Assessing parosmia patients: a study on the evaluation method using a self-administered odor questionnaire for parosmia.

BACKGROUND: Parosmia symptoms are difficult to quantify due to their heterogeneity among patients, and thus a clinical challenge. This study aimed to assess parosmia with Self-Administered Odor Questionnaire for Parosmia (SAOQ-P), a modification of the widely used SAOQ in Japan. The primary objective was to assess the effectiveness of SAOQ-P in identifying parosmia symptoms and its potential integration into the clinical assessment process. The study also explored traditional olfactory test differences between patients with and without parosmia. METHODS: Patients at Jikei Smell Clinic that presented between May 2022 and November 2022 were recruited and administered the SAOQ-P, which had an added question about changes in the perception of 20 daily odors compared to the original SAOQ. Traditional olfactory tests utilized T&T olfactometry and Open Essence. RESULTS: Of 279 patients, 81 had parosmia, while 198 did not exhibit parosmic symptoms. Parosmia prevalence was influenced by the cause of olfactory dysfunction, with post-infectious and post-COVID-19 patients showing higher parosmia rates. Among parosmia patients, 87% reported changes in their perception of at least one odor assessed by SAOQ-P, with coffee, stool, and perfume most commonly affected. Traditional olfactory tests showed no significant differences between parosmia and non-parosmia groups. The number of odors causing parosmia was negatively correlated with age. CONCLUSION: SAOQ-P offers a promising approach to assess and quantify parosmia symptoms, seamlessly integrating into clinical assessments. SAOQ-P identified parosmia in 87% of patients and revealed insights into triggering factors. Traditional olfactory tests' limitations underscore the need for more accurate, patient-centric diagnostic approaches for parosmia.

Genetic variation across the human olfactory receptor repertoire alters odor perception.

Humans use a family of more than 400 olfactory receptors (ORs) to detect odors, but there is currently no model that can predict olfactory perception from receptor activity patterns. Genetic variation in human ORs is abundant and alters receptor function, allowing us to examine the relationship between receptor function and perception. We sequenced the OR repertoire in 332 individuals and examined how genetic variation affected 276 olfactory phenotypes, including the perceived intensity and pleasantness of 68 odorants at two concentrations, detection thresholds of three odorants, and general olfactory acuity. Genetic variation in a single OR was frequently associated with changes in odorant perception, and we validated 10 cases in which in vitro OR function correlated with in vivo odorant perception using a functional assay. In 8 of these 10 cases, reduced receptor function was associated with reduced intensity perception. In addition, we used participant genotypes to quantify genetic ancestry and found that, in combination with single OR genotype, age, and gender, we can explain between 10% and 20% of the perceptual variation in 15 olfactory phenotypes, highlighting the importance of single OR genotype, ancestry, and demographic factors in the variation of olfactory perception.

Physiological exercise loading suppresses post-traumatic osteoarthritis progression via an increase in bone morphogenetic proteins expression in an experimental rat knee model.

OBJECTIVE: To evaluate the dose-response relationship of exercise loading in the cartilage-subchondral bone (SB) unit in surgically-induced post-traumatic osteoarthritis (PTOA) of the knee. DESIGN: Destabilized medial meniscus (DMM) surgery was performed on the right knee of 12-week-old male Wistar rats, and sham surgery was performed on the contralateral knee. Four weeks after the surgery, the animals were subjected to moderate (12 m/min) or intense (21 m/min) treadmill exercises for 30 min/day, 5 days/week for 4 weeks. PTOA development in articular cartilage and SB was examined using histological and immunohistochemical analyses, micro-computed tomography (micro-CT) analysis, and biomechanical testing at 8 weeks after surgery. Gremlin-1 was injected to determine the role of bone morphogenetic protein (BMP) signaling on PTOA development following moderate exercise. RESULTS: Moderate exercise increased BMP-2, BMP-4, BMP-6, BMP receptor 2, pSmad-5, and inhibitor of DNA binding protein-1 expression in the superficial zone chondrocytes and suppressed cartilage degeneration, osteophyte growth, SB damage, and osteoclast-mediated SB resorption. However, intense exercise had little effect on BMP expression and even caused progression of these osteoarthritis (OA) changes. Gremlin-1 injection following moderate exercise caused progression of the PTOA development down to the level of the non-exercise DMM-operated knee. CONCLUSIONS: Exercise regulated cartilage-SB PTOA development in DMM-operated knees in a dose-dependent manner. Our findings shed light on the important role of BMP expression in superficial zone chondrocytes in attenuation of PTOA development following physiological exercise loading. Further studies to support a mechanism by which BMPs would be beneficial in preventing PTOA progression are warranted.

