Usefulness of the Palliative Prognostic Index in Predicting Prognosis when Considering the Transition from Hospital to Home Care in Patients with Terminal Stage Cancer.

BACKGROUND: No accurate prognostic tool is available for patients with cancer who spend their final days at home. In this study, we examined whether performance status (PS) and the palliative prognostic index (PPI), a well-known prognostic tool in palliative care units, could be used to predict prognosis in the home care setting at the time of intervention by home physicians. SUBJECTS AND METHODS: Using medical records, we conducted a retrospective analysis of 132 patients who were referred to the Home Clinic Naginoki for home care for terminal stages of carcinoma in situ. Based on the status at the time of the first visit, the PPI-Low group was defined as those scoring six or below and the PPI-High group as those scoring greater than six. RESULTS: The PPI-high group had a significantly poorer prognosis within 21 days than the PPI-low group (21-day-OS; Low 71.4% vs. High 13.2%; p<0.001). The Eastern Cooperative Oncology Group (ECOG) PS alone predicted better prognosis in the group with PS of one or two (21-day survival 90.1%), and the PPI score further significantly stratified the prognosis for patients with PS three or four, with a trend toward poor prognosis (p ≤ 0.005). CONCLUSION: ECOG PS 1 or 2 has a favorable prognosis and that using PPI in ECOG PS 3 or 4 leads to a more accurate prognosis prediction. PPI evaluated during the hospital-based treatment of patients with terminal cancer can also be used to predict prognosis if the patient is transitioned to a home care environment.

Grimontia kaedaensis sp. nov., isolated from the estuary of Kaeda river in Miyazaki, Japan.

Strain 020920NT was isolated from the estuary of the Kaeda river in the Miyazaki prefecture in Japan. Phylogenetic analysis based on the 16S rRNA gene showed the strain's close evolutionary relationship with bacteria from the genus Grimontia, in the family Vibrionaceae. Phenotypic and chemotaxonomic features of the strain were investigated. Whole genome sequencing revealed that the strain 020920NT genome consists of two chromosomes and a plasmid, for a total of 5.52 Mbp. Calculations of whole genome average nucleotide identity and phylogenetic analysis based on the whole genome sequence showed that the strain represents a new species in the genus Grimontia, for which we propose the name Grimontia kaedaensis sp. nov. with the type strain 020920NT (=LMG 32507T=JCM 34978T).

Preparation of Mechanically Anisotropic Polysaccharide Composite Films Using Roll-Press Techniques.

Natural polysaccharides are biocompatible and biodegradable; therefore, they can be used as feedstock for biodegradable structural materials and biomaterials. In this study, anisotropic polysaccharide composite films consisting of chondroitin sulfate C (CS) and chitosan (CHI) were fabricated from their polyion complex (PIC) gels by roll-press techniques. The obtained films (CS/CHI films) were thin and transparent, similar to the composite films prepared by hot-press techniques. The roll-press conditions were optimized, and it was observed that the molecular weight of CHI did not significantly affect the formability of the films, whereas the roll temperature and rolling speed were important. The tensile tests of the roll-pressed films revealed that the mechanical strength of the films in the mechanical direction (MD) was approximately 5 times higher than that in the transverse direction (TD), indicating that the roll-press techniques imparted mechanical anisotropy to the films. Additionally, the films shrank in the MD and expanded in the TD after immersion in aqueous solutions, followed by drying. Such anisotropic shrinking and expanding properties indicate that these films can be used as shape-memory materials.

Clinical impact and early prediction of carbapenem-resistant Pseudomonas aeruginosa bacteraemia in allogeneic hematopoietic stem cell transplantation recipients.

