Posaconazole is a triazole antifungal with a broad spectrum of activity against moulds including Aspergillus spp. Emerging data suggest posaconazole may be effective in the treatment of allergic bronchopulmonary aspergillosis (ABPA) complicating cystic fibrosis (CF). Rarely, posaconazole can cause pseudohyperaldosteronism, manifesting as hypertension and electrolyte abnormalities, with a number of cases recently reported in individuals without CF. We describe two cases of children with CF who developed hypertension, likely due to pseudohyperaldosteronism, following the initiation of posaconazole for the treatment of ABPA. Posaconazole is a triazole antifungal with a broad spectrum of activity against moulds including Aspergillus spp. Rarely, it can cause pseudohyperaldosteronism. We describe two cases of children with cystic fibrosis who developed hypertension, likely due to pseudohyperaldosteronism, following the initiation of posaconazole for the treatment of allergic bronchopulmonary aspergillosis. Posaconazole is a triazole antifungal with a broad spectrum of activity against moulds including Aspergillus spp. Emerging data suggest posaconazole may be effective in the treatment of allergic bronchopulmonary aspergillosis (ABPA) complicating cystic fibrosis (CF).Pseudomonas aeruginosa who had been taking ivacaftor/lumacaftor for 1 year developed cough and wheeze. His blood pressure (BP) was 100/60 mmHg. Aspergillus fumigatus complex was cultured from sputum and chest x‐ray showed coarsened bronchovascular markings with focal opacification. Clinical response to anti‐pseudomonal antibiotics and a short course of prednisolone were poor and IgE was elevated (1029 kU/L [<72 kU/L]). Itraconazole was initiated and oral prednisolone re‐commenced. Computed tomography (CT) imaging of the chest showed changes consistent with ABPA including new bronchiectasis and endobronchial secretions in all lobes with associated branching airspace opacity. Monthly pulsed intravenous (IV) methylprednisolone (15 mg/kg for 3 days) was commenced and prednisolone ceased. BP became elevated following methylprednisolone (maximum BP 125/90 mm/Hg) above the 95th centile for age and height (118/78 mmHg).A 9‐year‐old male (homozygous p.Phe508del) known to be colonized with As itraconazole levels remained subtherapeutic despite dose adjustment, antifungal therapy was changed to posaconazole (delayed‐release tablets). Therapeutic levels (3.78 mg/L) were attained within 2 weeks. Prior to the second methylprednisolone pulse, BP was elevated (115/80 mmHg) and IgE had normalized (367 kU/L).He remained clinically stable and, prior to the fifth methylprednisolone pulse, BP was elevated at 120/80 mmHg and increased to 165/110 mmHg following the pulse; amlodipine (5 mg) was commenced for hypertension. Hypokalaemia (3.0 [3.3–4.9 mmol/L]) and hypophosphataemia (0.79 [0.90–2.00 mmol/L]) were noted. Pulsed methylprednisolone was ceased following clinical improvement. Amlodipine was ceased 1 month later; however, BP remained elevated (130/75 mmHg) requiring amlodipine to be restarted. His IgE has remained low (85 kU/L) and symptoms of ABPA have not flared. Posaconazole was ceased after a total of 9 months; BP remained stable (on amlodipine). Amlodipine was ceased 4 months later when BP was normal.A 7‐year‐old girl with CF (homozygous p.Phe508del) and episodic ABPA over the preceding 4 years developed worsening cough and deterioration in appearance of CT chest. Ivacaftor/lumcaftor had been recently commenced. Previous ABPA treatment included oral prednisolone, IV methylprednisolone, itraconazole, posaconazole and inhaled liposomal amphotericin. Posaconazole had previously been discontinued after a week due to elevation in hepatic enzymes and clinical response with itraconazole was poor, with associated difficulties attaining therapeutic levels. Use of oral steroids had been previously limited due to significant associated behavioural changes. Omalizumab was precluded due to severe needle phobia. She had previous episodes of hypertension with concurrent administration of ivacaftor/lumacaftor, itraconazole and steroids; however, these episodes were asymptomatic and self‐resolving.Despite recent treatment with inhaled liposomal amphotericin and oral prednisolone, no clinical improvement was observed and serum IgE increased to 1223 kU/L. Baseline BP was 100/60 mmHg. Posaconazole 200 mg three times a day was initiated, with the plan to initiate mepolizumab as a steroid‐sparing agent. Two weeks following posaconazole initiation, she developed headache and facial flushing. BP was elevated to 136/98 mmHg. Posaconazole serum levels were high (8 mg/L), further doses were withheld and clonidine was started for hypertension. Mild hypokalaemia was present (3.0 mmol/L). Repeat CT imaging demonstrated new high attenuation endobronchial material in all lobes, consistent with worsening disease. Pulse methylprednisolone (22 mg/kg for 3 days) was given. Posaconazole was restarted at 200 mg twice daily and mepolizumab (40 mg monthly) commenced. On discharge, BP was controlled on clonidine between 96/40 and 110/75 mmHg.Headaches and hypertension worsened despite clonidine and a reduced serum posaconazole level (4 mg/L). She redeveloped hypokalaemia (2.5 mmol/L). Posaconazole dose was reduced further (200 mg in the morning and 100 mg in the evening). Her BP control was maintained with clonidine and amlodipine (5 mg twice daily) at 105/60 mmHg and hypokalaemia resolved. Her IgE has reduced to 250 kU/L after 2 months of mepolizumab. Posaconazole was ceased after 4 months, her BP remains stable (105/60 mmHg) while antihypertensives are being weaned.We report two cases of hypertension with associated hypokalaemia following the initiation of posaconazole for the treatment of ABPA. The likely mechanism for hypertension in both these cases is posaconazole‐induced pseudohyperaldosteronism.A. fumigatus.ABPA is a type 2 hypersensitivity reaction, mainly triggered by Ivacaftor/lumacaftor is a CF transmembrane conductance regulator modulator that is currently licenced in Australia for individuals with CF who are homozygous for the p.Phe508del mutation from 24 months of age.In terms of hypertension as a side effect from oral antifungals, both posaconazole and itraconazole can cause hypertension, and voriconazole does not cause hypertension.Unfortunately, in both cases described here, the potential pseudohyperaldosteronism was not recognized until the resolution of hypertension and confirmatory urine and blood tests to assess the renin–angiotensin–aldosterone pathway were not obtained. The likely mechanism in both cases was posaconazole‐induced pseudohyperaldosteronism as persistent BP elevation was only noted after the initiation of posaconazole. Concomitant administration of ivacaftor/lumacaftor and posaconazole may reduce posaconazole levels; however, effects on BP are unclear.Close monitoring of BP, serum electrolytes and trough posaconazole levels should be implemented following the initiation of posaconazole in patients with ABPA to ensure early detection of this adverse effect.In conclusion, we describe two cases of likely posaconazole‐induced pseudohypoaldosteronism presenting with hypertension and hypokalaemia in children receiving treatment for ABPA complicating CF. Hypertension may be multifactorial in this setting, given the frequent concomitant administration of steroids, ivacaftor/lumacaftor together with posaconazole. When prescribing posaconazole in children with ABPA, respiratory clinicians should be aware of this potential adverse effect and ensure appropriate monitoring is in place.Funding was received from the Child and Adolescent Health Service Research Fellowship.None declared.Appropriate written informed consent was obtained for publication of this case report.Rachael Marpole prepared the first draft of this paper under the supervision of Adelaide L. Withers. The draft was revised by Daniel K. Yeoh.


Egg consumption is one of the many inconsistencies in evidence linking dietary cholesterol to cardiovascular disease (CVD). In addition, the gut microbiota and its metabolite, trimethylamine‐N‐oxide (TMAO), have been shown to play a crucial role in the development of CVD. The fact that egg is rich in choline suggests that excessive egg consumption may increase TMAO production by altering the gut microbiota. However, the effects of egg consumption on vascular function and gut microbiota remain unclear. Here, the diet of nine young male subjects was supplemented with two boiled eggs daily for 2 weeks. Changes in vascular function, inflammation, metabolism, oxidative stress, and gut microbiota were examined. We found that egg consumption increased flow‐mediated dilation and decreased brachial‐ankle pulse wave velocity. Furthermore, egg consumption positively modulated the gut microbiota function but had no effects on the levels of C‐reactive protein, glucose, lipid profile, malondialdehyde, superoxide dismutase, or TMAO. The current study provides evidence that egg consumption improves vascular function, which may be related to the alterations seen in the gut microbiota. Therefore, moderate egg consumption may help to improve vascular and intestinal function in individuals at low risk of developing CVD and other metabolic disorders. Egg consumption improves vascular and gut microbiota function but has no effects on inflammatory, metabolic, and oxidative status. This trial was registered at the Chinese Clinical Trial Registry (ChiCTR2100046956).2.2g for 10 min at 4°C, and the plasma was collected. Levels of biochemical, lipid profile, and C‐reactive protein (CRP) were tested in the clinical laboratory of the First Affiliated Hospital, Sun Yat‐sen University. The levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in the blood were measured using Lipid Peroxidation MDA Assay Kit (Beyotime) and Total Superoxide Dismutase Assay Kit with WST‐8 (Beyotime) respectively, which were all performed according to the standard protocols recommended by the manufacturer.Whole blood was collected from participants at baseline and at the end of the trial. After a 12 hr overnight fast, blood was drawn into EDTA and SST blood collection tubes and centrifuged at   1811 × 2.3All the procedures were performed by the same skilled technician. Flow‐mediated dilation (FMD) was performed on a high‐resolution ultrasonography equipment  as described in our previous study  and ankle‐brachial index (ABI) were performed using an automatic measuring instrument (Colin Co. Ltd.) as described in our previous study , which was equilibrated with 30% solution A  and 70% solution B (acetonitrile) under isocratic elution with the flow rate of 0.3 ml/min. The ESI was operated in positive mode, and the mass spectrometer was run in multiple‐reaction monitoring mode. The settings for the mass transition of TMAO and IS were m/z 76.1 → 58.3 and m/z 85.1 → 66.3.The concentrations of TMAO in the fasting plasma and urine were detected on a liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) system consisting of an Agilent 1260 high‐performance liquid chromatography (HPLC) and 6420 triple quadrupole mass spectrometer with an electrospray ionization source (ESI) (Agilent). One hundred microliters of the specimen was mixed with internal standard (IS) working solution (d9‐TMAO), and 300 μL of acetonitrile was added to the sample and then vortexed, and the mixture was centrifuged at  15,294 × 2.5Fecal samples were collected from every participant at baseline and at the end of the trial and then frozen at −20°C for subsequent analysis. DNA was extracted using the GHFDE100 DNA isolation kit according to the manufacturer's protocol. PCR amplification of the bacterial 16S rDNA genes V4 region was performed using a Phusion High‐Fidelity PCR Master Mix (New England Biolabs) with the forward primer 515F (5'‐GTGCCAGCMGCCGCGGTAA‐3') and the reverse primer 806R (5'‐GGACTACHVGGGTWTCTAAT‐3'). Next, PCR amplicons were purified with Agencourt AMPure XP Beads (Beckman Coulter) and quantified using the PicoGreen dsDNA Assay Kit (Invitrogen). Finally, the sequencing was performed using the Illumina NovaSeq 6000 platform.The sequencing data were processed using the Quantitative Insights Into Microbial Ecology  pipeline , and the graphs were plotted by GraphPad Prism (Version 7.0). Continuous variables with normal distribution were presented as mean ± standard error of the mean, and the comparisons between two groups were performed with the paired 33.12. Participants consumed two boiled eggs on schedule, and no intervention‐related adverse events were reported. There were no intervention‐related differences in heart rate, blood pressure, CRP, glucose, creatinine, or lipid profile. The clinical characteristics and laboratory results are summarized in Table Twelve subjects were enrolled, of which nine completed the trial Figure . The ave3.2FMD, baPWV, and ABI were measured before and after dietary intervention to investigate the effect of egg consumption on vascular function. Notably, egg consumption improved FMD Figure  and baPW3.3Egg consumption did not affect MDA levels  Figure  and SOD 3.4A heatmap of bacterial distribution illustrates the abundance of different communities at the genus level Figure . The Ven3.5N‐acetylglucosaminidase, but not DNA ligase  and EC (Enzyme Commission) prediction. Egg intervention resulted in downregulation of functional orthologs, including the voltage‐gated potassium channel pathway, ATP‐dependent target DNA activator pathway, and tryptophanase, etc. In contrast, DNA ligase 1, heptosyltransferase I, type VI secretion system protein VasI, and type VI secretion system protein ImpI were enriched in the post‐treatment group Figure . Moreovee Figure . For GMMe Figure .4In this study, we found that a daily intake of two eggs improved FMD and baPWV and positively modulated the function of the gut microbiota but exerted no effects on CRP, glucose, lipid profile, MDA, SOD, or TMAO. To our knowledge, this is the first study to evaluate the impact of hard‐boiled egg intake on vascular function, metabolism, inflammation, oxidative stress, and gut microbiota in healthy, young male subjects. The results suggest that moderate egg consumption may improve vascular and intestinal function in individuals with low risk of developing CVD and other metabolic disorders.Eggs are rich in essential proteins, nutrients, vitamins, and minerals, and high in cholesterol and choline  was associated with increased total cholesterol, LDL‐cholesterol, and non‐HDL‐cholesterol, but exerted a beneficial effect on HDL‐C and triglycerides ; Formal analysis ; Investigation ; Writing—original draft . Yijia Shao: Formal analysis ; Investigation ; Project administration . Jiapan Sun: Formal analysis ; Investigation . Jiazichao Tu: Investigation . Zhichao Wang: Investigation . Jun Tao: Conceptualization ; Funding acquisition ; Supervision ; Writing—review & editing . Jimei Chen: Conceptualization ; Data curation ; Funding acquisition ; Supervision ; Writing—review & editing .


