In vitro screening of chemically synthesized dipeptide-antisense oligonucleotide conjugates to identify ligand molecules enhancing their activity.

Oligonucleotide therapeutics, particularly antisense oligonucleotides (ASOs), have emerged as promising candidates in drug discovery. However, their effective delivery to the target tissues and cells remains a challenge, necessitating the development of suitable drug delivery technologies for ASOs to enable their practical application. In this study, we synthesized a library of chemically modified dipeptide-ASO conjugates using a recent synthetic method based on the Ugi reaction. We then conducted in vitro screening of this library using luciferase-expressing cell lines to identify ligands capable of enhancing ASO activity. Our findings suggest that N-(4-nitrophenoxycarbonyl)glycine may interact with the thiophosphate moiety of the phosphorothioate-modification in ASO. Through our screening efforts, we identified two ligands that modestly reduced luciferase luminescence in a cell type-selective manner. Furthermore, quantification of luciferase mRNA levels revealed that one of these promising dipeptide-ASO conjugates markedly suppressed luciferase RNA levels through its antisense effect in prostate-derived DU-145 cells compared to the ASOs without ligand modification.

Association between changes in nutritional status and ability to perform activities of daily living in older patients with heart failure: A stratified analysis by frailty status.

OBJECTIVES: We aimed to determine the association between changes in nutritional status and the activities of daily living (ADL) at discharge, considering frailty status of older patients with heart failure (HF). METHODS: This study included 491 older inpatients with HF categorized into the following groups based on their clinical frailty scale (CFS) scores: low, intermediate, and high. Changes in nutritional status were assessed using the Controlling Nutritional Status score at admission and discharge. The outcome variable was Barthel Index (BI) at discharge. RESULTS: Multivariate logistic regression analysis indicated an association between improvement in nutritional status and high BI at discharge in both the low and intermediate CFS groups (odds ratio [OR], 2.18 [95% confidence interval, 1.04-4.58]), (OR, 2.45 [1.21-4.95]), respectively. CONCLUSIONS: Improvement in the ADL at discharge in older patients with HF was associated with improved nutritional status during hospitalization in the low and intermediate CFS groups.

Relationship between progressive improvement in gait ability one year after discharge and skeletal muscle characteristics of stroke survivors.

BACKGROUND: The clinical importance of skeletal muscle characteristics for improving gait ability of stroke survivors is increasing. We aimed to examine the association between muscle quantity and quality at discharge and changes in gait independence at the time of 1 year after discharge in patients with stroke. METHODS: This prospective observational study included 100 patients with stroke who were admitted to a convalescent rehabilitation ward. We defined muscle quantity and quality operationally as muscle thickness and echo intensity observed in ultrasonography images, respectively, and measured quadriceps muscle on the paretic and non-paretic sides at the time of discharge. The outcome measured in our study was changes in gait independence 1 year after discharge, as assessed by the Functional Independence Measure gait assessment tool score. RESULTS: Among the study participants, 23 (23.0 %) were assessed to have reduced gait independence, while 77 (77.0 %) were evaluated to have improved or maintained gait independence. Our multivariate logistic regression analysis revealed that only muscle quantity on the paretic side was significantly associated with an improvement or maintenance of gait independence (odds ratios 3.32; 95 % confidence interval 1.01-10.95; p = 0.049). CONCLUSIONS: Our findings revealed that an improvement in gait independence 1 year after discharge was influenced by quadriceps muscle quantity on the paretic side at the time of discharge in patients with subacute stroke. This finding highlights the importance of lower limb muscle quantity on the paretic side as a clinically significant factor that influences the improvement in gait ability after hospital discharge.

Prognostic evaluation of the Ki-67 labeling system in histological grading of non-small round cell sarcoma: a supplementary analysis of a randomized controlled trial, JCOG1306.