OBJECTIVE: Although antipseudomonal agents are administered in high-risk patients, no reports have focused on the risk of carbapenem-resistant (CR) Pseudomonas aeruginosa bacteraemia in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. METHODS: We retrospectively studied a cohort of adult allo-HSCT recipients with P. aeruginosa bacteraemia, focusing on a comparison between carbapenem-sensitive (CS) and CR P. aeruginosa after initiating conditioning chemotherapy at our institute between January 2005 and December 2020. The incidence, all-cause 30-d mortality of P. aeruginosa bacteraemia, and risk factors for carbapenem resistance among patients with P. aeruginosa bacteraemia in allo-HSCT recipients were evaluated. RESULTS: Forty-eight patients with P. aeruginosa bacteraemia were included, with an incidence of 3.84/100 recipients (CS = 1.92 vs. CR = 1.92). The all-cause 30-d mortality was significantly higher in CR P. aeruginosa bacteraemia (CS = 4.2% vs. CR = 39.1%; P = 0.003). The factor significantly associated with CR P. aeruginosa bacteraemia was carbapenem use for at least 3 d within 30 d before the onset of bacteraemia (odds ratio = 8.92; 95% confidence interval: 1.35-58.90). Inappropriate antimicrobial selection was significantly more frequent in CR P. aeruginosa bacteraemia (CS = 0% vs. CR = 29.2%; P ˂ 0.009). CONCLUSION: Empirical combination therapy with reference to antimicrobial susceptibility profiles in each institution should be considered when CR P. aeruginosa bacteraemia is suspected in allo-HSCT recipients based on the risk of carbapenem exposure.

Mutational analysis of DNMT3A improves the prognostic stratification of patients with acute myeloid leukemia.

Nucleophosmin1 (NPM1) mutations are the most frequently detected gene mutations in acute myeloid leukemia (AML) and are considered a favorable prognostic factor. We retrospectively analyzed the prognosis of 605 Japanese patients with de novo AML, including 174 patients with NPM1-mutated AML. Although patients with NPM1-mutated AML showed a high remission rate, this was not a favorable prognostic factor for overall survival (OS); this is contrary to generally accepted guidelines. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNA methyltransferase 3A (DNMT3AR882 mutations) were a strong predicative factor indicating poor prognosis in all AML (p < 0.0001) and NPM1-mutated AML cases (p = 0.0020). Furthermore, multivariate analysis of all AML cases showed that DNMT3AR882 mutations and the co-occurrence of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD), NPM1 mutations, and DNMT3AR882 mutations (triple mutations) were independent factors predicting a poor prognosis related to OS, with NPM1 mutations being an independent factor for a favorable prognosis (hazard ratios: DNMT3AR882 mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3AR882 mutations and triple mutations on prognosis and according to the classification of NPM1-mutated AML into three risk groups based on DNMT3AR882 /FLT3-ITD genotypes, we achieved the improved stratification of prognosis (p < 0.0001). We showed that DNMT3AR882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3AR882 mutations were excluded, NPM1 mutations were a favorable prognostic factor. This revealed that ethnological prognostic discrepancies in NPM1 mutations might be corrected through prognostic stratification based on the DNMT3A status.

Examination on Factors Affecting Symptom Change after Drug Withdrawal in Patients with Mild Erosive Gastroesophageal Reflux Disease Undergoing Symptom-Controlled Maintenance Therapy with Acid-Secretion Inhibition Drugs.

INTRODUCTION: In patients with gastroesophageal reflux disease (GERD) on maintenance therapy with acid-suppressive drugs, it is not clear what background factors allow patients to discontinue the drugs. The aims of this study were to examine the relationship of the changes in the frequency and severity of gastrointestinal symptoms after discontinuation of acid-secretion inhibitors for erosive GERD (eGERD) with possible patient background factors and to identify factors that influence these changes. METHODS: This is a multicenter, open-label, interventional, exploratory study. eGERD patients with mild mucosal injury whose symptoms were under control and who were on maintenance therapy with acid-suppressive drugs were withdrawn from the drug treatment for 4 weeks. We examined the relationship of patient backgrounds (sex, age, body mass index, alcohol consumption, smoking habits), esophageal hiatal hernia, Helicobacter pylori infection, pepsinogen I and II concentrations and I/II ratios, blood gastrin levels before and after drug discontinuation with total score change in Frequency Scale for the Symptoms of GERD (FSSG). RESULTS: Of the 92 patients whose symptoms could be assessed before and after drug withdrawal, 66 patients (71.7% of the total) had FSSG <8 and no symptom relapse after the withdrawal. Furthermore, patient background factors that may be related to symptom relapse/non-relapse were examined, but no related factors were detected. The maintenance medications before discontinuation in the above 92 patients were a proton pump inhibitor (PPI) and vonoprazan (VPZ, a potassium ion competitive acid blocker). Since PPI and VPZ were administered to about the same number of patients, though incidentally, we additionally examined the relationship between patient background factors and symptom relapse/non-relapse by treatment group. As a result, no relevant background factors were detected in both groups. Although there were no significant differences between the two groups, the severity and frequency of symptom recurrence in the VPZ group tended to be higher than in the PPI group. CONCLUSIONS: Consideration of background factors is unlikely to be required in the discontinuation of maintenance therapy for eGERD. There was no significant difference in the extent of disease or frequency of recurrence during the discontinuation period, regardless of whether the drug before discontinuation was a PPI or VPZ.

