A case of inguinal lymphaticovenular anastomosis for refractory lymphatic ascites after uterine cancer surgery.

We herein report a case of refractory lymphatic ascites after uterine cancer surgery treated with bilateral inguinal lymphaticovenular anastomosis (LVA). LVA was performed four months after the uterine cancer surgery in a patient with refractory ascites that had developed one month after the gynecologic surgery. One year and eight months after LVA, there was no recurrence of ascites accumulation.

A super-geriatric patient with gastrostomy underwent life-threatening prothrombin time-international normalized ratio prolongation by warfarin following fasting and antibiotic therapy.

Key Clinical Message: A 97-year-old woman with gastrostomy had a drastic enhancement for PT-INR after starting antibiotic therapy. Possible causes include (1) vitamin K deficiency due to fasting and (2) a combination of warfarin and antibiotics. Abstract: Geriatric and Asian-descent patients are more sensitive to the effects of warfarin, a key anticoagulant drug. In this report, we present a 97-year-old bedridden woman being treated with warfarin for cardiogenic cerebral infarction and femoral neck replacement as part of in-home medical care with a gastrostomy and was admitted to our hospital after developing pneumonia. We discontinued warfarin and started antibiotics, and her pneumonia-related symptoms improved. Eleven days after restarting warfarin, the patient's PT-INR surpassed the upper limit for measurement (over 10). We considered the mechanism might be triggered by (1) fasting, low nutrition status; and (2) antibiotics secondary to risk factors such as gastrostomy and being a super-geriatric woman. We recommend careful monitoring of PT-INR in patients treated with warfarin and antibiotics, especially in the setting of gastrostomy or older persons.

Risk Assessment for Heart Failure in Patients with Type 2 Diabetes Mellitus Treated with Dipeptidyl Peptidase 4 Inhibitor Using a Large Claims Dataset.

Heart failure is a prevalent comorbidity in patients with diabetes mellitus (DM). However, it is unclear whether the risk factors for heart failure in DM patients treated with dipeptidyl peptidase-4 (DPP-4) inhibitors are the same as those for the general population. In this study, we evaluated the factors of new-onset heart failure in working-age patients with diabetes who started DPP-4 inhibitor therapy. This study included 7938 working-age patients. The primary endpoint of the study was the proportion of patients developing heart failure within 12 months of starting DPP-4 inhibitor therapy, which was found to be 1.89% (n = 150). In these patients, risk factors of new-onset heart failure were aging, history of atrial fibrillation, and hypertension but not sex, smoking, high body mass index, weight gain of over 10 kg from 20 years of age, levels of low-density lipoprotein or glycated hemoglobin A1c (HbA1c), history of angina pectoris, myocardial infarction, and chronic kidney disease. We confirmed that cardiovascular comorbidities are risk factors for new-onset heart failure in patients with DM, while general risk factors are not. In conclusion, physicians and pharmacists need to carefully monitor working-age patients with cardiovascular history who start DPP-4 inhibitor therapy even if they do not exhibit general risk factors for heart failure.

Dilemma Facing Patients Aged 75 Years and Older on Fluid Restriction When Drug Package Inserts Advise Use of a Lot of Water: A Cross-Sectional, Descriptive, and Hypothesis-Generating Study Using a Large Claims Database.