BACKGROUND: Soft tissue sarcoma (STS) has various histological types and is rare, making it difficult to evaluate the malignancy of each histological type. Thus, comprehensive histological grading is most important in the pathological examination of STS. The Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system is most commonly used in daily pathological analysis of STS. Among the FNCLCC grading system parameters, mitotic count is a key morphological parameter reflecting the proliferative activity of tumor cells, although its reproducibility may be lacking. Here, we compared the prognostic utility of the conventional and modified FNCLCC grading systems in JCOG1306. METHODS: We analyzed 140 patients with non-small round cell sarcoma. We performed Ki-67 immunostaining using open biopsy specimens before preoperative chemotherapy in all patients. We assessed histological grade in individual cases by conventional FNCLCC grading (tumor differentiation, mitotic count, and necrosis) and modified FNCLCC grading using the Ki-67 labeling index instead of mitotic count. We conducted univariable and multivariable Cox regression analyses to investigate the influence of grade on overall survival. RESULTS: In univariable analysis, prognosis was worse for patients with conventional FNCLCC Grade 3 tumors compared with Grade 1 or 2 tumors (hazard ratio [HR] 4.21, 95% confidence interval [CI] 1.47-12.05, P = 0.008). Moreover, prognosis was worse in patients with modified FNCLCC Grade 3 tumors compared with Grade 1 or 2 tumors (HR 4.90, 95% CI 1.64-14.65, P = 0.004). In multivariable analysis including both conventional and modified FNCLCC grading, the modified grading more strongly affected overall survival (HR 6.70, 95% CI 1.58-28.40, P = 0.010). CONCLUSIONS: The modified FNCLCC grading system was superior to the conventional system in predicting the prognosis of patients with non-small round cell sarcoma according to this supplementary analysis of data from the randomized controlled trial JCOG1306.

Protocol digest of a randomized controlled adaptive Phase II/III trial of neoadjuvant chemotherapy for Japanese patients with oesophagogastric junction adenocarcinoma: Japan Clinical Oncology Group Study JCOG2203 (NEO-JPEG).

Treatment strategies for oesophagogastric junction adenocarcinoma have not been standardized despite its poor prognosis due to differences in the incidence rates between Western countries and Asia. This randomized Phase II/III trial was initiated in June 2023 to determine which neoadjuvant chemotherapy regimen, docetaxel, oxaliplatin and S-1 or fluorouracil, oxaliplatin and docetaxel, is a more promising treatment in Phase II and confirm the superiority of neoadjuvant chemotherapy with docetaxel, oxaliplatin and S-1 or fluorouracil, oxaliplatin and docetaxel followed by surgery and postoperative chemotherapy over upfront surgery and postoperative chemotherapy in terms of overall survival in patients with Clinical Stage III or IVA oesophagogastric junction adenocarcinoma in Phase III. A total of 460 patients, including 150 patients in Phase II and 310 patients in Phase III, are planned to be enrolled from 85 hospitals in Japan over 5 years. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031230182 (https://jrct.niph.go.jp/latest-detail/jRCTs031230182).

Lymph node dissection in small peripheral lung cancer: Supplemental analysis of JCOG0802/WJOG4607L.

OBJECTIVE: The optimal region of lymph node dissection (LND) during segmentectomy in patients with small peripheral non-small cell lung cancer requires clarification. Through a supplemental analysis of the Japan Clinical Oncology Group (JCOG) 0802/West Japan Oncology Group (WJOG) 4607L, we investigated the associated factors, distribution, and recurrence pattern of lymph node metastases (LNMs) and proposed the optimal LND region. METHODS: Of the 1106 patients included in the JCOG0802/WJOG4607L, 1056 patients with LNDs were included in this supplemental analysis. We investigated the distribution and recurrence pattern of LNMs along with the radiologic findings (with ground-glass opacity, part-solid tumor; without ground-grass opacity component, pure-solid tumor). RESULTS: The radiologic findings were the only significant factor for LNMs. Of 533 patients with part-solid tumors, 8 (1.5%) had LNMs. Further, only 3 (0.5%) patients had pN2 disease, and no patients had interlobar LNMs from nonadjacent segments. Of the 523 patients with pure-solid tumors, 55 (10.5%) had LNMs, and 28 (5.4%) had pN2 disease. Five patients had metastases to nonadjacent interlobar lymph nodes (LNs). Two (2.0%) patients with S6 tumors had upper mediastinal LNMs. In addition, the incidence of mediastinal LN recurrence in patients with S6 lung cancer was greater in those who underwent selective LND than those who underwent systematic LND (P = .0455). CONCLUSIONS: Nonadjacent interlobar and mediastinal LND have little impact on pathologic nodal staging in patients with part-solid tumors. In contrast, selective LND is recommended at least for patients with pure-solid tumors.

