Implementation of Guideline-Based HBV Reactivation Management in Patients with Chronic HBV Infections of HBsAg or Resolved HBV Infection Undergoing Immunosuppressive Therapy.

INTRODUCTION: Although patients with HBV have a risk of reactivation after immunosuppressive therapy (IST), the status of their risk management is unclear in Japan. This study aims to describe the proportion of patients who received preventive management of HBV reactivation during ISTs in patients with chronic HBV infection of HBsAg or resolved HBV infection. METHOD: A retrospective cohort study was conducted using the JMDC Japanese claims database from April 2011 to June 2021. Patients with HBV infections of HbsAg who received ISTs or patients who had resolved HBV infections who received ISTs were identified from the database and evaluated for appropriate management to prevent HBV reactivation. RESULTS: In total, 6242 eligible patients were identified. The proportions of patients with appropriate HBV reactivation management, stratified by the HBV reactivation risk level of IST, was 43.1% (276/641) for high-risk, 40.2% (223/555) for intermediate-risk and 14.9% (741/4965) for low-risk patients. When the evaluation period for the outcome calculation was shortened from 360 to 180 days, the proportion for high risk increased to 52.7%. The odds ratios of large hospitals for receiving appropriate management were 2.16 (95% CI 1.12-4.44) in the high-risk, 4.63 (95% CI 2.34-10.25) in the intermediate-risk and 3.60 (95% CI 3.07-4.24) in the low-risk patients. CONCLUSION: HBV reactivation management was tailored according to the reactivation risk associated with IST. However, adherence to HBV reactivation management guidelines was sub-optimal, even among high-risk patients. This is especially the case for ensuring smaller-sized medical institutions, highlighting the need for further educational activities.

The study assesses the implementation of guideline-based management of hepatitis B virus reactivation during immunosuppressive therapy in Japan. The appropriate management of hepatitis B virus treatment involves prophylactic nucleos(t)ide analog (NUC) therapy and regular monitoring of hepatitis B virus DNA. This study aims to assess the extent to which these management practices are implemented in a clinical setting in Japan using a retrospective cohort study using the Japanese Medical Claims Database. The analysis identified 6242 eligible patients and identified whether they received appropriate management to prevent hepatitis B virus reactivation based on the level of risk associated with their immunosuppressive therapy. Based on the guidelines, the proportions of patients receiving appropriate reactivation management were 43.1% for high-risk, 40.2% for intermediate-risk and 14.9% for low-risk immunosuppressive therapy patients. Shortening the evaluation period from 360 to 180 days showed an increase in the proportion of high-risk patients to 52.7%, which indicated the potential challenge for continued monitoring after immunosuppressive therapy administration. The study shows that large hospitals present higher odds of patients receiving appropriate management. Overall, adherence to hepatitis B virus reactivation management guidelines was suboptimal, especially in smaller medical institutions, emphasizing the need for additional educational activities.

Correction: The Usefulness of AirSeal™ Intelligent Flow System in Gas Insufflation Total Endoscopic Thyroidectomy.

[This corrects the article DOI: 10.1007/s12070-022-03257-0.].

Renal outcomes with sodium-glucose cotransporter 2 inhibitors in Japanese people with grade 3 chronic kidney disease and type 2 diabetes: Analysis of medical administrative databases.

