Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios alone or combined with prostate-specific antigen for the diagnosis of prostate cancer and clinically significant prostate cancer.

Objective: We evaluated whether the blood parameters before prostate biopsy can diagnose prostate cancer (PCa) and clinically significant PCa (Gleason score [GS] ≥7) in our hospital. Methods: This study included patients with increased prostate-specific antigen (PSA) up to 20 ng/mL. The associations of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) alone or with PSA with PCa and clinically significant PCa were analyzed. Results: We included 365 patients, of whom 52.9% (193) had PCa including 66.8% (129) with GS of ≥7. PSA density (PSAD) and PSA had better the area under the curve (AUC) of 0.722 and 0.585, respectively with p=0.001 for detecting PCa compared with other blood parameters. PSA combined with PLR (PsPLR) and PSA with NLR (PsNLR) had better AUC of 0.608 and 0.610, respectively with p<0.05, for diagnosing GS≥7 population, compared with PSA, free/total PSA, NLR, PLR, and PsNPLR (PSA combined with NLR and PLR). NLR and PLR did not predict PCa on multivariate analysis. For GS≥7 cancer detection, in the multivariate analysis, separate models with PSA and NLR (Model 1: PsNLR+baseline parameters) or PSA and PLR (Moder 2: PsPLR+baseline parameters) were made. Baseline parameters comprised age, digital rectal exam-positive lesions, PSA density, free/total PSA, and magnetic resonance imaging. Model 2 containing PsPLR was statistically significant (odds ratio: 2.862, 95% confidence interval: 1.174-6.975, p=0.021) in finding aggressive PCa. The predictive accuracy of Model 2 was increased (AUC: 0.734, p<0.001) than that when only baseline parameters were used (AUC: 0.693, p<0.001). Conclusion: NLR or PLR, either alone or combined with PSA, did not detect PCa. However, the combined use of PSA with PLR could find the differences between clinically significant and insignificant PCa in our retrospective study limited by the small number of samples.

Utility of P-wave abnormalities for distinguishing embolic stroke from non-embolic stroke.

BACKGROUND: Our aim was to analyze the incidence of P-wave abnormalities in embolic and non-embolic strokes, and evaluate its clinical usefulness for predicting stroke etiology. METHODS: We included 376 consecutive patients hospitalized for acute ischemic stroke from January 2015 to September 2021. Among the patients in sinus rhythm at admission, 31 had ischemic stroke due to atrial fibrillation (AF)-related embolism, 59 had embolic stroke of unknown source (ESUS), and 143 had non-embolic stroke. P-wave abnormalities were defined as 1. P-wave axis abnormality (PWAA); 2. P-wave terminal force in V1 (PTFV1) ≤ -4000 µV*ms; 3. advanced inter-atrial block (A-IAB). RESULTS: The prevalence of each type of abnormality was consistently lower in patients with non-embolic stroke than in those with AF-related embolism (AF-related vs. ESUS vs. non-embolic; PWAA, 45% vs. 20% vs. 14%; PTFV1, 36% vs. 37% vs. 15%; and A-IAB, 55% vs. 31% vs. 13%, respectively). The identification of at least one type of P-wave abnormality improved the sensitivity compared to using a single abnormality parameter (sensitivity 72%, specificity 62%), while at least two types of abnormality had low sensitivity, but high specificity (sensitivity 29%, specificity 95%). Multivariate regression analysis revealed that identification of at least one type of P-wave abnormality was independently associated with embolic stroke (odds ratio 3.11, 95%CI 1.46-6.63). CONCLUSIONS: The incidence of each type of P-wave abnormality was significantly lower in patients with non-embolic stroke. A combination of PWAA, PTFV1, and A-IAB parameters could be useful for distinguishing embolic from non-embolic stroke.

Utility of Cognitive Neural Features for Predicting Mental Health Behaviors.

