Infection of endothelial cells results in the exocytosis of WeibelPalade bodies. These contain the Von Willebrand Factor responsible for micro-clotting and angiopoietin-2 which increases vascular permeability and plays a key role in the Acute Respiratory Distress Syndrome. To test this hypothesis this paper reports proof of concept studies in which MR blockade using spironolactone and low dose dexamethasone (SpiDex) was given to PCR-confirmed COVID-19 patients. In 80 patients with moderate to severe respiratory failure 40 were given SpiDex and 40 conventional treatment with high dose dexamethasone (HiDex). There was 1 death in the HiDex group and none in the SpiDex. As judged by clinical, biochemical and radiological parameters there were clear statistically significant benefits of SpiDex in comparison to HiDex. A further 20 outpatients with COVID-19 were given SpiDex. There was no control group and the aim was to demonstrate safety. No adverse effects were noted and no patient became hyperkalaemic. 90% were asymptomatic at 10 days. The very positive results suggest that blockade of the MR can produce major benefit in COVID19 patients. Further larger controlled studies of inpatients and outpatients are required not only for SARS-CoV-2 infection per se but also to determine if this treatment affects the incidence of Long COVID.This paper suggests that ATP release induced by the SARS-CoV-2 virus plays a key role in the genesis of the major symptoms and complications of COVID-19. Infection of specific cells which contain the Angiotensin-Converting Enzyme 2 (ACE2) receptor results in a loss of protection of the Mineralocorticoid Receptor (MR). Local activation by cortisol stimulates the release of ATP initially into the basolateral compartment and then by lysosomal exocytosis from the cell surface. This then acts on adjacent cells. In the nose ATP acts as a nociceptive stimulus which results in anosmia. It is suggested that a similar paracrine mechanism is responsible for the loss of taste. In the lung ATP release from type 2 alveolar cells produces the non-productive cough by acting on purinergic receptors on adjacent neuroepithelial cells and activating,  Early in the course of the SARS-CoV-2 pandemic it became clear that one of the commonest symptoms was loss of smell and/or taste. Self-reported alterations in smell and taste were detailed in a meta-analysis of 3563 confirmed cases of COVID-19  cells and in the cells of Bowman’s gland in both human and mice olfactory cells Figure 1As with the nose ACE2 receptors are not found in the taste bud receptor cells . StudiesThus the SARS-CoV-2 virus causes a very high incidence of anosmia and ageusia, often with no clinical evidence of an inflammatory response, but without directly infecting the olfactory nerves and taste buds. In the nose this appears to be by infecting adjacent cells. In the mouth the most likely targets would seem to be non-gustatory filiform papillae and salivary glands. This paper suggests that it is the release of ATP by cells infected by the virus that is responsible. The role that this mechanism might play in the complications of COVID-19 has been previously published . That woAfter the SARS-CoV-2 virus enters the cell using the ACE2 receptor this results in a failure of ACE2 conversion of angiotensin II to angiotensin (1-7). High levels of angiotensin II stimulate NADPH oxidase and hence produce high levels of Reactive Oxygen Species (ROS).The key cells infected by the virus in the nose, salivary glands and in the lung  Figure 1Oxidative stress produces loss of the normal MR protective mechanism resulting in cortisol activation of the receptor in man and by corticosterone in rats , 11–13. Using epithelial cells we have shown that the addition of aldosterone produced a rapid release of ATP from the basolateral aspects of the cells . Using Sin vivo and in vitro experiments have shown that apical P2 receptors inhibit sodium reabsorption in collecting ducts .The oxidative damage produced by ROS has a series of consequences including loss of the protection of the Mineralocorticoid Receptor (MR) and activation of ATP accumulation in lysosomes. The lysosomes move to the periphery of the cell.Cortisol activates the unprotected MR which stimulates the release of ATP into the basolateral compartment of the cell. This then acts on purinergic receptors which open Ca++ channels.The increase in intracellular calcium stimulates contraction of the cell and exocytosis of the ATP containing lysosomes from the apical surface of the cell with consequent high levels of extracellular ATP.Purinergic receptors play a key role in both taste and smell , 22. ATPOne of the authors (CRWE)has previously suggested that the mechanism described above for loss of smell and taste with COVID-19 is also responsible for the non-productive cough that is a common presentation in patients infected with the SARS-CoV-2 virus . The virElevated inflammatory cytokines play an important role in the pathogenesis of severe COVID even though the evidence for a cytokine storm is debated . The NLRExperiments using endothelial cells have shown that activation of the Mineralocorticoid Receptor stimulates the release of ATP, activates purinergic receptors, increases intracellular calcium and hence exocytosis of Weibel-Palade bodies . These cA recent study has shown that the expression of ACE2 differs markedly between endothelial and epithelial cells . The autKaneko et al.  looked aOf particular interest was that they coated the 3D models with fibronectin and then seeded them with endothelial cells. In stable blood vessels endothelial cells rest on a basement membrane consisting mainly of laminin and type IV collagen. This changes to fibronectin in unstable cells and is a key part of vascular remodelling in vascular disease . Thus paIf cortisol activation of the Mineralocorticoid Receptor (MR) is playing a key role in the pathogenesis of COVID-19 and its complications it suggests that MR blockade could be an effective therapy. In this context it is vital to appreciate that free cortisol circulates at 250 times higher levels than free aldosterone. Thus, if MR receptor blockers alone are used they have to be given at a higher than normal dose. An alternative is to combine the MR blocking drug with dexamethasone, not as an anti-inflammatory drug, but to suppress cortisol secretion. Dexamethasone unlike cortisol does not bind to the MR. Some very important evidence suggests that MR receptor blocking drugs may be very useful in both severe and mild COVID-19.Vicenzi et al.  gave canDoes MR receptor blockade have any effect if it is given earlier in the disease? The evidence here is limited but a paper by Lin et al.  is of paAnti-viral treatment alone in various combinations  had no significant effect on lowering viral detection