Tretinoin Enhances the Effects of Chemotherapy in Juvenile Myelomonocytic Leukemia Using an Ex Vivo Drug Sensitivity Assay.

PURPOSE: Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric malignancy with myelodysplastic and myeloproliferative features. Curative treatment is restricted to hematopoietic stem-cell transplantation. Fludarabine combined with cytarabine (FLA) and 5-azacitidine (AZA) monotherapy are commonly used pre-transplant therapies. Here, we present a drug screening strategy using a flow cytometry-based precision medicine platform to identify potential additional therapeutic vulnerabilities. METHODS: We screened 120 dual- and 10 triple-drug combinations (DCs) on peripheral blood (n = 21) or bone marrow (n = 6) samples from 27 children with JMML to identify DCs more effectively reducing leukemic cells than the DCs' components on their own. If fewer leukemic cells survived a DC ex vivo treatment compared with that DC's most effective component alone, the drug effect was referred to as cooperative. The difference between the two resistant fractions is the effect size. RESULTS: We identified 26 dual- and one triple-DC more effective than their components. The differentiation agent tretinoin (TRET; all-trans retinoic acid) reduced the resistant fraction of FLA in 19/21 (90%) samples (decrease from 15% [2%-61%] to 11% [2%-50%] with a mean effect size of 3.8% [0.5%-11%]), and of AZA in 19/25 (76%) samples (decrease from 69% [34%-100+%] to 47% [17%-83%] with a mean effect size of 16% [0.3%-40%]). Among the resistant fractions, the mean proportion of CD38+ cells increased from 7% (0.03%-25%; FLA) to 17% (0.3%-38%; FLA + TRET) or from 10% (0.2%-31%; AZA) to 51% (0.8%-88%; AZA + TRET). CONCLUSION: TRET enhanced the effects of FLA and AZA in ex vivo assays with primary JMML samples.

Randomized controlled phase III trial to investigate superiority of robot-assisted gastrectomy over laparoscopic gastrectomy for clinical stage T1-4aN0-3 gastric cancer patients (JCOG1907, MONA LISA study): a study protocol.

BACKGROUND: Laparoscopic gastrectomy (LG) is considered a standard treatment for clinical stage I gastric cancer. Nevertheless, LG has some drawbacks, such as motion restriction and difficulties in spatial perception. Robot-assisted gastrectomy (RG) overcomes these drawbacks by using articulated forceps, tremor-filtering capability, and high-resolution three-dimensional imaging, and it is expected to enable more precise and safer procedures than LG for gastric cancer. However, robust evidence based on a large-scale randomized study is lacking. METHODS: We are performing a randomized controlled phase III study to investigate the superiority of RG over LG for clinical T1-2N0-2 gastric cancer in terms of safety. In total, 1,040 patients are planned to be enrolled from 46 Japanese institutions over 5 years. The primary endpoint is the incidence of postoperative intra-abdominal infectious complications, including anastomotic leakage, pancreatic fistula, and intra-abdominal abscess of Clavien-Dindo (CD) grade ≥ II. The secondary endpoints are the incidence of all CD grade ≥ II and ≥ IIIA postoperative complications, the incidence of CD grade ≥ IIIA postoperative intra-abdominal infectious complications, relapse-free survival, overall survival, the proportion of RG completion, the proportion of LG completion, the proportion of conversion to open surgery, the proportion of operation-related death, and short-term surgical outcomes. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in January 2020. Approval from the institutional review board was obtained before starting patient enrollment in each institution. Patient enrollment began in March 2020. We revised the protocol to expand the eligibility criteria to T1-4aN0-3 in July 2022 based on the results of randomized trials of LG demonstrating non-inferiority of LG to open surgery for survival outcomes in advanced gastric cancer. DISCUSSION: This is the first multicenter randomized controlled trial to confirm the superiority of RG over LG in terms of safety. This study will demonstrate whether RG is superior for gastric cancer. TRIAL REGISTRATION: The protocol of JCOG1907 was registered in the UMIN Clinical Trials Registry as UMIN000039825 ( http://www.umin.ac.jp/ctr/index.htm ). Date of Registration: March 16, 2020. Date of First Participant Enrollment: April 1, 2020.