BACKGROUND: Several oral drugs are recommended to be taken with large amounts of water for reasons such as peptic ulcer prophylaxis. On the other hand, there are many patients with diseases that restrict water intake, and the actual frequency of patients receiving prescriptions in these conflicting situations is not clear. OBJECTIVE: Using a large claims database in Japan, this study aimed to determine the proportion of patients aged ≥ 75 years on fluid restriction who received drugs whose drug package insert mentioned "a large amount of water intake is needed when taking the drug". METHODS: We performed a prescription survey of older patients over 75 years of age using the Japan Medical Data Centre (JMDC) claims database. Out of approximately 8800 oral drugs used in Japan, we defined 29 drugs for which package inserts noted that a large amount of water intake is recommended during drug administration. We defined diagnosis codes for some common diseases for which restricted water intake is likely recommended: heart failure (NYHA class III or IV), liver cirrhosis with ascites, and chronic kidney disease stage 5, including dialysis patients. RESULTS: Of 5968 patients aged ≥ 75 years (men 47.7%), 320 (5.4%) patients with heart failure (2.8%, n = 170), liver cirrhosis (0.7%, n = 40), or chronic kidney disease (1.9%, n = 113), diagnoses likely associated with the need for fluid restriction, were prescribed drugs for which abundant fluid at intake was recommended. Among 29 identified drugs, 15 drugs were administered to older patients over 75 years with fluid restriction due to said diseases. CONCLUSIONS: Of patients 75 years and older with disease likely requiring water restriction, 5.4% faced the dilemma of following advice to restrict fluid intake due to their diagnoses or to adhere to instructions in drug package inserts to have abundant fluid intake when taking the drug. Our study raises awareness regarding the dilemma of water restriction and intake in clinical settings, highlighting the importance of considering individual patient needs. These real-world findings emphasize the need for information and guidelines to assist healthcare professionals in navigating this dilemma and making informed decisions for the benefit of their patients.

Deep intronic founder mutations identified in the ERCC4/XPF gene are potential therapeutic targets for a high-frequency form of xeroderma pigmentosum.

Xeroderma pigmentosum (XP) is a genodermatosis defined by cutaneous photosensitivity with an increased risk of skin tumors because of DNA repair deficiency. The worldwide prevalence of XP is ~1 to 4 in million, with higher incidence in some countries and regions including Japan (1 in 22,000) and North Africa due to founder mutations and a high degree of consanguinity. Among XP, the complementation group F (XP-F), is a rare form (1% of worldwide XP); however, this is underdiagnosed, because the ERCC4/XPF gene is essential for fetal development and most of previously reported ERCC4/XPF pathogenic variants are hypomorphs causing relatively mild phenotypes. From the largest Japanese XP cohort study, we report 17 XP-F cases bearing two pathogenic variants, both identified in deep intronic regions of the ERCC4/XPF gene. The first variant, located in intron 1, is a Japanese founder mutation, which additionally accounts for ~10% of the entire Japanese XP cases (MAF = 0.00196), causing an aberrant pre-mRNA splicing due to a miss-binding of U1snRNA. The second mutation located in intron eight induces an alternative polyadenylation. Both mutations cause a reduction of the ERCC4/XPF gene expression, resulting in XP clinical manifestations. Most cases developed early-onset skin cancers, indicating that these variants need critical attention. We further demonstrate that antisense oligonucleotides designed for the mutations can restore the XPF protein expression and DNA repair capacity in the patients' cells. Collectively, these pathogenic variants can be potential therapeutic targets for XP.

Dexamethasone to prednisolone rotation relieved hiccups in colorectal cancer patient continuing teleworking during anticancer therapy.

We present a case of chemotherapy-induced hiccups that were alleviated by steroid rotation. Hiccups are often overlooked, but they have an impact on the patient's quality of life. In the COVID-19 era, web-based teleworking has become an important tool, hiccups during a teleconference should be noted as a concern for patients.

Fresh human amniotic membrane wrapping promotes peripheral nerve regeneration in PGA-collagen tubes.

BACKGROUND: An artificial nerve conduit can interpose the peripheral nerve defect without donor site morbidity. However, treatment outcomes are often unsatisfactory. Human amniotic membrane (HAM) wrapping has been reported to promote peripheral nerve regeneration. We evaluated the effects of a combined application of fresh HAM wrapping and a polyglycolic acid tube filled with collagen (PGA-c) in a rat sciatic nerve 8-mm defect model. METHODS: The rats were divided into three groups: (1) the PGA-c group (n = 5), in which the gap was interposed with the PGA-c; (2) the PGA-c/HAM group (n = 5), in which the gap was interposed with the PGA-c bridge, then HAM (14 × 7 mm) was wrapped around it; and (3) the Sham group (n = 5). Walking-Track recovery, electromyographic recovery, and histological recovery of the regenerated nerve were evaluated at 12 weeks postoperatively. RESULTS: Compared to the PGA-c group, the PGA-c/HAM group showed significantly better recovery in terminal latency (3.4 ± 0.31 ms vs. 6.6 ± 0.72 ms, p < 0.001), compound muscle action potential (0.19 ± 0.025 mV vs. 0.072 ± 0.027 mV, p < 0.01), myelinated axon perimeter (15 ± 1.3 µm vs. 8.7 ± 0.63 µm, p < 0.01), and g-ratio (0.69 ± 0.0089 vs. 0.78 ± 0.014, p < 0.001). CONCLUSION: This combined application highly promotes peripheral nerve regeneration and may be more useful than PGA-c alone.

