Combination molecular targeted therapy with dabrafenib plus trametinib has been shown to improve progression‐free survival and overall survival in patients with BRAF V600 mutated unresectable or metastatic melanoma. In general, these agents are well tolerated. Kidney related adverse events are uncommon with only three case reports of acute interstitial nephritis and one case of a serious acute kidney injury. We report another case of interstitial nephritis related to these drugs.2 (from a baseline >90 ml/min/1.73 m2) and microalbuminuria . Renal biopsy revealed a granulomatous interstitial nephritis likely drug related. He was treated with prednisolone 1 mg/kg and ceased his targeted therapy with improvement in his renal function.A 37‐year‐old man diagnosed with metastatic melanoma (BRAF V600E mutation) who developed acute interstitial nephritis 5 years into his treatment with combination dabrafenib plus trametinib therapy. He presented with an asymptomatic acute kidney injury on routine surveillance pathology with a creatinine of 174 μmol/L (from baseline 80 μmol/L) and a corresponding estimated glomerular filtration rate (eGFR) of 42 ml/min/1.73 mAlthough rare, recognition of acute interstitial nephritis, a possible serious adverse outcome due to dabrafenib and trametinib is important and needs to be incorporated into current Australian cancer therapy guidelines. Specifically, only three case reports of acute interstitial nephritis, and one case of a serious acute kidney injury (AKI)22.We present the case of a 37‐year‐old male was diagnosed with invasive malignant melanoma of his scalp in June 2011, with no evidence of metastatic disease and excision of his scalp lesion was undertaken (Breslow thickness 3.5 mm and Clark level 3). He worked in administration, had no other significant medical history at the time of his diagnosis. His baseline creatinine was 80 μmol/L with an estimated glomerular filtration (eGFR) rate of >90 ml/min/1.73 mIn 2012 he had recurrence in a left cervical lymph node and he underwent radical left neck dissection, with one out of twenty nodes showing metastatic melanoma but no evidence of extracapsular extension. He did not receive adjuvant radiotherapy. In 2014 he again developed recurrence of disease with PET scan in July 2014 showing left perineal subcutaneous nodule, which were resected, confirming metastatic melanoma and molecular analysis showed BRAF V600E mutation positivity. Following this resection, he was deemed disease free; however, early surveillance imaging several months later in November 2014 showed recurrence of the previous PET FDG avid metastases with metastatic disease involving bilateral axillary lymph nodes, supraclavicular nodes and anterior mediastinal nodes, multiple subcutaneous deposits, soft tissue deposit adjacent to the left hip joint, in addition to a large peritoneal deposit and some intramuscular deposits in the abdomen. Subsequently, in December 2014 he commenced targeted therapy with combination dabrafenib and trametinib.The patient tolerated therapy well, with his only side effect being occasional non‐infectious febrile responses. First of these episodes started within first month of initiation of dabrafenib and trametinib, there were other two more episodes in first 3 months and a severe episode in November 2017 requiring hospital admission. These were successfully managed with brief cessation of his therapy, and short courses of corticosteroids and paracetamol. In October 2016 his FDG‐PET/CT demonstrated complete response and remained disease free since then. He showed no evidence of other organ dysfunction.In late 2019, (5 years into his targeted therapy treatment) he had recurrence of a febrile illness which coincided with a FDG‐PET/CT demonstrating abnormal uptake in the neck (SUV max of left neck lesion 2.7). Biopsy was undertaken and showed evidence of necrotising granulomatous lymphadenitis with features possibly consistent with cat‐scratch lymphadenitis. Serology was performed for cat scratch, toxoplasmosis, CMV, which were all negative. QuantiFERON gold test was also negative. No other evidence of infection or recurrence of malignancy was identified, and he remained on his combination targeted therapy throughout this time.2 (stage 2 as per KDIGO classification 2012)However, several months later in March 2020, he was noted to have developed a significant AKI with a creatinine of 174 μmol/L and an eGFR of 42 ml/min/1.73 m2  was performed and returned negative. The cause of interstitial nephritis was thought secondary to his combination metastatic melanoma treatment BRAF and MEK inhibitors. He was initially continued on these agents while high dose prednisolone were commenced at 60 mg daily (1 mg/kg). Despite steroids, his kidney function did not show significant improvement and the decision was made to cease his targeted therapy while continuing steroid treatment. With cessation of his treatment, there has been improvement in his AKI, with a creatinine in July 2020 being 127 μmol/L and an eGFR 62 ml/min/1.73 m3Our patient was commenced on dabrafenib and trametinib in December 2014, with normal baseline renal function, after he progressed with BRAF V600E mutated metastatic melanoma; he achieved excellent sustained disease control. His sudden renal impairment and microalbuminuria with biopsy proven granulomatous interstitial nephritis, after 5 years of this treatment is likely drug related can be attributed to this combination treatment as there were also no other possible culprit medications or other cause identified after careful investigations. This is supported by improvement in renal function after ceasing his targeted therapy. It is important to report this adverse reaction, given renal injury, in particular acute interstitial nephritis is not a well‐recognised side effect of this combination therapy.Renal toxicity with dabrafenib was much less commonly reported compared with vemurafenib, another BRAF inhibitor,2 and recurrent BRAF V600E mutant melanoma, which had failed first line nivolumab treatment.2.Jansen et al has reported a case with stage IIIB BRAF V600E mutant melanoma, treated with dabrafenib and trametinib who developed bilateral pedal oedema and erythematous back and upper arm rash, found to have AKI. The patient's skin and kidney biopsy indicated granulomatous inflammation and was attributed to the combination of dabrafenib and trametinib.Management of acute interstitial nephritis due to targeted therapy is cessation of offending agents.4This case highlights the importance of monitoring renal function when patients are on combination therapy of dabrafenib and trametinib. Our case of AKI secondary to interstitial nephritis occurred 5 years into the patient's treatment with molecular therapy, emphasising the ongoing need for surveillance throughout treatment courses, even if initially tolerated.The authors declare that they have no conflict of interest.Conceptualization, G.K., L.N., M.D.J.; Data Curation, A.K., K.W.; Investigation, K.W.; Resources, V.K.M., L.N., K.W.; Supervision, G.K., L.N., M.D.J.; Writing‐Original Draft, A.K., V.K.M.; Writing‐Review & Editing, V.K.M.All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Written consent has been obtained from the patient for the purposes of this case report. There are no objections from the institutions providing care for this patient in publishing this case report.


It can be classified into two categories, inherited, and acquired. Acquired agranulocytosis is not commonly caused by auto‐immune diseases such as systemic lupus erythematosus (SLE). We report a case of a patient suffering from agranulocytosis related to SLE at disease onset, associated with other rare disease involvements.Agranulocytosis is a rare acute condition characterized by severe a < gft (neutropenia in which the neutrophils count is less than 100/mm Hematological manifestations are frequent in systemic lupus erythematosus. Agranulocytosis is a rare condition frequently caused by drug toxicity. Systemic lupus is an exceptional cause of agranulocytosis. It occurs in 20%–47% of the cases.We report a case of a patient suffering from agranulocytosis related to SLE at disease onset, associated with other rare disease involvements.2This is a case of a 45‐year‐old woman, with a history of type 2 diabetes for 8 months. Diagnosed, in January 2021, with rheumatoid arthritis; she had polyarthritis affecting the two wrists, the MCPs and the PPIs, the elevation of the sedimentation, rate, and a positive rheumatoid factor at 473 IU. she was treated with diclofenac at a dosage of 150 mg/day, 10 mg/week of methotrexate (MTX), 30 mg/day of corticosteroids (CS) (0.5 mg/kg/day) for 3 weeks then gradual taper in combination with adjuvant therapy.3 with polynuclear neutrophils (PNN) predominance, lymphopenia at 420/mm3, biological inflammatory syndrome with a sedimentation rate >130 mm/h, CRP at 144 mg/L, and fibrinogen at 6.2 g/L. Protein electrophoresis was normal. Bacteriological examination of the urine was negative. Hands, feet, hips, pelvis, and shoulders X‐rays were normal.In august 2021, she was admitted to our department for a relapse of her polyarthralgia causing walking difficulties associated with neck