beyond 7 days, recovery in less than 7 days or symptoms lasting less than 7 days. Adding spironolactone (100mg twice daily until recovery) to AZI+HCQ significantly reduced viral detection beyond 7 days (p<0.011), recovery beyond 7 days (p<0.001) and symptoms greater than 7 days ((p<0.0066). The most effective combination was adding spironolactone to AZI+NTZ . Unfortunately, they did not test spironolactone alone. Dutasteride also had a significant effect when given with AZI+NTZ but only 28 patients were given this. The authors suggested that the benefits of the drugs were in relation to the role of the androgen protease TMPRSS2, the cell surface protein that primes the viral spike protein and enables viral cell entry. The dose of spironolactone used is highly likely to have produced Mineralocorticoid Receptor blockade. Unfortunately, in their multivariate logistic regression of symptoms they did not include anosmia or ageusia so the effect of treatment on this was unclear.To determine if spironolactone and low dose dexamethasone were effective in the treatment of COVID-19 we have carried out the following studies.A series of 80 consecutive patients with PCR-confirmed COVID-19. All patients were hospitalised for radiologically confirmed pneumonia due to SARS-CoV-2 infection and were cared for in the Vinnytsia Hospital Infection Unit. All patients received usual care treatment which included: Ceftriaxone 2 g/day intravenously, Ambroxol 90 mg/day orally, Enoxaparine 0.6 ml (6000 IU subcutaneously daily).40 patients were given dexamethasone 16 mg orally per day for 10 days (HiDex group I) and 40 given dexamethasone 4 mg per day and spironolactone 100 mg per day for 10 days (SpiDex group II). Clinical characteristics, co-morbidities and clinical parameters of the patients are listed in Table 1General characteristics, clinical parameters at baseline of Study 1.Before treatment and after 5 days on either HiIDex (Group I) or SpiDex (Group II) body temperature, cough frequency, blood pressure, respiratory rate, and blood oxygen levels (%) were recorded. C-reactive protein (CRP), D-dimer, and fasting blood glucose were determined at the same time. Chest X-rays were taken prior to treatment and on day 5 after starting treatment. Composite outcomes including clinical improvement, radiological evidence of pneumonia resolution or deterioration, need for invasive ventilatory support and/or all-cause inhospital mortality were noted during in-hospital follow-up.This was a study of the safety of treating 20 outpatients with PCR-confirmed COVID-19 without pneumonia within 2-3 days of first symptoms. They were treated with dexamethasone 4 mg daily and spironolactone 100 mg daily. The general characteristics, co-morbidities and clinical parameters of these patients are listed in For normally-distributed demographics and clinical characteristics, data were expressed as the mean and standard deviation. Frequencies and percentages were calculated for categorical variables. The differences between the groups defined as receiving HiDex or SpiDex therapy were compared using Student’s t test. A p value of <0.05 was considered to be statistically significant.All standard biosecurity and institutional safety procedures were adhered to.The results of study 1 comparing high dose dexamethasone (HiDex- Group 1) with low dose dexamethasone and spironolactone (SpiDex Group II) are shown in Table 2Study 1. Repeated measures analysis comparing changes in variables from baseline to 5 days treatment (T1).The results of the outpatient study designed to test the safety of the regimen are given in This paper tries to explain the consequences of the SARS-CoV-2 virus infecting key cells which express ACE2 receptors, mineralocorticoid receptors and the cortisol inactivating enzyme 11βHSD2. These cells are normally aldosterone selective but SARS-CoV-2 infection results in a loss of the specificity of the mineralocorticoid receptor protective mechanism. It is well known that the MR can be activated by normal levels of glucocorticoids when tissues are damaged by Reactive Oxygen Species generation , 34. SARThis loss of MR selectivity allows cortisol to activate the MR and stimulate the basolateral release of ATP. The subsequent increase in intracellular calcium following purinergic receptor activation then stimulates the exocytosis of the ATP containing lysosomes. This is similar to the process that has been described for the exocytosis of Weibel-Palade bodies from endothelial cells , 27. It The two proof of concept studies produce important evidence that favours the hypothesis. In the first inpatient study we compared high dose dexamethasone with low dose dexamethasone and spironolactone. In the outpatient study we used low dose dexamethasone and spironolactone and had no control group given dexamethasone alone. This was on the basis of the observations made in the RECOVERY study which showed that patients with COVID-19 who were not on oxygen did not benefit from dexamethasone .via lowering extracellular ATP levels. Freeman and Swartz . In the outpatient study 90% of the patients had loss of taste and smell at baseline but only 1 patient (5%) had this symptom after 10 days of SpiDex treatment.The mechanism by which the SARS-CoV-2 virus gets into cells using the ACE2 receptor has been extensively studied. Much less well understood is how the virus exits the cell. An important paper by Ghosh et al.  has suggAs discussed above ATP can be released from the cell by lysosomal exocytosis. This raises a fascinating question – could inhibition of the release of lysosomes have an effect on both ATP and SARS-CoV-2 exocytosis? The evidence reviewed above demonstrates that MR blockade can inhibit the release of ATP. The results obtained by Lin et al.  showed tIn addition to its conventional diuretic effect and its inhibition of exocytosis it is of interest that MR receptor antagonism with spironolactone has been shown to markedly increase the synthesis and expression of ACE2 receptors . If the If this hypothesis is correct then following your nose may provide an important clue as to how the SARS-CoV-2 works and also provide insight into how this very challenging condition can be treated.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the University Bioethical Committee, Vinnytsia National Pirogov Memorial Medical University, Vinnytsia, Ukraine. The patients/participants provided their written informed consent to participate in this study.CE - hypothesis, original clinical studies on specificity of MR, purinergic receptors, and ATP release. OK- clinical studies in Ukraine. LH - clinical studies in Ukraine. YK- laboratory studies using scanning ion conductance microscopy to study action of aldosterone. All authors contributed to the article 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.