Negative effects of rivaroxaban observed in a patient with multiple common risks triggered by a bicycle accident.

The negative effects of anticoagulants are well-known in patients with renal impairment, drug-drug interaction, lower physical conditions, and multiple comorbidities. We highlight that even in patients with controllable multiple risks for rivaroxaban use, add-on inevitable risks will lead to negative effects greater than those expected.

Real-World Safety and Tolerability of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis: Interim Report of a Post-Marketing Surveillance in Japan.

INTRODUCTION: Nintedanib is recommended for the treatment of idiopathic pulmonary fibrosis (IPF); however, treatment discontinuation due to adverse events (AEs) is common. A large-scale post-marketing surveillance study is investigating the real-world tolerability/safety of nintedanib in Japanese patients with IPF in routine clinical practice. Here, we report a 12-month interim analysis of this study. METHODS: The study included Japanese patients with IPF who started nintedanib between 31 August 2015 and 25 December 2018. The primary outcome was the frequency of adverse drug reactions (ADRs), defined as AEs for which a causal relationship with nintedanib could not be excluded. The secondary outcome was change from baseline in forced vital capacity (FVC). Outcomes were analysed in patients who stopped ('discontinued' subgroup) and continued ('continued' subgroup) nintedanib after 12 months. A multivariate analysis was performed to determine potential risk factors for treatment discontinuation. RESULTS: Of 5578 patients in the safety analysis set, 2795 (50.1%) discontinued nintedanib within 12 months of treatment initiation. Overall, 3767 patients (67.5%) had ADRs, with 1356 (24.3%) discontinuing nintedanib because of an ADR. Among patients in the 'discontinued' subgroup (n = 2795), 1442 (51.6%) discontinued because of an ADR. The most common ADRs causing discontinuation within 3 and 12 months were hepatic function abnormal (n = 137/730; 18.8%) and diarrhoea (n = 190/1442; 13.2%), respectively. At 12 months, the decrease in FVC from baseline was smaller in the 'continued' versus the 'discontinued' subgroup (adjusted mean ± standard error change - 104.4 ± 10.9 ml vs. - 311.2 ± 29.2 ml). Stage III/IV IPF and FVC < 70% predicted at baseline were risk factors for early treatment discontinuation. CONCLUSION: About 50% of Japanese patients with IPF discontinued nintedanib within the first year of treatment, with worse lung function being associated with an increased risk of early treatment discontinuation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02607722; European Union electronic register of Post-Authorisation Studies: EUPAS10891.

Nationwide time-series surveys of pressure ulcer prevalence in Japan.

OBJECTIVE: The Japanese Society of Pressure Ulcers (JSPU) has two purposes: first, to improve knowledge and skills among health professionals related to preventing and managing pressure ulcers (PUs); and second, to represent those in the field managing PUs, including with government and health authorities. Since 2006, JSPU has conducted fact-finding surveys about every four years to identify PU prevalence in Japan (2006, 2010, 2013 and 2016). Based on the prevalence identified by these surveys, an attempt was made to validate the achievements of JSPU's activities. METHOD: Information from one-day surveys of hospitals, long-term care health facilities, long-term care welfare facilities, and home visit nursing care stations was analysed. We used generalised estimating equations to estimate the proportions of PUs and their 95% confidence intervals (CIs) for each survey. RESULTS: A total of 662,419 patients in 2631 facilities participated in the surveys. The estimated proportions for all facilities (95% CI) in chronological order, from the first to the fourth survey, were: 2.67% (2.52-2.83); 2.61% (2.43-2.80); 1.99% (1.83-2.17); and 1.79% (1.65-1.94), respectively. In all facility types, the proportion of PUs was lower in the fourth survey than the first survey. CONCLUSION: The proportion of PUs showed a decreasing trend and was low according to global standards, demonstrating the efficacy of JSPU's activities.

circRNAs May Be Involved in Dysfunction of Neutrophils of Type 2 Diabetic Mice through Regulation of Specific miRNAs.