pain and acute liquid diarrhea, she was receiving the treatment prescribed for her rheumatoid arthritis. Physical examination has shown: apyrexia, sinus tachycardia at 100 beats per minute, lower lip erosions Figure , tongue The joint flare was treated with three pulses of 100 mg /day of Methylprednisolone 3 days in a row with a favorable response; the disappearance of polyarthritis and decrease of CRP level to 27 mg/L within 5 days.3, hemoglobin at 7.2 g/dl with a positive direct Coombs test type immunoglobulin G, and platelets at 125,000/mm3. The patient was isolated and infectious investigation was performed returning negative: aerobic, anaerobic, and sabouraud blood cultures, cytobacteriological examination of urine, stool culture, parasitological examination of stool, Wright and Widal serology, serology of atypical bacteria, hepatitis B C, and HIV serology, Epstein Barr virus, cytomegalovirus, and parvoB19 virus serology. The cardiac ultrasound showed no signs of endocarditis and thoracoabdominalo‐pelvic CT showed an intraperitoneal effusion blade.Six days later, she developed febrile pancytopenia; white cells level at 610/mmMacrophage activation syndrome was very likely due to the presence of hypertriglyceridemia at 6.1 mmoL/L, the high level of ferritin at 655.5 ng/ml and the lactate dehydrogenase level at 2.7 times normal; however, bone marrow aspiration showed no sign of hemophagocytosis but a rarefaction of all hematopoietic lines.The albumin was decreased at 28 g/L with normal protidemia at 65 g/L. The 24‐h proteinuria fluctuated between 0.43 and 1.65 g/24 h without hematuria.3, the PNN 0/mm3, the lymphopenia 260/mm3, the thrombopenia 11,000/mm3, and the hemolytic autoimmune anemia (HAIA) 6.5 g/dl with an increase of CRP to 49 mg/L. Filgrastim(a human recombinant granulocyte colony‐stimulating factor [G‐CSF])at a dosage of 5 μg/kg/day and intra venous folinic acid aa t dosage of 15 mg/day were administrated for 5 days. A bone marrow aspiration showed the beginning of regeneration.Empirical antibiotic therapy targeting a digestive infection was initiated based on cefotaxime 1 g*3/days, ciprofloxacin 500 mg/days, and metronidazole 1.5 g/days with clinical improvement in 3 days but worsening of pancytopenia; The leukopenia reached 320/mmThese antibiotics were replaced, 7 days later, by Tazobactam, Teicoplanin, and ciprofloxacin because of a reappearance of fever at 40°C and increase of CRP to 208 mg/L with good evolution within 2 days.Table In the meantime, the immunological tests came back positive and the diagnosis of systemic lupus erythematosus was retained according to the ACR criteria with skin, joint, hematological, renal involvement, and positive anti‐nuclear antibodies (AAN) exceeding 1/1280 with elevated anti‐DNA levels (>800 IU/L) and positive anti‐nucleosome, anti‐centromere, anti‐SSAA, anti SSB, and anti RO52level.The anti‐citrullinated cyclic peptides, antiphospholipid antibodies, cryoglobulinemia, and anti‐transglutaminase antibodies were negative.Kidney biopsy was risky due to thrombopenia and anemia.Pulses of methylprednisolone (1 g/day for 3 days) and hydroxychloroquine at 400 mg/day were introduced. It was associated with adjuvant therapy, iron, and folic acid. High doses of CS (1 mg/kg/day) were maintained for 8 weeks. Then, we began tapering.Fourteen days after hospitalization, she had paroxysmal retrosternal chest pain and tachycardia at 140 beats per minute with a high level of troponin and d‐dimers and a respiratory alkalosis with a pH at 7.49. The diagnosis of pulmonary arterial hypertension was made on the cardiac ultrasound (PAH at 60 mmHg) and was attributed to SLE given the absence of pulmonary embolism on the thoracic CT angiography.The next day, she had epigastralgia with lipasemia and amylasemia twice the normal therefore an abdominal CT was performed revealing stage B pancreatitis of Balthazar with a severity score of 4, bilateral pleuritis, and small peritoneal effusion. Triglyceridemia level was normal, as well as calcemia, the anti‐smooth muscle, anti‐liver‐kidney microsomal and anti‐mitochondrial antibodies, were negative. So, we related pancreatitis to the.Oral nutrition was stopped for 7 days and substituted with intravenous one. Then, a semi‐liquid regimen was used.The evolution was good with the disappearance of epigastralgia, fever, diarrhea, leukoneutropenia, and thrombocytopenia. The HAIA took time to improve. Their hemoglobin level was 6.6 g/dl. The CRP level decreased to 32 mg/L. The amylase and lipase levels were back to normal. The pericarditis and PAH disappeared on the 10th day of CS.3Agranulocytosis is usually caused by drug toxicity,AA physiopathology is explained by two main mechanisms3, and the PNN 1470/mm3. Polynucleosis and thrombocytosis occurred 9 days after G‐CSF therapy and disappeared after 27 days.Our patient was isolated once the diagnosis was made. She received large spectrum antibiotics and had a negative infection investigation. The MTX and NSAIDs were already stopped in the last 8 days. Intravenous G‐CSF and folinic acid were administered for 5 days. Within 5 days, the white cells reached 3190/mmThe AA prognosis is related to the septic state, the duration of agranulocytosis, early initiation of antibiotics, advanced age (>65 years), renal failure, and rapid discontinuation of the drug in question.Nonchemotherapy drug‐induced agranulocytosis is a rare adverse reaction that is due to immunologic or cytotoxic mechanisms.Several infections could be responsible for neutropenia. Among viral infections, adenovirus infections have been frequently reported as a cause of febrile neutropenia.Treatment with hematopoietic cell growth factors seemed to be associated with a shorter duration of nonchemotherapy drug‐induced agranulocytosis and a reduction in the number of infectious and fatal complications in patients who were asymptomatic at presentation.Methotrexate is a dihydrofolate reductase inhibitor. It can, even at a low dosage (7.5–25 mg/week), slow or halt the hematopoietic cells' maturation and reduce blood cell counts across all cell lineages.However, it was reported in the literature that pancytopenia occurs in 1.4%–2% of cases.Our patient was taking MTX for 6 months. It was stopped 5 days before the pancytopenia. Although NSAID intake would have increased the hematological toxicity risk, the long duration of MTX intake (>6 weeks), its withdrawal before the pancytopenia, and the lack of AA‐induced by this drug in literature allow us to clear MTX responsibility for the AA.So, the AA is explained, in our case, by a multisystemic flare of SLE.Our patient presented several other particularities that make it unique and difficult to diagnose. First, she suffered from isolated polyarthritis at disease onset. Joint involvement is frequent in SLE. It is reported in 53%–76% of cases at disease onset.Second, our patient presented liquid diarrhea with negative infection investigation and ascites. Although we do not have a bowl scan to confirm it, a bowl involvement remains possible. Lupus enteritis is defined as either vasculitis or inflammation of the small bowel wall that is supported by either imaging or biopsy findings.Third, our patient suffered from PAH. It is defined as a mean pulmonary artery pressure (mPAP) > 20 mmHg, measured by right heart catheterization, pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and a pulmonary vascular resistance (PVR) ≥ 3 Wood units (WU).Forth, our patient presented acute pancreatitis (AP). AP is a rare and severe SLE involvement.Systemic lupus erythematosus patients with severe pancreatitis are characterized by younger onset age, higher disease activity, fever, and multiple organ involvement .9/L.At last, we need to highlight the potential role of G‐CSF in exacerbating SLE. G‐CSF is a hematopoietic cytokine that increases neutrophil production, differentiation, and survival by stimulating the growth of neutrophil bone marrow progenitors, and the rate of maturation and release into the circulation. It also enhances adhesion and phagocytosis of mature neutrophils.Our patient suffered from SLE flare with skin, joint, renal, and hematological involvement before G‐CSF administration. Five days after it, she developed PAH and AP. They could be related to the initial severe flare of the disease or secondary to G‐CSF therapy. So, this therapy should be used with great caution in SLE patients.4Systemic lupus erythematosus has a large spectrum of clinical and biological manifestations. We need to keep in mind the rare involvements, to have a diagnosis and treat it on time to save the patient's prognosis.R Ben Salah and O Frikha collected data and information and were the major writers of the present work. A Mefteh and M Snoussi performed, described, and analyzed the data, and contributed to manuscript writing. Z Bahloul, F Frikha, and S Marzouk contributed to data analysis and manuscript writing.NONE.The authors declare that they have no competing interests.The authors declare that all the digital photographs included in this work have not been modified, edited, or adulterated in any way.The patient has consented to publication the case, imaging and all data.Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.