Epstein-Barr Virus-Related Hemophagocytic Lymphohistiocytosis with Central Nervous System Symptoms.

Hemophagocytic lymphohistiocytosis (HLH) involves pathological histiocytes and phagocytosis of normal blood cells through activation of inflammatory cytokines. We report a case of Epstein-Barr virus-HLH in a 75-year-old woman who presented with fever, thrombocytopenia, and loss of consciousness. Epstein-Barr virus-HLH was diagnosed after we identified massive hemophagocytosis in bone marrow and Epstein-Barr virus DNA in cerebrospinal fluid. The HLH-2004 protocol was applied, and lactate dehydrogenase levels-which reflect HLH disease status-decreased. However, persistent loss of consciousness and multiple organ failure led to the patient's death on day 18. Most cases of primary and secondary HLH involve pediatric patients; adult cases are rare. Few cases of central nervous system involvement in older adults have been reported. Therefore, accumulation of more data will help in developing better treatment strategies.

Safety and efficacy of high-dose cytarabine MEAM therapy and other treatments for auto-peripheral blood stem cell transplantation: A retrospective comparative study.

AIM: The MEAM regimen consisting of ranimustine (MCNU), etoposide (ETP), cytarabine (Ara-C), and melphalan (MEL) is widely used before auto-peripheral blood stem cell transplantation (auto-PBSCT) for malignant lymphoma in Japan. The MEAM regimen generally consists of 200-400 mg/m2 for 4 days, but we decided to increase the dosage of Ara-C from the standard to 2 g/m2 for 2 days with the aim of increasing drug transferability to the central nervous system. We evaluate the safety and therapeutic efficacy of high-dose Ara-C MEAM therapy. METHODS: The high-dose Ara-C MEAM protocol consisted of MCNU 300 mg/m2 on day -7, ETP 200 mg/m2 on days -6, -5, -4, -3 and Ara-C 2 g/m2 on day -4 -3, and MEL 140 mg/m2 on day -2. We retrospectively analyzed 37 cases of malignant lymphoma at our institution between May 2014 and July 2020. RESULTS: All patients got engraftment and there were no cases of treatment-related mortality. In all cases, the 3-year overall survival (OS) and progression-free survival (PFS) after transplantation were 80.6% and 65.7%, respectively. Twenty-one cases of diffuse large B-cell lymphoma recurrence, for which there is proven usefulness of auto-PBSCT, showed good results after transplantation, with the 3-year OS and PFS after transplantation being 100% and 74.3%, respectively. CONCLUSION: The safety and efficacy of high-dose Ara-C MEAM therapy were demonstrated, but the expected therapeutic effect on central nervous system lesions could not be fully evaluated owing to the small number of cases.

Guest edited collection serological study of SARS-CoV-2 antibodies in japanese cats using protein-A/G-based ELISA.

BACKGROUND: Little is known about the epidemic status of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in cats in Japan due to insufficiently reliable seroepidemiological analysis methods that are easy to use in cats. RESULTS: We developed a protein-A/G-based enzyme-linked immunosorbent assay (ELISA) to detect antibodies against SARS-CoV-2 in cats. The assay was standardized using positive rabbit antibodies against SARS-CoV-2. The ELISA results were consistent with those of a conventional anti-feline-immunoglobulin-G (IgG)-based ELISA. To test the protein-A/G-based ELISA, we collected blood samples from 1,969 cats that had been taken to veterinary clinics in Japan from June to July 2020 and determined the presence of anti-SARS-CoV-2 antibodies. Nine cats were found to have SARS-CoV-2 S1-specific IgG, of which 4 had recombinant receptor-binding domain-specific IgG. Of those 9 samples, one showed neutralizing activity. Based on these findings, we estimated that the prevalence of SARS-CoV-2 neutralizing antibodies in cats in Japan was 0.05% (1/1,969 samples). This prevalence was consistent with the prevalence of neutralizing antibodies against SARS-CoV-2 in humans in Japan according to research conducted at that time. CONCLUSIONS: Protein-A/G-based ELISA has the potential to be a standardized method for measuring anti-SARS-CoV-2 antibodies in cats. The infection status of SARS-CoV-2 in cats in Japan might be linked to that in humans.