To evaluate the practice of aminoglycoside use/monitoring in Kenya and explore healthcare worker (HCW) perceptions of aminoglycoside monitoring to identify gaps and opportunities for future improvements, given the low therapeutic index of aminoglycosides.This was a two-phase study whereby we reviewed patients’ medical records at Kenyatta National Hospital (October–December 2016) in Phase 1 and interviewed HCWs face to face in Phase 2. Outcome measures included describing and evaluating the practice of aminoglycoside use and monitoring and compliance to guidelines. Data were analysed using descriptive and inferential analysis.Overall, out of the 2318 patients admitted, 192 patients (8.3%) were prescribed an aminoglycoside, of which 102 (53.1%) had aminoglycoside doses that did not conform to national guidelines. Aminoglycoside-related adverse effects were suspected in 65 (33.9%) patients. Monitoring of aminoglycoside therapy was performed in only 17 (8.9%) patients, with no therapeutic drug monitoring (TDM), attributed mainly to knowledge and skill gaps and lack of resources. Out of the 28 recruited HCWs, 18 (64.3%) needed training in how to perform and interpret TDM results.The practice of using and monitoring aminoglycosides was suboptimal, raising concerns around potential avoidable harm to patients. The identified gaps could form the basis for developing strategies to improve the future use of aminoglycosides, not only in Kenya but also in other countries with similar settings and resources. Systemic aminoglycoside antibiotics  are high-risk medicines.Despite the need for strategies to monitor its use, neither therapeutic drug monitoring (TDM) nor treatment protocols for aminoglycosides are currently available in Kenyatta National Hospital (KNH), the largest referral hospital in Kenya, apart from the national Basic Paediatric Protocol (BPP) for the management of critically ill paediatric patients.The study consisted of two phases: the first phase was a medication-use review of aminoglycosides in paediatric patients over a 3 month period from October to December 2016 on the four general paediatric wards (GPWs) and the newborn unit (NBU) in KNH. This included evaluation of key processes in the medication-use cycle including prescribing, administration, monitoring, drug safety issues and patient outcomes. The second phase was structured interviews with HCWs.The study cohort for Phase 1 was paediatric patients admitted to the GPWs/NBU of KNH during the study period who were on any aminoglycoside, with ages between 0 and 12 years. Patients were excluded if they were discharged before recruitment, not on any aminoglycosides during the period of the study, admitted to paediatric wards other than the GPWs or the NBU or were older than 12 years. Phase 2 included a structured interview of the HCWs in the GPWs and NBU.n = 40), senior house officers (n = 15), pharmacists (n = 4), nurses who were mainly responsible for the paediatric wards (n = 6) and laboratory technicians (n = 3) were contacted by phone as well as approached after completion of their ward rounds and asked to participate in the study.Universal sampling was used. For Phase 1, all the files of patients meeting the inclusion/exclusion criteria were sampled and reviewed. The sampling was done within 48 h after the aminoglycoside was prescribed. Signed consent to collection of the data was given by the parents/guardians for children aged <7 years and both parental consent and child assent was obtained for children aged ≥7 years. For Phase 2, paediatrician specialists  was developed by modifying a sample questionnaire for the Knowledge, Attitude and Practice (KAP) study on rational drug use by doctors.In Phase 2, a questionnaire .n = 169/192); however, the weight of a significant number of patients  in the GPWs was not recorded.A total of 2318 paediatric patients were admitted to the GPWs and NBU during the study period, of which 192 (8.3%) patients were prescribed aminoglycosides (Table n = 118/192). The main indication for an aminoglycoside was neonatal sepsis , followed by suspected infections with a presentation of respiratory distress . A total of 39.6% (n = 76/192) had two comorbidities and 33.3% (n = 64/192) had one medical condition.Gentamicin was the most commonly used aminoglycoside  on 2 medicines (Table n = 163/192) receiving 2 antibiotics at a time.The median total number of medicines per patient, including aminoglycosides, was 3 (range: 1–8), with 38% n = 73/19 on 2 medn = 107/192) were started on gentamicin/benzylpenicillin as the first-line antibiotic combination (Table n = 29/192) combination. Only 48 (25%) patients were switched from one antibiotic combination to another. Out of these, 35.4% (n = 17/48) were switched from gentamicin/benzylpenicillin to amikacin/ceftazidime, followed by a switch to oral antibiotics . Fourteen patients (7.3%) had oral antibiotics administered with an aminoglycoside, with erythromycin being the most common .More than half of the patients , IV furosemide , NSAIDs  and aciclovir .Nephrotoxic drugs were concurrently administered with an aminoglycoside to 14 patients (7.3%), which included vancomycin , only 40.7% (n = 24/59) of patients were prescribed the recommended dose of gentamicin of 5 mg/kg/day, with 37.3% (n = 22/59) and 22.0% (n = 13/59) being underdosed and overdosed, respectively. For neonates weighting <2 kg, the mean dose was significantly higher than the recommended dose , with only 13.6% (n = 3/22) of neonates prescribed the exact recommended dose and the majority  being overdosed. Among those patients who were not prescribed the recommended aminoglycoside dose (n = 49), 19 (38.8%) had neonatal sepsis.Although the prescribed mean gentamicin dose for neonates aged <7 days and weighing ≥2 kg was not significantly different from the recommended dose in the BPP protocol ; however, only 14.3% (n = 2/14) were prescribed the exact recommended dose, with the majority  being underdosed, of which 75% (n = 6/8) had neonatal sepsis. Similarly, the prescribed mean amikacin dose was not significantly different from the recommended dose of 15 mg/kg/day (P = 0.552) for all patients; however, 33.0% (n = 36/109) were underdosed.For those aged >7 days, the mean gentamicin dose was not significantly different from the recommended dose  were on an aminoglycoside for at least 72 h, with 39.6% (n = 76/192) treated for at least 7 days. Slightly less than half  of the patients did not complete the prescribed duration of therapy, mainly due to discharge , change to other antimicrobials  or death .In terms of duration of therapy, most of the patients  received all their daily doses of aminoglycoside within 1 h of the prescribed administration time; however, 16.7% (n = 32/192) missed some aminoglycoside doses over the treatment course, of which the majority  missed one dose and 28% (n = 9/32) missed two doses. No reason was reported for the missed dose for the majority of cases . Lack of an IV line was the reported reason in 10 cases (31.3%).All the patients received an aminoglycoside as an IV injection once daily. In all cases, gentamicin and amikacin were administered as a bolus infusion over 30 s. Half of the patients , mostly for those aged 2 to 6 years , with the least among those aged ≤30 days . Among those patients with baseline creatinine level, 8.3% (n = 11/132) had a documented baseline creatinine level above 120 μmol/L. Out of these 11 patients, aminoglycoside therapy was discontinued after one dose in 1 patient and after two doses in 2 patients. It was not documented whether the discontinuation was informed by the elevated creatinine level or other patient factors.Baseline and follow-up creatinine levels stratified by age categories are presented in n = 17/192) of the patients, mostly in those aged 30 days to 24 months , with the least among those aged 2 to 6 years  (n = 2/17) had follow-up creatinine levels above 100 μmol/L, while 29.4% (n = 5/17) had an 11.7%–405% increase in their follow-up creatinine level compared with baseline values. Among patients who were on aminoglycoside therapy for ≥7 days (n = 76), nine patients (11.8%) had a follow-up creatinine level at least twice a week. The median baseline creatinine level was 56 μmol/L (range: 17–239.7 μmol/L). The median follow-up creatinine level was 62.2 μmol/L (range: 26–128.3 μmol/L). An increase in baseline creatinine level of >30% was observed in one patient only, who received gentamicin/benzylpenicillin for 2 days then amikacin/ceftazidime for 6 days before being changed to meropenem for another 7 days.At least one follow-up creatinine level was measured in only 8.9% (n = 1/6) . Out of n = 131/192) were successfully managed with the first-line antibiotic combination and were discharged without switching to other antimicrobials. Adverse drug effects were suspected in 33.9% (n = 65/192) of patients. Fever resolved in all 53 patients who were febrile. Some patients  died during the course of treatment.The majority of the patients  and electrolyte imbalance , of which 60% (n = 3/5) had hyperkalaemia, 20% (n = 1/5) had hypokalaemia and 20% (n = 1/5) had hypernatraemia; 80% of them (n = 4/5) were on gentamicin/benzylpenicillin. There was no significant difference in the incidence of suspected adverse drug effects between males and females [60% (n = 39/65) versus 40% (n = 26/65), P = 0.790); however, a higher incidence was observed in the NBU .Some of the suspected aminoglycoside-related adverse drug effects were nausea and vomiting , 8 senior house officers (response rate 53.3%), 4 pharmacists (response rate 100%), 6 nurses (response rate = 100%) and 3 laboratory technologists (response rate = 100%) , with a median age of 38.5 years (range: 26–74 years) and a median duration of practice of 12.5 years (range: 3–45 years).The majority of the participants were female  reported using existing paediatric protocols and guidelines in determining aminoglycoside doses, mostly pharmacists  (Table n = 13/28) stated they determined the dose based on weight and age, mostly nurses , followed by senior house officers . Four respondents (14.3%) reported consideration of renal function tests when determining the dose, mostly pharmacists . The majority  were unsure about current monitoring practices, mainly laboratory technologists ; six (21.4%) stated it is not currently performed and seven (25%) reported using renal function tests as a method of monitoring aminoglycoside therapy, mainly senior house officers   reported lack of a double-checking system before administration of an aminoglycoside, six (21.4%) were unsure and the remaining seven (25%) reported the existence of several such double-checking systems, mostly paediatricians  (Table n = 4/7) reported a review by the consultants during ward rounds, confirmation by nurses before administration  and cross-checking by pharmacy staff before issuance of the drugs .The majority  (Table n = 4/4), followed by nurses  (Table n = 14/28).Sixteen respondents 57.1%) reported previous experience with ordering and performing TDM, mostly senior house officers . In terms of the barriers, a knowledge gap was reported by 12 participants (42.9%) followed by a lack of willingness  , followed by information guidance around aminoglycoside-associated adverse drug effects  did not conform to the recommendations in the national BPP. Furthermore, a reasonable number of patients  received aminoglycosides for ≥7 days, which is more than the recommended duration in most current international and national guidelines.The study findings demonstrated several issues and concerns. Aminoglycoside doses for the majority of the patients  of the patients did not receive their aminoglycoside doses within 1 h of the prescribed dose time, with some patients missing a dose for the entire day. This, combined with 30.3% of patients missing some aminoglycoside doses during the course of therapy, may contribute to decreased effectiveness and hence treatment failure, increasing mortality and resistance.Incorrect dosing of aminoglycosides (either underdosing or overdosing) was one of the major and serious issues identified. However, it was difficult to establish the direct impact of this on patients’ clinical outcomes since the majority of these patients were prescribed an aminoglycoside in combination with other antibiotics. Consequently, the effect of aminoglycoside underdosing may not be detected immediately if