbon scaffolds enabled rapid access to new C(sp3)-enriched chemical space. Here, the authors present in-line TBADT recovery with organic solvent nanofiltration (OSN) as an answer to the concerns surrounding the scale-up of decatungstate HAT reactions, i.e., catalyst loading and cost. In HAT, the photoexcited catalyst abstracts a hydrogen atom resulting in the formation of reactive radical species, which are exploited for highly selective functionalization. To achieve this selectivity, careful tuning of the steric and electric properties of the HAT photocatalyst and substrate has to take place. Among the limited selection of photocatalysts promoting HAT, arguably the most versatile HAT photocatalyst is the decatungstate anion, which found application in a wide range of transformations, including alkylation8, arylation9, acylation10, amination14, fluorination17, trifluoromethylation18, sulfinylation19 and oxygenation  presented itself as a versatile strategy for the late-stage functionalization of C could be a suitable strategy for catalyst recovery in continuous-flow systems. OSN is a membrane-based process where selective separation of the species present in the solution is obtained based on their size39. Molecules smaller than the so-called molecular weight cut-off (MWCO) of the membrane will pass through the membrane, while species larger than the MWCO are selectively retained. Typical MWCO values for commercial OSN membranes range from 150 to 1000 Da, thus making them ideal for the selective separation between homogeneous catalysts having a large molecular weight, such as TBADT (3320 Da), and smaller reaction products40. Additionally, OSN has the distinct advantage of low energy requirements since phase transitions such as evaporation are avoided in this separation technique. The absence of thermal transitions also removes the issue of thermal stress for the recovered catalyst, which is present in other recovery techniques. The work of Livingston and co-workers highlighted the performance of OSN with commercial membranes for the recovery of a homogeneous catalyst in Heck couplings performed in continuous flow41. Additionally, recent studies from Guerra et al. and O’Neal and Jensen demonstrated the suitability of coupling OSN for catalyst recovery with flow microreactors. Similarly, O’Neal and Jensen implemented a small-scale custom OSN unit in an automated setup performing ring-closing metathesis with a recycled second-generation Hoveyda-Grubbs catalyst42. Some other reports focused on a combination of photocatalysts with classical polymers to synthesize recyclable photocatalysts43. Kappe et al. developed a macromolecular Ru(bpy)32+-based dendrimeric catalyst as a photocatalyst, and proved its facile recycling with OSN technology in continuous-flow condition40. Although recent works showcased the potential of OSN in flow chemistry, they also highlighted the challenges of catalyst synthesis, deactivation, and membrane fouling.Despite the potential of tetrabutylammonium decatungstate (TBADT) for synthetic applications, the adoption of photocatalytic HAT in industrial processes is still limited. To understand this, one has to consider that while catalyst cost and removal or recycling are minor concerns in demonstrating a new synthetic method, these aspects become major focal points in the transition from small-scale  to large-scale production Fig. 22,23. Th3)–H alkylation and amination reactions carried out with recycled TBADT –H functionalization reaction in continuous flow with in-line catalyst recycling via nanofiltration, suitable commercial membranes were initially evaluated. While the large molecular weight and stability of TBADT make it an ideal candidate for membrane-based recovery, its poor solubility in solvents other than acetonitrile and acetone20 represents a significant challenge due to the limited compatibility of commercial OSN membranes with such solvents. Five commercial membranes were evaluated for potential use for TBADT recovery (see Section 2.5 of Supplementary Information for membrane specifications): three membranes from the Evonik PuraMem product line , and two membranes from SolSep BV (NF080105 and NF030306). Commercial membranes were screened using a Zaiput 10 cross-flow cell and by measuring the flux and selectivity during filtration of 1 mM TBADT solutions in acetonitrile . The cell design is detailed in Supplementary Information, Section 44.The potential negative impact on catalyst activity of the recycling process was taken into consideration and tested by performing alkylation reactions with TBADT that were obtained either via OSN or via non-solvent extraction and filtration. In both cases, product yields comparable to those achieved with pristine TBADT were measured . The starting material was changed to avoid any UV-vis absorbance of the substrate and product in the same wavelength range of the TBADT peak, thus enabling the determination of the TBADT concentration from the measurement of UV-vis spectra of the retentate and permeate streams obtained during filtration experiments. The validity of the previously identified optimal reaction conditions was confirmed by varying the catalyst loading, the number of cyclohexane equivalents, and the residence time of the reaction involving the new substrate . Cyclopentane underwent the C–C bond-forming reaction promptly, transforming the unactivated alkyl substrate into a targeted hydroalkylated compound (4). Esters  were used as H-donors for the radical addition of dimethyl maleate, which afforded the targeted products  in excellent yields. Promisingly, for all entries in the scope, the product yields are similar to those obtained without catalyst recycling, proving the generality of our in-line catalyst recycling strategy.The in-line TBADT recovery proves the potential of OSN for catalyst recovery, thus helping bridge the gap between small-scale HAT transformation and their scaled-up counterparts. Another advantage of the use of OSN for catalyst recovery is the flexibility to either scale up by numbering up, with the possibility to explore different configurations between stages, or to size up. To further highlight the potential of this technique, a small scope for the model photocatalytic hydroalkylation was performed Fig. , reporti3)–H amination. Using the same in-line catalyst recycling strategy, within 27 h, a total TON of 8423 was obtained 2, (Ir[(dF(CF3)ppy)]2(dtbpy))PF6)) ) Fig.  were scrTo conclude, this work presents in-line TBADT recovery as an answer to the concerns surrounding the scale-up of TBADT-catalyzed photocatalytic HAT reactions, where catalyst loading, cost, and removal are major concerns. A suitable OSN membrane was identified, and the operating conditions and experimental design were optimized to achieve suitable catalyst and product recovery. Notably, the product yield of reactions performed with in-line catalyst recovery is comparable to those carried out with