Liver transection using indocyanine green fluorescence imaging and hepatic vein clamping.

BACKGROUND: Three-dimensional (3D) imaging has facilitated liver resection with excision of hepatic veins by estimating the liver volume of portal and hepatic venous territories. However, 3D imaging cannot be used for real-time navigation to determine the liver transection line. This study assessed the value of indocyanine green (ICG) fluorescence imaging with hepatic vein clamping for navigation during liver transection. METHODS: Consecutive patients who underwent liver resection with excision of major hepatic veins between 2012 and 2013 were evaluated using ICG fluorescence imaging after clamping veins and injecting ICG. Regional fluorescence intensity (FI) values of non-veno-occlusive regions (FINon ), veno-occlusive regions (FIVO ) and ischaemic regions (FIIS ) were calculated using luminance analysing software. RESULTS: Of the 21 patients, ten, four and seven underwent limited resection, monosegmentectomy/sectionectomy and hemihepatectomy respectively, with excision of major hepatic veins. Median veno-occlusive liver volume was 80 (range 30-458) ml. Fluorescence imaging visualized veno-occlusive regions as territories with lower FI compared with non-veno-occlusive regions, and ischaemic regions as territories with no fluorescence after intravenous ICG injection. Median FIIS /FINon was lower than median FIVO /FINon (0·22 versus 0·59; P = 0·002). There were no deaths in hospital or within 30 days, and only one major complication. CONCLUSION: ICG fluorescence imaging with hepatic vein clamping visualized non-veno-occlusive, veno-occlusive and ischaemic regions. This technique may guide liver transection by intraoperative navigation, enhancing the safety and accuracy of liver resection.

Subchondral plate porosity colocalizes with the point of mechanical load during ambulation in a rat knee model of post-traumatic osteoarthritis.

OBJECTIVE: This study investigated the association between spatiotemporal cartilage-subchondral bone plate alterations and mechanical load during ambulation in an experimental rat model of destabilized medial meniscus (DMM). DESIGN: Twelve-week-old Wistar rats (n = 38) underwent DMM surgery on the right knee and sham surgery on the left knee. At 2 and 4 weeks after surgery, subchondral bone changes were evaluated via micro-computed tomography with various knee flexion angles to simulate weight-bearing during rat ambulation under a 3-dimensional motion capture apparatus. Additionally, the biomechanical properties, histology, and ultrastructure of the medial tibia and femoral condyle were evaluated. RESULTS: Focal subchondral bone plate perforations were confirmed in the medial tibia within 2 weeks after surgery and were aggravated rapidly 2 weeks later. This subchondral plate porosity colocalized with articular cartilage lesions as confirmed by histology and scanning electron microscopy, and coincided with the likely point of contact between the posterior femoral condyle and tibial plateau during ambulation. Biomechanical properties were confirmed at the medial tibia, at which stiffness was reduced to approximately half that of the sham-operated knee at 4 weeks after surgery. CONCLUSIONS: Cartilage-subchondral bone plate alterations localized in the region of the point of mechanical load during ambulation in DMM-operated knees, at which the mechanical integrity of cartilage was impaired. These results indicate that DMM-induced increases in mechanical load play an important role in the pathogenesis of early post-traumatic osteoarthritis (OA), and it might accelerate the development of the disease via cartilage-subchondral bone plate crosstalk through increased subchondral plate perforations.

Exercise intervention increases expression of bone morphogenetic proteins and prevents the progression of cartilage-subchondral bone lesions in a post-traumatic rat knee model.

