Locating Transition States by Variational Reaction Path Optimization with an Energy-Derivative-Free Objective Function.

Locating transition states is essential for understanding molecular reactions. We propose a double-ended transition state search method by revisiting a variational reaction path optimization method known as the MaxFlux method. Although its original purpose is to add temperature effects to reaction paths, we conversely let the temperature approach zero to obtain an asymptotically exact minimum energy path and its corresponding transition state in variational formalism with an energy-derivative-free objective function. Using several numerical techniques to directly optimize the objective function, the present method reliably finds transition states with low computational cost. In particular, only three force evaluations per iteration are sufficient. This is confirmed on a variety of molecular reactions where the nudged elastic band method often fails. The present method is implemented in Python using the Atomic Simulation Environment and is available on GitHub.

Regulation mechanisms of the dual ATPase in KaiC.

KaiC is a dual adenosine triphosphatase (ATPase), with one active site in its N-terminal domain and another in its C-terminal domain, that drives the circadian clock system of cyanobacteria through sophisticated coordination of the two sites. To elucidate the coordination mechanism, we studied the contribution of the dual-ATPase activities in the ring-shaped KaiC hexamer and these structural bases for activation and inactivation. At the N-terminal active site, a lytic water molecule is sequestered between the N-terminal domains, and its reactivity to adenosine triphosphate (ATP) is controlled by the quaternary structure of the N-terminal ring. The C-terminal ATPase activity is regulated mostly by water-incorporating voids between the C-terminal domains, and the size of these voids is sensitive to phosphoryl modification of S431. The up-regulatory effect on the N-terminal ATPase activity inversely correlates with the affinity of KaiC for KaiB, a clock protein constitutes the circadian oscillator together with KaiC and KaiA, and the complete dissociation of KaiB from KaiC requires KaiA-assisted activation of the dual ATPase. Delicate interactions between the N-terminal and C-terminal rings make it possible for the components of the dual ATPase to work together, thereby driving the assembly and disassembly cycle of KaiA and KaiB.

Multimeric structure enables the acceleration of KaiB-KaiC complex formation induced by ADP/ATP exchange inhibition.

Circadian clocks tick a rhythm with a nearly 24-hour period in a variety of organisms. In the clock proteins of cyanobacteria, KaiA, KaiB, and KaiC, known as a minimum circadian clock, the slow KaiB-KaiC complex formation is essential in determining the clock period. This complex formation, occurring when the C1 domain of KaiC hexamer binds ADP molecules produced by the ATPase activity of C1, is considered to be promoted by accumulating ADP molecules in C1 through inhibiting the ADP/ATP exchange (ADP release) rather than activating the ATP hydrolysis (ADP production). Significantly, this ADP/ATP exchange inhibition accelerates the complex formation together with its promotion, implying a potential role in the period robustness under environmental perturbations. However, the molecular mechanism of this simultaneous promotion and acceleration remains elusive because inhibition of a backward process generally slows down the whole process. In this article, to investigate the mechanism, we build several reaction models of the complex formation with the pre-binding process concerning the ATPase activity. In these models, six KaiB monomers cooperatively and rapidly bind to C1 when C1 binds ADP molecules more than a given threshold while stabilizing the binding-competent conformation of C1. Through comparison among the models proposed here, we then extract three requirements for the simultaneous promotion and acceleration: the stabilization of the binding-competent C1 by KaiB binding, slow ADP/ATP exchange in the binding-competent C1, and relatively fast ADP/ATP exchange occurring in the binding-incompetent C1 in the presence of KaiB. The last two requirements oblige KaiC to form a multimer. Moreover, as a natural consequence, the present models can also explain why the binding of KaiB to C1 reduces the ATPase activity of C1.

Molecular Mechanism of Acceleration and Retardation of Collective Orientation Relaxation of Water Molecules in Aqueous Solutions.

The collective orientation relaxation (COR) of water molecules in aqueous solutions is faster or slower with an increase in the concentration of the solutions than that in pure water; for example, acceleration (deceleration) of the COR is observed in a solution of sodium chloride (tetramethylammonium chloride) with increasing concentration. However, the molecular mechanism of the solution and concentration dependence of the relaxation time of the COR has not yet been clarified. We theoretically investigate the concentration dependence of the COR of water molecules in solutions of tetramethylammonium chloride (TMACl), guanidinium chloride (GdmCl), and sodium chloride (NaCl). Based on the Mori-Zwanzig equation, we identify two opposing factors that determine the COR of water molecules in any aqueous solution: the correlation of dipole moments and the single-molecule orientation relaxation. We reveal the molecular mechanism of the concentration dependence of the relaxation time of the COR in the TMACl, GdmCl, and NaCl solutions in terms of these two factors.

