Decline in the Conception Rate of Wild Japanese Monkeys after the Fukushima Daiichi Nuclear Power Plant Accident.

We examined the conception rate of wild Japanese monkeys (Macaca fuscata) in Fukushima City that were exposed to radiation as a result of the Fukushima Daiichi Nuclear Power Plant accident in March 2011. The conception rate in the year of delivery from 2009 to 2022 was estimated by dissecting individuals that were euthanized by the government for population control as a countermeasure against crop damage. To evaluate the effects of exposure, the cumulative exposure dose for each individual was calculated using the concentration of radiocesium deposited in the soil at the capture site and the concentration of radiocesium in muscle estimated from the aggregated transfer factor. There were no significant differences in conception rates across all age classes over time. In terms of conception rates by age class, there was a significant decrease post-exposure compared with pre-exposure in the age class ≥ 8 years, but no significant differences in the age class 5-7 years. The non-ovulation rate did not significantly differ between the pre- and post-exposure periods for any age class. Body fat index, which can affect fertility, was compared between the pre- and post-exposure periods, and no significant differences were found in either age class. In contrast, the median total cumulative exposure (cumulative internal exposure + cumulative external exposure) was significantly higher in the age class ≥ 8 years compared with the age class 5-7 years. These results suggest that the total cumulative exposure dose may be one of the reasons for the lower conception rate in the post-exposure period among the age class ≥ 8 years.

[Pharmacological and clinical profile of Onasemnogene Aveparvovec, the first gene therapy for spinal muscular atrophy (SMA)].

Onasemnogene abeparvovec (Zolgensma®; formerly AVXS-101) is a one-time gene therapy designed to address the genetic root cause of spinal muscular atrophy (SMA) by replacing the function of the missing or nonworking SMN1 gene via an adeno-associated AAV9 viral vector. On March 19, 2020, the Japanese Ministry of Health, Labor and Welfare approved onasemnogene abeparvovec for the treatment of SMA patients <2 years of age, including presymptomatic patients with a genetic diagnosis. Patients must be negative for elevated anti-AAV9 antibodies. Onasemnogene abeparvovec is administered through a single intravenous infusion, delivering a new working copy of the SMN gene into a patient's cells. Intravenous administration of onasemnogene abeparvovec to SMA model mice resulted in sustained expression of survival motor neuron (SMN) protein, weight gain, improvement of motor function, and prolongation of survival. Its clinical efficacy and safety have been demonstrated through the Phase I START and Phase III STR1VE-US, STR1VE-EU, and SPR1NT trials, and their long-term extension studies. SMA and presymptomatic patients treated with onasemnogene abeparvovec have achieved rates of survival not observed in the natural history of SMA. Treatment has led to rapid motor function improvement, often within one month of dosing, and developmental milestone achievement, including the ability to sit without support. The most commonly observed adverse effects after treatment were elevated liver enzymes, which often resolved with a course of prednisolone, and vomiting. This review discusses the rationale underlying gene replacement therapy for SMA, and describes the basic science, clinical trial experience, and use of onasemnogene abeparvovec.

Physicians' attitude toward recurrent hypercalcemia in terminally ill cancer patients.

BACKGROUND: There is no consensus regarding whether cancer-induced hypercalcemia should be treated up until the patient's death. The primary aim of this study was to clarify physicians' attitude toward treating recurrent hypercalcemia in terminally ill cancer patients and associated factors. METHODS: A nationwide, cross-sectional survey was performed involving 757 physicians of the Japanese Society for Palliative Medicine. Physicians' attitude toward treating hypercalcemia in terminally ill patients was assessed based on the response to the question: do you agree that you provide medical treatment for recurrent hypercalcemia up until a patient's death? As the potential determinants of physicians' attitudes, we examined their characteristics, beliefs about hypercalcemia, and beliefs about a good death. RESULTS: We obtained a total of 380 (50.2%) analyzable responses. A total of 163 physicians (43%) agreed that hypercalcemia should be treated up until the patient's death, while the remaining 217 physicians (57%) disagreed. The independent determinants of the attitude included the following: physicians' specialty, belief that hypercalcemia treatment improves pain, belief that hypercalcemia treatment improves nausea, belief that hypercalcemia treatment improves quality of life, belief that hypercalcemia treatment prolongs life, belief that the effect of hypercalcemia treatment reduces gradually, belief that death with hypercalcemia is less distressing, and the perception that being mentally clear is important for a good death. CONCLUSION: Japanese physicians had different attitudes toward treating hypercalcemia in terminally ill patients. Physicians' beliefs about the efficacy of medical treatment for hypercalcemia markedly influenced their attitudes. Clarifying evidence on the effect of hypercalcemia treatment on patients' symptoms and prognoses is strongly encouraged.