AIM: To evaluate whether sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy is associated with a reduction of renal events compared with other glucose-lowering drugs (oGLDs) among Japanese people with type 2 diabetes (T2D) and grade 3 (G3) chronic kidney disease (CKD) in a real-world clinical practice setting. MATERIALS AND METHODS: People with T2D who were newly prescribed an SGLT2i or an oGLD from April 2014 to November 2021 (without prior use of index drugs for ≥ 1 year prior to index date) and G3 CKD (estimated glomerular filtration rate [eGFR] ≥ 30 to < 60 mL/min/1.73 m2) were selected from the Medical Data Vision database (MDV-DB) and the Real-World Data database (RWD-DB). SGLT2i and oGLD users were matched (1:1) using propensity score on patient background characteristics. The primary endpoint was a composite of the development of end-stage kidney disease or a sustained decline in eGFR of 50% or more. Hazard ratios (HRs) were estimated using the Cox proportional hazards model. RESULTS: Overall, 3190 (1595 per group) patients in the MDV-DB and 2572 (1286 per group) patients in the RWD-DB were included in the analyses. The composite outcome was significantly lower in the SGLT2i group than in the oGLD group in the MDV-DB (HR 0.49, 95% confidence interval [CI] 0.33 to 0.74, P < 0.001) and in the RWD-DB (HR 0.57, 95% CI 0.37 to 0.88, P = 0.011). CONCLUSIONS: Japanese people with T2D and G3 CKD initiating an SGLT2i had a lower risk of renal events than people initiating an oGLD.

[Utilization of the standard questionnaire in specific health checkups].

Objectives　Interviewing people about their health behaviour in specific health checkups (SHCs) is thought to promote awareness of and help improve such behaviour. The standard questionnaire (SQ) for SHCs consists of 22 items presented in the guidelines of the Ministry of Health, Labour, and Welfare. However, using items other than those necessary for stratification for specific health guidance (SHG) is optional. We believe that clarifying the actual utilization of SQ items could contribute to improving the procedure used for the fourth SHCs and SHG, which will be initiated in 2024.　This study seeks to clarify the actual utilization of the SQ for (1) conducting SHCs, (2) planning, implementing, and evaluating SHG and health programs aimed at preventing lifestyle-related diseases, and (3) planning, implementing, and evaluating the data health plan.Methods　We enrolled 3,179 people from 1,741 departments in charge of national health insurance, 47 Japan Health Insurance Association branches, and 1,391 health insurance societies across all municipalities in Japan. One participant among the study participants was the main person in charge of SHCs and SHG at each facility. We conducted a self-reported survey on the implementation of SHCs and SHG in February 2022. This study was approved by the ethics review board of the institution to which the first author belongs.Results　A total of 1,221 (38.4%) were received. The proportions of valid responses from national health insurance departments, Japan Health Insurance Association branches, and health insurance societies were 816 (46.9%), 47 (100%), and 358 (25.7%), respectively. Over 96% of responders used the group SHCs method, and over 93% of those adopting the individual SHCs method used each of the 22 SQ items. However, 187 (18.2%) responders found it difficult to use the item "If you had the opportunity to receive health guidance for lifestyle improvement, would you take it?" The reason was that the on-request SHG system was misunderstood. Additionally, only approximately 50% of respondents used the SQ to develop, implement, and evaluate their health program.Conclusion　We believe there will be no problem in implementing the SQ even if using all its component items is required. However, the aforementioned item needs to be revised. Methods to encourage health insurers and their supporters to use the SQ for health-related data collection and health program planning should be devised.

Clinical classification of recurrent laryngeal nerve palsy.

Background: The application of intraoperative neurophysiological monitoring (IONM) has been accepted to avoid injury of a recurrent laryngeal nerve (RLN). Loss of the neuromonitoring signal indicates nerve injury and is subdivided into segmental type and global type nerve paralysis. This study aimed to determine the course of vocal cord function recovery after definitive loss of signal (LOS) types. Methods: This retrospective study included 1,442 patients (with 2,752 nerves at risk) who had thyroidectomies between January 2018 and December 2021. Preoperative and postoperative vocal cord functions were evaluated by laryngoscopic examination. Results: LOS occurred in 168 of 1,442 (11.7%) patients and 171 of 2,748 (6.2%) nerves at risk during surgery. Of LOS nerves of benign tumors, 74.2% showed global type. In cancer cases, segmental paralysis was more common, accounting for 51.3% of LOS nerves. Of nerves with segmental LOS in cancer patients, 55.3% needed partial layer resection for RLN invasion. Intraoperative recovery was seen in 9 of 62 nerves (14.5%) with segmental LOS and 32 of 109 (29.4%) nerves with global type LOS. The vocal cord palsy rate on postoperative days (PODs) 2-3 was lower after global type nerve paralysis (63.6%) than after segmental loss (84.9%). At 6 months postoperatively, the rate of vocal cord paralysis in benign tumors was not significantly different between segmental type and global type (P=0.586). However, cancer patients with segmental LOS significantly more often had vocal cord dysfunction than those with global LOS at 6 months postoperatively (rate of nerve palsy: segmental 40.0% vs. global 3.4%) (P<0.001). Conclusions: The intraoperative recovery rate and early nerve recovery rate are significantly higher for patients with global LOS than for patients with segmental LOS. Cancer patients with segmental LOS significantly more often had vocal cord dysfunction than those with global LOS at 6 months postoperatively.