Cognitive dysfunction underlies common mental health behavioral symptoms including depression, anxiety, inattention, and hyperactivity. In this study of 97 healthy adults, we aimed to classify healthy vs. mild-to-moderate self-reported symptoms of each disorder using cognitive neural markers measured with an electroencephalography (EEG). We analyzed source-reconstructed EEG data for event-related spectral perturbations in the theta, alpha, and beta frequency bands in five tasks, a selective attention and response inhibition task, a visuospatial working memory task, a Flanker interference processing task, and an emotion interference task. From the cortical source activation features, we derived augmented features involving co-activations between any two sources. Logistic regression on the augmented feature set, but not the original feature set, predicted the presence of psychiatric symptoms, particularly for anxiety and inattention with >80% sensitivity and specificity. We also computed current flow closeness and betweenness centralities to identify the "hub" source signal predictors. We found that the Flanker interference processing task was the most useful for assessing the connectivity hubs in general, followed by the inhibitory control go-nogo paradigm. Overall, these interpretable machine learning analyses suggest that EEG biomarkers collected on a rapid suite of cognitive assessments may have utility in classifying diverse self-reported mental health symptoms.

A case of complete response following the administration of pembrolizumab and metastasectomy for lung and bone metastases of bladder cancer.

INTRODUCTION: Patients with metastatic urothelial carcinoma have poor prognosis and limited treatment options. CASE PRESENTATION: The patient was a 60-year-old male with bladder cancer and multiple lung metastases. He underwent three courses of gemcitabine and cisplatin chemotherapy, despite left femoral bone metastases. Tumor resection and bone replacement surgery was performed. Following the administration of four courses of pembrolizumab, lung metastasis completely resolved. However, after nine courses, right femoral neck bone metastasis was observed; therefore, tumor resection and bone replacement surgery were repeated. Pathologically, PD-L1 expression was low in lung biopsy tissue and bone metastases. Pembrolizumab treatment continued for up to 20 courses; cancer recurrence and adverse events were not observed upon follow-up examination after 1 year. CONCLUSION: Patients responding well to systemic therapy may have resectable metastatic sites, and long-term survival might be achieved with adjunctive metastasectomy. The effect of pembrolizumab was not associated with positive PD-L1 expression.

Hard bilateral syphilitic testes with vasculitis: a case report and literature review.

BACKGROUND: We report the case of a patient with syphilitic testicular gumma and vasculitis with adrenal failure due to chronic steroid use. CASE PRESENTATION: A 63-year-old male presented with hard right eye swelling and very firm bilateral testes on palpation, which he had for 2 years. Testicular tumor markers were negative; syphilis test was positive. Radiological examination suggested aortitis and bilateral testicular malignancy. The patient received ampicillin for the infection and prednisolone for vasculitis. Left orchidectomy was performed to confirm the presence of testicular tumor; histological examinations revealed granulomatous orchitis. The prednisolone doses were adjusted because of relapses and adverse effects of steroid use. Unfortunately, the patient died in the intensive care unit because of uncontrolled blood pressure and pneumonia. CONCLUSIONS: This is a rare case of syphilis with testicular involvement and vasculitis. This report shows the importance of broadening the differential diagnoses of testicular firmness.

Lung adenocarcinoma diagnosed incidentally after renal biopsy for suspected right renal cancer.

We present a case of lung adenocarcinoma metastasizing to the right clear cell renal cell carcinoma diagnosed by computed tomography (CT)-guided renal biopsy and immunohistochemistry. A 72-year-old male patient had right lower abdominal pain for 3 days, followed by right loin pain for 10 days. On CT scan, renal cell cancer was suspected with multiple metastases. Renal cell cancer with metastatic lung adenocarcinoma was diagnosed on CT-guided renal biopsy with positive immunohistochemical markers. The patient, unfortunately, expired after few days of diagnosis. Tumor-to-tumor metastasis is an unusual disease, and its tumors are aggressive. A definite diagnosis of tumor-to-tumor metastasis is a clinical challenge. Immunohistochemistry helped us in the diagnosis without the primary lesion biopsy.