the causative organism is responsive to the second antibiotic used in the correct dose; however, it can be a cause for concern if the organism is not responsive to the second antibiotic. Furthermore, among aminoglycoside-underdosed patients, the switching rate to another antibiotic was higher in those patients who received an aminoglycoside as monotherapy compared with an aminoglycoside as combination therapy. Switching of patients to other antibiotics could be an indicator of non-response due to underdosing. It was not clear though whether switching to other antibiotics was necessitated by non-response or by a change to more appropriate antibiotics.n = 23/44). Although only 46.9% of patients received doses that conformed to the national paediatric protocol, this is higher than the 23% reported by Murgitroyd et al.et al.,et al.Incorrect dosing could have been due to the failure to record the body weight for the majority of patients in the GPWs  patients were on other nephrotoxic drugs, lower than for Oliveira Currently, TDM at KNH is only undertaken for tacrolimus and cyclosporine but not for aminoglycosides. Consequently, aminoglycoside-related toxicity may not be detected early enough for swift intervention. The current limiting factors for performing TDM include a lack of aminoglycoside test kits and the contract agreement that dictates which medicines can be analysed, which does not include aminoglycosides. However, it is essential to address and overcome the barriers identified in this study before the introduction of such a TDM service to ensure effective and efficient uptake and implementation.,n = 76/192). It is also critical to have effective implementation strategies to ensure optimal uptake by clinicians, such as academic detailing, educational sessions and clinicians’ active engagement in the protocol design, development and implementation.The current study findings clearly indicate significant gaps in the practice of aminoglycoside use. These findings could form the basis for suggested strategies to improve the future use of aminoglycosides to optimize patients’ safety and quality of care. This could involve including aminoglycosides in future antimicrobial stewardship programmes (ASPs), which might include clear local protocols for prescribing, administrating and monitoring aminoglycosides, including signs of toxicity. These could incorporate clear instructions on how to calculate the correct aminoglycoside dose, initially and subsequently, based on patients’ age and weight.We are aware of several limitations. One of the challenges was incomplete medical records. Unavailability of TDM and minimal follow-up of creatinine levels was a limitation to monitoring patients for aminoglycoside toxicity. There could also be misclassification of patients for nephrotoxicity.Whilst the questionnaire was not validated in this study, it has been designed and validated in other African countries with similar settings to Kenya.One strength was the use of both quantitative and qualitative approaches. The qualitative findings complemented/integrated the quantitative findings, the latter highlighting suboptimal practice in aminoglycoside dosing with reported potential aminoglycoside toxicity and adverse effects that indicate the need for and importance of having robust monitoring of aminoglycoside use, ideally through TDM. However, to perform TDM, it is crucial to understand the current situation at KNH in terms of facilitators and barriers for introducing TDM, most of which are provided by the qualitative findings.Aminoglycoside use appeared to be common among paediatric patients admitted to KNH. Adherence to the national treatment guideline was suboptimal and raises concerns around potential, avoidable harm to patients. Inadequate monitoring of paediatric patients on aminoglycosides is another matter of concern that requires urgent attention. The identified gaps highlight the need for potential strategies to improve the practice of aminoglycoside use including the development of ASPs. This situation analysis study has identified gaps and areas for quality improvement interventions, with the study findings serving as a baseline for any future interventions.dlz087_Supplementary_DataClick here for additional data file.


Higher rates of death by suicide are recognized both in individuals of any age with cancer and, separately, among adolescents and young adults (AYA) without cancer. Given this intersection, identifying risk factors associated with suicidal risk among AYA with cancer is critical.To identify characteristics associated with suicide among AYA with cancer.A retrospective analysis of AYA (aged 15–39) during 1975–2016 from the Surveillance, Epidemiology, and End Results database was conducted. Clinical and demographic factors associated with death by suicide among the AYA cancer population were compared to (i) US population normative data  and (ii) other AYA individuals with cancer (odds ratios).In total, 922 suicides were found in 500,366 AYA with cancer (0.18%), observed for 3,198,261 person‐years. The SMR for AYA with cancer was 34.1 . Suicide risk was particularly high in females , unmarried persons , those with metastatic disease , or certain histological subtypes . Risk generally reduced over time, however remained elevated ≥5 years following a cancer diagnosis . When comparing those who died from suicide and those who did not, the following factors demonstrated significant associations: sex , race (White ethnicity > Black/other ethnicity), relationship status (never married > other), and disease stage .Death due to suicide/non‐accidental injury is high compared to normative data, requiring increased awareness among health‐care providers, suicide risk monitoring in AYA, and appropriately tailored psychosocial interventions. Individuals diagnosed with cancer whilst adolescents or young adults have a more than 30 times increased risk of death by suicide/non‐accidental injury than the general population. This risk remains elevated ≥5 years following a cancer diagnosis necessitating awareness among both oncology and primary care health‐care providers. For AYA, a cancer diagnosis and its management may pose a variety of unique concerns. These include disruptions to educational and vocational goals, financial burdens, changes in emotional well‐being, treatment impacts on fertility and sexuality, physical changes or body image concerns, relationship adjustments, and confrontation of the possibility of very premature mortality.Higher rates of death by suicide are recognized both in individuals of any age with cancer and, separately, in AYA without cancer.22.1N = 9,417,271 tumor cases, Figure SEER*Stat program.This study was performed using data from the Surveillance, Epidemiology, and End Results (SEER) program.2.2Surveillance, Epidemiology, and End Results includes different registries covering various time periods and demographical areas. SEER 9 database of the 2018 submission includes nine registries covering the time period 1975–2016. This database was used to calculate SMRs cross‐sectionally and longitudinally . For cross‐sectional analysis, data are presented for categories in which 100,000 person‐years or more of survival time have been accrued, as has been reported previously.Surveillance, Epidemiology, and End Results 18 database of the 2018 submission includes 18 registries encompassing cases from 2000 to 2016. This includes 500,366 patients aged between 15 and 39 years, 922 (0.18%) of whom died due to suicide/self‐inflicted injury. This dataset was used to calculate odds ratios (ORs).The SEER dataset includes sex, age at diagnosis, year of diagnosis, number of primary tumors, interventions received , cancer site, and tumor grade variables. However, data on radiotherapy, chemotherapy interventions, comorbid physical or mental health conditions, and social demographics were not available for SMR calculations.Patients were considered to have died by suicide if the cause of death variable was coded as “Suicide and Self‐inflicted Injury (50220),” while patients with other causes of death, or who were alive at follow‐up, were not classified as deaths due to suicide. Thus, a dichotomous outcome variable was constructed .2.3In order to identify demographic and clinical factors associated with death by suicide among AYA cancer patients; SMRs and ORs were calculated. SMR is defined as the number of cause specific or total deaths in a given population as a percentage of the deaths that would have been expected if the age‐ and sex‐specific rates in a “standard” population were applied.p values of <0.05 were considered statistically significant.Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) version 8.3.6.1 was used to extract data related to AYA with cancer and to calculate SMRs. All statistical analyses were performed using R statistical software , version 3.6.1.3A total of 922 deaths 0.18%) from suicide/non‐accidental injury were found in 500,366 AYAs with cancer observed for 3,198,261 person‐years. Overall, AYA with cancer were 34 times more likely than the general population to have died by suicide/self‐inflicted injury  Figure ; Data S1p < 0.001); race ; relationship status ; disease stage ; or those with one tumor compared to those with multiple tumors (p = 0.014).A comparison was conducted between AYA cancer patients who had died due to suicide/self‐inflicted injury and other AYA cancer patients Figure . Regardi4Self‐harm and suicide are a significant and growing issue among young people in the United States with 6241 deaths by suicide recorded among individuals aged 15–24 years in 2017. This corresponds to the highest suicide rate identified in this age group since 2000.Elevated death by suicide risk in AYA with cancer has likewise been demonstrated in a number of European studies.In general, risk of death from suicide/non‐accidental injury decreased over time following a cancer diagnosis, affirming findings from other groups.The results of this study have important implications for the care of individuals who currently or previously have experienced a cancer diagnosis during the AYA years. While it may be noted that risk of death by suicide/self‐inflicted injury among this population generally decreased over time, substantial risk, beyond that of the general population, persisted for 5 years or more following diagnosis with cancer. It is noteworthy that at this juncture, for some individuals, the intensity of oncology‐specific follow‐up may have decreased, such as patients with early stage cancers who may be approaching completion of cancer surveillance schedules. Various factors complicate post‐treatment and survivorship care for this population in addition to standard survivorship concerns. These include a possibility of needing to transition to adult health facilities for some individuals, if diagnosed with cancer within the teenage years and initially managed by a pediatric oncology service; difficulties in navigating re‐integration into educational and vocational settings following disruptions due to treatment, and concerns for some regarding long‐term or ongoing medical complications of treatment such as cardiotoxicity or reduced fertility.A limitation that deserves acknowledgment in our analysis was the inability to consider the influence of mental health variables given these data are not captured within the SEER dataset. Higher frequency of suicidal ideation has been reported among cancer patients compared to the general population.In summary, a greater than 30 times increased risk of death by suicide/non‐accidental injury among the AYA cancer population was identified and risk remained elevated for more than 5 years following a diagnosis with cancer. Consequently, monitoring of suicide risk, developing suicide prevention strategies, and tailoring psychosocial interventions addressing the mental health in AYA cancer patients are required across both oncology and primary care settings. While AYA account for a small proportion of annual cancer cases, the complexity of this subgroup places them at a disproportionately high risk of premature death and negative long‐term health outcomes.Ethics approval was not required for this study given data utilized was a publicly available registry .Jeremy Lewin: Consulting/advisory: Bayer. The rest of the authors have no disclosures or conflict of interest.Data S1Click here for additional data file.