Randomized phase II study comparing neoadjuvant 5-fluorouracil/oxaliplatin/docetaxel versus docetaxel/oxaliplatin/S-1 for patients with type 4 or large type 3 gastric cancer.

Macroscopic type 4 and large type 3 gastric cancer, mostly overlapping with scirrhous or linitis plastica type, exhibit a highly invasive nature and show unfavorable prognosis after curative surgery, even with adjuvant chemotherapy. A randomized phase III trial (JCOG0501) failed to demonstrate a survival advantage of neoadjuvant chemotherapy with S-1 plus cisplatin for this population. The current authors initiated a randomized phase II study comparing neoadjuvant chemotherapy with 5-fluorouracil/oxaliplatin/docetaxel versus docetaxel/oxaliplatin/S-1 for type 4 and large type 3 gastric cancer. 76 patients are planned to be enrolled over two years. The primary end point is the proportion of patients with a pathological response (grade 1b or higher) and secondary end points include overall survival and adverse events. Clinical Trial Registration: jRCTs031230231 (rctportal.niph.go.jp).

Impact of intravenous injection of glucagon on anastomotic leakage in esophagectomy.

Background: Anastomotic leakage after esophagectomy affects the early postoperative state and prognosis. However, effective measures to prevent anastomotic leakage in esophagogastric anastomosis have not been established. Methods: This single-center, retrospective, observational study included 147 patients who underwent esophagectomy for esophageal cancer between 2010 and 2020. Glucagon was administered to extend the gastric tube in patients who underwent esophagectomy from January 2016. The patients were divided into two groups: a glucagon-treated group (2016-2020) and a control group (2010-2015). The incidence of anastomotic leakage was compared between the two groups for evaluation of the preventive effects of glucagon administration on anastomotic leakage. Results: The length of the gastric tube from the pyloric ring to the final branch of the right gastroepiploic artery was extended by 2.8 cm after glucagon injection. The incidence of anastomotic leakage was significantly lower in the glucagon-treated group (19% vs. 38%; p = 0.014). Multivariate analysis showed that glucagon injection was the only independent factor associated with a reduction in anastomotic leakage (odds ratio, 0.26; 95% confidence interval, 0.07-0.87). Esophagogastric anastomosis was performed proximal to the final branch of the right gastroepiploic artery in 37% patients in the glucagon-treated group, and these cases showed a lower incidence of anastomotic leakage than did those with anastomosis distal to the final branch of the right gastroepiploic artery (10% vs. 25%, p = 0.087). Conclusions: Extension of the gastric tube by intravenous glucagon administration during gastric mobilization in esophagectomy for esophageal cancer may be effective in preventing anastomotic leakage.

Is Palliative Gastrojejunostomy for Malignant Gastric Outlet Obstruction an Optimal Choice for Very Elderly Patients? A Report from a Long-Lived Country.