Achievements and challenges of the Sakigake designation system in Japan.

The Sakigake designation system (Sakigake) has been launched to encourage the pioneered development of innovative new medical products for the effective treatment of severe illness in Japan, which allows leveraging the several advantages in prioritized consultation, rapid review, premium drug pricing and extended data-protection period. We retrospectively analysed the Sakigake products including drugs and regenerative medical products to clarify the achievements and the future issues in this system. From April 2015 to August 2020 (the first 5-year trial period of Sakigake), 37 products were designated, and 10 of those were approved in Japan in which 7 new active substances achieved the first-in-world approvals. Oncology, neurology and cardiovascular disease were the major therapeutic areas, and those 3 accounted for 75.7% of all products. Sakigake achieved some first-in-world approvals by the Pharmaceuticals and Medical Devices Agency/the Ministry of Health, Labor and Welfare of innovative new medical products, although in some therapeutic areas, there remains room in stimulating drug development.

MRI-guided conservative management of a left segmental testicular infarction.

Segmental testicular infarction is a rare condition. Patients present with clinical features similar to torsion and testicular tumors, with most undergoing surgery. A 55-year-old male patient presented with left scrotal pain. We did a Doppler ultrasonogram and magnetic resonance imaging to diagnose his condition and rule out testicular torsion and tumor. We decided not to operate and asked the patient for follow-up. There was no pain in the left testis, and magnetic resonance imaging showed a reduction in the left testicular lesion after 4 months.

Rationales of delay and difference in regulatory review by Japan, the USA and Europe among new drugs first approved in Japan.

AIMS: To clarify the rationales of delay or difference in the review of new drug applications among regulatory authorities for new drugs, those first approved in the world being in Japan. METHODS: Among 80 new drugs first approved in Japan from 2008 to 2019, we identified those subsequently approved in the USA or Europe. Significant delays in approval time (boxplot outliers) and the rationales for the delays were assessed among the Pharmaceuticals and Medical Devices Agency (PMDA), the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). RESULTS: Of the 80 Japan-first approvals, 25 and 24 were approved in the USA and Europe, respectively, and their median approval times in Japan, the USA and Europe were 285, 334 and 477 days, respectively. Significant delays were identified for pirfenidone (1806 days, FDA), alogliptin benzoate (1856 days, FDA), insulin degludec (1457 days, FDA) and romosozumab (750 days, PMDA; 994 days, FDA; 748 days, EMA). Due to concerns about cardiovascular risk, alogliptin benzoate and insulin degludec were requested for additional clinical trials by the FDA, and romosozumab required a much longer review period than the standard approval time in all three regions. CONCLUSIONS: Among the new drugs significantly delayed in approval time in Japan, the USA or Europe, there were some differences in the requirements, the participating regions and the assessment of clinical trials. The regulatory views on the cardiovascular risk also differed among the three regions. These divergences may be associated with the differences in approval histories.

Evolving Landscape of New Drug Approval in Japan and Lags from International Birth Dates: Retrospective Regulatory Analysis.

The Pharmaceuticals and Medical Devices Agency (PMDA) has approved hundreds of new drugs in recent years. We retrospectively analyzed the new drugs approved in Japan from 2008 to 2019, and identify the first-in-world approvals and clarify the current drug lag. The new drug and the drug lag were defined as a drug with a new active substance and a difference between the approval date in Japan and the international birth date, respectively. Among 400 new drugs approved in Japan during the last 12 years, 80 (20.0%) were first approved in Japan, and 320 were outside Japan (the United States: 202, 50.5%; Europe: 82, 20.5%; other regions: 36, 9.0%). Of these, 45 new drugs have not yet been approved outside Japan, and the remaining 355 have been globally approved in Japan and overseas. The number of new drug approvals were the largest in oncology followed by metabolic/endocrine and infectious diseases. The median drug lags (year) among all 400 new drugs and 355 new drugs with global approvals were 4.3 and 4.7 in the first tertile (2008-2011), 1.5 and 2.6 in the second tertile (2012-2015), and reduced to 1.3 and 2.2 in the third tertile (2016-2019), respectively. Substantial drug lag remains in neurology, psychiatry, and therapeutic areas where the number of new drug approvals was relatively small. Collectively, one-fifth of the new drugs approved in Japan are first-in-world approvals. Drug lag has been greatly decreased, although it still exists.