Prevalence of multimorbidity and its associations with hospitalisation or death in Japan 2014-2019: a retrospective cohort study using nationwide medical claims data in the middle-aged generation.

OBJECTIVE: To describe the prevalence of multimorbidity and its associations with clinical outcomes across age groups. DESIGN: Retrospective cohort study using nationwide medical claims data. SETTING: Carried out in Japan between April 2014 and March 2019. PARTICIPANTS: N=246 671 Japanese individuals aged 20-74 enrolled in the health insurance were included into the baseline data set for fiscal year (FY) 2014. Of those, N=181 959 individuals were included into the cohort data set spanning FY2014-FY2018. EXPOSURES: Multimorbidity was defined as having ≥2 of 15 chronic conditions according to the International Classification of Diseases 10th Revision codes of the Charlson Comorbidity Index. PRIMARY AND SECONDARY OUTCOMES: Primary outcome: the standardised prevalence of multimorbidity across age groups was evaluated using data from FY2014 and extrapolated to the Japanese total population. SECONDARY OUTCOME: hospitalisation or death events were traced by month using medical claims data and insurer enrolment data. Associations between multimorbidity and 5-year hospitalisation and/or death events across age groups were analysed using a Cox regression model. RESULTS: The standardised prevalence rate of multimorbidity in the nationwide Japanese total population was estimated to 26.1%. The prevalence rate with age was increased, approximately 5% (ages 20-29), 10% (30-39), 20% (40-49), 30% (50-59), 50% (60-69) and 60% (70-74). Compared with individuals aged 20-39 without multimorbidity, those with multimorbidity had a higher incidence of clinical events in any age group (HR=2.43 (95% CI 2.30 to 2.56) in ages 20-39, HR=2.55 (95% CI 2.47 to 2.63) in ages 40-59 and HR=3.41 (95% CI 3.23 to 3.53) in ages ≥60). The difference in the incidence of clinical events between multimorbidity and no multimorbidity was larger than that between age groups. CONCLUSIONS: Multimorbidity is already prevalent in the middle-aged generation and is associated with poor clinical outcomes. These findings underscore the significance of multimorbidity and highlight the urgent need for preventive intervention at the public healthcare level.

Surgical and Biochemical Outcomes in Nerve Monitored Reoperation Surgery for Recurrent Papillary Thyroid Carcinoma.

OBJECTIVE: To study the surgical and biochemical outcomes in nerve-monitored reoperation or revision surgery for recurrent thyroid cancers. STUDY DESIGN: A single-center retrospective study. SETTING: Tertiary center. METHODS: We identified patients with recurrent papillary thyroid carcinoma (PTC) who underwent reoperation/revision surgery. Study outcomes were surgical complications frequency, recurrence, distant metastasis, and biological complete response (BCR) by comparing preoperative and postoperative thyroglobulin (Tg) levels. RESULTS: Out of 227 patients, 33.9% presented for ≥2 reoperation surgeries. Nineteen (8.4%) had permanent preoperative hypoparathyroidism while 22 patients (9.7%) had preoperative vocal cord paralysis (VCP). Following reoperation surgery, there were 12 cases (5.3%) of permanent hypocalcemia and no cases of unexpected postoperative VCP. BCR was achieved in 31 patients (35.2%) with complete Tg data. Mean preoperative Tg was 47.7 ng/mL and was 19.7 ng/mL postoperatively (p = .003). The cervical nodal recurrence rate after final surgery was 7.0% (n = 16). CONCLUSION: Reoperation surgery for recurrent PTC may help achieve biochemical remission regardless of age or the number of prior surgeries.