pristine catalyst, proving that not only TBADT recovery is technically feasible, but it also does not compromise reaction performance. Considering the widespread interest in decatungstate-enabled HAT photocatalysis, we expect this in-line catalyst recovery protocol will be particularly useful for process chemists to reduce the overall operational cost of the scaled-up process.3CN was added to acquire a total volume of 50 mL. The prepared solution was transferred to the holding tank and delivered to a Vapourtec UV-150 Reactor  via HPLC pump. The outlet solution of photoreactor is directly injected into the two-stage flow cells. Samples from permeate and retentate solutions were collected and analyzed until reaching the equilibrium of the membrane. Another solution with olefin and H-donors in acetonitrile was prepared, which was delivered to the holding tank by the peristaltic pump. Meanwhile, the retentate feed was put into the holding tank, and mixing with the fresh starting material solution. The samples were collected from two permeate feeds and analyzed with 1H-NMR. After a certain experimental time, pure acetonitrile was used to push out the solution left inside the system. A total TON was calculated by combining solutions in permeate feeds and remaining in the system. A detailed description of the experimental setup and protocols is available in Section 3.3 of the Supplementary Information.A 50 mL volumetric flask was charged with olefin , H-donors  and TBADT . Next, CHSupplementary Information


In this review, we discussed the impact of novel immune therapies on the treatment of child and adult acute lymphoblastic leukemia (ALL). Based on the promising results achieved in the relapsed/refractory (R/R) setting, several trials are currently evaluating the clinical benefit of incorporating these new drugs into frontline treatments. The results emerging from the most recent studies are opening new avenues to further the significant improvements in the clinical outcome of this disease.Novel immune therapies are currently being used for patients with R/R ALL based on their ability to induce not only hematologic but also molecular remission. Despite promising results, specific clinical conditions, such as high tumor burden or extra medullary relapse, are still associated with a remarkably poor clinical outcome. Therefore, how to optimize the choice and the timing of such new treatments within different clinical settings remains a matter of debate. In addition, with the aim of increasing the rate and depth of molecular remission, clinical studies are currently evaluating the combination of these immunotherapies with chemotherapy in the contest of frontline treatment. The preliminary data suggest that this approach may increase the cure rate and perhaps reduce the use of allogeneic stem cell transplantation  in first remission. In Ph-positive ALL, reproducible results are showing that frontline treatment programs, based on the combination of tyrosine kinase inhibitors and immunotherapy, can achieve unprecedented rates of hematologic and molecular remission as well as a long-term cure, even in the absence of chemotherapy and alloHSCT. The results from these studies have led to the development of potentially curative treatment modalities, even for older ALL patients who cannot be treated with conventional intensive chemotherapy. The present review examined the evidence for an appropriate use of the new immunotherapies in ALL patients and provided some appraisal of the current and future possible uses of these drugs for achieving further therapeutic improvement in the treatment of this disease. Acute lymphoblastic leukemia (ALL) is a hematologic malignancy that originates from the proliferation of a single B- or T-lymphocyte progenitor, which proliferates and accumulates in the blood; the bone marrow; and, possibly, the extramedullary sites. This disease represents the most frequent cancer in the pediatric population, especially in infants aged 1–4 years, with a subsequent decrease in the overall incidence which reaches its lowest point in young adults aged 25–45 years. The majority of ALL is of B-cell origin. Remarkable advances have been achieved in the treatment of ALL thanks to the optimal use of intensive chemotherapy, the implementation of minimal residual disease monitoring, and better supportive care, allowing most pediatric and adult patients to achieve a complete hematologic remission (CR). Despite these significant advances in treatment, less than 50% of adult patients survive 5 years or more, and about 15–20% of children suffer a relapse. Relapsed or refractory (R/R) ALL is still a major concern, with a dismal prognosis in both children and adults and with an overall survival of 3 to 12 months depending on the duration of the first remission and the number of lines of salvage therapy. In the last few years, the advent of novel targeted immunotherapies, specifically blinatumomab, inotuzumab, and chimeric antigen receptor T cells (CAR-T cells), has changed the therapeutic landscape of R/R B-cell precursor ALL (BCP-ALL). These novel immunotherapies showed impressive results in terms of response rates and a greater likelihood of proceeding to allogeneic stem cell transplantation  consolidation, thus significantly changing the perspectives of this very unfavorable condition. Based on the promising results in the R/R setting, immunotherapies are currently under investigation in the early phases of the disease. Moreover, these targeted immunotherapies are usually well tolerated, so the associated clinical benefit is not limited to younger and fit patients but also to older and frail patients. The main objectives of this review were to focus on how to choose among these novel agents according to specific conditions and to highlight the important challenges to be addressed in the coming years.p < 0.001). Given the better response, the likelihood of proceeding alloHSCT was greater for the blinatumomab group (70% vs. 43%) [Bispecific T-cell engagers (BiTE) are a class of bispecific antibodies designed for cancer immunotherapy . Among tvs. 43%) . In a paThe efficacy of blinatumomab has also been tested as a single agent in patients with R/R Ph+ ALL , showing a response rate of 36% associated with a rate of complete MRD response of 88%, which was close to that reported in R/R Ph-negative ALL. Among the responders, 44% proceeded to alloHSCT. After a median follow-up of 16.1 months, the median relapse-free survival (RFS) was 6.8 months, while the median OS was 9.0 months in the whole cohort and 19.8 months in the blinatumomab responders [−3), blinatumomab induced an excellent 78% molecular response rate after the first cycle. The median OS was 36.5 months, and a prolonged survival was occasionally achieved without alloHSCT [Based on the significant results obtained in the R/R setting, blinatumomab was also evaluated in patients with molecular evidence of MRD in their