In EvoProDom, we describe a general method to collate orthologous protein annotation from KEGG, and protein domain content from protein sequences using tools such as KoFamKOAL and Pfam. To summarize, EvoProDom presents a novel model for protein evolution based on the ‘mix and merge’ of protein domains rather than DNA‐based evolution models. This confers the advantage of considering chromosomal alterations as drivers of protein evolutionary events.Here, we introduce a novel ‘evolution of protein domains’ (EvoProDom) model for describing the evolution of proteins based on the ‘mix and merge’ of protein domains. We assembled and integrated genomic and proteomic data comprising protein domain content and orthologous proteins from 109 organisms. In EvoProDom, we characterized evolutionary events, particularly, translocations, as reciprocal exchanges of protein domains between orthologous proteins in different organisms. We showed that protein domains that translocate with highly frequency are generated by transcripts enriched in  The evolutionary model of protein domains builds new proteins. It is based on the ‘mix and merge’ of protein domains by means of chromosomal translocations, insertions, deletions, or duplication events in organisms during evolution. The changes have been identified in orthologous protein families using preserved, gained, and/or missing protein domains that appeared on evolutionary conserved chromosomal regions. DAdomain architectureEvoProDomevolution of protein domainsKEGGKyoto Encyclopedia of Genes and GenomesKOKEGG orthologPPIprotein–protein interactionde novo domains and the appearance of de novo genes   [Carassius auratus, goldfish), CHL Chinchilla lanigera, long‐tailed chinchilla), ECTE , ccar , and lav , each contains at least one protein which gained and lost domain FERM_C in FRMD6 and MYLIP, respectively. The second group, B*, which includes CHA , MIO , PEM , cge , ola , and rno , each contains at least one protein which gained and lost domain FERM_C in MYLIP and FRMD6, respectively  , 25, 26.ly Table , Fig. 3.dx be a mobile domain between Ai and Bi in ki, where i=1,2, Ai,Bi are sets of organisms and ki are KO groups. Let A∗=A1∩B2 and B∗=A2∩B1.Assumptions: Let dx undergoes translocation if A∗,B∗≥4. Otherwise, an indel event has occurred.Algorithm: Mobile domain Translocations and indel events were formally defined as follows:*, B*), were classified based on superdomain taxonomy, namely, Eukaryota, Viruses, and Bacteria. Briefly, each organism group was assigned to the superdomain taxonomy shared by all organisms; otherwise, the group was assigned as ‘Mixed’. In these superdomain taxonomy assignments of organism groups, translocations were classified based on superdomain taxonomy, represented as composites of individual organism group assignments  was found in Alphaproteobacteria , Betaproteobacteria , Gammaproteobacteria , and Deltaproteobacteria . The second orthologous protein group is 13703, ABHD11; abhydrolase domain‐containing protein 11 found in Alphaproteobacteria  and Verrucomicrobia  of indel events involve only eukaryotes Table . The mosia Table . These rUnique putative Pfam domains form the basis for defining mobile and translocation events. For duplication events, putative domains were considered so as to retain nonoverlapping duplicates of Pfam domains see . These pdx be a putative domain, kobe the KO group with da1,da2,⋯.,dam DAs of putative domains. Then, dxis ‘nonduplicated’ in, ko if the copy number of dx is the same in each, otherwise dx is ‘duplicated’.Assumptions: Let dx is duplicated if the difference between the number of KO groups where dx is ‘duplicated’ and the number of KO groups where it is ‘nonduplicated’ is significant (above 99% of the cumulative sum of the differences). A nonduplicated domain is similarly defined.Algorithm: Duplication was formally defined as follows:Chimeric transcripts are combined transcripts derived from two genes. Frenkel‐Morgenstern and Valencia  analyzedTranslocation events observed in the SH3 super‐family members were as follows: SH3_2 (239 translocations), SH3_1 (198 translocations), and SH3_9 (193 translocations). SH3 (src Homology‐3) domains are small protein domains approximately 50 amino acids in length  and are Here, we presented a novel protein evolution model, EvoProDom, which was based on the ‘mix and merge’ of protein domains. The EvoProDom model was implemented with and tested on EvoProDomDB, which consists of genomic and proteome data, along with orthologous protein and protein domain data, from 109 organisms from diverse taxa. In the EvoProDom model, translocations, and indel and duplication events were defined to reflect changes in domain content of a protein in orthologous groups. Moreover, in this model, such changes in protein domain composition were manifested at the organism level. Thus, SH3, which binds ligands , 38 and The introduction of new organisms into EvoProDomDB required only full genomes and annotated proteomes. Orthologous protein and protein domain content data were identified from protein sequences using KoFamKOALA  and the The authors declare no conflict of interest.MFM designed, supervised the study and wrote the paper; GC and AG produced the data, verified results, and wrote the paper.Table S1. EvoProdom translocations.Table S2. Superdomain translocations counts based on mobile domain.Table S3. Raw indel events.Table S4. Indel frequencies for indel classes based on mobile domain.Table S5. Indel events per superfamily (counts).Click here for additional data file. Click here for additional data file.


Acute kidney injury (AKI) is a life‐threatening complication of liver cirrhosis. Here, we evaluated the risk factors and characteristics of AKI in cirrhosis.This was a single‐center retrospective study. A total of 199 Japanese patients with decompensated liver cirrhosis  were enrolled and received tolvaptan orally. Survival rates and new onset of AKI were monitored, and risk factors were evaluated.P < 0.01). The rates of hepatic encephalopathy (P < 0.01) and chronic kidney disease  were significantly increased in patients with AKI. The rate of proton pump inhibitor (PPI)/H2 blocker treatment (P = 0.04) was significantly lower, whereas that of ascites drainage was significantly higher in the AKI cases (P < 0.01). The AKI risk was significantly increased in patients with hepatic encephalopathy . In contrast, the incidence of AKI was significantly lower in patients with a higher serum albumin level . Treatment with PPI/H2 blockers  or kanamycin/rifaximin  was significantly associated with a reduced risk of AKI development.Forty‐six patients (23.1%) suffered an AKI complication and exhibited significantly poorer survival (AKI incidence was increased in patients with decreased liver function and was associated with poor survival. PPI/H2 blocker or kanamycin/rifaximin treatment may reduce the risk of AKI. In cirrhosis, AKI incidence was increased in patients with encephalopathy and poor liver function. While proton pump inhibitor/H2 blocker or kanamycin/rifaximin treatment may reduce the risk of AKI. Acute kidney injury (AKI) is a common and frequently life‐threatening complication of liver cirrhosis.When liver disease progresses, decreased renal perfusion causes activation of the renin–angiotensin–aldosterone system, resulting in sodium and water retention and extrasplanchnic vasoconstriction.The recommended treatment for cirrhosis has been updated in the Clinical Practice Guidelines for Decompensated Cirrhosis proposed by the European Association for the Study of the Liver (EASL) in 2018.Here, we evaluated the effects of AKI on survival and considered the risk and protective factors of AKI in cirrhotic patients with ascites receiving tolvaptan therapy.2 defined as CKD.This was a single‐center, retrospective observational study conducted between September 2013 and 2020. A total of 199 Japanese patients with liver cirrhosis , diagnosed based on imaging and biochemical results, complicated with ascites who received tolvaptan at 3.75–7.5 mg once per day  were enrolled in the study. The patients were treated with conventional diuretics, including 0–160 mg/day furosemide and/or 0–400 mg/day spironolactone, and a salt‐restricted diet. Diagnosis of AKI and determination of the AKI grade were based on the KDIGO practice guidelines.This study was conducted in accordance with the principles of the Declaration of Helsinki and the ethics regulations of Tokyo Women's Medical University Hospital . The TWMU Institutional Review Board approved the study protocol.A1c; prothrombin time (PT%); PT international normalized ratio; blood urea nitrogen (BUN); creatinine; eGFR; cystatin C (Cys C); Cys C‐based glomerular filtration rate; uric acid; serum sodium and potassium; ammonia; C‐reactive protein; neutrophil‐to‐lymphocyte ratio; α‐fetoprotein (AFP); and des‐γ‐carboxy prothrombin (DCP). Child–Turcotte–Pugh (CTP)The following baseline characteristics of the patients were assessed: age, sex, clinical history, underlying hepatic diseases, complications of cirrhosis , complications of diabetes mellitus, hypertension, CKD, SBP, cell‐free and concentrated ascites reinfusion therapy (CART) or ascites drainage, administration of diuretics, and treatment with ursodeoxycholic acid (UDCA), branched‐chain amino acids (BCAA), amino‐acid preparations for hepatic insufficiency, proton pump inhibitor (PPI)/H2 blockers, lactulose, kanamycin/rifaximin, carnitine, zinc agents, intestinal regulators, and/or laxatives. CART featured drainage of 3 L of ascites each time. Otherwise, the ascites drainage volume was 1–3 L each time, usually accompanied by intravenous albumin. Cases with suspected SBP did not undergo CART; however, all other cases were prescribed CART to minimize the use of blood products. Paracentesis was performed before and after tolvaptan treatment for patients whose ascites accumulations were severe. All patients received diuretics and medications for cirrhosis for more than 7 days. Blood samples for biochemistry and hematological data were collected at the time of administration of tolvaptan. Laboratory tests were performed to determine the serum concentrations of albumin, total bilirubin, aspartate aminotransferase, alanine transaminase, and γ‐glutamyl transferase; platelet count; fasting blood glucose; hemoglobin The patients were hospitalized and administered tolvaptan. All cases receiving tolvaptan were monitored 8 h later (or on the next day). After discharge, patients were followed up every 1–2 months at the outpatient clinic. Renal function was monitored at the clinic during regular follow‐up and blood samples were taken when patients visited the outpatient clinic because of illness. The prognosis was evaluated in terms of survival time until death or liver transplantation after tolvaptan treatment. The observation periods were from the date of initiation of tolvaptan to death, liver transplantation, and the time of censoring (January 2021).