Simultaneous detection of JAK2, CALR, and MPL mutations and quantitation of JAK2 V617F allele burden in myeloproliferative neoplasms using the quenching probe-Tm method in i-densy IS-5320.

INTRODUCTION: Accurate detection of myeloproliferative neoplasms (MPN)-associated gene mutations is necessary to correctly diagnose MPN. However, conventional gene testing has various limitations, including the requirement of skilled technicians, cumbersome experimental procedures, and turnaround time of several days. The gene analyzer i-densy IS-5320 allows gene testing using the quenching probe-Tm method. Specifically, pretreatment of samples including DNA extraction, amplification and detection of genes, and analysis of results are performed in a fully automatic manner after samples and test reagents are added into this system, which is compact and can be easily installed in a laboratory. The aim of this study is to investigate the sensitivity and specificity associated with the simultaneous detection of MPN-associated gene mutations. METHODS: We conducted an analysis of MPN-associated genes using i-densy IS-5320. We analyzed 384 samples (171 JAK2 V617F mutations, 10 JAK2 exon12 mutations, 104 CALR mutations, and 26 MPL mutations) that had been examined using conventional approaches such as allele-specific polymerase chain reaction (PCR), droplet digital PCR, and the direct sequencing method. RESULTS: The detection accuracy of JAK2 V617F, JAK2 exon 12, CALR, and MPL was 100.0% (383/383), 99.7% (383/384), 100.0% (370/370), and 99.7% (377/378), respectively. There was a strong positive correlation between the JAK2 V617F allele burden measured using conventional methods and i-densy IS-5320 (r = .989). CONCLUSION: Overall, i-densy IS-5320 exhibited good accuracy in terms of analyzing MPN-associated genes; thus, it can serve as a replacement for conventional methods of MPN-associated gene testing.

Molecular epidemiological study of germline APC variant associated with hereditary gastrointestinal polyposis in dogs: current frequency in Jack Russell Terriers in Japan and breed distribution.

BACKGROUND: Cases of gastrointestinal (GI) neoplastic polyps in Jack Russell Terriers (JRTs) have increased in Japan since the late 2000s. We recently demonstrated that JRTs with GI polyps heterozygously harbor an identical germline variant in the adenomatous polyposis coli (APC) gene, c.[462_463delinsTT]; therefore, this is an autosomal dominant hereditary disease. We conducted a molecular epidemiological study to explore the current frequency of the APC variant in JRTs in Japan and the breed distribution of this disease. RESULTS: Peripheral blood samples from 792 JRTs were collected at 93 veterinary hospitals in Japan in 2020. Using an established polymerase chain reaction-restriction fragment length polymorphism assay, the germline APC variant was detected in 15 JRTs, with an overall frequency of 1.89%. The frequency was not significantly different for sex, age, and coat type criteria. Notably, the variant carriers had a current or previous history of GI neoplastic polyps, providing further evidence of the association of the germline APC variant with GI polyposis. Pedigree analysis of carrier dogs revealed that the germline APC variant was no longer confined to a few specific families but was widely spread among JRTs in Japan. Furthermore, some ancestors of the carriers were from Australia or New Zealand, suggesting the possible presence of carriers in countries other than Japan. Next, we retrospectively investigated the germline APC variant status of dogs with GI epithelial tumors using genomic DNA samples extracted from archived pathological specimens (28 purebred dogs of 14 breeds and four mixed-breed dog), as well as those stored in a canine genome bank (38 dogs of 18 breeds and a mixed-breed dogs). In total, 66 purebred dogs of 25 breeds, including another four JRTs, and five mixed-breed dogs were examined. While three variant carriers were found in JRTs, the germline APC variant was not detected in any of the other breeds. CONCLUSION: The current frequency of the germline APC variant was approximately 2% in JRTs in Japan and the frequency remained roughly flat during the last 15 years. In addition, hereditary GI polyposis associated with the variant was virtually specific to JRTs.