The transient occlusion of the terminal thoracic duct is a rare disease responsible for renitent supraclavicular cysts. The aim of this study was to describe the clinical characteristics, evolution, and treatment.A retrospective multicenter study and literature review was carried out. The literature search (PubMed) was conducted including data up to 31 December 2020 and PRISMA guidelines were respected.This study identified 6 observational cases between September 2010 and December 2020. The search results indicated a total of 24 articles of which 19 were excluded due to the lack of recurrent swelling or the unavailability of full texts (n = 5). Fourteen patients (8 from literature) mostly reported a noninflammatory, painless renitent mass in the supraclavicular fossa which appeared rapidly over a few hours and disappeared spontaneously over an average of 8 days (range: from about 2 hours to 10 days). Anamnesis indicated a high-fat intake during the preceding days in all cases and 7 from literature found in the Medline databases. Recurrences were noted in 10 patients. Thoracic duct imaging was performed in all cases to detect abnormalities or extrinsic compression as well as to eliminate differential diagnoses.A painless, fluctuating, noninflammatory, and recurrent swelling of the left supraclavicular fossa in patients evoking an intermittent obstruction of the terminal portion of the thoracic duct was identified. A low-fat diet was found as safe and effective treatment. The thoracic duct extends superiorly in the posterior mediastinum to collect thoracic lymph via posterior intercostal channels to empty into the junction of the left subclavian and jugular veins.,3 The pathogenesis of these cysts includes congenital weakness in the duct wall, an acquired inflammatory process, as well as the postoperative or traumatic disruption of lymphatic drainage. When supraclavicular cysts are persistent, patients are most often referred to a surgeon who will discuss surgical intervention which most often results in thoracic duct ligation and includes lymphovenous anastomosis.–9 Less frequently, paroxysmal cysts of the terminal part of the duct appear as a renitent mass above the left clavicle.–12 Diagnosis can be difficult in these cases and physical examinations or imaging might be performed after the mass has disappeared. The aim of this study was to describe and review cases of recurrent lymphangiectasia of the left supraclavicular fossa. The epidemiological, clinical, evolutionary, and therapeutic aspects of this rare occurrence were also analyzed. Cases were collected according to 2 methods. The first was a case collection from memory from the centers of Lyon, Clermont-Ferrand, and Le-Puy-En-Velay from September 2010 to October 2020. The second was completed with a systematic review of the literature.Even though it is rare, lymphoceles or cysts on the terminal part of the duct can develop and become permanent supraclavicular masses.2The Departments of Internal Medicine at Le-Puy-En-Velay, Lyon, and Clermont-Ferrand were first contacted to collect memory observational cases of recurrent thoracic duct cyst of the left supraclavicular fossa. This initial process resulted in 6 observations from September 2010 to December 2020. Information on the study and its written consent was sent to all patients involved. Institutional review board of the hospital of Le-Puy-En-Velay approved the study. The search parameters were limited to Medline databases which included PubMed and the National Library of Medicine in Bethesda, MD. Publication titles and abstracts were initially screened followed by a reading of the full applicable texts. Original papers published in English or French were eligible for inclusion.The literature review was based on a search for articles concerning intermittent terminal thoracic duct cysts that were published before December 31, 2020 and performed according to the PRISMA guidelines.The following PubMed search strategy was used: ((thoracic duct [MeSH Terms]) AND (cyst [MeSH Terms])) OR (lymphangiectasia [MeSH Terms]). All articles were selected without time restrictions. Reference lists of articles were scanned for references not initially identified in the primary search. No exclusions for study type, sample size, or setting were applied. The extracted variables consisted of the type of study, age, gender distribution, disease duration, recurrences (both in number and frequency), complications, triggering factors, treatment, and the duration of follow-up. Studies fulfilling these inclusion criteria were reviewed by all authors.All titles that were irrelevant to this study were excluded during the first identification phase. Only articles that contained clinical data about recurrent thoracic duct cysts around the left supraclavicular fossa were retained. Abdominal or intestinal cysts, as well as permanent supraclavicular thoracic duct cysts were rejected. Studies containing only therapeutic or radiological data were not considered for the following case descriptions. Risk of biases was not evaluated because of all the studies were case reports.https://www.crd.york.ac.uk/prospero/, (number CRD42021246163) and the protocol was not prepared. Authors declare no conflict of interest.The study was registered on 3Six observational cases were identified by contacting the internal medicine departments of 3 hospitals in southeastern France  from September 2010 to December 2020. The following are descriptions of these original series (n = 6) of observational cases 1 to 6.3.1A 50-year-old man with a medical history of surgery for an inguinal hernia was urgently admitted for a left supraclavicular swelling which appeared when he woke up the same morning. He was not taking any medication and there was no history of occupational exposure. The mass was neither painful nor inflamed and subsequent laboratory tests were clear. A computed tomography (CT)-scan showed an infiltration of the soft tissue located on the left side of the neck and in the posterior mediastinum. The left internal jugular vein appeared tubular which suggested thoracic duct thrombosis. There was also an upstream expansion associated with a minor pleurisy on the left side Fig. . A Doppl3.2A 74-year-old woman was admitted to the hospital because of a sudden swelling of the left supraclavicular fossa. She had a history of high blood pressure and hypothyroidism due to a partial thyroidectomy. She had taken L-thyroxin and an angiotensin-converting enzyme inhibitor. One year prior, she suffered from a similar episode which resolved itself within a few days without treatment. A high-fat meal and alcohol intake preceded both of these events. Laboratory tests were normal, however, a CT-scan showed a minor bilateral pleural