The Usefulness of AirSeal™ Intelligent Flow System in Gas Insufflation Total Endoscopic Thyroidectomy.

Total endoscopic thyroidectomy (TET) using low CO2 insufflation provides cosmetic advantage, excellent working space and visibility. On the contrary, suctioning blood or mist/smoke produced by energy device application causes narrowing of working space especially in neck surgery. In this regard, AirSeal intelligent flow system would be particularly suitable in TET. However, the benefit of AirSeal is unknown in TET unlike abdominal surgery. Therefore, the impact of AirSeal was evaluated in TET in this study. Twenty patients who underwent total endoscopic hemithyroidectomy were retrospectively analyzed. Insufflation was conducted by either conventional or AirSeal system according to the surgeon's preference. Short-term surgical outcomes including operation time, bleeding, frequency of scope cleaning, and disappearance of subcutaneous emphysema were compared as well as actual visibility. AirSeal application dramatically reduced obstacle smoke/mist and prevented narrowing working space by suctioning. Frequency of scope cleaning was significantly less in AirSeal group than that in conventional group (p = 0.016). In patients with nodule < 5 cm, intraoperative hemorrhage was less in AirSeal group than that in the counterpart (p = 0.077) regardless of larger nodule size in AirSeal group (p = 0.058). Notably, subcutaneous emphysema around surgical cavity disappeared significantly earlier in AirSeal group than in the counter parts (p = 0.019). On the contrary, AirSeal application did not shorten operation time in the current study. AirSeal provided excellent visibility and seamless operation. AirSeal has great potential to decrease not only surgeon's stress but surgical invasion on patients. The results in this study give rational to AirSeal application to TET. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-022-03257-0.

Role of Surgery in Patients with Stage IE Primary Thyroid MALT Lymphoma Staged by a Modified Classification System: The Tokyo Classification.

PURPOSES: To establish the appropriate staging system and assess the role of curative thyroidectomy alone (Surgery) vs. involved-site radiation therapy after open biopsy (OB-ISRT) in stage IE mucosa-associated lymphoid tissue (MALT) lymphoma. METHODS: We examined the Tokyo Classification as a modified classification. This retrospective cohort study included 256 patients with thyroid MALT lymphoma; 137 underwent standard therapy (i.e., OB-ISRT) and were enrolled for the Tokyo classification. Sixty stage IE patients with the same diagnosis were examined to compare Surgery with OB-ISRT. RESULTS: Overall survival (p = 0.0092) and relapse-free survival (0.00113) were significantly better in stage IE vs. stage IIE under the Tokyo classification. No OB-ISRT and Surgery patients died, but three OB-ISRT patients relapsed. The incidence of permanent complications was 28% in OB-ISRT (mainly dry mouth) and 0% in Surgery (p = 0.027). The number of painkiller prescription days was significantly greater in OB-ISRT (p < 0.001). During follow-up, the rate of the new appearance/change of the low-density area in the thyroid gland was significantly higher in OB-ISRT (p = 0.031). CONCLUSIONS: The Tokyo classification allows an appropriate discrimination between stages IE and IIE MALT lymphoma. Surgery can provide a good prognosis in stage IE cases; it also avoids complications, shortens painful periods during treatment, and simplifies ultrasound follow-up.

A multicenter evaluation of near-infrared autofluorescence imaging of parathyroid glands in thyroid and parathyroid surgery.