[Lung Cancer Associated with Atrial Septal Aneurysm Detected on Preoperative Echocardiogram].

We herein report a case of 71-year-old man who was diagnosed as right lung cancer associated with atrial septal aneurysm (ASA). ASA was incidentally detected on transthoracic echocardiography as a routine preoperative examination. Although upper lobectomy was performed without any postoperative event in this case, generally care must be taken for important comorbidity of cerebral infarction as a potential source of systemic thromboembolism both in pre- and post-surgery.

Heterogeneous IgE reactivities to Staphylococcus pseudintermedius strains in dogs with atopic dermatitis, and the identification of DM13-domain-containing protein as a bacterial IgE-reactive molecule.

Staphylococcus pseudintermedius is one of the major pathogens causing canine skin infection. In canine atopic dermatitis (AD), heterogeneous strains of S. pseudintermedius reside on the affected skin site. Because an increase in specific IgE to this bacterium has been reported, S. pseudintermedius is likely to exacerbate the severity of canine AD. In this study, the IgE reactivities to various S. pseudintermedius strains and the IgE-reactive molecules of S. pseudintermedius were investigated. First, examining the IgE reactivities to eight strains of S. pseudintermedius using 141 sera of AD dogs, strain variation of S. pseudintermedius showed 10-63% of the IgE reactivities. This is different from the expected result based on the concept of Staphylococcus aureus clonality in AD patients. Moreover, according to the western blot analysis, there were more than four proteins reactive to IgE. Subsequently, the analysis of the common IgE-reactive protein at ∼15 kDa confirmed that the DM13-domain-containing protein was reactive in AD dogs, which is not coincident with any S. aureus IgE-reactive molecules. Considering these, S. pseudintermedius is likely to exacerbate AD severity in dogs, slightly different from the case of S. aureus in human AD.

Epigenetic Priming with Decitabine Augments the Therapeutic Effect of Cisplatin on Triple-Negative Breast Cancer Cells through Induction of Proapoptotic Factor NOXA.

Epigenetic alterations caused by aberrant DNA methylation have a crucial role in cancer development, and the DNA-demethylating agent decitabine, is used to treat hematopoietic malignancy. Triple-negative breast cancers (TNBCs) have shown sensitivity to decitabine; however, the underlying mechanism of its anticancer effect and its effectiveness in treating TNBCs are not fully understood. We analyzed the effects of decitabine on nine TNBC cell lines and examined genes associated with its cytotoxic effects. According to the effect of decitabine, we classified the cell lines into cell death (D)-type, growth inhibition (G)-type, and resistant (R)-type. In D-type cells, decitabine induced the expression of apoptotic regulators and, among them, NOXA was functionally involved in decitabine-induced apoptosis. In G-type cells, induction of the cyclin-dependent kinase inhibitor, p21, and cell cycle arrest were observed. Furthermore, decitabine enhanced the cytotoxic effect of cisplatin mediated by NOXA in D-type and G-type cells. In contrast, the sensitivity to cisplatin was high in R-type cells, and no enhancing effect by decitabine was observed. These results indicate that decitabine enhances the proapoptotic effect of cisplatin on TNBC cell lines that are less sensitive to cisplatin, indicating the potential for combination therapy in TNBC.

Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia.