effusion (predominant on the left side), an infiltration of the left side of the neck expanding to the left hollow armpit and the mediastinum, several supraclavicular adenomegalies, and an unraveled appearance of the left internal jugular vein which was deemed congruent with a possible thrombosis. An anticoagulant therapy was therefore started. Doppler ultrasound was performed 72 hours after admission and did not reveal any thrombosis and treatment was discontinued. The patient's outcome was spontaneously favorable in 24 to 48 hours and a CT-scan was subsequently performed later which came back normal.3.3A 45-year-old woman was seen in the internal medicine unit complaining of pain in the left supraclavicular fossa. She had a history of right shoulder surgery for calcifying tendinopathy following corticoid infiltration and she complained of headaches. She was using a copper intrauterine device but was not taking any medication. For a few months, she experienced night sweats without any weight loss and for 1 month, she suffered from a painful swelling of her left supraclavicular fossa as well as difficulties in swallowing. Fifteen days after the onset of these symptoms, she had a fever lasting 24 hours. Ultrasonography was performed which showed inflamed and infiltrated subcutaneous tissue on the supraclavicular fossa and on the omohyoid muscle. A CT-scan confirmed the findings and also indicated an extended inflammatory infiltrate in the retroperitoneum. Laboratory tests were normal. During examination, the patient was in good general condition; however, there was a swollen and painful mass on her left supraclavicular fossa. During an abdominal examination, there was pain in the right hypochondrium and iliac fossa. The outcome was spontaneously favorable within 48 to 72 hours. A magnetic resonance imaging (MRI) scan of the thoracic duct showed a small cyst on the cervical portion. After 3 years of follow-up, no recurrence occurred.3.4 on both sides with the left side impregnation being the slowest. There was also a 14 mm adenopathy. Simple monitoring was proposed.A 65-year-old woman was seen in the internal medicine unit for an intermittent swelling of her left supraclavicular fossa located on a preexisting area of chronic infiltrations Fig. . Her med3.5A 64-year-old woman was referred for an internal medicine consultation for reoccurrence of diffuse abdominal pain associated with a left supraclavicular edema  with recurrent duct cysts of the left supraclavicular fossa. The first case had recurrent swelling for 3 months and the diagnostic was established by echography, MRI and surgery (lymphatic fluid in the cyst). The second case patient had a recurrent mass in the left supraclavicular fossa for 7 months corresponding to a duct cyst after being detected with an echography, RMI, and surgery. The third case had swelling in the left supraclavicular fossa for 10 years. Diagnosis of the duct cyst was made by echography, tomodensitometry, and surgery. The last case consulted for a mass in the left supraclavicular fossa for several weeks. Echography, tomodensitometry, and surgery made the diagnostic of these recurrent thoracic duct cysts. All 4 patients did not have a significant medical history and took estrogen-containing medication at the onset of neck mass enlargement. Surgery was performed because the cyst was cosmetically disturbing (mass were noninflammatory). Recurrence after surgery only appeared in the fourth case.4.Zatterstrom et al reported the follow-up of a 55-year-old man who was consulted 25 years ago for a fluctuant supraclavicular mass that appeared a few months before. The diagnosis was established by tomodensitometry, fluid puncture, and pedal lymphography. No treatment was made. Nine years after, there was a progression of the cyst, followed by the cyst diminishing spontaneously 13 years later and disappearing 25 years after. Retrospectively, it was reported that a high fat diet triggered the swelling.5.Van Den Bussche et al described the case of a patient with swelling on the left side of the neck spontaneously appear . This patient was an 83-year-old woman. Echography, tomodensitometry, and puncture confirmed duct cyst. Moreover, the cyst was punctured and was kept on a medium chain triglyceride diet. No recurrence appeared at the follow-up (1 month later). The authors of the 4 articles were mostly surgeons,9,15,16 and the remaining article was written by a radiologist.The data from 8 external cases along with cases from our institutions are shown in Table Studied patients were predominately female  with only 1 case from the literature search described as a male and 1 man was included in our case reports. The mean age of patients included in this study was 51 years old  and there was no difference between our data and the literature found on Medline. All patients presented a painless mass of the left supraclavicular fossa. The mass was always noninflammatory, renitent, transient, nonpulsatile, and compressible. Palpation of the mass was painless and compressible. Clinical examinations between relapses were strictly normal. The mean duration of the episodes was 8.4 days and ranged from a few hours to 1 month with a median of 9 days . The evolution duration of the mass could only be included in 9 cases because Preyer et al did not specify this data, and Zatterström described a fluctuating mass  that had existed for 25 years and had grown constantly until a change in diet made it disappear.,16Two cases were associated with ascites and pleuritis.3.8 Two other cases showed a high-fat diet was consumed a few days before the episodes. Zatterström et al described the disappearance of the supraclavicular mass after the patient initiated a change in diet. In the cases handled by the authors of this study, a high-fat diet has been clearly identified in 4 cases and was strongly suspected in the 2 other cases since dietary intervention made it possible to resolve the symptoms.A triggering factor was identified in 12 of the 14 cases. Preyer et al assumed the intermittent obstruction of the terminal portion of the thoracic duct was due to an estrogen pill, but the article did not specify data related to the patient's diet prior to the appearance of the swelling.3.9,12 Tomodensitometry showed an inconsistent cystic mass in the left supraclavicular region combined with an infiltration of the soft tissue in the left side of the neck.,16 Tomodensitometry could also have shown pleural effusion or ascites. All subsequent examinations were normal following the acute phase. Laboratory tests were deemed normal and a lack of any inflammatory syndrome was evident.All patients underwent an ultrasound. Tomodensitometry was used in 13 cases, with an MRI in 3, and positron emission