Streptomyces sporoverrucosus’ by Shreyans K. Jain et al., RSC Adv., 2013, 3, 21046–21053, https://doi.org/10.1039/c3ra42884b.Correction for ‘Chrysomycins A–C, antileukemic naphthocoumarins from  The authors regret that incorrect versions of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


QTc prolongation is key in diagnosing long QT syndrome (LQTS), however 25%–50% with congenital LQTS (cLQTS) demonstrate a normal resting QTc. T wave morphology (TWM) can distinguish cLQTS subtypes but its role in acquired LQTS (aLQTS) is unclear.Electronic databases were searched using the terms “LQTS,” “long QT syndrome,” “QTc prolongation,” “prolonged QT,” and “T wave,” “T wave morphology,” “T wave pattern,” “T wave biomarkers.” Whole text articles assessing TWM, independent of QTc, were included.x axis. MCS detected aLQTS more significantly than QTc. Flatness, asymmetry and notching, J‐Tpeak; and Tpeak‐Tend correlated with QTc in aLQTS. Multichannel block in aLQTS was identified by early repolarization (ERD30%) and late repolarization (LRD30%), with ERD reflecting hERG‐specific blockade. Cardiac events were predicted in cLQTS by T wave flatness, notching, and inversion in leads II and V5, left slope in lead V6; and COG last 25% in lead I. T wave right slope in lead I and T‐roundness achieved this in aLQTS.Seventeen studies met criteria. TWM measurements included T‐wave amplitude, duration, magnitude, Tpeak‐Tend, QTpeak, left and right slope, center of gravity (COG), sigmoidal and polynomial classifiers, repolarizing integral, morphology combination score (MCS) and principal component analysis (PCA); and vectorcardiographic biomarkers. cLQTS were distinguished from controls by sigmoidal and polynomial classifiers, MCS, QTpeak, Tpeak‐Tend, left slope; and COG Numerous TWM biomarkers which supplement QTc assessment were identified. Their diagnostic capabilities include differentiation of genotypes, identification of concealed LQTS, differentiating aLQTS from cLQTS; and determining multichannel versus hERG channel blockade. Numerous T wave morphology biomarkers, which can supplement QTc assessment in long QT syndrome (LQTS), have been identified. Their diagnostic capabilities include differentiation of genotypes, identification of concealed LQTS, differentiating acquired LQTS from congenital LQTS; and determining multichannel versus hERG channel blockade. The familial form is diagnosed based on symptoms, electrocardiogram (ECG), and family history. Diagnostic criteria have been codified by Peter Schwartz, combining clinical features with family history and abnormalities of repolarization on the ECG, to provide a low (≤1 point), intermediate (1.5 to 3 points), or high (≥3.5 points) probability of LQTS ; LQT2, caused by mutations in KCNH2 , which accounts for ~40% of genotyped cases and LQT3, caused by mutations in SCN5A, which accounts for ~10% of genotyped cases. These three common subtypes can be differentiated by characteristic TW morphology (TWM) patterns. These include early onset broad TWs in LQT1 (KCNQ1), bifid (notched) TWs in LQT2 (KCNH2), and late onset TWs in LQT3 , or another associated clinical precipitant  independently located records and extracted data. Full‐text publications were reviewed independently if either reviewer considered the manuscript eligible for inclusion. Resolution of disputes was mediated by means of consensus with a third reviewer (A.H.).2.2Studies were included if they reported on the assessment of TWM in cLQTS or aLQTS, independent of QTc. All publications were full‐length, peer‐reviewed articles limited to human subjects, and written in English. Studies were not restricted by study design, subject characteristics, or methodology surrounding TWM analysis. Studies assessing single components of the TW only or describing simple architectural TW changes secondary to an intervention were excluded. The following publications were excluded: case reports, conference abstracts, editorials, expert opinions and commentaries; and textbook chapters.33.1Search results are summarized in Figure 3.2Table Of the studies which specified sex differences, 2462 females and 2481 males were included. Of the remaining studies approximately two‐thirds of subjects were female and one‐third were male, lending to a female predominance overall , 7 (KCNH2) and 11  were recorded at rest in the supine position  additional time intervals Figure , (ii) TWproprietary T wave program : concordance between ventricular depolarization and repolarization sequencesEarly (ERD) and late (LRD) repolarization: time from the peak of the TW loop to 30% of the baseline toward the beginning of the TW (ERD30%) and end of the TW . A reduction in TW amplitude in lead II was seen in chromosome 7 mutations (0.13 ± 0.07 millivolts [mV]) compared to chromosome 3 (0.36 ± 0.14 mV) and chromosome 11 .Moss et al.  noted prp = .0002; Couderc et al., 6 discriminated between LQTS (86.8%) and concealed LQTS (83.3%) compared to control, based on Tpeak‐Tend, left slope; and COG x axis , longer Tpeak‐Tend (109 vs. 92 ms) and smaller COG , with the slope of the RI sigmoid differentiating between hERG and KvLQT1 mutations in leads V2, V5, and II, with a sensitivity and specificity of 100%  and p < .018 (Vmax: 0.16 ± 0.07 mV s in LQT1 and 0.10 ± 0.05 mV s in LQT2), respectively , LQT1 from LQT2  and cLQTS with normal QTc  and spatial mean QRS‐T angle  to the TWM features used in the SVM “extended” model, in addition to the “baseline” model coefficients of age, sex, RR‐interval, QT‐interval and QTc, improved AUC, sensitivity and specificity in cLQTS individuals compared with genotype negative family members  , quinidine (p < .01 to p < .001), and ranolazine  and quinidine (p < .001), and Tpeak‐Tend for dofetilide (p < .001), quinidine (p < .001), and ranolazine (p < .013) which was significant on the basis of a concentration‐dependent analysis  compared to moxifloxacin and placebo  and males with pore‐located mutations , versus nonpore mutations, from a cohort with LQT2  and COG last 25% in lead I (p = .005) in LQT1 and LQT2  as the best predictive marker , architectural patterns on an independent  or combined  basis, functions, and integrals derived from TW slopes , vectorcardiographic biomarkers; and unique measures pertaining to the Mayo Clinic's 4.1.1Tpeak‐Tend is a measure of spatial dispersion of ventricular depolarization, representing late repolarization, understood to predict arrhythmic risk  of the ascending and descending parts of the TW .Vectorcardiographic biomarkers varied across the five studies (Couderc et al., 4.1.5proprietary T wave analysis program, produced using a MATLAB package, enabled automatic ECG feature extraction which are detected by a Bayesian statistical peak delineation algorithm. TW components included the specific fiducial points of amplitude and Tpeak‐Tend, left and right slopes, enclosed TW area; and the unique measure of COG allowing for determination of the x/y coordinates of the COG of the first and last 25% of the TW (Sugrue, Rohatgl, et al., While each method of analyzing TWM has demonstrated some merit in the diagnosis of LQTS, one significant challenge pertains to standardization of all relevant TW interrogation methodologies into a single model which can be applied to both cLQTS and aLQTS cohorts. Sugrue and colleagues' (Sugrue et al., The robustness of this model has been tested in an aLQTS cohort following initiation of dofetilide and sotalol (Sugrue et al., International Long‐QT Syndrome registry (Moss & Schwartz, CredibleMeds initiative (Credible Meds, proprietary T wave analysis program by incorporating the additional analytical process of automated polynomial functions, introducing complex matters surrounding intellectual property but also the need to test the subsequent new model across the same clinical circumstances already investigated (Hermans et al., With the establishment of the 4.2QTc prolongation continues to be considered the most useful warning signal for TdP, with the risk of life‐threatening arrhythmias increasing by 15% for each 10 ms increment in QTc duration (Giudicessi et al., QT alert system (Haugaa et al., The process of ECG recording and digitization allowing for uploading a centralized database, to which standardized TWM analysis programming can be applied, is critical. Integrating such a system with the electronic medical record and medication chart would enable capturing associated QT‐prolonging factors, thus determining mortality risk as has been described using the 4.3Proof of concept work has suggested a role for AI in diLQTS (Attia et al., With the advent of mobile devices being incorporated into clinical care within the cardiac electrophysiology realm, the capacity for longer periods of monitoring in an inexpensive and less invasive manner is made possible (de Marvao et al., Castelletti et al.  showed tDespite mobile devices only recording from a single lead, preliminary results on information extracted are promising (Bos et al., Regardless of the means of ECG data acquisition, key stages of development will be enabling digitization and application of TW analysis programming which can then be added to the patient's electronic medical record, allowing for remote access by the relevant treating physician and contemporaneous comparison, which will enhance the utility of this common and essential clinical investigation. As such, specific education‐based curriculums of relevant clinicians will undoubtedly be required, using the example of transitioning the simple clinical skill of ECG lead placement and recording toward the aforementioned digitized processes.This is indeed an exciting time for the delivery of healthcare, particularly in relation to the possibilities allowing for mitigating the risk of SCD in the setting of LQTS. Another interesting perspective relates to economics, specifically performing relevant cost benefit analyses as this technology is increasingly applied in a clinical capacity. In considering the ultimate cost associated with this devastating disease process, that being the loss of life secondary to this devastating disease process, at this stage striving to transition relevant translational research into a clinically meaningful tool which can be applied to patients in the real world is essential5TWM biomarkers provide a substantial amount of supplementary information, aiding the diagnosis of abnormal repolarization and risk stratification process in both cLQTS and aLQTS. Current major challenges relate to a lack of standardization in programming and biomarkers used which are applicable to both cLQTS and aLQTS groups, ECG digitization and automated analyses, integration of AI; and translation into clinical settings. Despite these obstacles, there is great promise in this ever‐evolving area in relation to QTc monitoring. This progress provides the foundations for integrating TWM biomarkers into the process of risk stratification, to achieve the fundamental goal of preventing the devastation associated with SCD.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.DT performed the literature review and collation of data for review. DT, MP, RS, JV and AH contributed to planning, writing and editing of the manuscript and figures.Institutional ethics approval was not required because the data analyzed are from previous published studies, in which informed consent, or a waiver of consent was obtained. The PRISMA guidelines have been utilized for reporting purposes.


EditorThe people‐centred model of care for psoriasis emphasizes the importance of prioritizing patient's needs and preferences in clinical decisions, along with physician‐rated disease severity.The current analyses used data from the Pruri‐Impact studyk = 0.36 for trunk, k = 0.49 for arms and k = 0.41 for legs. There was no significant difference between patients' and physicians' reports of total %BSA , but significant differences between raters for the PASI categories of area affecting the head , trunk , arms  and legs  were found. The examination of direction of disagreement showed that physicians were more likely to rate %BSA lower than the patients  = 3.83, P = 0.001; Table R2 = 0.31, Nagelkerke's R2 = 0.44; χ2(16) = 28.24, P = 0.030; Table In addition, a greater extent of disagreement was significantly associated with more quality of life (QoL) impairments, higher levels of depression and lower levels of anxiety .N. da Silva, C. Hilbring and C. C. von Stülpnagel declare no conflict of interest. M. Augustin has served as consultant and/or paid speaker for and/or has received research grants and/or honoraria for consulting and/or scientific lectures for and/or got travel expenses reimbursed and/or participated in clinical trials sponsored by LEO Pharma. R. Sommer has received speaker and/or research honoraria and/or travel expenses by Leo Pharma.This study was part of the project ‘Significance of chronic pruritus for social stress and disfigurement in psoriasis – health care study to characterize the need for action and awareness’ (Pruri‐Impact), which was supported by LEO Pharma GmbH.