first or later CR. In a multicenter phase II study, which was conducted in 116 adult patients with ALL in hematologic CR but with a high MRD level >10−3, blinaFinally, an escalation phase Ib study NCT04521231) is investigating the safety and efficacy of subcutaneous blinatumomab for the treatment of adults with R/R BCP-ALL. Blinatumomab given subcutaneously does not only simplify its administration but also maximizes the pharmacokinetics and dynamics while decreasing the patients’ discomfort. Preliminary results are in keeping with this hypothesis [31 is invTo sum up, despite the high rate of responses leading to the approval of blinatumomab as a single agent in R/R ALL, the cure rate remains rather limited without subsequent consolidation with alloHSCT . Based oInotuzumab ozogamicin is an anti-CD22 antibody conjugated to calicheamicin. Its regular approval by the FDA and the EMA for R/R B-cell precursor ALL came from a phase III trial, the INOVATE trial  . CompareNonetheless, the survival with the inotuzumab single agent remained suboptimal. For this reason, inotuzumab was combined with low-intensity chemotherapy based on 8 cycles of mini-hyper-CVD with or without blinatumomab in 96 patients with BCP-ALL in their first relapse (29 with blinatumomab and 67 without). The majority of the patients achieved CR or CRi (80% for the entire cohort and 91% for those in their first relapse). Among 75 evaluable patients, for MRD assessment through MFC, 62 patients (83%) achieved negative MRD, with higher rates of MRD negativity in those in their first relapse (89%). Forty-four patients (46%) received alloHSCT. The 3-year OS rate was 33% for the entire cohort and 42% for those in their first relapse, which was superior to that observed with either inotuzumab or blinatumomab single agents when using a propensity score analysis ,17,18,19In summary, inotuzumab is approved as a single agent for relapsed/refractory B-cell precursor ALL due to the high rate of response in terms of CR and MRD negativity, but its efficacy remains limited by a short duration of response. As mentioned later in the review, to improve the clinical benefit of inotuzumab, ongoing studies are exploring its use in frontline therapies or as a bridge to allogeneic transplants or CAR-T cell therapy. Finally, VOD is still a concern, but the hematologic community is progressively learning to prevent this serious complication by avoiding a dual-alkylator conditioning regimen and by increasing the time between the last dose of inotuzumab and the conditioning regimen.Cellular immunotherapy with chimeric antigen receptor T-cell (CAR-T cell) anti-CD19 represents an attractive therapeutic option in the R/R setting. Different generations of CAR-T cells have been developed with different costimulatory domains (commonly 4–1 BB or CD28), which are relevant due to their expansion and persistence . TisagenBased on the excellent remission rates and the significant clinical benefit observed particularly in the responding patients who achieved MRD negativity, the COG cooperative group launched the first trial of the earlier use of CAR-T cell therapy in the setting of patients with MRD positivity. The AALL1721/Cassiopeia study  was a phase II single-arm trial of tisagenlecleucel in children and young adults in CR1 with high-risk criteria and persistent MRD positivity (>0.01% through flow cytometry) at the end of chemotherapy. The primary end point of this study was the 5-year DFS, and the secondary end points included the overall survival, safety, the percentage of patients in remission without alloHSCT at 1 year, and the time to reach B-cell recovery.In the adult patients, although the impressive rate of CR was confirmed, the long-term outcomes achieved with academic CAR-T cells were initially less significant, with a median EFS and OS of 6.1 months and 12.9 months . The larMore recently, the single-arm ZUMA-3 trial evaluated KTE-X19 CAR-T cell therapy in the largest population of adults with R/R B-cell precursor ALL to date. KTE-X19 allowed 39 patients (71%) to achieve CR or CRi, and 97% of these responders obtained MRD negativity. After a median follow-up of 16 months, the median overall survival was 18 months across all the treated patients. The safety profile of KTE-X19 was manageable and was without deaths due to cytokine release syndrome. These survival outcomes compare favorably with those achieved by blinatumomab and inotuzumab, leading the FDA to approve KTE-X19 as the first CAR-T cell product for adult ALL patients. . OverallA novel second-generation CD19 CAR-T cell therapy with a fast binding off rate for CD19 (AUTO1), designed with the aim to reduce toxicity and to improve persistence, was tested in a phase I study of 20 adult patients with R/R ALL. Interestingly, the study design planned a double infusion of CAR-T cells at different dosages according to the blast percentage. The preliminary results of this study were encouraging, with a high remission rate (85% had a MRD negative response) and an EFS and OS at 12 months of 48% and 64%, respectively. No patients experienced ≥ grade III CRS, and 15% experienced grade III neurotoxicity that resolved within 72 h with steroids . To imprNew approaches to overcoming the main obstacles of CAR-T cell therapy, such as the high costs and logistical complexity of the transduction viral process, and to allowing lymphodepleted patients to access CAR-T cell treatment are underway. In addition, the time of production may be clinically relevant, as some patients may face disease progression during this time, precluding the treatment itself. In this regard, to replace patient-derived CAR-T cells with ready-to-go cellular products, such as off-the-shelf allogeneic CAR-T cells, represents an ambitious goal of the ongoing research. However, the possibility of life-threatening graft-versus-host disease (GvHD) with an allogenic cell therapy product raises major concerns. Therefore, clinical research with immune cells other than “conventional” T cells is underway A,B.ALL represents acute lymphoblastic leukemia, CAR represents chimeric antigen receptor, CIK represents cytokine-induced killer cells, CRS represents cytokine release syndrome, ICANS represents immune-effector-cell-associated neurotoxicity syndrome, NK represents natural killer, GVHD represents graft-versus-host disease, PD represents programmed death, T-reg represents regulatory T cells, and TRAC represents T-cell receptor alpha constant gene.BioRender.com.The figure was created with p = 0.0265). For the 21 patients treated at the 2 highest dose levels, the median EFS and OS were 4 and 12 months, respectively. The median DOR of the 16 patients in CR was 9.5 months, with a 6-month DOR of 54.4% (SE = 13.8). CRS occurred in nine patients (four patients with grade I CRS and five with grade II CRS), and immune-effector-cell-associated neurotoxicity (ICAN) (grade III) occurred in two patients at the two highest doses. Although 