Prostate cancer detection rate and Gleason score in relation to prostate volume as assessed by magnetic resonance imaging cognitive biopsy and standard biopsy.

OBJECTIVE: This study aimed to assess the relationship of the prostate cancer and Gleason scores (GSs) or ISUP Grade system with prostate volume (PV) as assessed by magnetic resonance imaging (MRI) cognitive biopsy and standard biopsy. MATERIAL AND METHODS: Data were collected from 659 patients who underwent MRI cognitive biopsy and standard biopsy from January 2014 to January 2018. The biopsies were performed because of increased prostate-specific antigen (PSA) levels (>4 ng/mL) and/or abnormal digital rectal examination findings. Transrectal ultrasound was used to measure PV. RESULTS: Prostate cancer detection rates in patients with increased PVs of ≤40 cc and >40 cc were 68.8% and 51.6% (p<0.001), respectively. ISUP Grade group ≥2 (Gleason score ≥3+4) detection rates for increased PVs of ≤40 cc and >40 cc were 68% and 73%, and 22.3% and 37.8%, respectively, for those with ISUP Grade group ≥4 (Gleason score ≥8) (p=0.003). Among the patients with PV>40 cc, univariate logistic regression showed a significant relationship between ISUP Grade group ≥2 and PSA, free/total PSA, PSA density, and MRI (p<0.05). On multivariable logistic regression, MRI (p=0.014) and PSA (p=0.039) predicted ISUP Grade group ≥2 in patients with PV>40 cc. CONCLUSION: Although the detection rates of prostate cancer decreased as PV increased, the detection of prostate cancer aggressiveness increased as PV increased. This increase in high ISUP Grade lesions with the rise in PV is due to the use of MRI during prostate biopsy with standard biopsy.

Molecular characterization of a carbon dioxide-dependent Escherichia coli small-colony variant isolated from blood cultures.

A carbon dioxide-dependent small-colony variant of Escherichia coli SH4888 was isolated from blood cultures of a patient with cholangitis. To date, little is known regarding the molecular mechanisms leading to formation of carbon dioxide-dependent phenotypes in clinical isolates, but abnormalities in the carbonic anhydrase are thought to cause carbon dioxide autotrophy. In this study DNA sequence analysis of the carbonic anhydrase-encoding can locus in the carbon dioxide-dependent E. coli SH4888 revealed that the isolate had a 325-bp deletion spanning from the 3'-terminal region of can to the 3'-terminal region of hpt, which encodes a hypoxanthine phosphoribosyltransferase. To confirm that the carbon dioxide-dependent SCV phenotype of E. coli SH4888 was due to the can mutation, we performed a complementation test with a plasmid carrying an intact can that restored the normal phenotype. However, E. coli SH4888 had increased virulence compared to the can-complemented E. coli SH4888 in a murine infection model. In conclusion, these data confirm that impaired carbonic anhydrase function can cause a carbon dioxide-dependent SCV phenotype in E. coli SH4888 and provides a fitness advantage in terms of infection.

Joint attention is intact even when visuospatial working memory is occupied.