The Ohsaki Cohort 2006 Study: design of study and profile of participants at baseline.

BACKGROUND: Large-scale cohort studies conducted in Japan do not always include psychosocial factors as exposures. In addition, such studies sometimes fail to satisfactorily evaluate disability status as an outcome. METHODS: This prospective cohort study comprised 49 603 (22 438 men and 27 165 women) community-dwelling adults aged 40 years or older who were included in the Residential Registry for Ohsaki City, Miyagi Prefecture, in northeastern Japan. The baseline survey, which included psychosocial factors, was conducted in December 2006. Follow-up of death, immigration, cause of death, cancer incidence, and long-term care insurance certification was started on 1 January 2007. RESULTS: The response rate was 64.2%. In general, lifestyle-related conditions in the study population were similar to those of the general Japanese population; however, the proportion of male current smokers was higher in the cohort. The association between age and the proportion of those reporting psychological distress showed a clear U-shaped curve, with a nadir at age 60 to 69 years in both men and women, although more women were affected by such distress than men. The proportion of those who reported a lack of social support was highest among those aged 40 to 49 years. Most men and women surveyed did not participate in community activities. Among participants aged 65 years or older, 10.9% of participants were certified beneficiaries of the long-term care insurance system at baseline. CONCLUSIONS: The Ohsaki Cohort 2006 Study is a novel population-based prospective cohort study that focuses on psychosocial factors and long-term care insurance certification.

Factors associated with psychological distress in a community-dwelling Japanese population: the Ohsaki Cohort 2006 Study.

BACKGROUND: In Asia, there has been no population-based epidemiological study using the K6, a 6-item instrument that assesses nonspecific psychological distress. METHODS: Using cross-sectional data from 2006, we studied 43,716 (20,168 men and 23,548 women) community-dwelling people aged 40 years or older living in Japan. We examined the association between psychological distress and demographic, medical, lifestyle, and social factors by using the K6, with psychological distress defined as 13 or more points out of a total of 24 points. RESULTS: The following variables were significantly associated with psychological distress among the population: female sex, young and old age, a history of serious disease (hypertension, diabetes mellitus, stroke, myocardial infarction, or cancer), current smoking, former alcohol drinking, low body mass index, shorter daily walking time, lack of social support (4 of 5 components), and lack of participation in community activities (4 of 5 components). Among men aged 40 to 64 years, only "lack of social support for consultation when in trouble" and a history of diabetes mellitus remained significant on multivariate analysis. Among men aged 65 years or older, age was not significantly associated with psychological distress, and the significant association with current smoking disappeared on multivariate analysis. Among women aged 40 to 64 years, a history of stroke was not associated with psychological distress. Among women aged 65 years or older, the significant association with current smoking disappeared on multivariate analysis. CONCLUSIONS: A number of factors were significantly associated with psychological distress, as assessed by the K6. These factors differed between men and women, and also between middle-aged and elderly people.

Raloxifene and stroke risks in Japanese postmenopausal women with osteoporosis on postmarketing surveillance.

OBJECTIVE: The aim of this study was to assess whether the risks of stroke and stroke death in Japanese postmenopausal women with osteoporosis exposed to raloxifene increased in comparison with those of the general Japanese female population. METHODS: Safety data associated with use of raloxifene were collected in observational settings from 6,970 women with a median follow-up period of 366 days on postmarketing surveillance conducted in Japan. The stroke incidences in raloxifene-treated women were compared with population stroke rates derived from epidemiology studies conducted at three distinct locations in Japan, yielding standardized morbidity ratios for stroke for the purpose of stroke risk assessment. RESULTS: Exposure to raloxifene totaled 7,474 patient-years and 23 stroke cases were reported, including 4 fatal cases. Multiple stroke risk factors were present in three of four women with fatal outcome. The standardized stroke morbidity ratios in raloxifene-treated women versus women from the three reference regions, including Akita Prefecture, Takashima town in Shiga Prefecture, and Okinawa Prefecture, were 0.68 (95% CI, 0.45-1.02), 0.54 (95% CI, 0.35-0.83), and 0.82 (95% CI, 0.54-1.24), respectively. CONCLUSIONS: In this initial interim analysis, there seems to be no significant increased risk of stroke among Japanese women with 1 year of raloxifene use in comparison to Japanese epidemiological data. An increased risk of fatal stroke in the treatment population was indeterminable because of the small number of observed fatal cases. However, ongoing safety monitoring of stroke risk among raloxifene women will continue.