10 out of 27 had experienced GvHD after the previous alloHSCT, GvHD never occurred after treatment with CARCIK-CD19 [In a recent phase I and II clinical trial NCT03389035), we examined the treatment feasibility of BCP-ALL patients who relapsed after alloHSCT with donor-derived anti-CD19 CAR-T cells (CARCIK-CD19) engineered with the sleeping beauty (SB) transposon. A complete response was achieved in 18 out of 27 patients (66.7%) and in 16 out of the 21 patients treated with the 2 highest doses (76.2%). A total of 14 (77.8%) of the overall responders and 13 of the responders at the highest doses (81.3%) were MRD negative. With a median follow up of 2.8 years, a significantly better EFS was observed in the patients treated with the highest doses -restricted manner, other “nonconventional” allogeneic cells used in CAR-T cell technology are natural killer (NK) cells. Preliminary promising results have been reported in different tumors, such as multiple myeloma or neuroblastoma ,42, but In conclusion, CAR-T cell therapy represents a potential curative treatment for R/R ALL, particularly when used for a low burden relapse or MRD positive disease. Given the complexity of this therapy, its possible early placing in ALL therapy remains a major open spot. Moreover, a subsequent allogeneic transplant is a matter of debate, and some biological parameters, such as B-cell aplasia and CAR-T cell persistence, could be helpful parameters in this difficult choice. A longer follow-up on the pivotal clinical trial will probably address some of these questions. Finally, there are many new platforms developed with the aim to make manufacturing easier and faster as well as to improve cell therapy efficacy. In this regard, it is worth noting that the time of production may be clinically relevant, as some patients may undergo clinical disease progression during this time, precluding the treatment itself.A summary of the evidence leading to the regulatory approval of the immunotherapies  for R/R ALL is presented in Different mechanisms of tumor escape after treatment with novel immunotherapies have been described, and, in general, either the capacity of the leukemic clone to escape from the therapy-related immune selection or the inability of the immune system to generate an adequate response against leukemia can be referred to . Some ofThe efficacy of blinatumomab depends on cytotoxic CD3+ T-cell engagement against CD19-expressing cells. The emergence of CD19-negative leukemic clones has been observed in about one-third of patients who relapsed after blinatumomab . MultiplSimilar to blinatumomab, downregulation or antigen loss is a common mechanism of tumor escape after anti-CD19 CAR-T cell therapy, with observed CD19-negative relapse rates of 10–25% in several clinical trials ,24,27,54Among the different modalities of CD19 modulation, genetic and posttranscriptional aberrations have been well documented: frameshift code insertions; deletions in exons 2–5; and mRNA splice variants, in particular exon 2, are associated with the loss of either the transmembrane domain, with the consequent absence of surface antigen expression , or the The mechanisms of resistance to InO are less defined and are quite dissimilar from those described previously, giving a different targeted antigen and distinctive mode of action. In particular, a loss of CD22 expression by the leukemia at relapse is not frequent and has been described only in the case reports of both pediatric and adult BCP-ALL patients ,67. WhenThe possible mechanisms of tumor escape after exposure to the novel immunotherapies are schematized in Ag represents antigen, ALL represents acute lymphoblastic leukemia, CAR represents chimeric antigen receptor, PD represents programmed death, TCR represents T-cell receptor.BioRender.com.The figure was created with According to the available literature, among pediatric and adult patients, nearly 40% of relapses occur in the extramedullary sites  either isolated or along with a hematologic relapse. In the absence of head-to-head comparisons, the previously described immunotherapies seem to perform differently in this setting. In a subanalysis of the TOWER trial, blinatumomab proved to be less effective in patients with EMD  reportedIn a post hoc study on the pivotal trial INOVATE, De Angelo and colleagues analyzed the efficacy of inotuzumab among 18 patients with EMD or lymphoblastic lymphoma. The CR/CRi rate was 66.7%, with 58% of the responders achieving MRD negativity. Among the patients with baseline EMD, 71% achieved CR/CRi with a durable resolution of the EMD .In a real-world analysis, the use of CAR-T cells in patients with non-CNS-EMD proved effective even though the bone marrow response was higher and quicker compared to that of the extramedullary sites . InteresBased on the limited experience in the previously quoted studies, at our institution we considered inotuzumab to be the first option for R/R ALL patients with extramedullary disease. For patients with limited SNC involvement, CAR-T cells may represent a valuable option.In both the pivotal trials assessing the value of blinatumomab and inotuzumab, high-burden disease was defined by a marrow blast count greater than 50%. The use of blinatumomab in this setting was clearly associated with a reduced probability of achieving CR ,77. EvenA post hoc analysis of the INOVATE study  divided Similar to blinatumomab, the impact of the disease burden in CAR-T cell therapy seems to be unfavorable. In a study from MSKCC , patientIn summary, these data suggest a preference for inotuzumab for patients with high-burden disease. In such cases, a proper tumor lysis syndrome prophylaxis and, possibly, inpatient management for the first cycle could be considered. The use of blinatumomab likely remains preferable in patients lacking a robust expression of CD22, those who were previously treated with inotuzumab, or those with a higher risk of hepatotoxicity. In this respect, no more than two cycles of inotuzumab should be advised in patients who are candidates for subsequent consolidation with allogeneic transplantation. Inotuzumab may also represent an ideal bridging therapy for CAR-T cells due to the possibility of providing a sequential target therapy on two different antigens.At present, the need for subsequent alloHSCT in patients successfully treated with blinatumomab, inotuzumab, or CAR-T cells remains a matter of debate. This uncertainty is partly due to the fact that none of the published studies were designed to assess the role of alloHSCT in posttreatment consolidation, and the decision for alloHSCT was left to the treating physician. With these limitations, a clear clinical benefit for patients proceeding to alloHSCT after blinatumomab has not yet been demonstrated ,81 but hA post hoc analysis of the INOVATE trial revealed better outcomes in the patients achieving MRD negativity and proceeding to alloHSCT compared to the nontransplanted subjects ,86. In aWhen considering CAR-T cells, different studies showed high rates of response and a prolonged survival with a different proportion of patients subsequently treated with alloHSCT after treatment with CAR-T cells. The pivotal phase II trial ELIANA showed a rate of RFS up to 60% at 1 year and 49% at 5 years, with only a minority of patients receiving alloHSCT ,25. UsinAll in all, with the novel immunotherapies, a prolonged clinical benefit can be achieved in a fair proportion of the responding patients who also achieved an MRD negative status. In this context, a subsequent alloHSCT should be taken into consideration as a possible effective strategy at least for younger and fit patients in order to limit the risk of an early relapse after immunotherapy.