Mutations of CCAAT/enhancer-binding protein alpha (CEBPAmu) are found in 10% to 15% of de novo acute myeloid leukemia (AML) cases. Double-mutated CEBPA (CEBPAdm) is associated with a favorable prognosis; however, single-mutated CEBPA (CEBPAsm) does not seem to improve prognosis. We investigated CEBPAmu for prognosis in 1028 patients with AML, registered in the Multi-center Collaborative Program for Gene Sequencing of Japanese AML. It was found that CEBPAmu in the basic leucine zipper domain (bZIP) was strongly associated with a favorable prognosis, but CEBPAmu out of the bZIP domain was not. The presence of CEBPAmu in bZIP was a strong indicator of a higher chance of achieving complete remission (P < .001), better overall survival (OS; P < .001) and a lower risk of relapse (P < .001). The prognostic significance of CEBPAmu in bZIP was also observed in the subgroup with CEBPAsm (all patients: OS, P = .008; the cumulative incidence of relapse, P = .063; patients aged ≤70 years and with intermediate-risk karyotype: OS, P = .008; cumulative incidence of relapse, P = .026). Multivariate analysis of 744 patients aged ≤70 years showed that CEBPAmu in bZIP was the most potent predictor of OS (hazard ratio, 0.3287; P < .001). CEBPAdm was validated as a cofounding factor, which was overlapping with CEBPAmu in bZIP. In summary, these findings indicate that CEBPAmu in bZIP is a potent marker for AML prognosis. It holds potential in the refinement of treatment stratification and the development of targeted therapeutic approaches in CEBPA-mutated AML.

Anaphylaxis after vaccination for cats in Japan.

Severe adverse reactions in cats after vaccination were examined from 316 cases reported to the Ministry of Agriculture, Forestry and Fisheries (MAFF) in Japan during 15-year period from April 2004 to March 2019. We found that 130 (41%) showed anaphylaxis, and 99 (76%) of the 130 cases of anaphylaxis resulted in death. Veterinarians should be well prepared to deal with vaccine-associated anaphylaxis in cats. Bovine serum albumin (BSA) as indicator of purification was detected at high levels in commercially available feline vaccines. BSA might derive from fetal calf serum in culture media. This study provides useful information about anaphylaxis including critical details of the potential clinical signs associated with adverse events to feline vaccination.

Tannin-phytobezoars with Gastric Outlet Obstruction Treated by Dissolution with Administration and Endoscopic Injection of Coca-Cola®, Endoscopic Crushing, and Removal (with Video).

A 77-year-old man complained of postmeal vomiting and sustained general fatigue. An abdominal computed tomography scan showed massive gastric expansion and fluid storage. Gastroscopy revealed four gastric bezoars that were considered to have caused pyloric ring obstruction. The patient was asked to drink 500 mL per day of Coca-Cola® for 4 days. On the fourth day, we performed endoscopic crushing and removal by injecting Coca-Cola®, cutting the softened bezoar with endoscopic snares, and collecting the pieces with endoscopic nets. We herein report (with a video presentation) a rare case of tannin-phytobezoars endoscopically removed with the administration and injection of Coca-Cola®.

[Uniportal Video-assisted Thoracoscopic Surgery for Acute Empyema].

A 70-year-old man was referred to our department for the treatment of acute empyema. Since the chest drainage was of little effect due to the fibrinous loculation, deloculation followed by curettage and decortication under uniportal video-assisted thoracoscopic surgery( VATS) with flexible endoscopy was performed. Complete re-expansion of the lung was successfully achieved and the chest tube was removed on the fourth postoperative day. However, on the seventh postoperative day, purulent discharge was noted from the wound resulting in relapse of empyema which was successfully treated with the cleaning and negative pressure suction by re-insertion of the chest tube.

Successful hemostasis for refractory colonic diverticulum bleeding by clipping with polyglycolic acid sheets.

Video 1Endoscopic clipping with polyglycolic acid sheets for colonic diverticulum bleeding.

IgE reactivity to milk components in dogs with cutaneous adverse food reactions.

We investigated the IgE reactivity to crude and purified milk antigens in the sera of 112 dogs with cutaneous adverse food reactions (CAFRs). Of the 112 dogs, 33 (29%) had specific IgE for crude milk antigens. In the dogs with milk-specific IgE, IgE reactivity to casein, bovine serum albumin (BSA), α-lactalbumin, ß-lactoglobulin, and bovine IgG were 81%, 85%, 39%, 27%, and 35%, respectively. Casein and BSA may be important allergens in dogs with CAFRs. Some canine vaccines contain casein hydrolysate as a stabilizer and the pooled serum with anti-casein IgE showed IgE reactivity to the vaccines containing it. Information about IgE reactivity to casein in dogs with CAFRs could be useful for predicting adverse reactions to the vaccines including casein hydrolysate.