Diabetes is known to delay wound healing, and this delay is attributed to prolonged inflammation. We found that microRNAs (miRNAs) might be involved in the dysfunction of diabetic-derived neutrophils, and dynamics of neutrophil and chronic inflammation might be initiated by miRNA-regulated genes. Moreover, studies of miRNA function in nephropathy have suggested that circular RNAs (circRNAs), which function as sponges of miRNA to regulate their expression, are potential biomarkers and new therapeutic targets for the diagnosis of diabetic nephropathy. Accordingly, to investigate the molecular mechanism of the regulation of inflammation in diabetic-derived neutrophils, we identified circRNAs in diabetic-derived neutrophils obtained from BKS.Cg-Dock7m +/+ Leprdb/J (Leprdb/db and Leprdb/+) mice using microarrays. Neutrophils from pooled bone marrow of three diabetic and three non-diabetic mice were isolated and total RNA was extracted. Microarray analysis was performed using the Arraystar Mouse Circular RNA Array. The results showed that three circRNAs were significantly increased and six circRNAs were significantly decreased in diabetic-derived neutrophils compared with non-diabetic-derived neutrophils. The expressions of some circRNAs in diabetic-derived neutrophils were more than double those in non-diabetic-derived neutrophils. The circRNAs contain binding sites of miRNAs, which were differentially expressed in diabetic-derived neutrophils. Our results suggest that circRNAs may be involved in the regulation of inflammation in diabetic-derived neutrophils.

Aicardi-Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test.

Aicardi-Goutières syndrome (AGS) is a rare genetic disorder characterised by progressive encephalopathy, involving microcephaly, intracranial calcification, and cerebrospinal fluid lymphocytosis with increased interferon-α concentrations. The clinical features of AGS overlap with fetal cerebral anomalies caused by congenital infections, such as TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpes), or with those of other genetic disorders showing neonatal microcephaly, including Cockayne syndrome (CS) with transcription-coupled DNA repair deficiency, and Seckel syndrome (SS) showing aberrant cell-cycle checkpoint signaling. Therefore, a differential diagnosis to confirm the genetic cause or a proof of infection should be considered. In this report, we describe an individual who showed primordial dwarfism and encephalopathy, and whose initial diagnosis was CS. First, we conducted conventional DNA repair proficiency tests for the patient derived fibroblast cells. Transcription-coupled nucleotide excision repair (TC-NER) activity, which is mostly compromised in CS cases, was slightly reduced in the patient's cells. However, unscheduled DNA synthesis (UDS) was significantly diminished. These cellular traits were inconsistent with the diagnosis of CS. We further performed whole exome sequencing for the case and identified a compound heterozygous loss-of-function variants in the SAMHD1 gene, mutations in which are known to cause AGS. As SAMHD1 encodes deoxyribonucleoside triphosphate triphosphohydrolase, we reasoned that the deoxyribonucleoside triphosphate (dNTP) pool size in the patient's cells was elevated, and the labeling efficiency of UDS-test was hindered due to the reduced concentration of phosphorylated ethynyl deoxyuridine (EdU), a nucleoside analogue used for the assay. In conclusion, UDS assay may be a useful diagnostic tool to distinguish between AGS with SAMHD1 mutations and other related diseases.

Identification of the Components of Proton Pump Inhibitors and Potassium-Competitive Acid Blocker That Lead to Cardiovascular Events in Working-Age Individuals: A 12-Month Retrospective Cohort Study Using a Large Claims Database.