BACKGROUND: The usefulness of incorporating near-infrared autofluorescence into the surgical workflow of endocrine surgeons is unclear. Our aim was to develop a prospective registry and gather expert opinion on appropriate use of this technology. METHODS: This was a prospective multicenter collaborative study of patients undergoing thyroidectomy and parathyroidectomy at 7 academic centers. A questionnaire was disseminated among 24 participating surgeons. RESULTS: Overall, 827 thyroidectomy and parathyroidectomy procedures were entered into registry: 42% of surgeons found near-infrared autofluorescence useful in identifying parathyroid glands before they became apparent; 67% correlated near-infrared autofluorescence pattern to normal and abnormal glands; 38% of surgeons used near-infrared autofluorescence, rather than frozen section, to confirm parathyroid tissue; and 87% and 78% of surgeons reported near-infrared autofluorescence did not improve the success rate after parathyroidectomy or the ability to find ectopic glands, respectively. During thyroidectomy, 66% of surgeons routinely used near-infrared autofluorescence to rule out inadvertent parathyroidectomy. However, only 36% and 45% felt near-infrared autofluorescence decreased inadvertent parathyroidectomy rates and improved ability to preserve parathyroid glands during central neck dissections, respectively. CONCLUSION: This survey study identified areas of greatest potential use for near-infrared autofluorescence, which can form the basis of future objective trials to document the usefulness of this technology.

Impact of Age on Prognosis in Papillary Thyroid Carcinoma: How Should Age be Incorporated into the Treatment Strategy?

BACKGROUND: Age has been recognized as one of the strong prognostic indicators for thyroid cancer. However, treatment strategies for papillary thyroid cancer (PTC) are usually determined only by the extent of disease progression, without considering the patient's age. The aim of this study was to investigate how the surgical strategy for PTC should take into account patient age. METHODS: To exclude the effect of treatment strategy, 837 patients treated with uniform treatment strategies (hemithyroidectomy without radioiodine therapy) between 1986 and 1995 were the subjects of this study. Using a Cox proportional hazard model, clinical risk factors related to disease-specific survival (DSS), disease-free survival (DFS), and distant metastasis-free survival (DMFS) were analyzed. A receiver-operating characteristic (ROC) curve analysis was performed to identify the optimal cutoff points. RESULTS: Significant risk factors related to DSS and DMFS were age, extrathyroidal extension (ETE), and numbers of metastatic lymph nodes (NMLNs), but age was not significantly related to DFS. The 20-year DSS and DMFS rates were fair in patients without ETE regardless of age or NMLNs. However, in patients with ETE, DSS and DMFS rates were significantly worse in elderly patients than in young patients. ROC curve analysis showed that the optimal cutoff age was 48 years for discriminating DSS in patients with ETE. CONCLUSION: Regardless of age, PTC patients without ETE are candidates for a treatment strategy not using RAI, and more aggressive treatment may be recommended for elderly PTC patients with ETE.

[A Survey of Illegal Medication Trading through Twitter in Japan].

Non-medical use of prescription medications is a serious public health crisis. The black market for prescription medications should be routinely surveyed to encourage their appropriate use. Herein, we focused on Twitter to investigate the possibility of illicit drug trading in Japan. From March 1 to 8, 2021, we examined the characteristics of Twitter posts, identified using the search term "Okusuri Mogu Mogu", a Japanese argot used for trading of medications. The captured data included the date of the posts, whether with a hashtag was used, an indication of the trades type (buy, sell, self-administration, and unknown), and the name of the mentioned pharmaceutical products. The number of named medications in the posts was counted and further categorized according to the Anatomical Therapeutic Chemical (ATC) classification. Two hundred and thirty-eight posts were identified with the searching term "Okusuri Mogu Mogu", of which 154 (64.7%) named specific medications. Of note, 73 posts (30.7%) were associated with buying or selling medications. We examined the 73 posts. These posts included 118 medications (26 types), of which 107 (88.4%) were classified as nervous system drugs. Hypnotics and sedatives were the most frequently mentioned medications. The present study sheds light on pharmaceutical medication trading via Twitter. Reinforcing the surveillance practices or cracking down on traders by authorities may be insufficient. We consider the possible effectiveness of socially supportive approaches to help those who lack support to access the appropriate psychiatric care.