Local infiltration analgesia (LIA) and adductor canal block (ACB) provide postoperative analgesia for total knee arthroplasty (TKA). ACB blocks the saphenous nerve and has smaller impacts on quadriceps muscle weakness. ACB theoretically does not have enough analgesic effects on posterior sensory nerves. LIA may increase its analgesic effects on the posterolateral knee. The purpose of this study was to evaluate whether ACB combined with a LIA cocktail of ropivacaine, morphine, and betamethasone has superior analgesic effect than LIA for TKA.A total of 86 patients were assessed for eligibility from February 2019 to May 2019. 26 of those were excluded, and 60 patients were divided into 2 groups by computer-generated random number. Group A (LIA group) received LIA cocktail of ropivacaine, morphine and betamethasone. Group B (LIA+ ACB group) received ultrasound-guided ACB and LIA cocktail of ropivacaine, morphine and betamethasone. Postoperative visual analogue scale (VAS) resting or active pain scores, opioid consumption, range of motion (ROM), functional tests, complications and satisfaction rates were measured. The longest follow-up was 2 years.P > 0.05). ACB combined with LIA had significantly lower resting and active VAS pain scores, better ROM, better sleeping quality and higher satisfaction rates than LIA alone within 72 h postoperatively (P < 0.05). Complications, or adverse events and HSS score, SF-12 score were observed no significant differences within 2 years postoperatively.Two groups have no differences in terms of characteristics, preoperative pain or function (Adductor canal block combined with Local infiltration analgesia provide better early pain control. Although the small statistical benefit may not result in minimal clinically important difference, Adductor canal block combined with Local infiltration analgesia also reduce opioid requirements, improve sleeping quality, and do not increase the complication rate. Therefore, Adductor canal block combined with Local infiltration analgesia still have good application prospects as an effective pain management for total knee arthroplasty.ChiCTR1900021385, 18/02/2019.Chinese Clinical Trial Registry,  The proportion of total knee arthroplasty (TKA) procedures judged as “excellent” quality has reached more than 90% ; howeverLocal infiltration analgesia (LIA) is given as a peri- and intra-articular injection during the operation and has been reported to be a safe and effective method, which not only reduces postoperative pain, but also significantly decreases the consumption of opioids –7. The mAdductor canal block (ACB) is a new technique that blocks the saphenous nerve and vastus medialis nerve under ultrasound guidance to achieve an analgesic effect. ACB has a similar analgesic effect to the previously common femoral nerve block (FNB) procedure. However, with the possibility of motor block, FNB will lead to instability of functional exercise after TKA, increasing the risk of falling. In addition, FNB did not block the obturator nerve and related branches of sciatic nerve. ACB resolves the defect that the injection of drugs into the femoral triangle does not diffuse the socket, greatly increases the success rate of analgesia, minimizes the strength of the affected limb, and maintains the stability of the patient’s early functional exercises. ACB has smaller impacts on quadriceps muscle weakness which translates to a lower risk of postoperative falls –12. HoweThe objective of this randomized controlled trial was to evaluate the analgesic effect of ACB combined with a LIA cocktail of ropivacaine, morphine, and betamethasone for TKA. The hypothesis was that ACB combined with LIA would provide similar or better postoperative analgesic effects and pain control than LIA alone. The follow-up time was 2 years. This study will be of great significance for clinicians and researchers to select appropriate analgesic models for perioperative pain management of TKA.This prospective single-center randomized controlled trial was approved by the Institutional Review Board of Sichuan University, West China Medical Center, China. The work was registered in the Chinese Clinical Trial Registry . Informed consent was obtained from all participants.Patients were enrolled undergoing unilateral primary TKA between February 2019 and May 2019 in the trial. Patients were included with diagnoses of primary osteoarthritis or rheumatoid arthritis who were undergoing unilateral primary TKA and provided written informed consent. The included patients were aged from 18 to 80 years old, gender and other demographic data were not limited. Patients were excluded who declined to participate; those who had not been diagnosed with primary osteoarthritis or rheumatoid arthritis, for example, traumatic arthritis; those who had an active local or systemic infection, any contraindication for general anesthesia, or an American Society of Anesthesiologists (ASA) physical health classification above grade III; those who were allergic or intolerant to local analgesia, NSAIDs or opioids; those who had progressive neurological deficits in the femoral or sciatic nerve distribution; those who had undergone another surgery in the past 6 months; those who had utilized opioids or neurological pain medicine within the past 6 months; those who had preoperative hepatic or renal dysfunction; those who had severe cardiac comorbidities or coagulopathy; and those who were pregnant at the time of the study.Patients were randomized into 2 groups using a computer-generated list of random numbers. If the random number is odd, they are divided into Group A, and if the random number is even, they are divided into Group B. The allocation of random numbers was performed by other nurses other than surgeons and follow-up researchers. Patients and researchers did not know the grouping status until the data analysis stage at the end of the study. Group A  received LIA with 200 mg ropivacaine, 10 mg morphine, 5 mg betamethasone diluted with normal saline to 60 ml. Group B  received ultrasound-guided ACB with 0.5% ropivacaine 20 ml (100 mg) and LIA with 200 mg ropivacaine, 10 mg morphine, 5 mg betamethasone diluted with normal saline to 60 ml. Group A also received 20 ml normal saline injection into the adductor canal to keep the total amount of fluid injected equal for blinding. The CONSORT flow diagram is shown in Fig. All patients received general anesthesia. ACBs were performed on patients after general anesthesia but before skin incision. ACBs were performed using real-time ultrasonography with a color Doppler ultrasound machine. A high-frequency linear array ultrasonic transducer was used to scan the middle of the thigh to identify the adductor canal. The anterolateral hyperechoic structures, such as the saphenous nerve, were identified as the injection target, and 0.5% ropivacaine or normal saline 20 ml was injected. Local periarticular infiltration analgesia was injected into patients in all groups after osteotomy was completed but before the prostheses were implanted. All Groups received 200 mg ropivacaine, 10 mg morphine, 5 mg betamethasone diluted with normal saline to 60 ml. LIA was performed around the medial collateral ligament, lateral collateral ligament, medial capsule, lateral capsule, posterior capsule, vastus medialis obliquus muscle and quadriceps tendon, prepatellar tissues, and subcutaneous tissues. No tourniquet was used during the operation.All patients were given second generation cephalosporin to prevent infection. Additionally, all patients underwent postoperative multimodal pain management according to the standard practice at the study institution. Parecoxib was administered at 20 mg twice a day to every patient from immediately after the operation until discharge, and oxycodone or morphine was used when patients reported an immediate pain which was greater than 4 on a 0–10 visual analogue scale (VAS). Continuous movement exercises were started postoperatively to promote recovery.Preoperatively, demographic and baseline characteristics were collected, including preoperative (VAS) pain scores, Hospital for Special Surgery (HSS) scores, range of motion (ROM), as listed in Table The primary outcomes were pain evaluation and functional recovery. Pain at rest (resting pain) and pain during physical activity (active pain) were assessed on a VAS, in which patients assigned their pain a numeric rating score (NRS) ranging from 0 to 10 points . Based on these s cores, the intensity of pain was sorted into five levels: very painful (8–10), painful (6–8), moderately painful (4–6), slightly painful (2–4), and nearly painless (0–2). Pain evaluation were collected at 6 hours postoperatively (PO 6 h) as well as PO 12 h, 24 h, 36 h, 48 h, 72 h, 7 days (7d), 14d, 2 months (2 m), 6 m,1 year (1y) and 2y. The location of pain was evaluated at PO 48 h. Opioid consumption was measured from the completion of surgery to PO 48 h and 72 h. Total opioid consumption was calculated by converting opioids consumed to morphine equivalents (ME). All patients had similar pain management from discharge to removal of stitches (approximately PO 14 d); therefore, analgesics utilized from discharge to PO 14 d were not recorded. Any other analgesics utilized from PO 14 d to PO 2 m were recorded. Knee ROM was measured at PO 24 h, 48 h, 72 h, 7d, 14d, 2 m, 6 m, 1y and 2y. The straight leg raise test was conducted and recorded within PO 72 h, evaluating whether and when patients could complete the action without using their hands. Similarly, we recorded whether patients could get out of bed and try to stand with the help of a walking aid, then, walking 20 m with a walking aid was also recorded. Sleeping quality was evaluated by Epworth sleepless scale (ESS), which used self-administered and validated questionnaires to measure patients’ daytime drowsiness, and scores were used to quantify excessive daytime drowsiness . ESS scores were recorded on the morning of day 1, day 2 and day 3.The secondary outcomes included adverse events, length of hospitalization, satisfaction rate, HSS score and SF-12 score. Adverse events occurring within PO 2 m were recorded. Postoperative nausea (PON) was defined as the unpleasant sensation associated with awareness of the urge to vomit. Postoperative vomiting (POV) was defined as the forceful expulsion of gastric contents from the mouth. The presence or absence of PON/V was recorded, and the severity level was assessed on a 4-point scale . Dizziness, hypotension, uroschesis, and pruritus, wound infection were also recorded. The length of a patient’s postoperative hospital stay was defined as the time from the completion of surgery to discharge. At PO 72 h, we evaluated the patients’ satisfaction with their functional recovery and pain control to calculate the satisfaction rates. A four-point Likert scale  was utilized to record the outcomes. At 6 months, 1 year and 2 years postoperatively the HSS and SF-12 score were used to evaluate functional recovery and health related quality of life. HSS score is a scoring system for evaluating knee joint function which total score was 100. The main items were pain evaluation, function score, range of motion, muscle strength, flexion deformity, joint stability. SF-12 quality of life scale mainly evaluates physical and mental health, including a total of 12 questions . The tot2 tests or Fisher’s exact tests. The Kruskal-Wallis H test was used to analyze ordinal rank data such as satisfaction rate and PON/V. All raw significance levels were set at α = 0. 05, and P < 0.05 indicated a significant difference. VAS rest scores were determined as the primary outcome parameter to calculate the sample size. The 2-point difference was determined to be the minimum clinically important difference (MCID) because the average acceptable VAS pain score difference following surgery was approximately 1 to 2 points based on previous studies [https://www.jamovi.org). The charts were drawn using GraphPad Prism 8.0 (GraphPad Software).All continuous data were presented as the mean ± standard deviation (95%CI Upper – lower limit) and were analyzed by independent-sample Student’s t tests. All discontinuous data were presented as frequencies (percentages) and were analyzed by Pearson’s χ studies –20. Mini studies . 30 partA CONSORT-compliant flow chart of the procedure and participants is shown in Fig. P < 0.05), However, none of the between-group differences exceeds the MCID, No significant differences between two groups after PO 72 h to PO 2y (P > 0.05). Total postoperative opioid consumption was recorded at PO 24 h and 72 h. opioid consumption was 14.5 ± 5.2 mg in Group A, while only 8.2 ± 4.5 mg in Group B. LIA + ACB had significantly less opioid consumption than LIA. The location of pain was recorded at PO 48 h. LIA Group had more anterior knee pain than LIA + ACB group, while the posterior knee pain had no significant differences. Analgesic use from PO 14d to PO 2y did not significantly differ between the two groups. Regarding functional recovery, ROM showed significant differences between the two groups up to PO 48 h: the groups that received LIA + ACB had better ROM than LIA alone. There was no significant difference between the two groups after 48 h to 2y. Nearly all patients could complete the straight leg raise and get out of bed at PO 48 h, although there were significant differences up to PO 12 h, LIA + ACB had a better degree of completion in terms of straight leg raise. There were significant differences between the two groups in terms of the get out of bed test and the Walking 20 m test. The primary outcomes are listed in Table The primary outcomes are listed in Table Regarding the length of hospitalization, no significant differences were found, as shown in Table From the results of the study, important findings were observed that supported our hypotheses: ACB (ropivacaine) combined with LIA  provided significantly better postoperative analgesic effects and pain control than LIA alone; reduced opioid consumption up to PO 48 h; while the pain differences between two groups are below the MCID. Moreover, ACB combined with LIA enhanced early recovery in terms of functional measures such as ROM, leg raising; and improved sleep quality.Multimodal analgesia has become the most important and effective method in the ERAS model for pain management as applied to TKA. Effective pain management is conducive to early rehabilitation and improves the patient satisfaction rate , 22. LIAP < 0.05). This result was similar to the findings of Nader et al. [FNB is a kind of nerve block which has been widely used in total knee arthroplasty to reduce pain. However, FNB may reduce the strength of quadriceps muscles, so as to increase the risk of falls, and may be harmful to early rehabilitation , 23, 26.r et al. , who comOur study had some shortcomings. First, the samples were rather small; thus, the pairwise differences between groups were often statistically nonsignificant. We often used conservative statistical methods for comparisons between groups; thus, an increased sample size might help reveal the significant differences. Second, our sample contained more females than males, and the recovery process may be different for different genders. Finally, in order to increase the sensitivity of the functional results, the accuracy of the tests may need to be improved.ACB combined with LIA provide better early pain control. Although the small statistical benefit may not result in minimal clinically important difference, ACB combined with LIA also reduce opioid requirements, improve sleeping quality, and do not increase the complication rate. Therefore, ACB combined with LIA still have good application prospects as an effective pain management for TKA, and it is suggested that the combined application should be used to better control knee pain.