The gaze of another modulates and shifts an observer's spatial attention toward this gaze direction. This phenomenon is termed joint attention. Although previous studies found joint attention was induced during a spatial working memory task, it remains an open question whether spatial working memory interferes with joint attention. To address this question, we conducted a dual task paradigm consisting of gaze cuing and spatial working memory tasks. The gaze cuing task requires that participants respond to the location of an abrupt onset of a target while ignoring the gaze of a facial image located at the center of the display. In the spatial working memory task, participants memorized two or three locations of small dots and judged whether these locations changed in the probe screen. In the dual task condition, while participants were maintaining spatial information of the spatial working memory task, they performed the gaze cuing task. In Experiment 1, maintaining spatial information did not impair the magnitude of joint attention. In Experiment 2, we increased load of spatial working memory task, and still observed results similar to Experiment 1. In Experiment 3, we replicated the findings in Experiment 1 when an identification task was conducted. In addition, we measured electrooculographic signals to investigate eye movements of participants during the task. The study provides that joint attention is intact even if spatial working memory is occupied.

In Vivo Roles of Fatty Acid Biosynthesis Enzymes in Biosynthesis of Biotin and α-Lipoic Acid in Corynebacterium glutamicum.

For fatty acid biosynthesis, Corynebacterium glutamicum uses two type I fatty acid synthases (FAS-I), FasA and FasB, in addition to acetyl-coenzyme A (CoA) carboxylase (ACC) consisting of AccBC, AccD1, and AccE. The in vivo roles of the enzymes in supplying precursors for biotin and α-lipoic acid remain unclear. Here, we report genetic evidence demonstrating that the biosynthesis of these cofactors is linked to fatty acid biosynthesis through the FAS-I pathway. For this study, we used wild-type C. glutamicum and its derived biotin vitamer producer BFI-5, which was engineered to express Escherichia coli bioBF and Bacillus subtilis bioI Disruption of either fasA or fasB in strain BFI-5 led to decreased production of biotin vitamers, whereas its amplification contributed to increased production, with a larger impact of fasA in both cases. Double disruptions of fasA and fasB resulted in no biotin vitamer production. The acc genes showed a positive effect on production when amplified simultaneously. Augmented fatty acid biosynthesis was also reflected in pimelic acid production when carbon flow was blocked at the BioF reaction. These results indicate that carbon flow down the FAS-I pathway is destined for channeling into the biotin biosynthesis pathway, and that FasA in particular has a significant impact on precursor supply. In contrast, fasB disruption resulted in auxotrophy for lipoic acid or its precursor octanoic acid in both wild-type and BFI-5 strains. The phenotypes were fully complemented by plasmid-mediated expression of fasB but not fasA These results reveal that FasB plays a specific physiological role in lipoic acid biosynthesis in C. glutamicumIMPORTANCE For the de novo biosynthesis of fatty acids, C. glutamicum exceptionally uses a eukaryotic multifunctional type I fatty acid synthase (FAS-I) system comprising FasA and FasB, in contrast to most bacteria, such as E. coli and B. subtilis, which use an individual nonaggregating type II fatty acid synthase (FAS-II) system. In this study, we reported genetic evidence demonstrating that the FAS-I system is the source of the biotin precursor in vivo in the engineered biotin-prototrophic C. glutamicum strain. This study also uncovered the important physiological role of FasB in lipoic acid biosynthesis. Here, we present an FAS-I enzyme that functions in supplying the lipoic acid precursor, although its biosynthesis has been believed to exclusively depend on FAS-II in organisms. The findings obtained here provide new insights into the metabolic engineering of this industrially important microorganism to produce these compounds effectively.

Synthesis and Alkali-Metal-Ion Complexation of P-Stereogenic Diphosphacrowns.

Phosphine is conformationally stable because of the high inversion energy barrier of the phosphorus atom, which allows the phosphorus atom to become a chiral center. Thus, enantiopure P-stereogenic 12-, 15-, 18-, and 21-membered aliphatic phosphines "diphosphacrowns" were synthesized from secondary P-stereogenic bisphosphine as a chiral building block. Their complexation behaviors with alkali metal ions are investigated in comparison with benzo-18-diphosphacrown-6 and benzo-18-crown-6. 15-, 18-, and 21-Membered diphosphacrowns captured alkali metal ions to form 1:1 metal complexes. Unique guest selectivity was observed, as diphosphacrowns encapsulated smaller alkali metal ions than common crown ethers; for example, 18-membered diphosphacrowns interacted more strongly with Na(+) than K(+). The difference in guest selectivity between diphosphacrowns and common crown ethers is speculated to result from the cavity size, owing to the large phosphorus atom as well as steric hindrance around the phosphine moiety.