tomography scan was done for 1 case. Lymphoscintigraphy was performed in 4 cases and showed an increased delay of impregnation on the axillary lymphatic vessel. During the acute phase, ultrasound imaging showed infiltrated subcutaneous tissue with a hypoechoic mass with liquid in the left supraclavicular fossa in some cases.,9,12 a puncture of the mass was performed but none were done in any of the cases in our study. In 4 cases, no puncturing occurred because ablation was directly performed. In the observational study case of the supraclavicular mass, which was associated with pleuritis, Veziant et al completed pleural puncturing because it was more easily carried out than a puncture procedure. When punctures of mass or pleura were accomplished, a milky fluid that contained numerous lymphocytes , low albumin level , high triglycerides levels , and no abnormal cells,9,12 was found in all subjects. The biochemical analyses of this liquid were in favor of chyle.In 3 cases found in the literature search,3.10 Van den Bussche et al described a case without reoccurrence and the follow-up lasted only 1 month.The duration of patient follow-up beginning with the detection of the renitent mass to diagnosis varied greatly with a mean duration of 4.7 years . Follow-up after therapeutic intervention depended on the proposed and short follow-ups were justified because 4 patients had undergone surgery quickly after diagnosis.3.11 Eight cases received a low-fat diet alone including 2 cases of literature,,15 In 1 case a no-fat diet was proposed first and surgery was done after the first recurrence 10 years later. In 1 case, patient had a low-fat diet associated with a mass puncture without recurrence but the follow-up was short (1 month). In our subjects, dietary intervention was the only treatment and all the patients were advised on dietary rules with 2 benefiting from a strict diet of light-chain triglyceride removal. No complication was described in the case of low-fat diet. Preyer et al reported a surgical complication related to a chylous fistula.In 4 cases surgery was performed quickly after diagnosis.4This study comprised the largest set of patients with recurrent lymphangiectasia of the left supraclavicular fossa. This disorder mostly affects middle-aged women and appears as a left supraclavicular mass which is neither inflammatory nor renitent. It is transient and regresses in an average of 8 days. A recent high-fat diet is a major triggering factor. In the acute phase, lymphoscintigraphy remains the benchmark because it can reveal thoracic duct obstruction; however, this procedure is increasingly being replaced by noninvasive tests. Imaging should be repeated after the acute episode to eliminate differential diagnoses. A low-fat diet is frequently proposed and it is most often effective in preventing recurrences.–8,17–19 sequelae of a prior injury ,,15,18 lymphangioma,17,19 or hematoma. In these cases, a clinical examination and medical imaging during the acute phase should guide a clinician. The most plausible explanations for this disorder are a weakness of the thoracic duct wall.,4,16 This weakness can be congenital, related to an inflammatory process, or stem from an anatomical conflict at the angle between the left intern jugular vein and the left subclavicular vein.Overall, despite some differences regarding clinical and imaging features, the stereotypical clinical history in all cases suggests the same disease. No large-scale studies describing clinical, imaging, prognosis, or treatment parameters were found in this study. Moreover, this disease has probably been underestimated and underdiagnosed since only 6 observed cases at 3 internal medicine departments were found over a 10-year period in the medical facilities. It should, however, remain a diagnosis of exclusion and it may be therefore crucial to exclude differential diagnoses such as a tumor-like metastatic lesions, a parathyroid or thymic cyst,,16,17,20 It is important to note that the cases involved combined oral contraceptive use dated from 1995 which was at a time when the average dosage of estrogen was high. A high-fat diet can be a triggering factor because it increases pressure in the thoracic duct canal with the resulting production of chyle that is composed mainly of lymphocytes and lipid-rich fats. The designation “Nutella Syndrome” that was found in 1 publication has sometimes been used because of the link between recurrences after consumption of a high-fat meal and we propose to name it.In most of our patients, triggering factors were a high-fat diet and combined oral contraceptive use.,10 Doppler ultrasonography should be carried out first in the case of swelling of the supraclavicular fossa since it is noninvasive and can be performed quickly.,20 It may show a cystic lesion, hypoechogenic to echofree mass, with no connections to vessels, sono compressible, sharply outlined, with no internal perfusion.,10,12,18 In the acute phase, tomodensitometry can show a dilation of the thoracic duct or cysts located adjacent to the left internal jugular vein.,18 Cervical soft tissue surrounding the cyst can appear infiltrated with edematous fluid. The mass is hypoechoic, homogenous, thin-walled, and emit water attenuation signal inside.–7Thoracic duct imaging is decisive because it reveals secondary causes of dilatation and/or malformation such as lymphangioma, stenosis of the terminal valve of the thoracic duct, extrinsic compression, and venous thrombosis, all of which require specific treatment plans.,18 sometimes with dilated a thoracic duct and apparent communication of the cyst with the thoracic duct.,7 Repeating radiological examinations after the acute phase is important because an edema present in the initial phase may mask abnormalities of the terminal portion of the thoracic canal.,9 In the case of the “Nutella Syndrome,” imaging taken after the acute crisis must be normal. Lymphoscintigraphy is the benchmark because it provides a proper analysis of the shape of the thoracic duct and can measure its drainage rate.,14,19,21 Today, CT-scans and MRIs are more commonly used.An MRI can highlight bright lesions on the T1 and T2-weighted imaging results arising from the thoracic duct close to the left subclavian vessels,,21 since normal diffusion time values are from 10 to 30 minutes and considered delayed after 120 minutes. In case of dilation of the thoracic duct, it increased delay of diffusion up to the thoracic duct, without extravasation.,15,18Lymphoscintigraphy is time-consuming, invasive, and can be difficult to interpret in the absence of standardized procedures,17 When the cyst is removed, immunohistochemical analysis can show CD31 CD34 factor VIII and keratin positivity which are biomarkers of the