EGFR) mutation testing is approved recently to use in clinical practice. However, it has not been used as a prognostic marker yet because of contradictory results.The plasma‐based epidermal growth factor receptor  who have mutant tumors and receive EGFR tyrosine kinase inhibitors (TKIs).This meta‐analysis aims to clarify the role of the EGFR‐plasma status with progression‐free survival (PFS) and overall survival (OS). A total of 35 eligible studies with 4106 patients were enrolled in the final analysis. Patients with concurrent EGFR mutations in pretreatment plasma have shorter PFS  and OS time  compared to the tumor‐only mutation cases. Besides, the persistence of EGFR‐activating mutations in post‐treatment plasma is associated with worse PFS  and OS outcome  compared to others. Notably, the prognostic value of the EGFR‐plasma test is also validated in treatment with third‐generation EGFR TKI and significance regardless of different detection methods.The PubMed/MEDLINE, Web of Science, Cochrane Library, and Google Scholar databases were searched for relevant studies by April 10, 2021. The hazard ratio (HR) from reports was extracted and used to assess the correlation of EGFR‐plasma mutations at pretreatment and after EGFR TKI initiation is the worse prognostic factor for PFS and OS in NSCLC.The presence of  Unfortunately, not all patients are eligible for biopsy procedures, while the failure rate of biopsy might be high as 20%, accompanied by dangerous complications.EGFR mutation testing in plasma samples is an alternative method that assists the initial diagnosis and also helps in treatment monitoring. Although the EGFR‐plasma test is approved to use in clinical practice recently,EGFR mutations in the blood are associated with improved PFS and OS outcomes, which are different from the evidence of recent clinical trials.EGFR‐positive and EGFR‐negative patients.EGFR‐negative patients are not introduced to treatment with EGFR TKIs,EGFR‐plasma test in mutant tumor NSCLC treated with EGFR TKIs.EGFR TKIs have been recommended as the first‐line agents in treatment for NSCLC patients for many years.2This meta‐analysis was conducted according to the guideline of preferred reporting items for systematic reviews and meta‐analyses (PRISMA).2.1The electronic database as PubMed/MEDLINE, Web of Science, and Cochrane Library were searched for relevant studies. The keywords used in searching include “EGFR,” “ctDNA or circulating tumor DNA,” “cfDNA or circulating free DNA,” “plasma or peripheral blood,” “NSCLC or non‐small cell lung cancer,” “lung cancer,” “lung carcinoma,” “survival,” “outcome,” “PFS,” and “OS.” Besides the above databases, Google Scholar was used for study searching. Moreover, the citation reports of potential studies were also reviewed for finding additional articles. The cut‐off date of database searching is April 10, 2021 (the start date was not applied). After searching, all relevant studies were exported into the EndNote list (4432 records) and removed duplicates  in tumor tissue and treated with EGFR TKIs as gefitinib, erlotinib, icotinib, afatinib, and osimertinib (first‐line and second‐line); (2) analyzed the association of EGFR status in paired tumor tissue and plasma/serum  with survival ; (3) have at least five patients in each comparison arms; and (4) have enough information to determine HR directly or indirectly. For the non‐trial studies, besides these criteria, the adjusted HR values must be available. Finally, 35 studies were included in this meta‐analysis .By screening titles and abstracts, 2588 records were excluded from the study, while 157 remained articles were assessed in detail for eligibility. Studies included in the meta‐analysis which are clinical trials meet criteria: (1) dealt with non‐small cell lung cancer who have 2.2The Newcastle‐Ottawa Scale (NOS), which comprises three aspects equivalent to a maximum score of 9 points ,EGFR mutations, treatment agent, length of follow‐up, outcome , HR value, method of survival analysis (univariate/multivariate), and NOS score. In cases of not availability, HR values were calculated indirectly according to the recommendations of Tierney JF.We extracted data from articles including author's name, publication year, country, study design, the number of patients in each arm, patient's age, clinical stage, sample type, sampling time‐point, the technique used to detect 2.3EGFR plasma status with survival outcomes. HR > 1 indicates an inferior survival for the patients with T + P+ mutations. In contrast, HR < 1 is the indicator of superior survival for T + P+ subjects. HR = 1 suggests that no correlations exist between EGFR plasma mutations and survival outcomes.Data analyses were done with the guidance of Harrer,I2‐statistics. Heterogeneity was determined as significant if I2 > 50% and p < .05. Accordingly, the subgroup analyses were performed to explore sources of heterogeneity that may come from clinical characteristics. Furthermore, we used the Leave‐one‐out statistic to detect studies with extreme effect sizes (outliers). Then, the pooled HR was estimated once removed outliers from the analysis and checked for the consistency of overall results. The potential of publication bias in the meta‐analysis was detected by the linear regression test for funnel plot asymmetry. In case of significant bias presence (p < .05), we used the Trim‐and‐fill method to impute missing studies and calculate the adjusted HR values.The heterogeneity of effect size (HR) between studies was measured by Higgin's and Thompson's 33.1EGFR mutations in prior‐treatment plasma (prior‐EGFR) with survival outcomes, including seven studies for PFS, three and 11 studies for OS, and both survival outcomes , which consists of 11 reports for PFS, one for OS, and 10 for both outcomes. The total number in prior‐treatment studies is 2483 patients, and in post‐treatment are 1623 cases. Ten studies used osimertinib in NSCLC treatment (two with first‐line and eight with second‐line), while others used the first‐ or second‐generation EGFR TKIs with/without chemotherapy. The polymerase chain reaction (PCR) methods were used in almost all studies, while the next‐generation sequencing (NGS) technique was only used in four reports to detect EGFR‐plasma mutations. The NOS score above six indicated that all included studies are of high quality.Among 35 studies included in this meta‐analysis,3.2EGFR, 1524 patients have the T + P+ EGFR mutations, whereas 959 others have the T + P‐ results. The PFS time of T + P+ patients was from 3.7 to 15.6 months, and of T + P‐ subjects were 8.3 months to “not reached” (NR). These OS values were 8.2–28.8 months and 25.3–NR months, respectively. The overall estimated HR for PFS was 2.00  and OS  were not statistically significant. Besides, funnel plot asymmetry tests indicated a lack of publication bias in these analyses .The subgroup analysis results for PFS and OS are presented in Tables 3.3EGFR clearance in plasma (T + P−) was recorded in a total of 1123 patients, while the persistence or recurrence of this mutation (T + P+) was noted in 500 cases. The median PFS of T + P+ patients was 1.8–11.1 versus 9.8–NR months in T + P− subjects. These OS values in T + P+ and T + P− patients were 7.5–27.0 and 23.7–NR months, respectively. Meta‐analyses have shown that EGFR+ in post‐treatment plasma is associated with shorter PFS , this parameter in the PFS analysis was substantial . This phenomenon also was observed in subgroup meta‐analyses (Tables p = .196), whereas the analyzed result remained significant . Because of the potential publication bias  for PFS, and 2.48  for OS.After treatment with EGFR TKIs (22 studies), s Tables . By excls Figure , we useds Figure  and show4EGFR‐plasma test in NSCLC treated with EGFR TKIs, however, with different conclusions.EGFR positive tumor NSCLC from 35 studies and noted that EGFR+ in both tumor tissue and plasma at baseline is the worse prognostic factor for PFS and OS. Additionally, the maintained detectable EGFR (EGFRE19del and EGFRL858R ± EGFRT790M) or recurrence of the mutation in plasma after EGFR TKI initiation is the inferior factor for survival outcomes. Significantly, the prognosis role of the EGFR‐plasma test is also validated in treatment with third‐generation EGFR TKI, and for different technique as PCR clamping, allele‐specific PCR, digital PCR, and NGS.Several studies have been conducted to assess the prognostic role of the EGFR mutations are classified into the shedding tumor group and associated with poor performance status, advanced clinical stage, increased metastatic site, and large tumor volume.EGFR plasma concomitance is correlated with a higher percentage of driver mutations and gene alterations .EGFR mutations. Moreover, baseline EGFR‐plasma and coexisting alterations are related to the mutation persisting in post‐treatment samplesEGFRT790M, EGFRC797S, and other acquired genetic changes.EGFR mutations (with or without secondary mutations) in plasma is the worse signature. Thanks to the benefit of prognosis, clinicians should require additional EGFR‐plasma mutation testing even though it has been confirmed positive in the tumor tissues. Also, bi‐monthly repeated monitoring of EGFR mutations in plasma after EGFR TKI initiation should be done in NSCLC management.Patients with plasma concurrent