−4) after early consolidation. A total of 149 BCP-ALL Ph-negative patients were enrolled (median age of 41 and range of 18–65) of whom 90% obtained a complete hematological response. No matter the MRD status after consolidation, blinatumomab was given to all the patients. MRD negativity improved from 72% achieved after consolidation chemotherapy up to 95% following one blinatumomab cycle (p = 0.018) [Both anti-CD19 and anti-CD22 immunotherapies have been explored in recent clinical trials as frontline treatments in association or sequentially to chemotherapy. In the phase II study GIMEMA LAL2317 (NCT03367299), blinatumomab was added to a pediatric-like risk-oriented regimen in a sequential manner following the early and late consolidation phases based on high-dose methotrexate and ara-C. Upfront alloHSCT was limited to patients with a very high clinical or cytogenetic risk profile at diagnosis and patients remaining MRD positive  . The use= 0.018) . Likewis= 0.018) . FurtherTaking into consideration the good safety profile shown by inotuzumab in combination with chemotherapy in the relapse setting, this association is now being explored in frontline treatments. In particular, a phase III trial comparing inotuzumab in addition to standard induction treatment in newly diagnosed young adult BCP-ALL patients is ongoing (NCT03150693). This study could further elucidate the feasibility of inotuzumab as a first-line treatment with intense chemotherapy in terms of the response rate, survival advantage, and expected toxicity. A summary of the main studies exploring the immunotherapies is available in the The treatment landscape of older patients is rapidly changing, and their results are improving thanks to the addition of innovative immunotherapies. The dismal outcome of older patients with an expected 5-year overall survival of less than 20%  will rapThe role of blinatumomab as the first-line treatment for older patients with BCP-ALL was investigated in the SWOG 1318 trial. In this chemo-free protocol, the bispecific antibody was given as an induction treatment for two cycles followed by an additional three consolidation cycles and POMP maintenance. Treatment was well tolerated, with no early deaths reported during the induction phase. Of the 29 evaluable patients (median age of 75 years), two-thirds obtained a complete response, with an estimated 3-year DFS and OS of 37% and 37%, respectively . In lineIn the Ph-positive setting, the introduction of tyrosine kinase inhibitors (TKIs) radically changed the natural history of this otherwise poor-prognosis subset. Given the high prevalence of older patients in this subset of BCP-ALL patients, several studies investigated the association of different TKIs with less-intensive chemotherapy, showing a high rate of induction responses and a lower induction toxic mortality, although the best consolidation strategy is still a matter of debate . In thisFollowing pioneering studies showing a high remission rate with TKIs only ,97,98, tThe recent and ongoing clinical trials on frontline immunotherapy in Ph+ ALL are available in the Among patients who relapsed after the immunotherapies, different mechanisms of escape have been described, and new studies are now investigating the efficacy of new combinations of treatments that target those pathways. In the patients who relapsed after blinatumomab, there is evidence that leukemic cells and the tumor microenvironment can lead to T-cell suppression. In particular, PD-L1 overexpression on BCP-ALL blasts and the upregulation of T-reg cells have been described as possible phenomena of resistance in relapsed patients . Thus, tBased on the results obtained in the R/R setting showing the ability of immunotherapies to induce not only hematologic but also molecular remission, several trials are currently evaluating their use as part of frontline treatments. All these trials may lead to the development of an innovative combination of chemoimmunotherapies for patients with ALL with less toxicity and to the establishment of their best positioning in future upfront therapeutic regimens with the goal of increasing the rate and quality of deep molecular responses in ALL . In our


Frontline Healthcare provider (HCP) burnout has dramatically increased due to the COVID 19 pandemic. Hospitals are supporting wellness programs and techniques to reduce burnout including the Transcendental Meditation (TM) technique. This study evaluated the use of TM on HCP symptoms of stress, burnout and wellness.A total of 65 HCPs at three South Florida hospitals were recruited and instructed in the TM technique which they practiced at home for 20 minutes twice a day. A parallel lifestyle as usual control group was enrolled. Validated measurement scales (Brief Symptom Inventory 18 (BSI-18), Insomnia Severity Index (ISI), Maslach Burnout Inventory-Human Services Survey [MBI-HSS (MP)] and the Warwick Edinburgh Mental Well Being Scale (WEMWBS) were administered at baseline, 2 weeks, one and three months.No significant demographic differences were seen between the 2 groups; however, some baseline scales were higher in the TM group. TM average weekly session completion rate was very high at 83%. After 2-weeks, symptoms of somatization, depression, and anxiety in the TM group had all shown near 45% reductions, while insomnia, emotional exhaustion, and well-being had improved by 33%, 16%, and 11% respectively ; no significant change was noted in the LAU group. At 3-months, in the TM group, the improvement in symptoms showed a mean reduction of in anxiety, 62%, somatization, 58%, depression, 50%, insomnia, 44%, emotional exhaustion 40%, depersonalization, 42%, and improvement of well-being 18% . P-values for between-group differences in change from baseline, based upon repeated measures ANCOVA covarying for baseline measurements, showed significance for all scales at 3-months.The study confirmed the reported significant and rapid benefits of the practice of TM and demonstrated its positive psychological impact on healthcare workers in a high stress setting. Healthcare provider (HCP) burnout is a national crisis, negatively affecting patient care, and contributing to