χ2 test using SPSS statistical software . Multivariate regression analysis was performed to compare the AKI and non‐AKI groups. Factors highly significant on univariate analysis were subjected to multivariate analysis. We assessed the variables by SPSS and there was no multicollinearity. The following factors were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs): sex, hepatic encephalopathy, CKD, SBP, CART or ascites drainage, alubumin, alanine aminotransferase, hemoglobin A1c, BUN, creatinie, AFP, DCP, CTP score, and treatment with PPI/H2 blockers, and kanamycin/rifaximin. In all analyses, P < 0.05 was taken to indicate statistical significance. The survival rate and cumulative incidence of AKI were subjected to Kaplan–Meier analysis. Differences between groups were analyzed using a log‐rank test. Multivariate Cox regression analysis was used to evaluate the risk of AKI development based on the time to AKI occurrence after administration of tolvaptan and estimate hazard ratios (HRs) and 95% CIs.Data are presented as medians with minimum and maximum values. Significant differences between the AKI and non‐AKI groups were assessed with the Mann–Whitney U‐test or The median age of the 199 patients receiving tolvaptan treatment was 61 (range 21–92) years, and 52.3% were male (Table P < 0.01) and CKD (P = 0.02) were significantly higher in the AKI group compared to the non‐AKI group (Table P = 0.05). In terms of the treatment of cirrhosis, the rate of PPI/H2 blocker treatment was significantly lower for AKI cases than for non‐AKI cases (P = 0.04). The rate of CART or ascites drainage was significantly higher for AKI cases than for non‐AKI cases (P < 0.01). With regard to biochemical findings, AKI cases exhibited lower levels of serum albumin , alanine aminotransferase , and AFP , and higher levels of BUN  and creatinine . Multivariate regression analysis indicated that hepatic encephalopathy  was positively associated with the occurrence of AKI, whereas treatment with PPI/H2 blocker  or kanamycin/rifaximin  were negatively associated.During the observation period, 46 cases 23.1%) suffered an AKI complication. The majority of these cases were classified as KDIGO stage 1 . HRS‐AKI was observed in eight cases. The rates of hepatic encephalopathy (% suffereP < 0.01)   Fig.  and in S03) Fig. . After tP = 0.05). The incidence of AKI was significantly higher in patients with CKD compared to non‐CKD cases (P = 0.04) , the incidence of AKI tended to be lower in patients treated with kanamycin/rifaximin with lactulose compared to those treated with lactulose alone (P = 0.06)    Fig. . We comp06) Fig. . Treatme03) Fig. , whereas01) Fig. .A1c, BUN, creatinie, AFP, DCP, CTP score, and treatment with PPI/H2 blockers, and kanamycin/rifaximin (Table P < 0.01). By contrast, the incidence of AKI was significantly lower in patients with a higher serum albumin level . Treatment with PPI/H2 blockers  or kanamycin/rifaximin  was significantly associated with a reduced risk of AKI development.We evaluated the factors that were predictive of AKI development in patients with cirrhosis via multivariate analysis using a Cox hazard model. The parameters included were sex, hepatic encephalopathy, CKD, SBP, CART or ascites drainage, alubumin, alanine aminotransferase, hemoglobin The results of this study indicate that the onset of AKI is associated with a poorer outcome in liver cirrhosis patients with ascites and the incidence of AKI is increased in patients with encephalopathy and decreased liver function. By contrast, PPI/H2 blocker or kanamycin/rifaximin treatment appeared to decrease the risk of AKI in these patients.P = 0.028). While renal function worsened with higher natriuretic agent doses in the control group, Mori et al.Our study population consisted of patients with decompensated cirrhosis requiring tolvaptan treatment. We previously reported the safety and efficacy profiles of long‐term tolvaptan.The creatinine level and the eGFR are commonly used to evaluate kidney function. Cys C enhanced the renal function in cirrhosis patients.P = 0.06). A leaky gut increases the risk of SBP in patients with ascites, and kanamycin/rifaximin has been reported to reduce SBP in such casesP < 0.001) and gastric variceal bleeding (P = 0.03).Ascites were the most common complication of cirrhosis (86.5%), followed by hepatic encephalopathy (37.8%), variceal bleeding (17.5%), HRS (6.3%), and SBP (6.1%).P < 0.01). We speculated that PPI treatment can reduce variceal bleeding, thus decreasing the risk of AKI by exerting protective effects on renal blood flow. Further studies are required to determine the mechanism underlying the protective effect of PPIs against AKI. Moreover, the combination of PPI and kanamycin/rifaximin treatment may help to decrease the incidence of AKI.PPI treatment has been reported to have negative effects in patients with cirrhosis.P < 0.01). CART or ascites drainage was associated with the development of AKI and should therefore be avoided. However, this did not remain a risk factor for AKI after multivariate analysis. Hence, we hypothesize that AKI development is associated with cirrhosis  were similar across the included patients, and thus, fair comparisons between patient groups could be made. The effects of drug combinations on cirrhosis should be evaluated in future prospective studies.In conclusion, AKI was associated with an increased mortality rate in patients with liver cirrhosis. In patients who develop decompensated liver cirrhosis with ascites, treatment with PPI/H2 blockers and kanamycin/rifaximin may reduce the incidence of AKI.All procedures were performed in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments.Informed consent was obtained from the patients.Table S1. AKI patients with and without CKD.Click here for additional data file.


Canine pancreatic carcinoma is a rare, aggressive tumour that is often diagnosed late in the course of disease. Effective treatment strategies have been elusive, and overall survival time is short. In humans, treatment with tyrosine kinase inhibitors alone, or in combination with IV gemcitabine, have been moderately effective. As canine and human pancreatic carcinomas share many clinical aspects, strategies that mimic human treatment regimens may confer a better outcome in canine patients. The aim of this study was to assess the role of the veterinary tyrosine kinase inhibitor, toceranib phosphate, in the treatment of cytologically or histologically confirmed canine pancreatic carcinomas.Retrospectively, medical records of dogs with confirmed pancreatic carcinoma treated with toceranib were reviewed. Eight dogs were identified that fit the inclusion criteria. Toceranib was well-tolerated by all patients. Six were treated in the gross disease setting. Four had image-based evaluation of clinical benefit . Of those patients, 1 achieved a partial response, 2 stable disease, and 1 had progressive disease, for an overall clinical benefit rate of 75 %. An additional dog had clinically stable disease that was not confirmed via imaging. The toceranib-specific median overall survival time was 89.5 days (range: 14–506 days).Although limited in patient number, this small study suggests that toceranib may have biologic activity in dogs with pancreatic carcinoma. Larger, prospective studies are needed to confirm these preliminary results and define the use of toceranib in the microscopic disease setting. Canine pancreatic carcinomas are rare, accounting for 0.01–0.07 % of all neoplasia diagnosed in dogs . They tyHuman pancreatic carcinoma is usually ductal in origin . HoweverElevated expression of several tyrosine kinase receptors and/or their activating ligands have been found in human pancreatic carcinoma and are associated with a worse clinical outcome. These include epidermal growth factor receptor (EGFR/HER-1/ErbB-1) , vasculaToceranib phosphate is a veterinary TKI that is similar to sunitinib, blocking VEGFR and PDGFR, among other tyrosine kinase receptors . Given tNine (9) cases were collected via the American College of Veterinary Internal Medicine (ACVIM) listservs spanning 5 years 2015–2020) from 6 institutions. One was excluded due to lack of toceranib use, leaving 8 for data analysis. This population had a mean weight of 19.3 kg (range: 5.3 to 26.4 kg) and a mean age of 9.75 years (range: 5.5 to 12 years). Additional population characteristics are outlined in Table 5–2020 frClinical signs at diagnosis were non-specific and most commonly included vomiting or regurgitation (50 %), anorexia and weight loss (25 %), and increased liver enzymes (25 %). One patient had no clinical signs, the pancreatic carcinoma was an incidental finding during a routine annual abdominal ultrasound for undisclosed reasons.n = 3), left lobe (n = 1), body (n = 2), both the left lobe and body (n = 1), or a diffuse thickening (n = 1) of the pancreas. In 6 dogs where the pancreatic mass could be adequately measured , the mean longest diameter was 3 cm (range: 1–7 cm). Measurements of the mass were most commonly completed via external imaging . Staging tests included chest radiographs (n = 5), abdominal ultrasound (n = 5), and CT scan (n = 1). All but one dog was evaluated for metastatic disease at presentation. In the remaining 7 dogs, 5 had evidence of metastatic disease (71 %), most commonly to the liver and lymph nodes.The mass was noted to be in the right lobe (n = 6) or microscopic disease after surgery (n = 2). Toceranib was administered at a mean of 2.5 mg/kg (range: 2.2 to 2.8 mg/kg) 3 days per week (n = 7) or every-other-day (n = 1). The mean time between diagnosis and toceranib start was 11 days (range 2–19 days). Seven dogs received toceranib as a single agent. One received concurrent steroids.Two patients were treated with definitive treatment prior to toceranib use. These patients both received surgery. No patients received IV chemotherapy, metronomic chemotherapy, immunotherapy, or radiation therapy prior to toceranib. Toceranib was used for non-surgical gross disease  experienced clinical benefit at least 41 days after starting toceranib. At that time, based on ultrasound evaluation, the pancreatic carcinoma (located in the right lobe of the pancreas) had decreased in size from 2.6 to 1.6 cm in longest diameter. In addition, previously noted lymphadenopathy had resolved, and multiple liver nodules suspected to be metastatic disease were stable. Unfortunately, 56 days after documentation of the partial response, progressive disease developed characterized by an increase in size of the pancreatic mass with invasion of the duodenum, appearance of an adjacent venous thrombus, pancreatic lymphadenopathy, progressive and more numerous liver nodules, and a small amount of peritoneal effusion for a toceranib-specific survival time of 97 days.Of the two patients treated in the microscopic disease setting following surgery, one had progressive disease 14 days after starting toceranib; the second had no evidence of tumour regrowth when it was lost to follow-up at 82 days after starting toceranib.n = 1), grade 1 diarrhoea (n = 1), grade 2 diarrhoea (n = 1), grade 1 anorexia (n = 1), and grade II neutropenia (n = 1). Two patients required a toceranib holiday due to chronic diarrhoea and anorexia (n = 1) or recurrent grade II neutropenia (n = 1). A dose reduction alleviated further adverse events. During the study time frame, palladia was discontinued in 7/8 dogs (88 %). In four dogs, this was due to the development of progressive disease. In two dogs, the reasons were not specifically stated, but were not due to drug intolerance or owner’s wishes. In one dog, toceranib was discontinued due to owner wishes.Toceranib was generally well-tolerated. Adverse events were noted in 37 % of dogs and included grade I nausea . Dogs with a cytologic or histologic diagnosis of pancreatic carcinoma, treated with toceranib, were eligible for inclusion. Data collected included signalment , presenting clinical signs, method of diagnosis, presence of metastatic disease, location and size of tumour in the longest diameter, toceranib dose (mg/kg), schedule and duration of treatment, best response, adverse events, concurrent chemotherapy and supportive medications, concurrent diseases, and cause of death, if known or applicable. Staging and follow-up intervals were at the discretion of the attending clinician and were variable. Best response to treatment was categorized as complete response, partial response, stable disease, or progressive disease based on the Response Evaluation Criteria for Solid Tumours v1.0 . AdverseFor dogs with measurable disease, clinical benefit was determined by best response to therapy and was defined as complete response, partial response, or stable disease > 10 weeks in duration, as has been previously described . Toceran