OBJECTIVE: This study aimed to determine whether treadmill walking (TW) prevents the progression of post-traumatic osteoarthritic changes in cartilage-subchondral bone unit, and whether the exercise timing changes the exercise efficacy in destabilized medial meniscus (DMM) rat knees. DESIGN: Twelve-week-old male Wistar rats underwent DMM surgery on their right knees and sham surgery on their left knees and were assigned to either the sedentary (n = 10) or walking (n = 24) groups. The rats in the walking group were subjected to TW from day 2 through 4 weeks, from 4 through 8 weeks, or from day 2 through 8 weeks (n = 8 per group). Osteoarthritic changes of cartilage and subchondral bone were assessed with micro-computed tomography, histology, and immunohistochemistry 8 weeks after surgery. RESULTS: TW prevented the progression of cartilage and subchondral bone lesions induced by the DMM, and increased bone morphogenetic protein (BMP)-2 and -6 expressions in superficial zone chondrocytes and bone-lining cells including osteoblasts. Furthermore, the TW-induced increase in BMPs varied with the exercise timing. Beginning TW 4 weeks after DMM surgery was the best option for increasing BMPs, coinciding with the most robust prevention of osteoarthritic changes. CONCLUSIONS: TW increased the expression of BMPs and prevented the progression of cartilage-subchondral bone lesions in rat knees with a DMM. Selective exercise timing may be a key factor in the development of an exercise regimen for preventing the progression of post-traumatic osteoarthritis (PTOA). Furthermore, exercise may have favorable effects even after the PTOA has been developed.

Serum levels of the soluble haemoglobin scavenger receptor CD163 in MPO-ANCA-associated renal vasculitis.

OBJECTIVES: The contribution of infections to the mortality of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is important, and early and careful infection control is necessary. We investigated the usefulness of the serum-soluble haemoglobin scavenger receptor CD163 for detecting the presence of infectious complications regardless of disease activity. METHOD: Soluble CD163 in serum obtained from 45 Japanese patients with myeloperoxidase (MPO)-AAV was measured by an enzyme-linked immunosorbent assay (ELISA). We evaluated 36 samples from active-vasculitis patients, 36 samples from inactive-vasculitis patients without infection, and 19 samples from inactive-vasculitis patients with infectious complications. Serum-soluble CD163 was also measured in 15 infectious patients without vasculitis and in 30 normal controls. RESULTS: The mean serum-soluble CD163 level was higher in the patients with infectious complications than in the active-vasculitis patients, inactive-vasculitis patients, and normal controls. There were significant positive correlations between serum-soluble CD163 levels and white blood cell (WBC) count, serum C-reactive protein (CRP) levels, and serum albumin levels, but only serum CRP levels were correlated with serum-soluble CD163 levels in a multiple regression analysis. On the receiver-operating characteristic (ROC) curve, serum-soluble CD163 levels had 80.6% sensitivity and 86.7% specificity for differentiating patients with infection from those without infection. Among the active-vasculitis patients, the mean serum-soluble CD163 level of the patients with alveolar haemorrhage was significantly lower than that of the patients with interstitial lung diseases and that of the patients without pulmonary lesions. CONCLUSIONS: The serum-soluble CD163 level may be a useful marker for the detection of infectious complications in MPO-AAV patients.

Effects of short-term gentle treadmill walking on subchondral bone in a rat model of instability-induced osteoarthritis.

OBJECTIVE: Subchondral bone cyst (SBC) growth, caused by osteoclast activity during early knee osteoarthritis (OA) pathogenesis, should be treated to prevent further progressions of OA. In the present study, we evaluated the effects of gentle treadmill walking on subchondral bone and cartilage changes in an experimental rat model of destabilized medial meniscus (DMM). METHOD: Twelve-week-old Wistar rats underwent DMM surgery in their right knee and sham surgery in their left knee and were assigned to either the sedentary group or walking group (n = 42/group). Animals in the walking group were subjected to treadmill exercise 2 days after surgery, which included walking for 12 m/min, 30 min/day, 5 days/week for 1, 2, and 4 week(s). Subchondral bone and cartilage changes were evaluated by micro-CT analysis, histological analysis, and biomechanical analysis. RESULTS: Treadmill walking had a tendency to suppress SBC growth, which was confirmed by micro-CT (P = 0.06) and positive staining for tartrate-resistant acid phosphatase (TRAP) activity for the osteoclast number per bone surface (P = 0.09) 4 weeks after surgery. These changes coincide with the prevention of cartilage degeneration as evaluated by the Osteoarthritis Research Society International (OARSI) score (P < 0.05) and biomechanically softening (P < 0.05). Furthermore, treadmill walking could suppressed increasing osteocyte deaths (P < 0.01), which was positively correlated with the OARSI score (r = 0.77; P < 0.01). CONCLUSION: These results indicate biomechanical and biological links exist between cartilage and subchondral bone; preventive effects of treadmill walking on subchondral bone deterioration might be partly explained by the chondroprotective effects.