epithelial and endothelial nature of a wall vessel, thus removing any doubt about cancer or a lymphocele.,12,15,22 Complications can occur when cysts become permanent and cause compression of the surrounding anatomical structures.,9,10In doubt of diagnosis, a puncture to the cyst can be performed to indicate a chyle-like liquid composed of 90% to 100% lymphocytes and rich in triglycerides.,17,23 because medium-chain triglycerides are directly absorbed into the portal system.,23 In our study, a dietary regime with or without total exclusion of long-chain triglyceride was offered systematically as a first step because it is safe and usually enough to control the disease. Surgical intervention is rarely considered and should be reserved for highly symptomatic and serious cases.Therapeutic treatment management is not well defined and should be guided by the patient's symptoms. According to the symptomatology, a restricted diet should be discussed first. The diet should exclude food rich in fat. If long-chain triglycerides are completely excluded from the diet, medium-chain triglyceride supplementation should be introducedOur study had several strengths. To our knowledge, it is the first literature review conducted on this disease. Of the 14 described cases, we reported 6 which had follow-ups on clinical outcomes allowing a better description of the pathology. Limitations were related to the retrospective nature of the study and lack of subsequent data. A potential recall bias may have occurred because some observations were solely based on 1 doctor's remembrance. As previously discussed, this disease is rare and potentially underdiagnosed. The prevalence of this disease is still unknown and other studies are required to determine its overall prevalence, clinical presentation, evolution, and pathophysiology with more accuracy.5An intermittent swelling of the left supraclavicular fossa should raise suspicion that an intermittent cyst may be in the terminal portion of the thoracic duct. It is important to look for any unusual intake of high-fat foods preceding symptoms. Thoracic duct imaging is crucial to eliminate differential diagnoses. Lymphography remains the benchmark for diagnosis, however, noninvasive imaging technics (MRI or CT-scan) are currently preferred. In most cases, therapeutic management is a conservative way to manage this disease with dietary intervention consisting of a low-fat diet.Conceptualization: Julie Planchette, Benjamin Castagne, Anne-Sophie Resseguier, Pascal Seve.Investigation: Julie Planchette, Clara Jaccard, Audrey Nigron, Jean-Baptiste Chadeyras, Guillaume Le Guenno, Benjamin Castagne, Anne-Sophie Resseguier, Pascal Seve.Methodology: Julie Planchette.Supervision: Yvan Jamilloux, Pascal Seve.Writing – review & editing: Yvan Jamilloux, Pascal Seve.


A 24-week self-directed digitally delivered intervention was found to improve pain and function in people with knee osteoarthritis (OA). However, it is possible that this intervention may be better suited to certain subgroups of people with knee OA compared to others.The aim of this study was to explore whether certain individual baseline characteristics moderate the effects of a self-directed digitally delivered intervention on changes in pain and function over 24 weeks in people with knee OA.An exploratory analysis was conducted on data from a randomized controlled trial involving 206 people with a clinical diagnosis of knee OA. This trial compared a self-directed digitally delivered intervention comprising of web-based education, exercise, and physical activity program supported by automated exercise behavior change mobile phone text messages to web-based education alone (control). The primary outcomes were changes in overall knee pain  and physical function  at 24 weeks. Five baseline patient characteristics were selected as the potential moderators: (1) number of comorbidities, (2) number of other painful joints, (3) pain self-efficacy, (4) exercise self-efficacy, and (5) self-perceived importance of exercise. Separate linear regression models for each primary outcome and each potential moderator were fit, including treatment group, moderator, and interaction between treatment group and moderator, adjusting for the outcome at baseline.P=.02). Posthoc assessment of the mean change in WOMAC function by treatment arm showed that each 1-unit increase in baseline pain self-efficacy was associated with a 1.52 (95% CI 0.27 to 2.78) unit improvement in the control group. In contrast, a reduction of 0.62 (95% CI –1.93 to 0.68) units was observed in the intervention group with each unit increase in pain self-efficacy. There was only weak evidence that pain self-efficacy moderated the effect of the intervention on pain and that number of comorbidities, number of other painful joints, exercise self-efficacy, or exercise importance moderated the effect of the intervention on pain or function.There was evidence that pain self-efficacy moderated the effect of the intervention on physical function compared to the control at 24 weeks (interaction With the exception of pain self-efficacy, which moderated changes in function but not pain, we found limited evidence that our selected baseline patient characteristics moderated intervention outcomes. This indicates that people with a range of baseline characteristics respond similarly to the unsupervised digitally delivered exercise intervention. As these findings are exploratory in nature, they require confirmation in future studies. Osteoarthritis (OA) is a condition of the synovial joints , with thThe use of digitally delivered interventions to support chronic condition management is rapidly increasing as a means of improving access to evidence-based health care . RecentlTo our knowledge, no previous studies have conducted formal moderation analyses to explore baseline patient characteristics associated with the effect of self-directed digitally delivered exercise for people with OA although 2 studies have explored baseline characteristics as predictors of outcomes from self-directed exercise. One study identified that increased age and the presence of a comorbidity at baseline predicted nonusage of a self-directed web-based physical activity intervention for patients with knee and hip OA . AnotherThis exploratory study sought to identify moderators of the effect of a self-directed digitally delivered exercise intervention on changes in pain and physical function at 24 weeks relative to the control in people with knee OA. The findings of this study will address a key knee OA research priority and provide direction for future confirmatory studies.We conducted exploratory moderation analyses  by usingIn the RCT, 206 people with knee OA were recruited from the Australia-wide