While many studies have reported on liver injury in patients with coronavirus disease 2019 (COVID‐19), none have specifically addressed the significance of hepatic jaundice. We aimed to determine the clinical consequences and etiologies of jaundice in patients with COVID‐19.We retrospectively analyzed clinical features, laboratory abnormalities, and rates of survival and intensive care unit admission in 551 patients with COVID‐19, hospitalized between 1 March 2020, and 31 May 2020 at a tertiary care academic medical center. Hepatic jaundice was defined as a serum total bilirubin concentration >2.5 mg/dL and a direct bilirubin concentration >0.3 mg/dL that was >25% of the total. Liver injury was characterized as cholestatic, mixed, or hepatocellular at the time of peak serum total bilirubin concentration by calculating the R factor.Hepatic jaundice was present in 49 (8.9%) patients and associated with a mortality rate of 40.8% and intensive care unit admission rate of 69.4%, both significantly higher than for patients without jaundice. Jaundiced patients had an increased frequency of fever, leukopenia, leukocytosis, thrombocytopenia, hypotension, hypoxemia, elevated serum creatinine concentration, elevated serum procalcitonin concentration, and sepsis. Nine jaundiced patients had isolated hyperbilirubinemia. Of the 40 patients with abnormally elevated serum alanine aminotransferase or alkaline phosphatase activities, 62.5% had a cholestatic, 20.0% mixed, and 17.5% hepatocellular pattern of liver injury.Hepatic jaundice in patients with COVID‐19 is associated with high mortality. The main etiologies of liver dysfunction leading to jaundice appear to be sepsis, severe systemic inflammation, and hypoxic/ischemic hepatitis. Jaundice is a hallmark of liver dysfunction. We show that hepatic jaundice in patients with COVID‐19 is associated with high mortality, similar to that observed with invasive mechanical ventilation. The main etiologies of liver dysfunction leading to jaundice appear to be sepsis, severe systemic inflammation, and hypoxic/ischemic hepatitis. Jaundice is a hallmark of liver dysfunction. Hepatocytes take up unconjugated bilirubin, a product of heme metabolism, conjugate it to bilirubin diglucuronide, and excrete it into the bile.Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the virus that causes coronavirus disease 2019 (COVID‐19), the respiratory illness responsible for a global pandemic and millions of deaths worldwide. Many published studies have reported on liver injury and liver‐related blood test abnormalities in patients with COVID‐19.The Columbia University Institutional Review Board approved the protocol with a waiver of informed consent. Participants included in the study were admitted to NewYork‐Presbyterian Hospital/Columbia University Irving Medical Center (CUIMC) between 1 March 2020, and 31 May 2020, with an encounter diagnosis of COVID‐19 . This code is only used for a confirmed diagnosis of COVID‐19 as documented by the provider. We used this eligibility criterion to include only patients who suffered from the disease caused by SARS‐CoV‐2 and exclude those who may have tested positive while admitted for other reasons. All subjects had a positive RT‐PCR nasal swab for SARS‐CoV‐2 RNA.Patient demographics, laboratory values, vital signs, clinical outcomes, and medical histories were obtained by query of the Epic Systems electronic health record, and outcomes were assessed at the time of data collection on 21 July 2020. Race and ethnicity were self‐reported in prespecified categories. Laboratory test abnormalities, per CUIMC laboratory reference ranges, were defined as follows: alanine aminotransferase (ALT) >50 U/L, alkaline phosphatase (ALP) >129 U/L, direct bilirubin >0.3 mg/dL, platelet count <156 000/μL, leukocyte cell count <3120 or >8440/μL, creatinine >1.3 mg/dL, C‐reactive protein >10.0 mg/L, erythrocyte sedimentation rate >15 mm/h, and procalcitonin >0.25 ng/mL. Hypotension was defined as a mean arterial pressure <60 mmHg and hypoxia as arterial oxygen saturation <90%.2 <32 mmHg, (iv) leukocyte count >12 000/μL or <4000/μL or over 10% immature forms or bands. Sepsis was defined as SIRS with a suspected source of infection.S. epidermidis were excluded due to the high frequency of contamination.Criteria for hepatic jaundice were a TBIL >2.5 mg/dL and a serum direct bilirubin concentration >0.3 mg/dL that was also >25% of TBIL. These criteria excluded patients with indirect hyperbilirubinemia from causes other than acquired liver dysfunction, such as hemolysis or Gilbert syndrome. While there is no precise value for TBIL causing detectable jaundice, we used 2.5 mg/dL, which is a frequently cited lower limit.Liver injury was characterized as cholestatic, mixed, or hepatocellular at the time of peak TBIL by calculating the R factor. The R factor is equal to serum ALT/ULN divided by serum ALP/ULN. R ≥ 5 is considered hepatocellular liver injury, R ≤ 2 cholestatic, and 2 < R < 5 as a mixed type of liver injury.P values ≤0.05 were considered statistically significant.All analyses were performed using MATLAB R2020a . Categorical variables were compared using Chi‐square analysis or Tukey's honest significant difference test, as appropriate. vs 55.6%; P = 0.007). Additionally, there was a significantly higher proportion of Hispanic/Latino  and obese patients  with jaundice.Of 551 patients fitting the inclusion criteria for having COVID‐19, 49 (8.9%) also met the criteria for having hepatic jaundice. There were a few demographic differences between the patients with hepatic jaundice and those without . Additionally, patients with jaundice were admitted to the intensive care unit (ICU) more frequently than those without jaundice .Hepatic jaundice in hospitalized patients with COVID‐19 was associated with significantly worse clinical outcomes  had isolated hyperbilirubinemia with normal ALT and ALP; therefore, we calculated the R factor for the 40 with an abnormal ALT or ALP at the time of peak TBIL. Of these, 62.5% had a cholestatic, 20.0% a mixed, and 17.5% a hepatocellular pattern of liver injury . Patients with isolated jaundice had a higher rate of thrombocytopenia than those with cholestatic injury .Outcomes, clinical features, and laboratory parameters for the 49 jaundiced patients overlapped substantially between those with a cholestatic, mixed, or hepatocellular injury or isolated direct hyperbilirubinemia Table . HoweverSince SARS‐CoV‐2 was first identified, there has been a rapidly emerging body of literature describing the nature of COVID‐19. Many studies have explored liver injury and liver blood test abnormalities; however, hepatic dysfunction manifested by jaundice in patients with COVID‐19 has not been a primary focus. Unlike liver injury as manifested by elevated serum aminotransferase or ALP activities, elevated serum direct bilirubin concentrations and jaundice are indicators of hepatic secretory dysfunction. Liver function may be completely normal in an individual with significantly elevated serum ALT and ALP activities; conversely, liver function may be abnormal in individuals with normal or near‐normal serum activities of these enzymes. We therefore described the outcomes and features of patients hospitalized with COVID‐19 with liver dysfunction as manifested by jaundice. We found that 8.9% of the hospitalized patients with COVID‐19 in our cohort had hepatic jaundice, consistent with previous studies reporting jaundice in 6.0–16.7% patients.Most studies of liver injury in patients with COVID‐19 primarily focused on serum aminotransferase and ALP activities. Some considered serum bilirubin concentrations in their analysis of patient outcomes, although not elevated to the degree or appropriately fractionated to be consistently indicative of hepatic jaundice. One meta‐analysis of several such studies revealed conflicting results regarding correlations between disease severity and TBIL.SARS‐CoV‐2 infection in and of itself does not appear to be a cause of jaundice. Even in our entire cohort of hospitalized patients with approximately 90% meeting criteria for SIRS, fewer than 9% were jaundiced. Our data show that jaundice in patients with COVID‐19 is associated with fever, leukopenia, leukocytosis, thrombocytopenia, hypotension, and hypoxemia. Jaundiced patients had an increased frequency of elevated serum creatinine concentration, indicative of acute kidney injury, as well as higher rates of elevated serum procalcitonin and positive blood cultures. These findings strongly suggest that complicating bacterial sepsis or severe systemic inflammation, beyond what meets the criteria for SIRS, are the major causes of jaundice in patients with COVID‐19.Sepsis is a common cause of jaundice, especially cholestatic jaundice or isolated hyperbilirubinemia.Another etiology of conjugated hyperbilirubinemia and jaundice is severe hepatocellular injury, including that which occurs in ischemic/hypoxic hepatitis.This study had several limitations. We used a retrospective observational cohort design with inclusion restricted to patients hospitalized at a single medical center with an encounter diagnosis of COVID‐19. This may have led to a selection bias according to how providers documented diagnoses in the electronic medical record. The association of jaundice with sepsis is challenging because the pathobiology of sepsis is still uncertain, and it can only be identified by a constellation of clinical signs and symptoms in a patient with suspected infection. The use of SIRS criteria to define sepsis has been challenged, as many hospitalized patients meet these criteria, including those who never develop infection.In conclusion, hospitalized patients with COVID‐19 who have hepatic jaundice have significantly more adverse outcomes, including increased rates of ICU admission and death. Hepatic jaundice in patients with COVID‐19 has a mortality rate similar to that observed in patients receiving invasive mechanical ventilation. The main etiologies of liver dysfunction leading to conjugated hyperbilirubinemia and jaundice appear to be sepsis, severe systemic inflammation greater than that of typical SIRS, and hypoxic/ischemic hepatitis.