Age-dependent factors affecting thoracic response: a finite element study focused on Japanese elderly occupants.

OBJECTIVES: The ultimate goal of this research is to reduce thoracic injuries due to traffic crashes, especially in the elderly. The specific objective is to develop and validate a full-body finite element model under 2 distinct settings that account for factors relevant for thoracic fragility of elderly: one setting representative of an average size male and one representative of an average size Japanese elderly male. METHODS: A new thorax finite element model was developed from medical images of a 71-year-old average Japanese male elderly size (161cm, 60 kg) postmortem human subject (PMHS). The model was validated at component and assembled levels against original series of published test data obtained from the same elderly specimen. The model was completed with extremities and head of a model previously developed. The rib cage and the thoracic flesh materials were assigned age-dependent properties and the model geometry was scaled up to simulate a 50th percentile male. Thereafter, the model was validated against existing biomechanical data for younger and elderly subjects, including hub-to-thorax impacts and frontal impact sled PMHS test data. Finally, a parametric study was conducted with the new models to understand the effect of size and aging factors on thoracic response and risk of rib fractures. RESULTS: The model behaved in agreement with tabletop test experiments in intact, denuded, and eviscerated tissue conditions. In frontal impact sled conditions, the model showed good 3-dimensional head and spine kinematics, as well as rib cage multipoint deflections. When properties representative of an aging person were simulated, both the rib cage deformation and the predicted number of rib fractures increased. The effects of age factors such as rib cortical thickness, mechanical properties, and failure thresholds on the model responses were consistent with the literature. Aged and thereby softened flesh reduced load transfer between ribs; the coupling of the rib cage was reduced. Aged costal cartilage increased the severity of the diagonal belt loading sustained by the lower loaded rib cage. CONCLUSIONS: When age-specific parameters were implemented in a finite element (FE) model of the thorax, the rib cage kinematics and thorax injury risk increased. When the effect of size was isolated, 2 factors, in addition to rib material properties, were found to be important: flesh and costal cartilage properties. These 2 were identified to affect rib cage deformation mechanisms and may potentially increase the risk of rib fractures.

Synthesis of enantiopure P-stereogenic diphosphacrowns using P-stereogenic secondary phosphines.

A new synthetic route to enantiopure P-stereogenic benzodiphosphacrowns using a P-stereogenic secondary bisphosphine as the key building block is reported. Syntheses of the enantiomer and P-stereogenic crowns with various ring structures, as well as deboranation of the crown compounds and subsequent reaction with a platinum complex, are described.

Hydrogen bonding in alcoholic beverages (distilled spirits) and water-ethanol mixtures.

The hydrogen-bonding properties of water-ethanol of alcoholic beverages and water-ethanol mixtures of the corresponding ethanol contents were examined on the basis of OH proton NMR chemical shifts and the Raman OH stretching spectra of water and ethanol. Japanese shochu, an unaged distilled spirit of 25% (v/v) alcoholic content made from various grains, was provided for the samples; it is a high-purity spirit as it contains only small amounts of dissolved components, like typical vodka, gin, and white rum. The hydrogen-bonding structure in shochu containing some acids was found to be different from that of the water-ethanol mixture with corresponding ethanol content. It was concluded that, by the presence of small amounts of organic acids, the water-ethanol hydrogen-bonding structure was strengthened, at the same time, the proton exchange between water and ethanol molecules was promoted in shochu, compared with the water-ethanol mixture. The NMR chemical shifts of fruit cocktail drinks suggested that the hydrogen bonding of water-ethanol in the solution was developed by organic acids and (poly)phenols from fruit juices.