Destabilization of the medial meniscus leads to subchondral bone defects and site-specific cartilage degeneration in an experimental rat model.

OBJECTIVE: This study aimed to investigate subchondral bone changes using micro-computed tomography (micro-CT) and regional differences in articular cartilage degeneration, focusing on changes of cartilage covered by menisci, in the early phase using a destabilization of the medial meniscus (DMM) model. METHOD: The DMM model was created as an experimental rat osteoarthritis (OA) model (12 weeks old; n = 24). At 1, 2, and 4 weeks after surgery, the rats were sacrificed, and knee joints were scanned using a Micro-CT system. Histological sections of the medial tibial plateau, which was divided into inner, middle, and outer regions, were prepared and scored using the modified OARSI scoring system. The cartilage thickness was also calculated, and matrix metalloproteinase 13 (MMP13), Col2-3/4c, and vascular endothelial growth factor (VEGF) expression was assessed immunohistochemically. RESULTS: Subchondral bone defects were observed in the middle region, in which the cartilage thickness decreased over time after surgery, and these defects were filled with MMP13- and VEGF-expressing fibrous tissue. The OARSI score increased over time in the middle region, and the score was significantly higher in the middle region than in the inner and outer regions at 1, 2, and 4 weeks after surgery. Col2-3/4c and MMP13 expression was observed primarily in the meniscus-covered outer region, in which the cartilage thickness increased over time. CONCLUSION: Loss of meniscal function caused cartilage degeneration and subchondral bone defects in the early phase site-specifically in the middle region. Furthermore, our results might indicate cartilage covered by menisci is easily degraded resulting in osmotic swelling of the cartilage in early OA.

The impact of rare cancer and early-line treatments on the benefit of comprehensive genome profiling-based precision oncology.

BACKGROUND: Comprehensive genome profiling (CGP) serves as a guide for suitable genomically matched therapies for patients with cancer. However, little is known about the impact of the timing and types of cancer on the therapeutic benefit of CGP. MATERIALS AND METHODS: A single hospital-based pan-cancer prospective study (TOP-GEAR; UMIN000011141) was conducted to examine the benefit of CGP with respect to the timing and types of cancer. Patients with advanced solid tumors (>30 types) who either progressed with or without standard treatments were genotyped using a single CGP test. The subjects were followed up for a median duration of 590 days to examine therapeutic response, using progression-free survival (PFS), PFS ratio, and factors associated with therapeutic response. RESULTS: Among the 507 patients, 62 (12.2%) received matched therapies with an overall response rate (ORR) of 32.3%. The PFS ratios (≥1.3) were observed in 46.3% (19/41) of the evaluated patients. The proportion of subjects receiving such therapies in the rare cancer cohort was lower than that in the non-rare cancer cohort (9.6% and 17.4%, respectively; P = 0.010). However, ORR of the rare cancer patients was higher than that in the non-rare cancer cohort (43.8% and 20.0%, respectively; P = 0.046). Moreover, ORR of matched therapies in the first or second line after receiving the CGP test was higher than that in the third or later lines (62.5% and 21.7%, respectively; P = 0.003). Rare cancer and early-line treatment were significantly and independently associated with ORR of matched therapies in multivariable analysis (P = 0.017 and 0.004, respectively). CONCLUSION: Patients with rare cancer preferentially benefited from tumor mutation profiling by increasing the chances of therapeutic response to matched therapies. Early-line treatments after profiling increase the therapeutic benefit, irrespective of tumor types.