Combined thoracoscopic and axillary subcutaneous endoscopic thyroidectomy: a novel approach for cervicomediastinal goiters.

PURPOSE: After our group described the first remote-access thyroidectomy series in 2000, the procedure has been further developed. Although a thoracoscopic approach with a conventional open cervical incision for thyroid goiters with mediastinal extension has been performed at many institutions, remote-access thyroidectomy for cervicomediastinal goiters has not been established. We have performed combined thoracoscopic and axillary subcutaneous endoscopic thyroidectomies (axillo-thoracic endoscopic thyroidectomies). Here, we describe a novel technique for performing a remote-access thyroidectomy for a cervicomediastinal goiter (CMG). PATIENTS AND METHODS: The patients with CMGs who agreed to an axillo-thoracic endoscopic thyroidectomy at one of two hospitals in Japan underwent a remote-access thyroidectomy. RESULTS: We performed the axillo-thoracic endoscopic right or left hemithyroidectomy successfully, but most of the patients did not require the thoracoscopic procedure. None of the patients had complications, and none was converted to an open thyroidectomy. CONCLUSIONS: Most thyroid goiters with substernal extension can be removed by the axillary approach, but some cases require a thoracoscopic approach. The novel approach described herein (axillo-thoracic endoscopic thyroidectomy) enables the safe excision of a CMG with high patient satisfaction for selected patients.

Scoping review of approaches used for remote-access parathyroidectomy: A contemporary review of techniques, tools, pros and cons.

After our coauthors described the first remote-access parathyroidectomy (RAP) series in 2000, several other approaches were developed. No systematic review has been performed to classify and evaluate RAP techniques. We performed a literature search using PubMed and Cochrane Library (CENTRAL). A total of 71 studies met our inclusion/exclusion criteria. RAP can be categorized into five approaches: (1) endoscopic and robotic axillary, (2) anterior chest, (3) transoral, (4) retroauricular, and (5) a combination of these approaches. The limited data in the literature suggest that the cure rates and safety of RAP are in no way inferior to those of open parathyroidectomy. Each approach has its advantages and disadvantages, and the recommendations for the selection of each approach are listed. The selection of approach methods might depend on the surgeon's experience and familiarity and the patient's preference and disease status.

Recurrent Laryngeal Nerve Invasion by Thyroid Cancer: Laryngeal Function and Survival Outcomes.

BACKGROUND: Recurrent laryngeal nerve (RLN) invasion by thyroid carcinoma represents an advanced disease status with potentially significant co-morbidity. METHODS: In a retrospective single-center study, we included patients with invaded RLNs operated on while using nerve monitoring techniques. We studied pre-, intra-, and postoperative parameters associated with postoperative vocal cord paralysis (VCP); 5-year recurrence-free survival (RFS); and 5-year overall survival (OS) in addition to two subgroup analyses of postoperative VCP in patients without preoperative VCP and based on source of RLN invasion. RESULTS: Of 65 patients with 66 nerves-at-risk, 39.3% reported preoperative voice complaints. Preoperative VCP was documented in 43.5%. The RLN was invaded by primary tumor in 59.3% and nodal metastasis in 30.5%. Papillary thyroid carcinoma was the most common pathologic subtype (80%). After 6 months, 81.8% had VCP. Complete tumor resection of the RLN was not associated with 5-year RFS (p = 0.24) or 5-year OS (p = 0.9). Resecting the RLN did not offer statistically significant benefit on 5-year RFS (p = 0.5) or 5-year OS (p = 0.38). Radioactive Iodine (RAI) administration was associated with improvement in 5-year RFS (p = 0.006) and 5-year OS (p = 0.004). Patients without preoperative VCP had higher IONM amplitude compared with patients with VCP. After a mean follow-up of 65.8 months, 35.9% of patients had distant metastases, whereas 36.4% had recurrence. CONCLUSION: Preoperative VCP accompanies less than half of patients with RLN invasion. Invaded RLNs may have existent electrophysiologic stimulability. Complete tumor resection and RLN resection were not associated with better 5-year RFS or OS, but postoperative RAI was. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:2285-2292, 2022.