BACKGROUND: Gastrojejunostomy (GJ) is a surgical option for malignant gastric outlet obstruction (mGOO). Confronting an aging society, the demand to treat elderly cancer patients with unresectable malignancies is increasing; however, the benefit of GJ to the very elderly (≥ 80 years of age) has never been investigated. METHODS: This multicenter, retrospective review included 108 patients who had undergone GJ for mGOO from two medical centers in Japan, one of the most long-lived countries. Patients were divided into two groups, with 80 years of age as the cut-off. Various factors, including surgical complications and patient survival, were compared. RESULTS: GJ in the very elderly (aged ≥ 80 years) was associated with a higher incidence of surgical complications (p = 0.049), such as delayed gastric emptying (DGE; p < 0.001), aspiration pneumonia (p = 0.029), and consequent mortality (p = 0.016). Age ≥80 years was also identified as an independent predictor of DGE (odds ratio 6.444, p = 0.005) and survival after GJ (hazard ratio 7.767, p = 0.016). In particular, the median survival time after GJ in the population aged ≥80 years with gastric cancer was only < 2 months. About the surgical procedure, antiperistaltic anastomosis with partial stomach partitioning (PSP) yielded the lowest occurrence rate of DGE (3.4%) and aspiration pneumonia (1.7%). CONCLUSIONS: GJ does not seem to be the optimal choice for very elderly patients, particularly those with gastric cancer. If performed, antiperistaltic anastomosis with PSP should be employed to reduce the surgical complications.

Ex Vivo Drug Sensitivity Correlates with Clinical Response and Supports Personalized Therapy in Pediatric AML.

Acute myeloid leukemia (AML) is a heterogeneous disease that accounts for ~20% of all childhood leukemias, and more than 40% of children with AML relapse within three years of diagnosis. Although recent efforts have focused on developing a precise medicine-based approach towards treating AML in adults, there remains a critical gap in therapies designed specifically for children. Here, we present ex vivo drug sensitivity profiles for children with de novo AML using an automated flow cytometry platform. Fresh diagnostic blood or bone marrow aspirate samples were screened for sensitivity in response to 78 dose conditions by measuring the reduction in leukemic blasts relative to the control. In pediatric patients treated with conventional chemotherapy, comprising cytarabine, daunorubicin and etoposide (ADE), ex vivo drug sensitivity results correlated with minimal residual disease (r = 0.63) and one year relapse-free survival (r = 0.70; AUROC = 0.94). In the de novo ADE analysis cohort of 13 patients, AML cells showed greater sensitivity to bortezomib/panobinostat compared with ADE, and comparable sensitivity between venetoclax/azacitidine and ADE ex vivo. Two patients showed a differential response between ADE and bortezomib/panobinostat, thus supporting the incorporation of ex vivo drug sensitivity testing in clinical trials to further evaluate the predictive utility of this platform in children with AML.

Intracorporeal reinforcing sutures reduce anastomotic leakage in double-stapling anastomosis for laparoscopic rectal surgery.

Introduction: In rectal surgery, double-stapled anastomosis is one of the most common techniques. However, the crossing of the staple line is considered a weakness of this method and could lead to anastomotic leakage (AL), which is one of the major complications of rectal cancer surgery. Aim: To investigate the usefulness of laparoscopic intracorporeal reinforcement suturing for preventing AL in laparoscopic rectal surgery. Material and methods: A total of 153 patients with rectal cancer underwent laparoscopic rectal resection with anastomosis using the double-stapling technique between January 2015 and December 2018. Patient characteristics, surgical data, and outcomes were recorded and retrospectively analysed. Patients who received intracorporeal reinforcing sutures (n = 72) were compared with those who did not receive the reinforcing sutures (n = 81). Results: AL was observed in 11 (7.2%) cases overall and in only 1 case in the group with intracorporeal reinforcing sutures. There were no associations between clinicopathological factors and the use of reinforcing sutures. Multivariate analysis revealed that a distance from the anal verge of less than 6.5 cm, diabetes mellitus, and the non-use of reinforcing sutures were independent risk factors for AL. Conclusions: Laparoscopic intracorporeal reinforcing sutures reduced the incidence of AL. Therefore, laparoscopic reinforcing sutures for double-stapled anastomoses seem useful for the prevention of AL.

Indocyanine green plasma clearance rate and 99mTc-galactosyl human serum albumin single-photon emission computed tomography evaluated preoperative remnant liver.