Pain and risk of completed suicide in Japanese men: a population-based cohort study in Japan (Ohsaki Cohort Study).

Unrelieved pain is a major factor that influences suicide risk among terminally ill patients, but little is known about the relationship between pain and the risk of completed suicide in the general population. We prospectively examined the association between self-reports of pain and subsequent risk of completed suicide in 26,481 men aged 40 to 79 years from the Ohsaki National Health Insurance Cohort study, a population-based, prospective cohort study initiated in 1994. On the basis of a five-item questionnaire on pain, individuals were classified as having no pain, very mild pain, mild pain, or moderate or severe pain. Completed suicide cases were documented from 1995 to 2001. During 131,027 person-years, 64 completed suicides were documented. After adjustment for covariates, the risk for completed suicide was significantly higher in the subjects with more pain. Multivariate hazard ratios (95% confidence intervals) relative to the subjects who had no pain were 1.36 (0.67-2.75), 2.11 (1.02-4.33), and 2.93 (1.34-6.42) in the subjects who had very mild pain, mild pain, and moderate or severe pain, respectively (P for trend=0.004). Stratified analysis showed that the positive association between pain and suicide risk was robust in the subjects with good health, low stress, adequate sleep, good physical activity, and no history of chronic diseases. Our results suggest that pain is associated with an increased risk of completed suicide among Japanese men. The association was consistently observed among apparently healthy subjects.

Sense of life worth living (ikigai) and mortality in Japan: Ohsaki Study.

OBJECTIVE: To investigate the association between the sense of "life worth living (ikigai)" and the cause-specific mortality risk. The psychological factors play important roles in morbidity and mortality risks. However, the association between the negative psychological factors and the risk of mortality is inconclusive. METHODS: The Ohsaki Study, a prospective cohort study, was initiated on 43,391 Japanese adults. To assess if the subjects found a sense of ikigai, they were asked the question, "Do you have ikigai in your life?" We used Cox regression analysis to calculate the hazard ratio of the all-cause and cause-specific mortality according to the sense of ikigai categories. RESULTS: Over 7 years' follow-up, 3048 of the subjects died. The risk of all-cause mortality was significantly higher among the subjects who did not find a sense of ikigai as compared with that in the subjects who found a sense of ikigai; the multivariate adjusted hazard ratio (95% confidence interval) was 1.5 (1.3-1.7). As for the cause-specific mortality, subjects who did not find a sense of ikigai were significantly associated with an increased risk of cardiovascular disease (1.6; 1.3-2.0) and external cause mortality (1.9; 1.1-3.3), but not of the cancer mortality (1.3; 1.0-1.6). CONCLUSIONS: In this prospective cohort study, subjects who did not find a sense of ikigai were associated with an increased risk of all-cause mortality. The increase in mortality risk was attributable to cardiovascular disease and external causes, but not cancer.

An introduction to the theory of constraint and how it can be applied to medical management.

This overview of a new way of thinking about medical management problems could help physicians executives think about those problems differently.

Negative psychological aspects and survival in lung cancer patients.

We conducted a prospective cohort study in Japan to investigate associations between negative psychological aspects and cancer survival. Between July 1999 and July 2004, a total of 1178 lung cancer patients were enrolled. The questionnaire asked about socioeconomic variables, smoking status, clinical symptoms, and psychological aspects after diagnosis. Negative psychological aspects were assessed for the subscales of helplessness/hopelessness and depression. Clinical stage, performance status (PS), and histologic type were obtained from medical charts. The subjects were followed up until December 2004, and 686 had died. A Cox regression model was used to estimate the hazards ratio (HR) of all-cause mortality. After adjustment for socioeconomic variables and smoking status in addition to sex, age, and histologic type, both helplessness/hopelessness and depression subscales showed significant linear positive associations with the risk of mortality (p for trend<0.001 for both). However, after adjustment for clinical state variables in addition to sex, age, and histologic type, these significant linear positive associations were no longer observed (p for trend=0.41 and 0.26, respectively). Our data supported the hypothesis that the association between helplessness/hopelessness and depression and the risk of mortality among lung cancer patients was largely confounded by clinical state variables including clinical stage, PS, and clinical symptoms.