EGFR‐plasma test in NSCLC treated with EGFR TKIs. However, some limitations still exist. First, substantial heterogeneity and publication bias is present in post‐treatment analyses, although non‐trial studies without adjusted HR values have been excluded. It might be due to differences in patient characteristics, therapy regimen, and HR extraction method between studies. Thus, cautious use of results is needed. Second, the sample size in some study arms is limited, while not all individual HR values are extracted directly, which might affect the overall results. Third, this study only finishes with the prognostic role of EGFR‐plasma as a single gene, which requires further clinical trials with a complex gene model to continue to update our results.This study highlights the prognostic role of the EGFR‐plasma mutations have poorer outcomes compared to those with tumor‐only mutations during EGFR TKI therapies. Besides, the persistence of EGFR mutations in post‐treatment plasma is the worse factor for PFS and OS.In conclusion, the results of this study indicated that NSCLC patients harboring The authors declare no conflict of interest.Conceptualization, data curation, formal analysis, investigation, methodology, software, supervision, validation, writing—original draft, writing—review and editing, T.P.; Data curation, formal analysis, investigation, resources, validation, writing—review and editing, V.T.; Data curation, formal analysis, investigation, validation, writing—original draft, writing—review and editing, B.‐T.T.; Data curation, formal analysis, investigation, resources, validation, visualization, writing—review and editing, T.H.; Data curation, investigation, validation, writing—review and editing, S.P.; Investigation, validation, writing—review and editing, V.L.; Data curation, investigation, validation, writing—review and editing, A.L.; Data curation, investigation, validation, writing—review and editing, H.N.; Conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, supervision, validation, writing—review and editing, S.N.Not applicable.Table S1 Characteristics of studies included in the meta‐analysisClick here for additional data file.


Many health‐care workers exposed to coronavirus disease 2019 (COVID‐19) are psychologically distressed. This study aimed to investigate the psychological impact of the COVID‐19 pandemic on hospital workers under the emergency declaration in Japan.This cross‐sectional, survey‐based study collected sociodemographic data and responses to 19 stress‐related questions and the Impact of Event Scale‐Revised (IES‐R), which measures post‐traumatic stress disorder (PTSD) symptoms, from all 3217 staff members at Kobe City Medical Center General Hospital from April 16, 2020 to June 8, 2020. Exploratory factor analysis was applied to the 19 stress‐related questions. Multiple regression models were used to evaluate the association of personal characteristics with each score of the four factors and the IES‐R.We received 951 valid responses; 640 of these were by females, and 311 were by respondents aged in their 20s. Nurses accounted for the largest percentage of the job category. Women, those aged in their 30s–50s, nurses, and frontline workers had a high risk of experiencing stress. The prevalence of stress (IES‐R ≥ 25) was 16.7%. The psychological impact was significantly greater for those aged in their 30s–50s and those who were not medical doctors.This is the first study to examine the stress of hospital workers, as measured by the IES‐R, under the emergency declaration in Japan. It showed that women, those aged in their 30s–50s, nurses, and frontline workers have a high risk of experiencing stress. Health and medical institutions should pay particular attention to the physical and psychological health of these staff members. This is the first study to examine the stress of hospital workers, as measured by the Impact of Event Scale‐Revised, under the emergency declaration in Japan. It showed that women, those aged in their 30s–50s, nurses, and frontline workers have a high risk of experiencing stress. Health and medical institutions should pay particular attention to the physical and psychological health of these staff members. In December 2019, a new infectious disease outbreak was reported in Wuhan, ChinaPrevious studies have reported on hospital workers' mental health as impacted by infections, such as the 2003 severe acute respiratory syndrome (SARS),In these systematic reviews, however, there are no reports related to COVID‐19 in Japan.On March 3, 2020, Kobe City Medical Center General Hospital (KCGH) admitted its first COVID‐19‐infected patient in Kobe, and by the end of October 2021, 1036 patients with severe COVID‐19 had been admitted. At the beginning of the outbreak, in April 2020, nosocomial infections occurred among seven inpatients and 29 staff members, and 349 employees were requested to standby at home in quarantine to prevent the spread of infection. We believe that hospital workers experienced more severe physical and psychological stress than ever before.To clarify the impact of the COVID‐19 pandemic on hospital workers, we distributed questionnaires to staff members working in a designated medical institution for COVID‐19 in Kobe, Japan. We then investigated the psychological impact of the COVID‐19 pandemic on hospital workers and how it varied by the characteristics of gender, age, job, and work environment.This was an observational, hospital‐based study. In April 2020, soon after the pandemic began in Kobe City, Japan, a questionnaire comprising questions on sociodemographic characteristics, 19 stress‐related questions, and the IES‐R were distributed to all 3217 employees at KCGH. The 289 employees on standby at home were sent the questionnaire by mail. Data were collected from April 16, 2020 to June 8, 2020. Written informed consent was obtained, but participants could also choose to remain anonymous. In accordance with the International Ethical Guidelines for Health‐related Research Involving Humans, all employees were notified of the research information and purpose; the disclosure document was sent via email and the employees were offered the opportunity to refuse. Questionnaires were completed by 1111 employees. Of these responses, 160 contained at least one missing answer, leaving 951 questionnaires (response rate: 29.6%) for analysis. The characteristics of the valid respondents are listed in Table Starting on April 16, 2020, self‐administered paper questionnaires were handed to all employees directly or placed in their mailboxes. Additionally, an e‐questionnaire, created using Microsoft Forms, was shared through email. Questionnaires were collected until June 8, 2020, the estimated peak of the first wave of the COVID‐19 pandemic in Kobe City.The questionnaire explained the study's purpose, which was to examine the stress experienced by hospital workers during the COVID‐19 pandemic. It comprised items covering sociodemographic characteristics, stress‐related questions associated with the COVID‐19 outbreak, and the IES‐R.Personal characteristics included gender, age group, job, and work environment during the COVID‐19 pandemic. The respondents were asked if they had experienced the Great Hanshin‐Awaji Earthquake and whether they had participated in a Disaster Medical Assistance Team (DMAT). Work environment was categorized into frontliner (a respondent working in the ward for COVID‐19 infection and the fever consultation center) and non‐frontliner (a respondent working in any other place).There were 19 questions related to stress Table . The resnot at all), 1 (a little bit), 2 (moderately), 3 (quite a bit), and 4 (extremely). The reliability and validity of the Japanese version of the IES‐R have been verified. A cut‐off score of 24/25 was used to define post‐traumatic stress disorder (PTSD) of clinical concern.The IES‐R is a self‐report measure of current subjective distress in response to a specific traumatic event. This 22‐item scale comprises three subscales representative of the major symptom clusters of post‐traumatic stress: intrusion, avoidance, and hyperarousal.The characteristics of the participants were summarized as numbers and percentages for categorical variables, and as mean and standard deviation (SD) for continuous variables.In our previous study, during the H1N1 influenza pandemic, we performed an exploratory factor analysis and identified four factors for evaluation  using a stress‐related questionnaire survey among hospital workers.t‐test or analysis of variance. We also evaluated the association of personal characteristics with each score and the IES‐R using multiple linear regression models. Participants with missing data were excluded from the regression analyses. The association between participants' characteristics and psychological impact (IES‐R) was tested using Fisher's exact test, and a two‐sided exact p value was reported. Two‐sided p‐values <0.05 were considered statistically significant.The total score of questionnaire items for each of the four factors was calculated. Each score of each factor and the IES‐R were compared between strata of each personal characteristic using either Student's lavaan package (Version 0.6‐8) was used.All analyses were performed using R statistical software (Version 4.1.0). For