BACKGROUND: Preoperative evaluation of future remnant liver reserves is important for safe hepatectomy. If the remnant is small, preoperative portal vein embolization (PVE) is useful. Liver volume analysis has been the primary method of preoperative evaluation, although functional examination may be more accurate. We have used the functional evaluation liver using the indocyanine green plasma clearance rate (KICG) and 99mTc-galactosyl human serum albumin single-photon emission computed tomography (99mTc-GSA SPECT) for safe hepatectomy. AIM: To analyze the safety of our institution's system for evaluating the remnant liver reserve. METHODS: We retrospectively reviewed the records of 23 patients who underwent preoperative PVE. Two types of remnant liver KICG were defined as follows: Anatomical volume remnant KICG (a-rem-KICG), determined as the remnant liver anatomical volume rate × KICG; and functional volume remnant KICG (f-rem-KICG), determined as the remnant liver functional volume rate based on 99mTc-GSA SPECT × KICG. If either of the remnant liver KICGs were > 0.05, a hepatectomy was performed. Perioperative factors were analyzed. We defined the marginal group as patients with a-rem-KICG of < 0.05 and a f-rem-KICG of > 0.05 and compared the postoperative outcomes between the marginal and not marginal (both a-rem-KICG and f-rem-KICG > 0.05) groups. RESULTS: All 23 patients underwent planned hepatectomies. Right hepatectomy, right trisectionectomy and left trisectionectomy were in 16, 6 and 1 cases, respectively. The mean of blood loss and operative time were 576 mL and 474 min, respectively. The increased amount of f-rem-KICG was significantly larger than that of a-rem-KICG after PVE (0.034 vs 0.012, P = 0.0273). The not marginal and marginal groups had 17 (73.9%) and 6 (26.1%) patients, respectively. The complications of Clavian-Dindo classification grade II or higher and post-hepatectomy liver failure were observed in six (26.1%) and one (grade A, 4.3%) patient, respectively. The 90-d mortality was zero. The marginal group had no significant difference in postoperative outcomes (prothrombin time/international normalised ratio, total bilirubin, complication, post-hepatectomy liver failure, hospital stay, 90-d, and mortality) compared with the not-marginal group. CONCLUSION: Functional evaluation of the remnant liver enabled safe hepatectomy and may extend the indication for hepatectomy after PVE treatment.

Three Cases of Boerhaave's Syndrome Treated via Laparoscopic Transhiatal Esophageal Repair.

Spontaneous esophageal perforation in Boerhaave's syndrome results in significant morbidity and mortality. The gold standard treatment for this disease is thoracotomy and laparotomy because it can be a life-saving procedure that can be performed in emergencies; however, minimally invasive surgery has recently been reported. This report describes three cases of Boerhaave's syndrome that were treated using laparoscopic transhiatal suture and omental patch. One patient recovered uneventfully and was discharged from the hospital after 12 days. The other 2 patients had postoperative complications, such as minor leakage and remnant abscess (Clavien-Dindo Grade II), but were discharged from the hospital after 17 days and 30 days, respectively. In the case of Boerhaave's syndrome with localized mediastinal collections, a good clinical course can be obtained by laparoscopic transhiatal esophageal repair to avoid surgical invasion due to thoracotomy.

Conjugation of oligonucleotides with activated carbamate reagents prepared by the Ugi reaction for oligonucleotide library synthesis.

The DNA-encoded library (DEL) is a powerful tool for drug discovery. As a result, to obtain diverse DELs, many DNA-compatible chemical reactions have been developed over the past decade. Among the most commonly used reactions in medicinal chemistry, multicomponent reactions (MCRs) can lead to the generation of various compounds in a one-step reaction. In particular, the Ugi reaction can easily provide a peptoid library. Thus, we herein report a solution-phase DEL synthesis based on the Ugi reaction. Using 6-(4-nitrophenoxycarbonylamino)hexanoic acid and N-4-nitrophenoxycarbonylglycine as carboxylic acids, peptoids with activated carbamate moieties were obtained as the products of the Ugi reaction. These peptoids were then treated with oligonucleotides bearing a 5'- or 3'-terminal aminohexyl linker to give various oligonucleotide-tagged peptoids in good yields. Moreover, the obtained peptoids could be substituted by a Suzuki cross-coupling reaction and by hydrolysis of the carboxylate ester, followed by condensation with amines. These advances should therefore promote pharmaceutical and medicinal research using DELs.