Alcohol consumption and suicide mortality among Japanese men: the Ohsaki Study.

The risk of suicide is well known to be increased among heavy alcohol drinkers. However, whether the risk is increased or decreased among light drinkers is still under debate. We investigated this association in a population-based sample of men in Japan. The Ohsaki Study was a population-based, prospective cohort study among Japanese adults aged from 40 to 79 years. Between October and December, 1994, 22,804 men in Miyagi Prefecture, Japan, completed a questionnaire on various health-related lifestyles, including alcohol drinking. During the subsequent 7 years follow-up, 73 participants committed suicide. We used the Cox proportional hazards regression model to estimate the hazard ratio (HR) for suicide mortality according to the quantity of alcohol consumed daily, with adjustment for potential confounders. There was a statistically significant positive and linear association between the amount of alcohol consumed and the risk of suicide: the multivariate HRs in reference to nondrinkers (95% confidence interval) were 1.2 (0.5-2.7), 1.5 (0.7-3.4), and 2.4 (1.2-4.6) in current drinkers who consumed /=45.6g of alcohol per day, respectively (P-trend=.016). Even after the early death cases were excluded, a significant linear association was observed between alcohol consumption and the risk of suicide, with the risk of suicide also being nonsignificantly higher among the light drinkers than among nondrinkers (multivariate HR=1.7). This prospective cohort study indicated a positive linear association between alcohol consumption and the risk of suicide, and the suicide risk among the light drinkers was not decreased as compared with that in nondrinkers.

Survival prediction of patients with advanced cancer: the predictive accuracy of the model based on biological markers.

To determine whether the addition of biological markers to performance status (PS) and physical symptoms would improve survival prediction among patients with advanced cancer, we developed two prediction models with a scoring system based on 294 consecutive patients with advanced cancer (training set), and then tested its validity on another 93 patients (testing set). We assessed the predictive accuracy of the models using receiver-operating characteristic analysis. Albumin (ALB), lactate dehydrogenase (LDH), and lymphocyte percentage (Lymp%) were significantly and independently associated with survival length. For prediction of 60-day survival, the predictive accuracy of Model 2, based on the above biological markers in addition to PS and symptoms, was significantly better than that of Model 1, based on PS and symptoms alone (area under the curve [AUC] for Model 2, 0.80+/-0.03; AUC for Model 1, 0.69+/-0.04; P<0.001). Addition of ALB, LDH, and Lymp% to PS and physical symptoms improved prediction accuracy, especially for longer survival.

Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study.