Remote-access hemithyroidectomy in a patient with papillary thyroid cancer after ipsilateral irradiation: a case report.

Remote-access thyroidectomy (RAT) is becoming a more frequently used approach that can avoid scars in the neck and provide better cosmetic results than open surgery. However, there has been no surgical indication for RAT in patients who have a history of cervical treatment (surgery or irradiation), and the use of RAT has been avoided in such patients. Here, we report a case in which a remote-access endoscopic hemithyroidectomy and central lymph node dissection by the anterior chest approach was successfully performed in a patient with papillary thyroid carcinoma (a 77-year-old Japanese male) after he had undergone ipsilateral cervical radiation therapy to parotid gland cancer (mucoepidermoid carcinoma) thirteen years earlier. Regarding trocar insertion, a 30-mm skin incision was made in the left anterior chest approx. 5 cm below the clavicle. Two 5-mm trocars were inserted through the 30-mm incision. We then insufflated with carbon dioxide to 6 mmHg. One additional 5-mm trocar was placed cephalad to the 30-mm incision. When we performed this RAT, we detected no effect of the prior irradiation. To the best of our knowledge, this is the first report of RAT after irradiation. The cosmetic outcome of RAT is clearly superior, and the present case demonstrates that a RAT can be safely performed in carefully selected patients even after irradiation.

Postal reminder with reduced burden of clinic information seeking for equitable participation in general health check-ups: A randomized controlled trial.

High participation rate and low inequality in participation are key to the program success of general health check-ups in Japan. This study examined the effectiveness of a postal reminder including nearest clinic information, compared to the standard postal reminder including details of all local clinics, on participation rate and income-based participation rate in general health checks. This was a single-blind, two-arm, prospective, randomized controlled study conducted at the Fukuoka Branch of Japan Health Insurance Association. Dependents (family members) of insured persons aged 40-69 years were randomly assigned (1:1) to the intervention group that received a tailored postal reminder intervention (showing information on the nearest clinic from each participant's address) or to the control group that received an original template postal reminder (containing just the URL of the website listing all available clinics). Allocation was concealed from participants and service providers of general health check-up. The primary outcome was participation in general health check-ups within 1 month of intervention. Between February 1 and February 10, 2017, 21,017 were randomly assigned to the intervention (n = 10,474) or control (n = 10,543) group. The participation rate in the intervention group was higher than control group (3.2% vs. 2.1%; OR: 1.55, 95% CI: 1.31-1.85, P < 0.001). The intervention effect was estimated to decrease as the income category increased (P for interaction = 0.037). Tailored postal reminders with information on the nearest clinic were able to improve the overall participation rate and reduce income-based inequality in participation for general health check-ups in Japan. Trial registration: UMIN-CTR, UMIN000042509, Registered 26 November 2020 - Retrospectively registered.

Analysis of triptan use during pregnancy in Japan: A case series.

To evaluate the safety of triptan use during pregnancy in a Japanese population, we descriptively analyzed the data on pregnancy and fetal outcomes from 128 pregnant women using triptans for migraine treatment at two Japanese facilities that provided counseling on drug exposure in pregnancy between 2001 and 2017. The risks of miscarriage, low birth weight, and preterm birth were similar to those reported in the demographic statistics in Japan. The incidence proportion of malformation was also within the baseline risk range. Accumulated data suggest that exposure to triptans during pregnancy does not clearly increase the risk of negative pregnancy and fetal outcomes. This finding can help reduce anxiety in pregnant women with migraines who are taking triptans.

MEK inhibition suppresses metastatic progression of KRAS-mutated gastric cancer.