A Polygenic Score for Type 2 Diabetes Improves Risk Stratification Beyond Current Clinical Screening Factors in an Ancestrally Diverse Sample.

A substantial proportion of the adult United States population with type 2 diabetes (T2D) are undiagnosed, calling into question the comprehensiveness of current screening practices, which primarily rely on age, family history, and body mass index (BMI). We hypothesized that a polygenic score (PGS) may serve as a complementary tool to identify high-risk individuals. The T2D polygenic score maintained predictive utility after adjusting for family history and combining genetics with family history led to even more improved disease risk prediction. We observed that the PGS was meaningfully related to age of onset with implications for screening practices: there was a linear and statistically significant relationship between the PGS and T2D onset (-1.3 years per standard deviation of the PGS). Evaluation of U.S. Preventive Task Force and a simplified version of American Diabetes Association screening guidelines showed that addition of a screening criterion for those above the 90th percentile of the PGS provided a small increase the sensitivity of the screening algorithm. Among T2D-negative individuals, the T2D PGS was associated with prediabetes, where each standard deviation increase of the PGS was associated with a 23% increase in the odds of prediabetes diagnosis. Additionally, each standard deviation increase in the PGS corresponded to a 43% increase in the odds of incident T2D at one-year follow-up. Using complications and forms of clinical intervention (i.e., lifestyle modification, metformin treatment, or insulin treatment) as proxies for advanced illness we also found statistically significant associations between the T2D PGS and insulin treatment and diabetic neuropathy. Importantly, we were able to replicate many findings in a Hispanic/Latino cohort from our database, highlighting the value of the T2D PGS as a clinical tool for individuals with ancestry other than European. In this group, the T2D PGS provided additional disease risk information beyond that offered by traditional screening methodologies. The T2D PGS also had predictive value for the age of onset and for prediabetes among T2D-negative Hispanic/Latino participants. These findings strengthen the notion that a T2D PGS could play a role in the clinical setting across multiple ancestries, potentially improving T2D screening practices, risk stratification, and disease management.

The Association between the Oral-Gut Axis and the Outcomes of Severe COVID-19 Patients Receiving Extracorporeal Membrane Oxygenation: A Case-Control Study.

The novel conceptual disease model, the oral-gut axis, which represents the immunomodulatory mutual relationship between oral and gut microbial compartments, has been attracting attention in relation to systemic health issues. We investigated whether this unique crosstalk influences the systemic condition of patients with COVID-19 infections who received extracorporeal membrane oxygenation (ECMO) in the intensive care unit (ICU) during April and December 2020. In this case-control study, patients were divided into two groups according to their survival (total entry size, n = 21; survivors, n = 13; non-survivors, n = 8). Patients were evaluated using the oral assessment guide from Fukuoka University (OAG-F) and the Bristol Stool Form Scale (BSFS) to examine the oral and fecal conditions. A blood-based inflammatory factor, the neutrophil-to-lymphocyte ratio (NLR), was used as an indicator of systemic immunity. The high total OAG-F scores were associated with both elevated BSFS and NLR values, and a mutually positive correlation between BSFS and NLR was observed. This indicated an interplay between oral deterioration, gut dysbiosis, and the impairment of immunity. Furthermore, oral deterioration was more frequently observed in non-survivors on day 14 of ICU admission. In addition, on days 7 and 21 of ICU admission, impaired immunity, reflected by an elevated NLR, was observed in non-survivors. However, the distribution of the gut microbiome-reflected by increased BSFS values-with the time it was examined was not directly observed in non-survivors. Taken together, these findings suggested that oral-gut health may be specifically associated with mortality in COVID-19 patients receiving ECMO in the ICU.