the CFA, the χ2 (df) = 394.0 (71), p < 0.001; GFI = 0.942; AGFI = 0.914; CFI = 0.911; RMSEA  = 0.064 (0.058–0.070).A total of 1111 employees completed the questionnaire. CFA was conducted using data from 1111 surveys. In this model, Factor 1 consisted of Items 1, 2, 5, 6, 7, and 11, representing “anxiety about infection.” Factor 2 included Items 14, 15, 16, and 17, indicating “exhaustion.” Factor 3 consisted of Items 3 and 4, which represented “workload.” Factor 4, which indicated “feeling of being protected,” was based on Items 9 and 10. Figure γ = 0.43, γ2 = 0.18, p < 0.001, n = 951; Factor 2 (exhaustion) γ = 0.57, γ2 = 0.32, p < 0.001, n = 951; Factor 3 (workload) γ = 0.31, γ2 = 0.10, p < 0.001, n = 951; Factor 4 (feeling of being protected) γ = −0.19, γ2 = 0.04, p < 0.001, n = 951. These results indicate some of the validity of the stress‐related questions associated with the COVID‐19 outbreak conducted in this study.There were moderate correlations between each score of the four factors and the IES‐R score (Pearson product–moment correlation). Factor 1 (anxiety about infection) The data of 951 (29.6%) participants were included in the regression analysis. Table β = 0.98, p < 0.001). Regarding gender, females reported higher levels of anxiety than males . Workers in their 40s experienced higher levels of anxiety than workers in their 20s . Related to job category, nurses and others had higher levels of anxiety about infection than medical doctors .For Factor 1, “anxiety about infection,” workers who were asked to standby at home had more anxiety than workers who were not asked to standby at home . Related to job category, nurses and others felt more exhausted than medical doctors . Regarding exposure to COVID‐19, frontliners felt more exhausted than non‐frontliners .For Factor 2, “exhaustion,” workers in their 30s, 40s, and 50s reported feeling more exhaustion than workers in their 20s . Workers in their 30s, 40s, and 50s reported more demanding workload than those in their 20s . Nurses reported that they had a greater workload than medical doctors . Related to exposure to COVID‐19, frontliners felt that they had a higher workload than non‐frontliners .For Factor 3, “workload,” workers who were asked to standby at home reported higher workload than workers who were not asked to standby at home . Regarding gender, females felt less well‐protected than did males . Workers in their 30s had less of a sense of being protected than those in their 20s . Regarding their job, nurses and others reported feeling less well‐protected than did medical doctors .For Factor 4, “feeling of being protected,” workers who were asked to standby at home had a stronger feeling of being protected than workers not asked to standby at home (p = 0.006). In regression analysis, the total IES‐R scores varied by age and job. The total IES‐R scores of workers in their 30s, 40s, and 50s were higher than those of workers in their 20s . Examined by job category, the total IES‐R score of nurses and others was higher than that of medical doctors .The mean (SD) total score on the IES‐R in 951 participants was 12.7 (13.3), with a range of 0–73. Notably, 159 (16.7%) respondents screened positive on clinical concern for PTSD Table . The resIn regression analysis, we included the experience of the great Hanshin‐Awaji earthquake and experience of engagement of DMAT as independent variables. We investigated whether the experience of the Great Hanshin‐Awaji Earthquake would be a vulnerability factor in re‐experiencing trauma, and whether the experience of DMAT participation would be a protective factor through prior education. Regression analysis showed that these experiences did not influence the total score for each of the four factors and the IES‐R.This is the first study examining stress of hospital workers, as measured by the IES‐R, under the emergency declaration in Japan. The study identified that among health‐care workers, women, those in their 30s–50s, nurses, and frontline workers faced multiple high‐risk factors while treating patients with COVID‐19.At the beginning of the COVID‐19 outbreak, nosocomial infections occurred, and 349 employees were required to standby at home to prevent the spread of infection. Workers who had to be quarantined felt higher levels of “anxiety about infection” and a higher “workload” than those who were not quarantined. However, quarantined workers also had a stronger “feeling of being protected” than nonquarantined workers. Continuous communication between health‐care workers and managers, including the provision of up‐to‐date facts about the progression of the outbreak, conveys institutional support. Similarly, it is essential that managers take steps to mitigate feelings of social isolation and stigmatization, especially among quarantined hospital health‐care workers.In our study, females experienced higher levels of anxiety and felt less well‐protected than did males. In contrast, “exhaustion,” “workload,” and the IES‐R scores did not significantly differ between genders. Similar results have been reported previously. Female gender has been consistently associated with higher levels of stressIn this study, “anxiety about infection” was stronger among workers in their 40s than those in their 20s. This could be because they have anxiety about themselves and their family members being infected, echoing results of studies on influenza pandemics in the United States.Hospital workers in their 30s, 40s, and 50s were more exhausted and reported that they had a greater workload than workers in their 20s. In terms of sociodemographic factors, younger age is a risk factor for burnout.Examined by job category, nurses, and others were significantly more anxious about infection and becoming exhausted, but they perceived receiving less protection than did medical doctors. Reported “workload” was significantly higher for nurses than medical doctors. Moreover, the total IES‐R score was significantly higher for nurses than medical doctors. Similar results were reported in studies of the 2003 SARS outbreakHospital workers in high‐risk environments (frontliners) experienced significantly higher levels of “exhaustion” and a higher “workload” than workers in low‐risk work environments (non‐frontliners). A systematic review by Serrano‐Ripoll et al. found that working in a high‐risk environment was associated with a variety of mental health problems.The “feeling of being protected” factor did not significantly differ between work environments. The total score for the “feeling of being protected” factor was low for workers in both high‐ and low‐risk areas. This could be because during the COVID‐19 pandemic in Japan, especially in the latter half of April and May 2020, national and local governments enacted infection‐control activities, but did not provide hospital workers with information about protection against or compensation for COVID‐19 infection acquired in the course of hospital duties. The supply of protective equipment was inadequate. Some staff required alternative accommodation to reduce the risk of infecting their families. In preparation for a pandemic, some studies have emphasized the need for communities and employers to take all reasonable precautions to prevent illness among health‐care providers, as well as to provide reliable compensation if workers become ill while carrying out required duties.Motivated by our study results, our hospital's director began the practice of sending regular messages of comfort, encouragement, and appreciation to the staff. We also received letters of appreciation and gifts from citizens and companies. Special allowances were also provided to all employees. We will need to examine how such efforts improve mental health among hospital health‐care workers.This study has several limitations. First, the present study used the CFA analysis to replicate the factors and their comprising items that were confirmed in the H1N1 influenza pandemic. However, the limitation of conducting CFA by the previous model may dismiss other models that fit more appropriately to the present pandemic. Second, the response rate of the present study was 29.6%. A low response rate can give rise to sampling bias if the nonresponse is unequal among the participants. However, the results of this study were consistent with those of previous studies and seemed to reflect the mental health of hospital health‐care workers. Third, we did not assess other common mental health problems, such as depression. However, the association between IES and depression has been pointed out in previous studiesHaruko Fukushima, Hissei Imai, Chisato Miyakoshi, Hiroyuki Miyai, Kyohei Otani, Shinsuke Aoyama, and Kunitaka Matsuishi were involved in study design. Hissei Imai and Chisato Miyakoshi contributed to data analysis. Haruko Fukushima, Hiroyuki Miyai, Kyohei Otani, and Kunitaka Matsuishi contributed to the acquisition of data. Haruko Fukushima drafted the initial manuscript, which was then revised by Hissei Imai, Chisato Miyakoshi, and Kunitaka Matsuishi. All authors approved the final manuscript.The authors declare no conflicts of interest.The study protocol was approved by the Ethics Committee of Kobe City Medical Center General Hospital (no. zn200726). Written informed consent was obtained from the participants.