This study aimed to identify the components of proton pump inhibitors (PPIs) or potassium-competitive acid blocker (PCAB) that lead to cardiovascular events in individuals of working age. We analyzed large claims data of individuals who were administered PPIs or PCAB. We enrolled working-age individuals administered PPI or PCAB without cardiovascular history with a 12-month screening and 12-month observation period and determined the proportion of cardiovascular events and the predictive factors of cardiovascular events in this population. Among the eligible individuals, 0.5% (456/91098) had cardiovascular events during the 12-month observation period. Predictive factors for cardiovascular events were age for +1 year (p < 0.0001), male sex (p < 0.0001), hypertension (p = 0.0056), and diabetes mellitus (p < 0.0001). The cardiovascular disease risk was higher in working-age individuals administered lansoprazole than in those administered other drugs (vs. rabeprazole; p = 0.0002, vs. omeprazole; p = 0.0046, vs. vonoprazan; p < 0.0001, and vs. esomeprazole; p < 0.0001). We identified the risk for cardiovascular events in individuals being treated with lansoprazole. Lansoprazole is known for its higher CYP2C19 inhibition activity compared with other PPIs or PCAB. A possible mechanism by which lansoprazole may lead to cardiovascular events is inhibiting the generation of epoxyeicosatrienoic acids from arachidonic acids, an intrinsic cardioprotective activator via CYP2C19 inhibition. Thus, we recommend avoiding administering lansoprazole to working-age individuals require PPIs or PCAB.

Simple determination of urine cefazolin concentration in pediatric patients with urinary tract infections using high-performance liquid chromatography.

Recently, global health concerns regarding increasing multidrug resistance have arisen. This study aimed to develop a simple, inexpensive and rapid high-performance liquid chromatography-ultraviolet (HPLC-UV) method for determining urinary concentrations of a first-generation cephem antibiotic in pediatric patients with urinary tract infections (UTIs). HPLC-UV was used to analyze urinary cefazolin concentrations at a detection wavelength of 254 nm. The assay used contained 10-fold diluted urine with an internal standard (cephapirin). The standard calibration curve for cefazolin was linear in the concentration range of 31.25-500 µg/ml (r2  > 0.999). The retention times of cefazolin and the internal standard were 4.2 and 4.9 min, respectively. The within- and between-day coefficients of variation were in the concentration ranges 1.2-15.2 and 5.5-19.2%, respectively. The urinary cefazolin concentration of a pediatric patient with a UTI was 1,476.6 µg/ml, which was over 700-fold higher than the minimum inhibitory concentration of cefazolin (≤2 µg/ml). The developed method is applicable to the confirmation of appropriate use for UTI treatment as therapeutic drug monitoring of cefazolin. Therefore, the findings of this study may contribute to the appropriate use of antibiotics to prevent antimicrobial resistance in pediatric patients with UTIs.

Longitudinal physiological remoulding of lower limb skin as a cause of diabetic foot ulcer: a histopathological examination.

OBJECTIVE: Diabetic foot ulcer (DFU) is recognised as a severe complication in patients with type 2 diabetes. With the increasing incidence of diabetes, it represents a major medical challenge. Several models have been proposed to explain its aetiology; however, they have never been assessed by longitudinal histopathological examination, which this study aims to address. METHOD: Multiplex-immunofluorescence analysis was carried out with lengthwise serial skin specimens obtained from the medial thigh, lower leg, ankle, dorsum of foot and acrotarsium close to the DFU region of a patient with type 2 diabetes receiving above the knee amputation. RESULTS: Proximal-to-distal gradual loss of peripheral nerve was demonstrated, accompanied by compromised capillaries in the superficial papillary plexus and distended CD31-positive capillaries in the dorsum of foot. Neural fibres and capillaries were also significantly compromised in the sweat gland acinus in the ankle and dorsum of foot. Injuries in the superficial papillary plexus, sweat gland acinus, and sweat gland-associated adipose tissues were accompanied by significant infiltration of macrophages. These results indicated that longitudinal impairment of local blood circulation could be the cause of peripheral neuropathy, which initiated ulcer formation. Resultant chronic inflammation, involving sweat gland-associated adipose tissue, gave rise to impairment of wound healing, and thus DFU formation. CONCLUSION: Longitudinal histopathological examination demonstrated that impairment of local microvascular circulation (rather than the systemic complication caused by type 2 diabetes) was considered the primary cause of peripheral neuropathy, which initiated ulceration. Together with chronic inflammation in the superficial papillary plexus and sweat gland-associated adipose tissue, it resulted in the development of a DFU. Although this is a study of just one individual's limb, our study provided a unique observation, contributing mechanistic insights into developing novel intervening strategies to prevent and treat DFUs.