provider shortages—at a cost of an estimated 4.5 billion dollars annually , 2. BurnThe COVID-19 pandemic has greatly magnified this ongoing issue of HCP burnout and has led to a marked increase in HCP stress levels , 9. In tTranscendental Meditation (TM) is a mind-body program that allows the practitioner to experience progressively quieter, less excited states of mental activity, with the growing experience of restful alertness in mind and body . It has This study was designed to evaluate the impact of TM on HCP symptoms of stress and burnout, wellness, at three Miami-based hospitals. We hypothesized that consistent practice of TM would quickly and significantly improve symptoms of burnout, insomnia, somatization, anxiety, depression, and overall wellbeing amongst healthcare workers.Sixty-five hospital-based healthcare providers (HCPs) volunteered for instruction in TM beginning in June 2020 at three Miami area hospitals: Baptist Hospital, Mercy Hospital, Encompass Hospital. A parallel control group of similar numbers of HCPs at each institution were also recruited, and matched to the extent possible for gender, age, type of HCP , and work schedule . Validated measurement scales were used to assess burnout and symptoms such as anxiety, depression, insomnia as well as well-being. The total duration of the subject study period was 3 months with the total study duration being 12 months.CT.gov Identifiers: NCT05239429.This study was carried out using GCP guidance and approved by US IRB, Miami Florida 104 (US IRB- CCCR 2020/01). Written informed consent was obtained from all participants. A total of 65 HCP at the 3 hospitals were recruited to volunteer for TM instruction. They received instruction at no charge and were reimbursed for their time for filling out the outcome measures. The parallel control group of 65 HCP was likewise recruited and reimbursed for their time filling out the outcome measures. The total n of 130 subjects was chosen based on previous studies  and our Subjects who met all of the following criteria were eligible for this study:Fulltime healthcare providers, medical doctors, physician assistants, nurses or other HCPs involved in active patient care or direct hospital administration.18 years or olderHaving treated COVID-19 patients or working at locations where COVID-19 patients are being treatedWilling to complete both baseline and post-testing as noted aboveIf being treated with psychoactive medications, the maintenance of a stable regimen for at least two months before enrollment.In the active treatment group, willing to dedicate the time to learning the TM technique and practicing it twice daily for approximately 20 minutes each time.Subjects who met any of the following criteria were not eligible for this study:Already instructed in the TM techniqueCurrently unstable psychiatric symptoms as demonstrated by self-report, medical chart, or psychiatric hospitalizations in the past six months;Transcendental Meditation (TM): TM is an effortless technique that produces a state of “restful alertness” associated with a more integrated style of brain functioning. TM was taught to participants by certified instructors of the program in a standardized format, delivered either in-person or remotely via a mobile application Two certified and experienced TM instructors conducted the instruction. The TM teachers were thoroughly trained in the teaching of the TM program, including teaching the initial course of instruction, verifying continued correctness of effortless practice of the technique, and conducting additional follow-up sessions. Initially, subjects were instructed in the technique in-person at official TM Centers, but the COVID-19 surge in South Florida prompted a transition to a system of remote instruction via a smartphone application.TM instruction involves 10 total sessions over 12 weeks. The core training in the TM technique is completed over five sessions. The five core instruction sessions include: a) Introductory/Preparatory Lecture—review of previous scientific research on the TM program and a discussion of the mechanics and origin of the TM technique; b) Personal Instruction—individual one-on-one instruction in the TM technique (75 minutes); c) First Day of Verification of Correct Practice and Further Instruction (75 minutes-group session); d) Second Day of Verification of Correct Practice—understanding the mechanics of the TM technique from personal experiences (75 minutes-group session); e) Third Day of Verification of Correct Practice—understanding the mechanics of the development of higher human potential and wellness (75 minutes-group session).Following the initial phase of the intervention (5 sessions), there are 3 additional group sessions, each 45 minutes in duration, provided once a month for the remainder of the 3-month intervention period. These sessions include: a) discussion of personal experiences and verification of correctness of practice of the TM technique, and b) knowledge of human potential and its relationship to mental and physical health.Home practice consisted of two 20-minute TM session–daily—morning and evening. Participants completed a practice diary to record sessions completed either using a paper diary or mobile phone-based survey sent using text-message reminders.Subjects in the control group continued with their usual lifestyle, with no TM instruction.Study outcomes were assessed at baseline, 2-weeks, 1-month, and 3-months posttest in both the TM and control group. The TM group also filled out daily diaries to chart their compliance with the TM technique.At the outset of the study, we attempted to use physical diaries distributed at the baseline visit and planned in-person follow-up visits, where study staff would administer paper surveys measuring the study’s endpoints. This proved to be quite difficult due to the COVID-19 pandemic, as many subjects were hesitant to take time off from their hospital duties or risk unnecessary exposure to others. We therefore developed a HIPAA and protocol compliant digital format to properly document their responses using text messages sent to subjects with links to complete the diaries and outcome measures through a secure web-based response system. This election was justified by prior research showing electronic diaries to be superior to paper diaries in achieving subject adherence .The BSI-18 was used to measure psychological distress in the study population. The BSI-18 is an 18-item scale composed of 3 six-item subscales: Somatization, Depression, and Anxiety; and a total score representing overall psychological distress. Items are each accompanied by a 5-point Likert-type scale ranging from 0  to 4 (extremely). The BSI-18 has shown good internal consistency in both subscales  and total score  .The ISI, a 7-item scale measuring severity of sleep problems, was used to measure insomnia among subjects. The ISI has satisfactory internal reliability  .The Maslach Burnout