PD).Agents targeting the metabotropic glutamate receptor 4 have emerged as a potentially attractive new class of drugs for the treatment of Parkinson's disease  and dyskinesia (secondary endpoint) did not improve significantly compared with placebo for either foliglurax dose. Treatment with foliglurax was generally safe, and there were no relevant safety signals.Although dose‐dependent decreases in daily awake Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder SocietyThere was no evidence in this study that foliglurax has efficacy in improving levodopa‐induced motor complications in PD. © 2022 The Authors.  Levodopa‐induced motor complications (response fluctuations and dyskinesia) remain a common barrier to the effective management of Parkinson's disease (PD).off time. The main secondary objective was to assess the efficacy of foliglurax on reducing the severity of LID.The metabotropic glutamate receptor 4 (mGlu4R) is a Gi/o protein‐coupled receptor extensively expressed in the basal ganglia and cerebellum that reduces exocytosis of neurotransmitter in response to activation by endogenous glutamate.off period and experienced both predictable wearing‐off fluctuations and LID for ≥3 months, with ≥2 hours of off time and ≥2 hours of on time with dyskinesia per day.This was a double‐blind, randomized, placebo‐controlled, parallel‐arm study of foliglurax as add‐on therapy in patients with PDclinicaltrials.gov (NCT03162874).The study was conducted between May 25, 2017, and March 2, 2020, in accordance with the Declaration of Helsinki; study protocols were approved by the ethics committee at each of the 42 European sites, and all patients provided written informed consent. The study was registered at Following a screening period (≥28 days), patients were randomly assigned (1:1:1) using a computer‐generated sequence to 28 days of double‐blind treatment with foliglurax 10 mg , 30 mg bid, or matching placebo. All patients, study site personnel, and the sponsor were blinded to group assignments. Stable concomitant medications were permitted except amantadine, apomorphine, levodopa/carbidopa intestinal gel infusion, and safinamide.off, on without dyskinesia, on with nontroublesome dyskinesia, and on with troublesome dyskinesia) every 30 minutes while awake before the baseline, day 14, and day 28 visits. Dyskinesia was assessed on site using the Unified Dyskinesia Rating Scale (UDysRS)on and experiencing maximum severity dyskinesia; assessments at days 14 and 28 were performed at the same time after morning levodopa dosing.Patients completed a 3‐day Hauser diaryoff time assessed by the Hauser diaries (average of 3 consecutive days). Secondary efficacy outcomes included change from baseline to day 28 in UDysRS objective (Parts 3 + 4) and total (Parts 1–4) scores and “good” on time (defined as on without troublesome dyskinesia). A responder analysis assessed the proportion of patients in each group achieving ≥1 hour reduction from baseline in off time. Changes from baseline to day 28 in other diary data were analyzed as exploratory measures.Blood samples for pharmacokinetic evaluation were drawn on day 1 and day 28. Pharmacokinetic analysis was conducted using noncompartmental procedures . Safety and tolerability assessments included treatment‐emergent adverse events (TEAEs), vital signs, laboratory tests, electrocardiogram.(ECG), physical examinations, and Columbia‐Suicide Severity Rating Scale.The primary efficacy assessment was the change from baseline to day 28 in off time between any active treatment and the placebo group, assuming an estimated standard deviation of 2 hours with a two‐sided α‐level of 0.05. Safety was assessed for all patients who received ≥1 dose of study medication (safety set), and pharmacokinetics were assessed for all patients in the safety set who had evaluable pharmacokinetic data. Efficacy endpoints were analyzed for the full analysis set, which included all patients in the safety set who had valid baseline and ≥1 valid postbaseline assessments of off time. A valid diary assessment was defined as a visit that had available data for ≥2 of the 3 preceding days . If valid data from only 2 days were available, the mean of these 2 days was used. Details of the mixed model for repeated measures approach to the primary and secondary efficacy analyses are provided in the supplemental information. Both doses were tested at a 5% one‐sided level without adjustment for multiplicity.A total of 45 evaluable patients in each arm were calculated to provide 80% power to detect a difference of −1.2 hours in Of 233 patients screened, 157 were randomly assigned to double‐blind treatment . Overalloff time decreased numerically with dose when compared with placebo, none of these differences were significant  for the odds ratios between each dose level and placebo spanned 1.Although least‐squares mean (LSM) differences in change from baseline to day 28 in daily awake nt Table , and theon time  between active treatment and placebo on good me Table  or any ome Table . Resultson and off phenomenon, dyskinesia, and headache. Eight patients had TEAEs that led to study withdrawal , of whom seven were receiving active treatment. There were no clinically relevant changes over time or differences between treatment groups with respect to clinical laboratory values, vital signs, or ECGs.TEAEs were reported for 52.8% of patients in the foliglurax 10‐mg bid group and 50.0% in the 30‐mg bid group compared with 42.3% in the placebo group  antagonists (MK‐801 or memantine), α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) antagonists (perampanel), and Metabotropic Glutamate Receptor 5 (mGlu5) allosteric modulators (mavoglurant). None of these development programs has succeeded so far.To date, the only oral antiparkinsonian treatment to have shown significant effects on both types of motor complications is a delayed‐release/extended‐release formulation of amantadine, which improved both off time, patients were recruited based on their dyskinesia, and some patients may have had very little off time at baseline.off time versus baseline continued to improve (decrease) from day 14 to day 28, the treatment effect versus placebo did not change. Moreover, 28 days was considered adequate to assess the safety of foliglurax at this early stage of development and to determine early proof‐of‐concept therapeutic effect on reducing off time compared with placebo (current adjuncts to reduce off time show significant effects within this time frame). Pharmacokinetic analyses showed that plasma concentrations were in the range of what was predicted to be efficacious from the animal modelsA strength of this study is that it recruited patients based on having both motor fluctuations and dyskinesia. Although previous studies with amantadine have shown reductions in Olivier Rascol has acted as a scientific advisor for drug companies developing antiparkinsonian medications , and Watermark) and has received unrestricted scientific grants from academic nonprofit entities  de Toulouse, France‐Parkinson, Institut National de la Santé et de la Recherche Médicale ‐Direction Générale de l'Offre de Soins (INSERM‐DHOS) Recherche Clinique Translationnelle, The Michael J. Fox Foundation, Programme Hospitalier de Recherche Clinique, and the European Commission ). Rossella Medori is currently employed by Accure Therapeutics and reports consultancy for Affiris AG within the past 12 months. Corine Baayen, Pedro Such, and Didier Meulien are employed by H. Lundbeck A/S.(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.O.R.: 1A, 1C, 3A, 3BR.M.: 1A, 1C, 3BC.B.: 1C, 2A, 2B, 2C, 3BP.S.: 1C, 3A, 3BD.M.: 1C, 3BFollowing is the AMBLED Study Group member list: Olivier Rascol, Alberto Albanese, Maria Alvarez Sauco, Ernest Balaguer Martinez, Caroline Bayreuther Giordana, Stephanie Bannier, Paolo Barone, Ubaldo Bonuccelli, Placido Bramanti, Camille Carroll, Jean‐Christophe Corvol, Paola Cudia, Phillipe Damier, Luc Defebvre, Bertrand Degos, Franck Durif, Roberto Eleopra, Giovanni Fabbrini, Jorge Hernandez Vara, Jean‐Luc Houeto, Jaime Kulisevsky Bojarski, David Maltete, Maria Jose Marti Domenech, Irene Martinez Torres, Pablo Mir Rivera, Sophie Molloy, Elena Moro, Thomas Mueller, Giampietro Nordera, Christian Oehlwein, Marco Onofrj, Nicola Pavese, Tino Prell, Jason Raw, Irma Schoell, Johannes Schwarz, Klaus Seppi, Alessandro Stefani, Fabrizio Stocchi, Stephane Thobois, Claudia Trenkwalder, Richard Walker, Jurgen Winkler, and Werner Poewe.Appendix S1: Supporting InformationClick here for additional data file.


Alitretinoin is the only registered systemic treatment of severe chronic hand eczema (HE), but it is most effective in hyperkeratotic HE.In one daily practice case series, patients showed moderate‐to‐good improvement of their HE after treatment with azathioprine.This trial aimed to compare alitretinoin to azathioprine in the treatment of severe chronic HE. Due to a high‐drop out ratio, the trial was unfortunately prematurely discontinued. Most prematurely discontinued studies remain unpublished, resulting in unwanted publication bias. Therefore, we decided to analyse our data.This was a randomized, open‐label trial in adult patients with severe chronic HE. Hyperkeratotic HE was not included since alitretinoin has proved itself effective in hyperkeratotic HE.The statistics methods can be found in Supporting Information Material n = 21/42). The dropout rate was the highest in the azathioprine group with 66.7% (n = 14/21) versus 33.3% (n = 7/21) in the alitretinoin group.In total, 42 patients (21 per group) were included. There were no significant differences in baseline characteristics between both groups (see Table p = 0.063). In the alitretinoin group, 57.1% had achieved ‘clear/almost clear’, compared to 14.3% in the azathioprine group (p = 0.032). Subjects in the alitretinoin group had a mean decrease of 69.1% of the HECSI score, compared to a decrease of 55.0% in the azathioprine group . Lastly, it is important to note that in three patients in the alitretinoin group, and two patients in the azathioprine group, ineffectiveness was a reason to drop out of the study.At the 24 weeks visit, the proportion of responders based on the photographic guide was 64.3% in the alitretinoin group and 14.3% in the azathioprine group (p = 0.058). The minimal important change (MIC) of 22 points improvement was achieved by 64.3% of the patients in the alitretinoin group and by 14.3% of the patients in the azathioprine group at Week 24 (p = 0.063).Regarding HRQoL, the absolute QOLHEQ score was decreased (improvement in HE‐specific HRQoL) in both groups after 12 and 24 weeks compared to baseline. The mean percentage decrease in QOLHEQ score was 57.8% in the alitretinoin group versus 36.6% in the azathioprine group after 24 weeks  in the alitretinoin group and nine out of 21 patients (42.9%) in the azathioprine group. An overview of all reasons for dropout can be found in the flowchart  in HEThe design of this study might have contributed to the high drop‐out rate. Since it was an open‐label head‐to‐head study: patients knew which treatment they received, including its side‐effects. This knowledge, giving patients certain expectations, plus the knowledge of other existing treatment options, for example, alitretinoin instead of azathioprine, might have made patients more eager to drop‐out of the study compared to blinded and placebo‐controlled studies.In conclusion, both alitretinoin and azathioprine gave improvement of HE severity and HE‐specific HRQOL in this study. Alitretinoin might give more improvement of severity scores and HRQoL, as found in the analysis of our data, but we are not able to draw any conclusions on differences in efficacy between the two treatments due to the study being underpowered and the study results are biased by the high drop‐out rate.Angelique N. Voorberg: Conceptualization; investigation; writing – original draft; writing – review and editing; visualization; validation; methodology; formal analysis; project administration; data curation; resources. Esmé Kamphuis: Formal analysis; project administration; data curation; resources; investigation; visualization; validation. Wietske A. Christoffers: Data curation; resources; project administration; writing – review and editing; visualization; validation; investigation. Geertruida L. E. Romeijn: Resources; data curation; project administration; validation; visualization; investigation. Jart A. F. Oosterhaven: Conceptualization; investigation; funding acquisition; writing – original draft; methodology; validation; visualization; writing – review and editing; project administration; data curation; supervision; resources. Marie L. A. Schuttelaar: Supervision; resources; data curation; writing – review and editing; project administration; writing – original draft; methodology; validation; visualization; investigation; conceptualization; funding acquisition.Marie L. A. Schuttelaar is an advisor, consultant, speaker and/or investigator for AbbVie, Pfizer, LEO Pharma, Regeneron, Sanofi Genzyme, Eli Lilly and Galderma. She has received grants from Regeneron, Sanofi Genzyme, Novartis and Pfizer. Wietske A. Christoffers is a speaker for Sanofi Genzyme, and has been a consultant for LEO Pharma. The remaining authors declare no conflict of interest.This study was approved by the Dutch national competent authority  and the local Ethical Review Board of the University Medical Center Groningen (METc 2015/176).Appendix S1 Supporting informationClick here for additional data file.Appendix S2 Supporting informationClick here for additional data file.