The CeCORD-J study on collagenase injection versus aponeurectomy for Dupuytren's contracture compared by hand function and cost effectiveness.

This study compared hand function and the cost-effectiveness of treatment between collagenase Clostridium histolyticum (CCH) injection and limited fasciectomy for patients with Dupuytren's contracture (DC). The CeCORD-J study is a prospective, multicenter, non-randomized controlled, observational study of two parallel groups. Participants were DC patients with multiple affected fingers, including flexion contracture of the proximal interphalangeal (PIP) joint. The primary outcome was the Hand10 score, as a patient-reported outcome measure (PROM). We set secondary outcomes of EQ-5D-5L (QOL) score, degree of extension deficit, and direct cost. Propensity score adjustment was used to balance differences in patient characteristics between groups. Participants comprised 52 patients in the Collagenase group and 26 patients in the Surgery group. There were no significant differences in the Hand10 and QOL scores between the two groups at 26 weeks. Mean direct cost was 248,000 yen higher in the Surgery group than in the Collagenase group. Extension deficit angle of the PIP joint was significantly larger in the Collagenase group at 26 weeks. Although the Collagenase group showed dominance in cost-effectiveness, there was no significant difference between the two groups in hand function at 26 weeks.

Intraoperative obturator nerve injury reconstructed using a PGA-collagen tube: Three case reports.

We herein report three cases of obturator nerve injury, which is rare in gynecological surgery. In all cases, it was difficult to suture both nerve ends without tension. Therefore, we used a PGA-collagen tube to interpose the nerve defect. After follow-ups of at least seven months, all three patients were able to adduct the hip joint and medial thigh sensations also improved. These results suggest the potential of a PGA-collagen tube in the treatment of obturator nerve injury.

Irinotecan-induced severe hypotension in a patient with lung cancer.

Most hypotension during chemotherapy is caused by an allergic mechanism. Conversely, non-allergic hypotension due to chemotherapy is rare. In this case report, we present a patient who suffered severe hypotension followed by the administration of irinotecan-based chemotherapy and some supportive care such as steroids for preventing emesis. A 71-year-old man with hypertension was diagnosed with stage IV small cell lung cancer (sT1cN3M0). Severe hypotension occurred in the patient after every administration of chemotherapy. Finally, he was able to receive all four courses of chemotherapy as planned along with the medical staff's support care. This case provides that a regimen that contained irinotecan and steroid could cause hypotension and the mechanism is partially explained by inhibiting choline esterase and adrenal insufficiency. We should be careful about non-allergic hypotension when we administer irinotecan-based chemotherapy.

Reconstruction of a Scrotum by Combining Two Skin Flaps in a Ball Shape.

Background: The scrotum functions to maintain spermatogenesis and hormonal production of Leydig cells by preventing the testicles from rising in temperature and protecting them from the outside world. The scrotum, along with the penis, is also an organ that symbolizes masculinity. Therefore, deformity or loss of the scrotum can be a major psychological problem. Various scrotal reconstruction techniques have been reported. In these papers, there is some discussion about the type of skin flap, but little discussion about the method of suturing the skin flap. We devised a way to reconstruct a scrotum to a natural size by suturing two skin flaps together to form a ball shape. Case Presentation. Case 1 was a patient with a missing scrotum due to Fournier's gangrene. Total resection of the scrotum, including the bilateral testes, was performed to save his life. Reconstructive surgery was performed 11 days after the initial surgery. Reconstruction was performed using bilateral gluteal fold flaps. Case 2 was a patient with a congenital defect of the scrotum. The testis on the right side exhibited cryptorchidism, and the scrotum was missing, and the testis on the left side was encased in a hypoplastic scrotum. Reconstruction was performed using an internal pudendal artery perforator flap. Conclusion: There are two types of scrotal defects: those with testes present and those with testes missing. This method can be used for both types of scrotal defects, and we were able to create a scrotum that satisfied each patient.