community via internet sources  and a volunteer database. Full RCT eligibility criteria are reported elsewhere  and inclFull details of the self-directed digitally delivered exercise intervention have previously been published ,20. To sAugmenting the strengthening exercise regimen was a 24-week automated exercise behavior change mobile phone text messaging program. The text messages were designed to monitor weekly exercise session completion and address exercise facilitators and barriers commonly encountered by people with knee OA. Program development systematically followed the Behavior Change Wheel Framework, which is a universally accepted approach to designing behavior change interventions . The proAfter randomization and enrolment into the study, intervention participants received an email containing website access, information about receiving text messages, the recommendation to access the website within a week to commence their exercise program, and were told they could continue to access the website at any time over the 24 weeks. Participants also received a text message encouraging website access. The control group received access to another custom-built website containing the same educational information as the intervention website. After randomization and enrolment into the study, control participants received an email containing website access, the recommendation to access the website within a week, and were told they could access the website at any time after the 24 weeks. Participants also received a single text message encouraging website access.All RCT outcomes were participant-reported and collected via REDCap electronic surveys at baseline and at 24 weeks. The 2 primary outcomes were (1) overall pain in the last week, measured using an 11-point numerical rating scale  and (2) physical function, measured using the physical function subscale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) . These measures are reliable and valid measures recommended for knee OA clinical trials -24. At 2The selection of moderators was based on evidence and theoretical rationale and involved a review of the literature ,17,25-29Number of comorbidities was collected via a question asking participants to select from a list of 13 comorbidities any of which were relevant to them see . A parti1. Heart disease 2. High blood pressure3. Problems caused by a stroke4. Leg pain when walking due to poor circulation5. Lung disease 6. Diabetes7. Kidney disease8. Diseases of the nervous system 9. Liver disease10. Cancer (within the last 5 years)11. Depression12. Arthritis in your back or other condition affecting your spine13. Rheumatoid arthritis or another kind of arthritis in addition to osteoarthritisThe number of other joints with pain was collected via a question asking participants to select any other joint they currently experience pain in, from a list of 9 joints, with responses converted into a continuous score of number of other joints with pain per participant. This resulted in a score range of 0 to 9.Pain self-efficacy relates to one’s confidence in their ability to control or manage pain ,31. PainExercise self-efficacy relates to one’s ability to continue exercising in the face of barriers to exercise . ExercisExercise importance was measured in response to the question “How important is it to you to do regular exercise to manage your knee condition?” Responses were collected using a 7-point Likert scale with a score range of 1 to 7, with higher scores indicating greater importance.Separate linear regression models were fit for each primary outcome with the baseline of the relevant outcome, treatment group, and one of the 5 potential moderators as covariates, including an interaction between treatment group and the relevant potential moderator. Results were calculated as the estimated mean effect of a 1-unit increase in the potential moderator for each treatment group. Using complete case data, fractional polynomials were employed to determine if nonlinear interaction models were warranted. All other analyses were performed on complete case data and multiply imputed data, including assessing regression assumptions of linearity and homoscedasticity using standard diagnostic plots. These potential moderator interactions were also assessed visually via plots of the difference in the change in the primary outcomes between groups versus the potential moderator. Multiply imputed data were the primary analysis in all interpretations. All statistical analyses were performed using Stata version 16.1 .In this study, 206 people with a clinical diagnosis of knee OA were recruited from all Australian states and territories and were enrolled into the study . Baseline characteristics of participants in both groups were similar . At the P=.02). Posthoc assessment of the mean change in WOMAC function by treatment arm following identification of an interaction effect showed that each 1-unit increase in baseline pain self-efficacy was associated with a 1.52 (95% CI 0.27 to 2.78) WOMAC units improvement in the control group. In contrast, with each unit increase in pain self-efficacy, a reduction of 0.62 (95% CI –1.93 to 0.68) WOMAC units was observed in the intervention group. There was only weak evidence that the other selected baseline variables moderated the effect of the intervention on physical function compared to the control at 24 weeks  improvement in function in the control group. In contrast, there was a reduction in function of 0.62 units (95% CI –1.93 to 0.68) for each unit increase in pain self-efficacy in the intervention group, although this finding is equivocal, given the confidence interval crossed zero. Pain self-efficacy refers to one’s confidence in their ability to control their pain and function while in pain  and deteThere is limited research investigating the moderating effects of self-efficacy on exercise outcomes in knee OA. One exploratory study found evidence that pain self-efficacy moderated the effect of a telehealth-delivered physiotherapist-prescribed exercise program combined with an automated pain coping skills training program for people with knee OA on changes in pain but not function when compared to an education control . This coP=.16), this observation may indicate that the self-directed digitally delivered intervention may be less beneficial for people with pain in multiple joints. Multi-joint pain can be indicative of complex pain presentations such as widespread pain and fibromyalgia [To our knowledge, this is the first study to investigate multi-joint pain and comorbidities as moderators of the effect of self-directed exercise on outcomes in people with OA. We found that neither of these baseline characteristics moderated the effect of the intervention