Inventory-Human Services Survey for Medical Professionals [MBI-HSS (MP)] was used to measure participant burnout in a healthcare setting. This measure has been used in prior research on TM’s impact on burnout symptoms . The MBIOverall well-being among participants was measured using the WEMWBS, a 14-item scale consisting of questions covering various aspects of well-being. Items in the WEMWBS are worded positively, and responses are organized on a 5-point Likert-type scale ranging from 1 (none of the time) to 5 . Total scores are calculated by the sum of the item scores, with higher total scores corresponding to greater mental well-being. The WEMWBS has shown strong internal reliability in a sample of the general population  .T-tests for independent samples were performed to compare TM and control groups on continuous demographic variables  and on outcomes measurements at baseline. On all other demographic characteristics chi-square tests were used to compare the two groups. Changes within each group from baseline to each posttest were evaluated using paired t-tests. To compare the two groups on changes in each outcome measure from baseline to the posttest measurements, data were analyzed using a multilevel linear mixed model for repeated measures, covarying for baseline values of the outcome measure. Effect sizes for between- group differences were expressed as the difference between groups on adjusted mean change from baseline to 3-months posttest, divided by the standard deviation at baseline. The statistical analyses were performed using IBM SPSS version 26.Overall, 124 subjects completed the trial through 2-weeks , 123 through one month , and 116 through 3-months  . SubjectOn a percent change basis, dramatic improvements were seen in TM group outcomes compared to controls, as shown in Tables Results for the between-groups comparisons controlling for baseline differences are shown in The results of this study indicate that the Transcendental Meditation technique appears to rapidly and dramatically reduce symptoms of HCP burnout, insomnia, and psychological distress while also improving overall well-being. Most notably, these significant effects were seen as soon as 2-weeks posttest for all outcome measures excluding depersonalization and professional accomplishment. At 3-months post-baseline, significant decreases were found in the TM group for all outcome measures of psychological distress except professional accomplishment , with a corresponding significant improvement in mental well-being. After adjusting for baseline differences between groups, significantly greater improvements were found among TM participants over control in all measures at the 3-month mark. The strongest effects were seen in insomnia, emotional exhaustion, and overall well-being.This study expands on the growing body of literature showing the effectiveness of TM in alleviating depression, anxiety, and other psychological symptoms. A single-arm pilot study with 32 emergency clinicians at Brigham and Women’s Hospital recently showed practice of TM significantly improved burnout, well-being, and sleep problems over a 3-month intervention period. Compliance with daily practice of meditation was good, with over 80% of the physicians meditating at least once day at 4-month posttest . An uncoIn an uncontrolled study with family caregivers, significant improvement was observed in symptoms of depression, anxiety, anger/hostility, fatigue, and optimism as well as other quality of life factors . A randoA recent phase II clinical trial published in Lancet Psychiatry and funded by the U.S. Department of Defense indicated efficacy of TM to reduce PTSD symptoms, depression, total mood disturbance, and improve overall quality of life in veterans with documented PTSD. TM was found to be non-inferior to the “gold standard” trauma-focused prolonged exposure therapy (PE), and superior to an active PTSD health education (HE) control group on all study outcomes. In the TM group 60% of participants exhibited clinically significant reductions in PTSD symptoms compared to 43% for PE and 32% for HE . A recenResearch indicates that Transcendental Meditation (TM) may significantly decrease anxiety and depression in both healthy adults and chronically ill patient populations. In a randomized controlled study with heart failure patients conducted at the University of Pennsylvania Medical School, patients practicing TM showed significant decrease in depression compared to a control group participating in a health education intervention over six months . HIV andPrior research on TM funded by the National Institutes of Health over the past several decades has further shown positive effects on cardiovascular disease risk factors and clinical events , 33–35.The COVID-19 pandemic has put immense stress on HCWs, calling for a strong need for rapid and effective psychological interventions. Prior research surrounding multiple disease states has shown a strong correlation between a lack of rapid treatment effect and patient discontinuation of that medical intervention , suggestStrengths of this study include high subject compliance to use the TM technique, which is higher than previously conducted studies on health care workers using the technique , 37. AddPossible limitations of this study include a lack of prospective randomized component and some differences between the TM and parallel control group at baseline. It should also be noted that the control group was a lifestyle as usual control group rather than an active control. Additionally, subjects in the control group were necessarily aware of the absence of treatment, which may have biased their responses. There is also a potential for lack of generalizability given our selection of South Florida area hospitals, resulting in a primarily white, Hispanic subject population. In the future we suggest a much larger, multi center randomized study with a very diverse racial/ethnic group that we believe will extend these findings.Overall, this study confirmed the previously reported benefits of practice of Transcendental Meditation and demonstrated its positive psychological impact on healthcare workers in a high stress setting. The study was conducted from Fall of 2020 through the summer of 2021, encompassing the peak surge of COVID-19 in the South Florida region. This calamitous set of events created a unique opportunity to analyze the benefits of TM in a healthcare worker population facing uniquely elevated levels of distress. The effects seen in the treatment group were not only overwhelmingly positive but were observed in as quickly as two weeks, suggesting that TM be considered as a rapid intervention for HCP burnout. Given the persistent nature of the pandemic and its lasting effects on healthcare, the results of this study definitively warrant further exploration.S1 Checklist(PDF)Click here for additional data file.S1 File(PDF)Click here for additional data file.