Clinical outcome of Brazilian patients with non-small cell lung cancer in early stage harboring rare mutations in epidermal growth factor receptor.

The common epidermal growth factor receptor (EGFR) mutations, such as the L858R point mutation in exon 21 and the in-frame deletional mutation in exon 19, have been definitively associated with response to EGFR-tyrosine kinase inhibitors (EGFR-TKI). However, the clinical outcome and response to treatment for many other rarer mutations are still unclear. In this study, we report the results of Brazilian patients in stage IB-IIIA non-small cell lung cancer (NSCLC) following complete resection with minimal residual disease and EGFR mutations treated with adjuvant chemotherapy and/or EGFR-TKIs. The frequency of EGFR mutations was investigated in 70 cases of early stage NSCLC. Mutations in exons 18 and 20, uncommon mutations in exons 19 and 21, as well as in exons 3, 7, 14, 16, 22, 27, and 28, and/or the presence of different mutations in a single tumor (complex mutations) are considered rare. EGFR mutations were detected in 23 tumors (32.9%). Fourteen cases carried rare mutations and were treated with platinum-based chemotherapy and two cases were treated with erlotinib. The clinical outcome is described case by case with references to the literature. Notably, we found two rare EGFR mutations and one of them with an unknown response to chemotherapy and/or EGFR-TKIs. We have provided complementary information concerning the clinical outcome and treatment of patients with early stage NSCLC for several rare EGFR mutations not previously or only rarely reported. Description of cases harboring rare mutations can support the decision-making process in this subset of patients.

Concomitant TP53 mutation in early-stage resected EGFR-mutated non-small cell lung cancer: a narrative approach in a genetically admixed Brazilian cohort.

TP53 mutations are frequent in non-small cell lung cancer (NSCLC) and have been associated with poor outcome. The prognostic and predictive relevance of EGFR/TP53 co-mutations in NSCLC is controversial. We analyzed lung tissue specimens from 70 patients with NSCLC using next-generation sequencing to determine EGFR and TP53 status and the association between these status with baseline patient and tumor characteristics, adjuvant treatments, relapse, and progression-free (PFS) and overall survival (OS) after surgical resection. We found the EGFR mutation in 32.9% of patients (20% classical mutations and 12.9% uncommon mutations). TP53 missense mutations occurred in 25.7% and TP53/EGFR co-mutations occurred in 43.5% of patients. Stage after surgical resection was significantly associated with OS (P=0.028). We identified an association between progression-free survival and poor outcome in patients with distant metastases (P=0.007). We found a marginally significant difference in OS between genders (P=0.057) and between mutant and wild type TP53 (P=0.079). In univariate analysis, distant metastases (P=0.027), pathological stage (IIIA-IIIB vs I-II; P=0.028), and TP53 status (borderline significance between wild type and mutant; P=0.079) influenced OS. In multivariable analysis, a significant model for high risk of death and poor OS (P=0.029) selected patients in stage IIIA-IIIB, with relapse and distant metastases, non-responsive to platin-based chemotherapy and erlotinib, with tumors harboring EGFR uncommon mutations, with TP53 mutant, and with EGFR/TP53 co-mutations. Our study suggested that TP53 mutation tends to confer poor survival and a potentially negative predictive effect associated with a non-response to platinum-based chemotherapy and erlotinib in early-stage resected EGFR-mutated NSCLC.

Body mass, tobacco smoking, alcohol drinking and risk of cancer of the small intestine--a pooled analysis of over 500,000 subjects in the Asia Cohort Consortium.

BACKGROUND: The evidence for a role of tobacco smoking, alcohol drinking, and body mass index (BMI) in the etiology of small intestine cancer is based mainly on case-control studies from Europe and United States. SUBJECTS AND METHODS: We harmonized the data across 12 cohort studies from mainland China, Japan, Korea, Singapore, and Taiwan, comprising over 500,000 subjects followed for an average of 10.6 years. We calculated hazard ratios (HRs) for BMI and (only among men) tobacco smoking and alcohol drinking. RESULTS: A total of 134 incident cases were observed (49 adenocarcinoma, 11 carcinoid, 46 other histologic types, and 28 of unknown histology). There was a statistically non-significant trend toward increased HR in subjects with high BMI [HR for BMI>27.5 kg/m2, compared with 22.6-25.0, 1.50; 95% confidence interval (CI) 0.76-2.96]. No association was suggested for tobacco smoking; men drinking>400 g of ethanol per week had an HR of 1.57 (95% CI 0.66-3.70), compared with abstainers. CONCLUSIONS: Our study supports the hypothesis that elevated BMI may be a risk factor for small intestine cancer. An etiologic role of alcohol drinking was suggested. Our results reinforce the existing evidence that the epidemiology of small intestine cancer resembles that of colorectal cancer.