on changes in pain or function relative to the control. Despite this, an interesting observation was a negative relationship between number of other joints with pain and changes in physical function for the intervention group . Although, this was supported by only weak evidence of an interaction effect (omyalgia , and peoomyalgia ,38. Furtomyalgia . Therefoomyalgia ,41. A syomyalgia . Similaromyalgia .There appears to be currently no research exploring patient characteristics as potential moderators of the effects of digitally delivered exercise in populations with OA and limited research in adult populations more broadly. We found 2 studies that conducted subgroup analyses of RCT data exploring potential moderators of the effect of digitally delivered physical activity interventions in adults. One study explored potential moderators of the effect of computer-tailored physical activity on changes in total weekly minutes of physical activity at 12 months in people aged 50 years and older . ModeratOverall, our findings suggest that our self-directed digitally delivered exercise intervention is similarly effective for pain for a range of people with knee OA. With respect to function, it may be that our 24-week intervention is less beneficial when compared to control for people with high baseline pain self-efficacy (eg, a score of over 9/10; see a priori while the selection of only a few variables aimed to minimize the risk of potentially erroneous findings. Our findings and the hypothesis generated can also be considered generalizable to the broader knee OA population owing to the limited inclusion criteria and nationwide community recruitment of participants in the RCT. Several limitations must also be acknowledged. This study was exploratory as the original RCT was powered to detect changes in pain and function and not to detect moderator effects. As this was exploratory, no adjustment for multiple testing was conducted. It is possible that a lack of power prevented the identification of potential moderators rather than the absence of an effect or that our finding occurred by chance, although a chance finding was controlled for by limiting the number of potential moderators to analyze. As such, further confirmatory studies are required. Additionally, despite our selection of variables being evidence-informed, it is possible that baseline variables other than those selected could be potential moderators.The strengths of this study include its robust design using reliable and valid clinical outcome measures -24 and aWith the exception of pain self-efficacy, we found little evidence that our selected patient characteristics moderated treatment outcomes. Although these findings are exploratory in nature, they do contribute to the sparse literature regarding moderators of the effect of digitally delivered exercise in adult populations and may inform future research aiming to improve the targeting of exercise treatments.


We use atomistic as well as coarse-grained molecular dynamics simulations to study the conformation of a single poly(3-hexylthiopene) chain as a function of temperature. We find that mainly bundle and toroid structures appear with bundles becoming more abundant for decreasing temperatures. We compare an atomistic and a Martini-based coarse-grained model which we find in very good agreement. We further illustrate how the temperature dependence of P3HT can be connected to that of simple Lennard–Jones model polymers in a vacuum. Upon adding solvent (THF) we observe the occurrence of a prominent swelling of the molecular size at a temperature of about 220 K. This swelling is in close agreement with the interpretation of recent spectroscopic experiments which allows us to explain the experimental observations by an increased frequency of bundle structures. Poly(3hexylthiophene) (P3HT) is a conjugated polymer widely used in optoelectronic devices like thin film-field effect transistors and organic photovoltaics because of its high field-effect mobilities and significant mechanical strength . These fA recent series of spectroscopic experiments on highly monodisperse, regioregular P3HT by Panzer et al. ,15 speciMotivated by these experiments, we here revisit the temperature-dependent single-chain behavior of P3HT using both atomistic as well as coarse-grained MD simulations. Our specific aim is to investigate explicitly the “planarized swollen coil” structure whose existence has been derived from an interpretation of the spectroscopic signatures in . For thii, We use the MD simulation package GROMACS  (versionIn the Lennard–Jones (LJ) polymer each monomer is modeled as a single LJ bead of the formb between two monomers was set to The equilibrium distance The stiffness of the polymer was tuned in two different ways. In the first method, we fix In all LJ model simulations, the time step was set to 1 fs, and the simulations for Bhatta et al.  developeSchematics showing the central part of the planar P3HT are shown in Similar to the LJ polymer in the previous section, the results below 600 K are averaged from 50 simulations of 5 ns each, and for above 600 K they are extracted from 125 ns NVT simulations with a timestep of 0.5 fs. Again, the first 500 ps of the simulations were discarded for analysis. Constraint algorithms, thermostat scaling, and periodic boundary conditions were kept the same as for the LJ polymers. Detailed results are provided in We adopted a coarse-grained (CG) model for P3HT directly from the work in . The forThe CG Martini model of solvent tetrahydrofuran (THF) contains one bead per molecule and is taken from Patti et al. .For the solvent simulations, we added 5000 THF molecules in a box of size (78.5 nm)In order to provide the necessary background for the P3HT investigations to be presented below, we start with a brief study of Lennard–Jones model polymers. Following , we plotEquation  for a postiff polymers  if the inter-monomer dihedral angle exceeds a particular threshold value. Following previous estimates of conjugation lengths in simulations of P3HT ,37 a thrThe calculated distributions of conjugation lengths for bundles and toroids are shown in In summary, our detailed comparison shows that P3HT in vacuum inherits various typical characteristics of flexible polymers, namely the sigmoidal increase in This swelling behavior is indeed reflected closely in the recent series of spectroscopic experiments by Panzer et al. ,15,38. PTo check the robustness of the observed effect, we conducted simulations with chain lengths of ments in  that theInterestingly, our simulations predict that this swelling is closely connected to the presence of the solvent THF which might make it a worthwhile effort to study the same transition in different in the future.