N = 91) at one university completed surveys on COVID-19 worries, resilience, and well-being between February and March 2021. All competitions had been postponed until the Spring 2021 semester. The findings revealed a negative correlation between COVID-19 worries and well-being  and a positive correlation between resilience and well-being . Additionally, multiple regression and simple slopes analyses showed that individuals with higher resilience endorsed greater scores of well-being, even when COVID-19 worries increased . In conclusion, our results suggest that resilience had a moderating effect on the relationship between COVID-19 worries and well-being.The onset of the COVID-19 pandemic was associated with robust declines in well-being for collegiate student-athletes. Worries about COVID-19 have frequently been associated with worsening well-being; therefore, it is important to examine protective factors against well-being decrements. Resilience, one's ability to respond to stress and adversity, may be one such factor. Despite this possible influence, resilience has not yet been studied in student-athletes in this context as the pandemic has progressed. Therefore, the purpose of this study was to examine the moderating role of resilience on the relationship between COVID-19 worries and well-being. In this cross-sectional design, National Collegiate Athletic Association Division III athletes ( On March 11th, 2020, the World Health Organization recognized the coronavirus disease of 2019 (COVID-19) as a pandemic  COVID-19 worries would be negatively associated with MWB, (2) resilience would be positively associated with MWB, and (3) resilience would moderate the relationship between COVID-19 worries and MWB such that the adverse relationship of COVID-19 worries on MWB would be weaker for athletes higher in resilience.M = 19.8, SD = 1.2) and participate in NCAA DIII varsity sports. No participants were excluded from the study if they met eligibility requirements. Initially, 97 participants completed the online questionnaires. However, due to a technological error, the first six participants were unable to complete the resilience measure. Therefore, the final sample consisted of 91 participants . Overall, student-athletes were recruited from 11 sports at a single institution and were between 18 and 23 years of age . The sample was 77% White and spread amongst first-year (n = 29), sophomore (n = 21), junior (n = 23), senior (n = 14), and graduate (n = 4) students.To be eligible for this study, all participants were required to be at least 18 years of age  to 4 . Higher scores indicate higher resilience. The 10-item variation is reliable (Cronbach's a = 0.85) and valid  to 7 (strongly agree). A sample item is “I live a purposeful and meaningful life.” Higher scores indicate more flourishing. Validation testing was conducted on international, geographically diverse, college students and is reliable (Cronbach's a = 0.87) and temporally stable (0.71). The Flourishing Scale has high convergent validity and was strongly correlated with similar well-being scales  to 5 (strongly applies) to gauge participant responses to: “I am nervous when I think about current circumstances,” “I am worried about my health,” “I am worried about the health of my family members,” and “I feel stressed about leaving my house.” This scale was highly reliable (Cronbach's a = 0.81) in a sample of college student-athletes .We measured COVID-19 worries using a 4-item scale designed for suggested use in the pandemic  at the university. The emails informed coaches about the nature of the study and requested that they disseminated the study to their respective student-athletes. Prospective participants received relevant information about the study, including the survey link and informed consent document, which participants completed before beginning the study. The survey stayed open for 2 weeks between February and March 2021. This survey was conducted using a Google Form restricted to the institution. The participants did not receive compensation.Preliminary analyses entailed estimating bivariate correlations between study variables. To test the primary study aims, multiple linear regression models were fit iteratively to assess main effects separately from interaction effects. In the first model, the main effect of COVID-19 worries on MWB was estimated. The second model added resilience as a covariate and, finally, the third model estimated the interaction between COVID-19 worries and resilience to test the hypothesis that resilience would moderate the association between COVID-19 worries and MWB. To further probe the interaction estimated in model 3 we plotted the interaction and estimated simple slopes of the association between COVID-19 worries and MWB at +/-1 standard deviation on resilience . Regression models controlled for participants' age, gender , race/ethnicity , and year in school. Analytic models were estimated in R software. All alphas were set at 0.05 to determine statistical significance.Excluding the previously described missing data for six participants on the CD-RISC, there was no other missing data. A preliminary screening suggested normally distributed data that met all assumptions for multiple regression analyses.Descriptive statistics and bivariate correlation coefficients are shown in positive association between COVID-19 worries and MWB (shown in the green solid line) indicating that those who reported more COVID-19 worries indeed reported greater MWB.The primary results, multiple linear regression models, are displayed in The purpose of the current study was to extend our understanding of COVID-19 worries on student-athletes' MWB by examining potential protective effects of resilience. Study findings only provided partial support of the first hypothesis that COVID-19 worries would be negatively associated with MWB; despite a significant correlation, the effect in the regression analysis narrowly missed the traditional statistical significance threshold when worries were measured on their own. In the final model, worries were once again significant. This nevertheless aligns with the results from several other COVID-19 era studies uncovering an inverse relationship between fear and worries of the virus and mental health and MWB (e.g., Bullard, We also found that resilience was positively correlated to and predictive of MWB, supporting our second hypothesis. This confirms the results of several other studies indicating that such a relationship exists (e.g., Killgore et al., The most unique contribution of our study was the moderating role of resilience on MWB. The results supported our third hypothesis that resilience would buffer the relationship between COVID-19 worries and MWB. This finding supports previous research indicating that resilience buffered the relationship between various negative pandemic related constructs and MWB (e.g., Killgore et al., increased as their COVID-19 worries increased. Although this finding seems somewhat counterintuitive, the current body of research on resilience in the pandemic offers some clues.Despite our hypothesis that this would occur, the strength and direction of the relationship between high resilience and MWB was somewhat unexpected. Specifically, there was a trend toward significance that for individuals with lower resilience, their MWB decreased as their worry increased. For those with high levels of resilience, their MWB actually The difference in MWB outcomes for those with high vs. low resilience throughout the course of the pandemic has been somewhat drastic (e.g., Paredes et al., One explanation for these findings could be the connection between coping behaviors and other traits often associated with resilience. For example, in a large sample of Italian participants, individuals with low resilience reported more maladaptive coping mechanisms than people with high resilience (Sampogna et al., The results of our study suggest that developing resilience in student-athletes could alleviate possible detriments to their MWB associated with the pandemic, which may generalize to other adverse circumstances that place high levels of strain on their lives and athletics. Although one long-term effect of the outbreak might be the growth of resilience (PeConga et al., Several authors have outlined suggestions on how to develop resilience (Fletcher and Sarkar, Much of the research on resilience in the pandemic suffers from cross-sectional designs with small sample sizes from single locations (Manchia et al., Despite these limitations, our study has several strengths. A majority of the currently published research explores the impact of the pandemic immediately in the aftermath of the pandemic declaration, season cancellations, and the onset of lockdowns (Kocjan et al., That main finding opens up several avenues for future research. In general, there is a continued need to monitor the various stressors and responses in resilience research (Den Hartigh et al., The results of our study indicate that resilience might be an important protective factor for MWB in collegiate student-athletes during the pandemic. Participants with greater resilience reported higher MWB, even with higher levels of COVID-19 worries. The continued existence of worries during the Spring 2021 semester suggest that athletic departments and stakeholders should still be working to ensure the health and MWB of their student-athletes. Specifically, implementing resilience training programs led by qualified individuals could lead to an overall improvement in the student-athlete experience.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Shenandoah University Institutional Review Board. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.CW and RH contributed to conception and design of the study. CW collected and organized the data. SG performed the statistical analysis. RH provided supervision over the project. All authors wrote sections of the first draft of the manuscript. All authors contributed revisions, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.