NF‐κB1 gene variants to gastrointestinal cancer risk, yet remains conflicting conclusions. Therefore, we conducted this most up‐to‐date meta‐analysis to evaluate the relationship between NF‐κB1 gene insertion (I)/deletion (D) polymorphism, namely −94ins/delATTG or rs28362491, and the susceptibility to gastrointestinal cancers. We searched PubMed, EMBASE and MEDLINE databases updated in April 2021 for relevant studies. Meta‐analysis was carried out by software Stata11.0. The quantification of the relationship was determined by computing the combined odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). Sensitivity analysis, the funnel plot and Begg's rank correlation test were also applied. Our findings indicate that −94ins/delATTG polymorphism could not significantly impact the susceptibility to gastrointestinal cancers. Under any five genetic models, −94ins/delATTG polymorphism was not remarkedly linked to the risk of colorectal, gastric and oesophageal cancer, respectively. The significant role of −94ins/delATTG was only observed in some certain subgroups. Findings here suggest that NF‐κB1 gene −94ins/delATTG polymorphism may not predispose to gastrointestinal cancer susceptibility.Nuclear factor‐kappa B1 (NF‐κB1), a pleiotropic transcription factor, functions as a critical contributor to tumorigenesis. Growing numbers of case‐control studies were carried out to analyse the potential contribution of  Among them, the rs28362491, namely the −94insertion/deletion ATTG polymorphism, ranks the most intensively investigated SNP.NFKB1 gene, thus influencing the stability of mRNA and efficiency of regulating translation. Research regarding NFKB1 gene −94insertion/deletion ATTG polymorphism on its association with gastrointestinal cancer risk was widely performed. However, the conclusions are still contradictory and inconsistent, partly attributed to the underpower and bias of independent studies, especially for small cohorts. Therefore, the exact association between NFKB1 −94insertion/deletion ATTG variant and risk of gastrointestinal cancer awaits to be determined. Here, a renewed meta‐analysis with all potential studies performed before April 2021 was analysed to acquire a clearer impact of NFKB1 −94insertion/deletion ATTG polymorphism on gastrointestinal cancer susceptibility.NF‐κB, short for nuclear factor kappa B, is a pluripotent and critical dimer transcription factor. NF‐κB orchestrates multiple physiological and pathological processes, particularly in cell survival, differentiation, inflammation and carcinogenesis.22.1We reported this meta‐analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) and Meta‐analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines.2.2NFKB1 or NF‐κB1 or nuclear factor kappa B1; (2) −94insertion/deletion ATTG or rs28362491 or SNPs or polymorphisms or polymorphism or variants; and (3) colorectal cancer or gastric cancer or gastrointestinal cancers or oesophageal cancer. To identify all the available studies, we also arranged two authors to screen eligible publications by hand‐searching the references of included publications.We applied an all‐sided literature retrieval using EMBASE, PubMed and MEDLINE up to April 2021. We used the following key words to carry out this procedure: (1) 2.3NFKB1 rs28362491 and gastrointestinal cancer risk; (2) case‐control study; and (3) enough data to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Editorials, meta‐analyses, reviews, research on animals and repetitively published articles were excluded.Publications are required to meet the following criteria for inclusion: (1) evaluating the relationship between 2.4We arranged two researchers (Hanqiang Wu and Jianrong Liang) to acquire the data independently by adopting the unified data table. The authors acquired the following information from all the studies: surname of the first author, source of control, year of publication, type of cancers, ethnicity of the study subject, numbers of cases and controls, genotyping method, and genotype of SNPs. If the extracted information is disputable, the authors would re‐check the references and make sure which extracted information is right. We assessed the methodologic quality of each study using the quality assessment criteria described by previous studies Table . We judg2.5NFKB1 rs28362491 and gastrointestinal cancer risk was evaluated by identifying the genotype frequencies of all cases and controls. Odds ratio (OR) and 95% confidence interval (CI) were adopted to assess this relationship. The meta‐analysis assessed association by using five different genetic models: homozygote model ; heterozygote model ; recessive model (II vs. ID/DD); dominant model (ID/II vs. DD); and allele contrast model (I vs. D). Stratification analyses were also performed by ethnicity, cancer type, source of control, score and HWE in controls, if applicable. We further analysed the heterogeneity among studies using Cochrane Q test. If p < 0.10 or I2 > 50% for the Q test, the random effects model (DerSimonian‐Laird method) was applied to conduct the analysis; if not, the fixed effects model (Mantel‐Haenszel method) was applied.p value < 0.05 indicates significant finding. Trial sequential analysis (TSA) was performed as described by us previously. Briefly, after adopting a level of significance of 5% for type I error and of 30% for type II error, the required information size was calculated, and TSA monitoring boundaries were built. All statistical analysis was performed using STATA, version 11.0 .We first test if the SNPs in the controls conformed to Hardy‐Weinberg equilibrium (HWE) by goodness‐of‐fit test. The association between 33.1The screening process of the current meta‐analysis was shown in Figure 3.2Among the 16 included studies . In cancer type subgroup analysis, NFKB1 −94ins/delATTG polymorphism still failed to impact the susceptibility in subgroup of colorectal cancer, gastric cancer and oesophageal cancer. Subgroup analysis of ethnicity indicated that significant decreased cancer risk was detected in Caucasians , but not in Asians. Further stratification analysis by source of control revealed that studies conducted as population base protect from cancer risk . Moreover, score subgroup indicated that studies >9 were linked to decreased cancer risk . Further stratification of HWE analysis in controls demonstrated that no significant association was detected in subgroup of both HWE ≤ 0.05 and HWE > 0.05.The detailed results of the meta‐analysis were presented in Table 3.4Here, we also carried out a sensitivity analysis by gradually deleting the included studies in a one‐by‐one manner. The no statistical fluctuation of the pooled OR value suggested that the analytic results were reliable and stable Figure .3.5Begg's funnel plot did not have significant asymmetry Figure . Statist3.6To minimize random errors and strengthen the robustness of our conclusions, we performed TSA Figure . This an4NFKB1 gene −94ins/delATTG polymorphism and gastrointestinal cancer risk. Our findings indicate that NFKB1 gene −94ins/delATTG polymorphism could not modify gastrointestinal cancer susceptibility. Of note, this is the first meta‐analysis performed by far on NFKB1 gene −94ins/delATTG polymorphism and gastrointestinal cancer susceptibility.In the current meta‐analysis, we comprehensively extract information from available epidemiology studies to assess the association between NFKB1 −94ins/delATTG polymorphism analysed here (rs28362491) in cancer susceptibility. Song et al.NFKB1 −94ins/delATTG polymorphism could enhance the susceptibility of colorectal cancer in a Southern Chinese population. However, role of NFKB1 −94ins/delATTG polymorphism in specific cancer is contradictory, namely a decreased cancer susceptibility or a null association. To solve this controversy, several meta‐analyses have been conducted. The first meta‐analysis was carried out in 2011 by Zou et al.NFKB1 −94ins/delATTG polymorphism protects from getting overall cancer in the homozygote model; heterozygote model; dominant model; and allele contrast. Stratified and subgroup analyses indicated decreased susceptibility for prostate cancer, ovarian cancer, lung cancer, nasopharyngeal carcinoma and oral squamous cell carcinoma, and this association also is significant for Asians, especially Chinese subjects, in hospital‐based studies, and in studies with quality score <9. Of note, by far, no available GWAS has identified the significant relationship between NFKB1 −94ins/delATTG polymorphisms and risk of gastrointestinal cancers.Growing evidence has pointed to the involvement of NFKB1 −94ins/delATTG polymorphism impact risk of gastrointestinal cancers. However, NFKB1 −94ins/delATTG polymorphism under any five genetic models has not enough ability to influence susceptibility to overall gastrointestinal cancer. Several merits existed in the current meta‐analysis. First, this is up to now the first and largest meta‐analysis regarding NFKB1 gene −94ins/delATTG polymorphism and gastrointestinal cancers susceptibility. Second, in sensitivity analysis, relative stability and credibility of the results were achieved as no significant changes after deleting each study at a time. Third, there existed no obvious publication bias, indicating the reliability of conclusion. Some limitations in the current meta‐analysis should be acknowledged. First, the number of subjects in the included studies is relatively small, especially in stratified analyses, which might result in a lack of statistical power and prevent a meaningful analysis of the results. Second, the association strength was only evaluated by unadjusted estimates. Adjustment analysis including gene‐gene, gene‐environment factors were not carried out because of the lack of original data. Third, in the included studies, the population sources were generally limited to Caucasians and Asians. Thus, the conclusion here should be interpreted in caution in Africans.Since then, several new relevant case‐control studies on gastrointestinal cancers have emerged. Therefore, we set as a pioneer to determine whether 5NFKB1 gene −94ins/delATTG polymorphism may not predispose to gastrointestinal cancers susceptibility. More attention should be paid to several research directions in future studies. First, more high‐quality studies with expanded sample sizes are necessarily called to further identify the relationship of the NFKB1 gene −94ins/delATTG polymorphism and gastrointestinal cancer risk, especially in Caucasian and African populations. Second, functional studies are needed to clarify the underlying mechanisms of NFKB1 gene −94ins/delATTG in gastrointestinal cancers.In all, our finding has concluded that The authors declare that there are no competing interests associated with the manuscript.Hanqiang Wu: Conceptualization ; Methodology ; Writing‐original draft ; Writing‐review & editing . Jianrong Liang: Conceptualization ; Data curation ; Investigation ; Software ; Supervision ; Validation ; Writing‐original draft ; Writing‐review & editing .Table S1Click here for additional data file.