CONTEXT: Green tea polyphenols have been extensively studied as cardiovascular disease and cancer chemopreventive agents in vitro and in animal studies. However, the effects of green tea consumption in humans remain unclear. OBJECTIVE: To investigate the associations between green tea consumption and all-cause and cause-specific mortality. DESIGN, SETTING, AND PARTICIPANTS: The Ohsaki National Health Insurance Cohort Study, a population-based, prospective cohort study initiated in 1994 among 40,530 Japanese adults aged 40 to 79 years without history of stroke, coronary heart disease, or cancer at baseline. Participants were followed up for up to 11 years (1995-2005) for all-cause mortality and for up to 7 years (1995-2001) for cause-specific mortality. MAIN OUTCOME MEASURES: Mortality due to cardiovascular disease, cancer, and all causes. RESULTS: Over 11 years of follow-up (follow-up rate, 86.1%), 4209 participants died, and over 7 years of follow-up (follow-up rate, 89.6%), 892 participants died of cardiovascular disease and 1134 participants died of cancer. Green tea consumption was inversely associated with mortality due to all causes and due to cardiovascular disease. The inverse association with all-cause mortality was stronger in women (P = .03 for interaction with sex). In men, the multivariate hazard ratios of mortality due to all causes associated with different green tea consumption frequencies were 1.00 (reference) for less than 1 cup/d, 0.93 (95% confidence interval [CI], 0.83-1.05) for 1 to 2 cups/d, 0.95 (95% CI, 0.85-1.06) for 3 to 4 cups/d, and 0.88 (95% CI, 0.79-0.98) for 5 or more cups/d, respectively (P = .03 for trend). The corresponding data for women were 1.00, 0.98 (95% CI, 0.84-1.15), 0.82 (95% CI, 0.70-0.95), and 0.77 (95% CI, 0.67-0.89), respectively (P<.001 for trend). The inverse association with cardiovascular disease mortality was stronger than that with all-cause mortality. This inverse association was also stronger in women (P = .08 for interaction with sex). In women, the multivariate hazard ratios of cardiovascular disease mortality across increasing green tea consumption categories were 1.00, 0.84 (95% CI, 0.63-1.12), 0.69 (95% CI, 0.52-0.93), and 0.69 (95% CI, 0.53-0.90), respectively (P = .004 for trend). Among the types of cardiovascular disease mortality, the strongest inverse association was observed for stroke mortality. In contrast, the hazard ratios of cancer mortality were not significantly different from 1.00 in all green tea categories compared with the lowest-consumption category. CONCLUSION: Green tea consumption is associated with reduced mortality due to all causes and due to cardiovascular disease but not with reduced mortality due to cancer.

Macromorphometric study on ciliary body location in canine eyes.

This macroscopic study firstly examined the precise locational information of the canine ciliary body, i.e., the ciliary crown and the ciliary ring in the beagle. The safe and effective transscleral laser photocoagulation technique requires the accurate location of the ciliary body. In both sides of the eyeball in 10 beagle dogs, the width of the ciliary ring and the distance from the limbus to the ciliary ring were measured with calipers using a stereomicroscope at the 8 points. The widest portion of ciliary body was found at the dorsal to ventro-temporal area of the lateral canthus (lateral portion of the eyelid; ear side). In contrast, the narrowest portion was seen at the ventro-nasal to nasal area of the medial canthus (medial portion of the eyelid; nasal quadrants). Use of transscleral photocoagulation at the present narrowest area of ciliary body may carry a high risk of destruction of the optic portion of retina.

Triangulation analysis of tele-palliative care implementation in a rural community area in Japan.

We conducted a comprehensive evaluation of tele-palliative care by triangulation method. This consisted of qualitative analyses of 2 patients and then performing quantitative analysis of a simulated model for tele-palliative care based on that experience. Semistructured interviews with 2 patients were conducted for qualitative analysis. The recorded conversations were analyzed using traditional categorization and coding techniques, looking for patterns and themes both within and across the interviews. A state-transition process was modeled using a Markov model to compare the costs for three different options for patients requiring palliative care: admission to the palliative care unit, home care only (8 physician visits), and tele-palliative care. The cost data were mainly derived from the reimbursement scale of the Japanese Health Insurance System. Sensitivity analysis was used to assess the influence of particular conditions or costs. The qualitative assessment identified some positive concepts, such as "expectation," "convenience," "reliance," and "communication." In the cost analysis, the reference case yielded the annual costs as follows: (1) costs for admission to the palliative care unit were 1,137,000 dollars; (2) costs for home care were 521,000 dollars; and (3) costs for telepalliative care were 478,000 dollars. One-way sensitivity analyses showed that home care was the most cost-saving strategy if the care was continued for more than 4 months or the number of physician visits during tele-palliative care could be reduced to less than 6 physician visits per month. The important issues in reducing the cost of tele-palliative care were (1) having adequate patient numbers, (2) reducing the number of physicians' visits, and (3) offsetting the costs of telemedicine against cost savings to the system to sustain the program. In addition, the qualitative analysis demonstrated patients positive views of tele-palliative care.

[The attempt to standardize treatment protocols for cancer-related hypercalcemia: developing a data-based flowchart].

We developed a flowchart for the treatment of cancer-related hypercalcemia based on the review of previous reports. The treatment protocols were standardized in each group of four different ranges of serum calcium concentration (< 12, 12-14, 14-16, < 16 mg/dl). In each Ca range, specific treatment was adjusted according to the clinical evaluation of symptoms and progression of illness of the patients.