Metastatic progression of tumors is driven by genetic alterations and tumor-stroma interaction. To elucidate the mechanism underlying the oncogene-induced gastric tumor progression, we have developed an organoid-based model of gastric cancer from GAstric Neoplasia (GAN) mice, which express Wnt1 and the enzymes COX2 and microsomal prostaglandin E synthase 1 in the stomach. Both p53 knockout (GAN-p53KO) organoids and KRASG12V -expressing GAN-p53KO (GAN-KP) organoids were generated by genetic manipulation of GAN mouse-derived tumor (GAN wild-type [WT]) organoids. In contrast with GAN-WT and GAN-p53KO organoids, which manifested Wnt addiction, GAN-KP organoids showed a Wnt-independent phenotype and the ability to proliferate without formation of a Wnt-regulated three-dimensional epithelial architecture. After transplantation in syngeneic mouse stomach, GAN-p53KO cells formed only small tumors, whereas GAN-KP cells gave rise to invasive tumors associated with the development of hypoxia as well as to liver metastasis. Spatial transcriptomics analysis suggested that hypoxia signaling contributes to the metastatic progression of GAN-KP tumors. In particular, such analysis identified a cluster of stromal cells located at the tumor invasive front that expressed genes related to hypoxia signaling, angiogenesis, and cell migration. These cells were also positive for phosphorylated extracellular signal-regulated kinase (ERK), suggesting that mitogen-activated protein kinase (MAPK) signaling promotes development of both tumor and microenvironment. The MEK (MAPK kinase) inhibitor trametinib suppressed the development of GAN-KP gastric tumors, formation of a hypoxic microenvironment, tumor angiogenesis, and liver metastasis. Our findings therefore establish a rationale for application of trametinib to suppress metastatic progression of KRAS-mutated gastric cancer.

Varied Recurrent Laryngeal Nerve Course Is Associated with Increased Risk of Nerve Dysfunction During Thyroidectomy: Results of the Surgical Anatomy of the Recurrent Laryngeal Nerve in Thyroid Surgery Study, an International Multicenter Prospective Anatomic and Electrophysiologic Study of 1000 Monitored Nerves at Risk from the International Neural Monitoring Study Group.

Background: The recurrent laryngeal nerve (RLN) can be injured during thyroid surgery, which can negatively affect a patient's quality of life. The impact of intraoperative anatomic variations of the RLN on nerve injury remains unclear. Objectives of this study were to (1) better understand the detailed surgical anatomic variability of the RLN with a worldwide perspective; (2) establish potential correlates between intraoperative RLN anatomy and electrophysiologic responses; and (3) use the information to minimize complications and assure accurate and safe intraoperative neuromonitoring (IONM). Methods: A large international registry database study with prospectively collected data was conducted through the International Neural Monitoring Study Group (INMSG) evaluating 1000 RLNs at risk during thyroid surgery using a specially designed online data repository. Monitored thyroid surgeries following standardized IONM guidelines were included. Cases with bulky lymphadenopathy, IONM failure, and failed RLN visualization were excluded. Systematic evaluation of the surgical anatomy of the RLN was performed using the International RLN Anatomic Classification System. In cases of loss of signal (LOS), the mechanism of neural injury was identified, and functional evaluation of the vocal cord was performed. Results: A total of 1000 nerves at risk (NARs) were evaluated from 574 patients undergoing thyroid surgery at 17 centers from 12 countries and 5 continents. A higher than expected percentage of nerves followed an abnormal intraoperative trajectory (23%). LOS was identified in 3.5% of NARs, with 34% of LOS nerves following an abnormal intraoperative trajectory. LOS was more likely in cases of abnormal nerve trajectory, fixed splayed or entrapped nerves (including at the ligament of Berry), extensive neural dissection, cases of cancer invasion, or when lateral lymph node dissection was needed. Traction injury was found to be the most common form of RLN injury and to be less recoverable than previous reports. Conclusions: Multicenter international studies enrolling diverse patient populations can help reshape our understanding of surgical anatomy during thyroid surgery. There can be significant variability in the anatomic and intraoperative characteristics of the RLN, which can impact the risk of neural injury.