Helicobacter pylori antibody levels in the blood are currently measured using an ELISA. In April 2016, FUJIFILM Wako Pure Chemical Corporation launched the “l‐type Wako Helicobacter pylori antibody J" test, which is based on the latex agglutination turbidimetric immunoassay. In this study, we investigated the usefulness of the Wako test.H. pylori antibody levels using both the ELISA and Wako test in 180 patients who underwent upper gastrointestinal endoscopy at our hospital between September 2017 and February 2019. Ninety patients were infected with H. pylori. We calculated the diagnostic accuracy, sensitivity, and specificity of each test and the concordance rate between the ELISA and Wako test. If lower limits of 90% confidence intervals (CIs) for each diagnostic validity exceeded the 85% threshold, the usefulness of the diagnostic test was confirmed.We measured κ = 0.8444).The diagnostic accuracy, sensitivity, and specificity were 94.4% , 94.4% , and 94.4% , respectively, when the Wako test was used, and 94.4% , 88.9% , and 100% , respectively, when the ELISA was used. The concordance rate between the two tests was high (H. pylori infection, due to its high sensitivity.We confirmed the usefulness of the Wako test, especially when screening for  l‐type Wako Helicobacter pylori antibody J” test is based on the latex agglutination turbidimetric immunoassay. Many samples can be analyzed simultaneously, rapidly, and more economically using this kit. l‐HP J test showed a high diagnosis performance, and is not inferior to ELISA. The l‐HP J test is useful, especially when screening for Helicobacter pylori infection, due to its high sensitivity.“ Helicobacter pylori (H. pylori), a gram‐negative bacillus, was discovered in 1983 by Warren and Marshall and is known to persistently infect the human gastric mucosa and induce histological gastritis accompanied by neutrophilic infiltration.H. pylori infection is associated with the development of gastric ulcer/duodenal ulcer and gastric cancer.H. pylori‐infected gastritis would be covered by health insurance starting February 2013; thus, diagnosing H. pylori infection became more prevalent.H. pylori infection with endoscopy include culture test, microscopic test, and rapid urease test, and the tests without endoscopy include urea breath test (UBT), serous H. pylori antibody test, and feces H. pylori antigen test.Diagnostic methods for H. pylori antibody test is convenient and is widely used to diagnose H. pylori infection in the current clinical practice. The prevailing methods for this antibody test are the ELISA  and the chemiluminescent method, both of which have limitations: they take a long time for analysis and require special measuring devices.The serous l‐type Wako H. pylori antibody J" (l‐HP J) test , which is based on the latex agglutination turbidimetric immunoassay.In April 2016, FUJIFILM Wako Pure Chemical Corporation launched the “H. pylori infection can be diagnosed and be prescribed drugs to eradicate H.pylori on the day of the blood test. Consequently, this kit might contribute to reduced medical costs. However, its accuracy has not been confirmed. In this study, we evaluated the diagnostic validity of the l‐HP J test, which has not been demonstrated before, by calculating its diagnostic accuracy, sensitivity, specificity, area under the curve (AUC), and concordance rate with ELISA.Since this kit can be used with a general‐purpose automatic analyzer, it is less complicated than ELISA. Many samples can be analyzed simultaneously, rapidly, and more economically using this kit Fig. . Using tH. pylori or had undergone gastrectomy; those who had taken proton pump inhibitors within 2 weeks before undergoing the UBT; those who had taken antibiotics within 4 weeks before the endoscopy; those who had undergone head and neck surgery and were unable to undergo the UBT; those in whom advanced gastric cancer was detected endoscopically; and those who were suspected of having type A gastritis endoscopically (cases with severe atrophic gastritis of the corpus and mild or no atrophic gastritis of the antrum). Our medical staff interviewed the patients to determine whether they had received eradication therapy for H. pylori or had undergone gastrectomy in the past. Major reasons for undergoing gastrointestinal endoscopy included screening, testing positive for H. pylori antibodies, having abdominal symptoms such as upper abdominal pain, and workup for early gastric cancer.This observational, validation study was conducted in clinical settings, and included consecutive patients who underwent gastrointestinal endoscopy between September 2017 and February 2019. The following patients were excluded: those who had received eradication therapy for H. pylori antibodies in‐house, in specimens from subjects who provided consent, using (i) the l‐HP J test and (ii) the E‐plate “Eiken” H. pylori antibody test (ELISA). Blood sampling was done on the day endoscopy was performed. Cutoff values used for these antibody tests were as follows: (i) l‐HP J test, 4 U/mL or more was considered positive for H. pylori , and (ii) ELISA, 10 U/mL or more was considered positive for H. pylori. Measurement using each kit was performed in‐house. In this study, we used a full auto microplate chemiluminescence analyzer  for ELISA, and Hitachi Labospect 008 automatic biochemistry analyzer (Hitachi High‐Technologies) for the l‐HP J test. There are two analyzing processes for ELISA  was performed with the Evis Lucera Elite system  and a GIF‐H290Z scope (Olympus Corporation). The grading of gastric mucosal atrophy by endoscopic findings was based on the Kimura–Takemoto classificationH. pylori infection.H. pylori infection status, we used these findings   were considered uninfected, while those who had findings of either gastric mucosal atrophy, or two or more active gastritis detected on EGD with positive UBT result were considered infected. Patients whose endoscopic findings and UBT results had a discrepancy, such as active gastritis detected endoscopically, indicating a current H. pylori infection were diagnosed as being positive or negative for H. pylori, and the sensitivity, specificity, and diagnostic accuracy of the l‐HP J test were determined. ELISA was performed in a similar manner, and the concordance rate with the l‐HP J test was calculated. In cases misdiagnosed by l‐HP J test, the test results correlated with the clinical findings.Subjects whose endoscopic findings and UBT results concurred in terms of the presence/absence of l‐HP J test for H. pylori positive cases were 96.4%  and 97.7% , respectively. Therefore, we set an expected value as 95%, and threshold value as 85% for both, sensitivity and specificity. Based on the binomial test, a sample size of 85 cases was deemed to be required for both uninfected and currently infected cases, using the following criteria: one‐sided alpha of 5%; and power of 90%. Ultimately, a total of 180 patients (90 uninfected and 90 currently infected cases) were enrolled to make up for any dropouts.According to a previous report from Japan, the sensitivity and specificity of κ statistic was used. The McNemar's test, which evaluates marginal homogeneity between two test methods, was used to compare the l‐HP J test and ELISA. To assess the diagnostic accuracies of the l‐HP J test and ELISA, a receiver‐operating characteristic (ROC) curve was constructed by plotting sensitivity versus 1‐specificity values for both the l‐HP J test and ELISA and its AUC was computed. Subsequently, we compared the AUC values with 95% CIs obtained for the l‐HP J test and ELISA using t‐tests. A P value <0.05 was considered statistically significant. Statistical analysis was performed using Statistical Analysis System (SAS) software 9.4 .All continuous variables were expressed as the median and range. For diagnostic performance, diagnostic accuracy, sensitivity, and specificity are presented as percentages with 90% confidence interval (90% CI). To evaluate concordance between the test methods for positivity and negativity, the This study was approved by the hospital's institutional review board, and written informed consent was obtained from all subjects.H. pylori infection. Among the patient characteristics between uninfected and currently infected cases, the median age and percentage of male patients were 57 years , and 65 years , 45.6% and 57.8%, respectively. The uninfected group was younger. Among the currently infected subjects, the degree of gastric mucosal atrophy (the Kimura–Takemoto classification) was C‐1 to C‐3 in 51.1% (46/90) and O‐1 to O‐3 in 48.9% (44/90). Although the major comorbidity among the currently infected subjects was early gastric cancer, this was seen only in one patient among the uninfected subjects  were uninfected and 90 patients (50%) had a H. pylori infection were 94.4% , 94.4% , and 94.4% , respectively, when the l‐HP J test was used, and 94.4% , 88.9% , and 100% , respectively, when ELISA was used  in terms of diagnostic accuracy, sensitivity, and specificity, the lower limits of 90% CIs for sensitivity of ELISA (81.9%) were lower than the threshold value (85%). Furthermore, the calculated AUC values were compared. AUC between the l‐HP J test  and ELISA  showed no statistical significance (P = 0.459).The diagnostic accuracy, sensitivity, and specificity for current ed Table . AlthougH. pylori antibody using the ELISA and l‐HP J test were 80 and 90, respectively. The concordance rates between l‐HP J test and ELISA were high (κ = 0.8444)  (Table The number of subjects who were positive for anti‐4) Table . Subsequ9) Table .l‐HP J test included five false‐negative cases (5.6%) and five false‐positive cases (5.6%) (Table Cases misdiagnosed by the %) Table . Among tH. pylori infection listed in the Japanese Society for Helicobacter Research guidelinesH. pylori antibody test, and feces H. pylori antigen test. Among them, the serous H. pylori antibody test is relatively convenient and widely used. A prevailing method for measuring this antibody is ELISA.Invasive diagnostic methods for l‐HP J test kit. The l‐HP J test can be performed using the commercially available automated analyzers, such as Hitachi 7180 (Hitachi High‐Tech), JCA‐BM6050 , ARCHITECT c16000 , and DxC700AU . The l‐HP J test was launched in April 2016 by FUJIFILM Wako Pure Chemical Corporation and is based on the latex agglutination turbidimetric immunoassay. To our knowledge, this is the first report about the diagnostic validity of this newly launched kit. We demonstrated that the diagnostic accuracy, sensitivity, and specificity of the l‐HP J test were approximately 95%, and the concordance rate between the l‐HP J test and conventional ELISA was high with a κ statistic of 0.8444. AUC of the two kits showed high diagnostic capability and showed no significant differences.In this study, we investigated a newly launched kit that can be used with a general‐purpose automatic analyzer: the l‐HP J test is a balanced kit.Although ELISA showed high specificity, the lower limits of 90% CIs for sensitivity of ELISA did not exceed the threshold value of 85%. In addition to this, ELISA significantly tended to evaluate the test cases as negative. From these findings, it can be considered that ELISA test has a higher rate of false‐negative results, and H. pylori infection is improved when two strains from genotypes commonly seen in the Japanese (#3 and #5)l‐HP J test we evaluated in this study used the same two antigens as the chemiluminescent test. Our findings showed that the l‐HP J test is no less accurate than ELISA, and is a balanced kit. About the false‐positive and false‐negative cases detected using the l‐HP J test, all but one false‐positive case were low‐positive titers (between 4 and 8.7 U/mL). It has been reported that approximately 10% of individuals with low‐positive titers detected using the l‐HP J test are uninfected.H. pylori infection correctly if the l‐HP J test is not consistent with the endoscopic findings, such as in the following two cases. First, when an individual has an open‐type mucosal atrophy and endoscopic findings suggest current infection, but the l‐HP J test result is negative; and second, when endoscopic findings suggest uninfection, but the l‐HP J test result is low‐positive titers (between 4 and 8.7 U/mL).The latex agglutination turbidimetric immunoassay is superior to ELISA in terms of throughput and saving labor, and is expected to greatly contribute to rapid testing. Kita et al. demonstrated that the diagnosis of H. pylori infection in those subjects whose UBT results and endoscopic findings were consistent. Therefore, subjects who were previously infected with H. pylori and those who had type A gastritis could be excluded from the study. Moreover, this was a prospective study and antibody measurements by both kits were performed in‐house, which increase the reliability of the study.In the present study, we considered both, the results of the UBT that has a high diagnostic accuracy,l‐HP J test, while stored serum (within 4 weeks) was used for the l‐HP J test; therefore, specimens with different conditions were used for these subjects. However, supplemental data from FUJIFILM Wako Pure Chemical Corporation showed no difference in the titers between fresh plasma and stored serum (within 4 weeks) under conditions of −20°C. Second, we used the UBT as the gold standard for diagnosing H pylori infection; however, its accuracy is not 100%.l‐HP J test. Fourth, the evaluation of H. pylori status was performed based on UBT result and endoscopic findings, not histological result. However, endoscopic findings used in this study reportedly have high diagnostic odds ratio and are helpful in the diagnosis of current H. pylori infection.H. pylori status in this study is reliable.There are some limitations of the study. First, in some subjects, fresh plasma was used for detection using ELISA and part of the l‐HP J test has a high diagnosis performance, and is not inferior to ELISA. The l‐HP J test is useful, especially when screening for H. pylori infection, due to its high sensitivity.In conclusion, the