Ferroelectric soft mode in a SrTiO3 thin film impulsively driven to the anharmonic regime using intense picosecond terahertz pulses.

The ferroelectric soft mode in a SrTiO(3) thin film was impulsively driven to a large amplitude using intense picosecond terahertz pulses. As the terahertz electric field increased, the soft-mode absorption peak exhibited blueshifting and spectral narrowing. A classical anharmonic oscillator model suggests that the induced displacement is comparable to that of the ferroelectric phase transition. The spectral narrowing indicates that the displacement exceeds that induced by any inhomogeneities in the film, demonstrating that the method can be used to explore intrinsic quartic anharmonicity.

Dietary patterns and risk of Parkinson's disease: a case-control study in Japan.

BACKGROUND: Nearly all epidemiologic studies examining the association between the risk of Parkinson's disease (PD) and diet have focused on single foods and specific nutrients. However, epidemiologic evidence for the association of dietary pattern with PD, namely the measurement of overall diet by considering the cumulative effects of nutrients is extremely limited. We conducted a hospital-based case-control study in Japan to examine the relationship between dietary patterns and the risk of PD. METHODS: Patients with PD diagnosed using the UK PD Society Brain Bank criteria (n = 249) and controls without neurodegenerative diseases (n = 368) were recruited. At the time of recruitment, dietary intake during the preceding 1 month was assessed using a validated, self-administered diet history questionnaire. Dietary patterns from 33 predefined food groups (energy-adjusted food g/day) were extracted by factor analysis. RESULTS: Three dietary patterns were identified: 'Healthy', 'Western' and 'Light meal' patterns. After adjustment for potential non-dietary confounding factors, the Healthy pattern, characterized by a high intake of vegetables, seaweed, pulses, mushrooms, fruits and fish, was inversely associated with the risk of PD with a border-line significance (P for trend = 0.06). Multivariate Odds ratio (95% confidence intervals) for PD in the highest quartile of the Healthy pattern was 0.54 (0.32-0.92) compared with the lowest quartile. No associations with PD were detected for the other two dietary patterns. CONCLUSION: In this case-control study in Japan, a dietary pattern consisting of high intakes of vegetables, fruits and fish may be associated with a decreased risk of PD.

Failure of preoperative co-morbidity indices to predict the successful use of the composite scapula free flap for maxillofacial reconstruction in patients with significant medical co-morbidities.

The aim of this study was to evaluate the accuracy of validated preoperative patient co-morbidity assessments, including the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP), with the use of the composite scapula free flap (CSFF) in maxillofacial reconstruction in patients with significant medical co-morbidities. A retrospective cohort review was performed at an academic institution, covering the period from July 2010 through January 2019. All patients who underwent reconstruction with a CSFF with significant medical co-morbidities were included. Co-morbidity assessments and risk factors were analyzed by comparing predicted versus observed early and late medical and surgical complications. Forty-five patients met the inclusion criteria. The surgical complication rate was 47%; the medical complication rate was 38%. Over 90% of patients returned to successful function at 3 months post-surgery. The ACS-NSQIP prediction of complications ranged from 58% to 75% for accuracy, 76% to 100% for sensitivity, and 50% to 69% for specificity. The prediction of a serious complication was statistically significant in patients with a Charlson Co-morbidity Index ≥7. Age ≥80 years did not significantly increase the risk of a serious complication (P = 0.23). The ACS-NSQIP failed to predict the successful use of the CSFF for patients with significant co-morbidities undergoing maxillofacial reconstruction. The selection of patients who will tolerate complex reconstruction cannot be based solely on co-morbidity charts and standardized preoperative indices.