An alternative interpretation of the slow KaiB-KaiC binding of the cyanobacterial clock proteins.

The biological clock of cyanobacteria is composed of three proteins, KaiA, KaiB, and KaiC. The KaiB-KaiC binding brings the slowness into the system, which is essential for the long period of the circadian rhythm. However, there is no consensus as to the origin of the slowness due to the pre-binding conformational transition of either KaiB or KaiC. In this study, we propose a simple KaiB-KaiC binding scheme in a hexameric form with an attractive interaction between adjacent bound KaiB monomers, which is independent of KaiB's conformational change. We then show that the present scheme can explain several important experimental results on the binding, including that used as evidence for the slow conformational transition of KaiB. The present result thus indicates that the slowness arises from KaiC rather than KaiB.

Author Correction: Conformational rearrangements of the C1 ring in KaiC measure the timing of assembly with KaiB.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Conformational rearrangements of the C1 ring in KaiC measure the timing of assembly with KaiB.

KaiC, the core oscillator of the cyanobacterial circadian clock, is composed of an N-terminal C1 domain and a C-terminal C2 domain, and assembles into a double-ring hexamer upon ATP binding. Cyclic phosphorylation and dephosphorylation at Ser431 and Thr432 in the C2 domain proceed with a period of approximately 24 h in the presence of other clock proteins, KaiA and KaiB, but recent studies have revealed a crucial role for the C1 ring in determining the cycle period. In this study, we mapped dynamic structural changes of the C1 ring in solution using a combination of site-directed tryptophan mutagenesis and fluorescence spectroscopy. We found that the C1 ring undergoes a structural transition, coupled with ATPase activity and the phosphorylation state, while maintaining its hexameric ring structure. This transition triggered by ATP hydrolysis in the C1 ring in specific phosphorylation states is a necessary event for recruitment of KaiB, limiting the overall rate of slow complex formation. Our results provide structural and kinetic insights into the C1-ring rearrangements governing the slow dynamics of the cyanobacterial circadian clock.

Mixed semiclassical-classical propagators for the Wigner phase space representation.

We formulate mixed semiclassical-classical (SC-Cl) propagators by adding a further approximation to the phase-space SC propagators, which have been formulated in our previous paper [S. Koda, J. Chem. Phys. 143, 244110 (2015)]. We first show that the stationary phase approximation over the operation of the phase-space van Vleck propagator on initial distribution functions results in the classical mechanical time propagation. Then, after dividing the degrees of freedom (DOFs) of the total system into the semiclassical DOFs and the classical DOFs, the SC-Cl van Vleck propagator and the SC-Cl Herman-Kluk (HK) propagator are derived by performing the stationary phase approximation only with respect to the classical DOFs. These SC-Cl propagators are naturally decomposed to products of the phase-space SC propagators and the classical mechanical propagators when the system does not have any interaction between the semiclassical and the classical DOFs. In addition, we also numerically compare the original phase-space HK (full HK) propagator and the SC-Cl HK propagator in terms of accuracy and efficiency to find that the accuracy of the SC-Cl HK propagator can be comparable to that of the full HK propagator although the latter is more accurate than the former in general. On the other hand, we confirm that the convergence speed of the SC-Cl HK propagator is faster than that of the full HK propagator. The present numerical tests indicate that the SC-Cl HK propagator can be more accurate than the full HK propagator when they use a same and finite number of classical trajectories due to the balance of the accuracy and the efficiency.

[USE OF QuantiFERON® TB-GOLD IN-TUBE IN A CONTACT INVESTIGATION TO DETERMINE THE ONSET OF TUBERCULOSIS WITH OR WITHOUT LATENT TUBERCULOSIS INFECTION TREATMENT].

PURPOSE: QuantiFERON® TB-Gold In-Tube (3G) testing was performed on tuberculosis-positive index cases and their contacts. The purpose of this study was to evaluate the relationship between 3G test results and the subsequent development of tuberculosis, and to identify effective strategies to prevent the onset of tuberculosis. METHODS: Index cases and their contacts were subjected to 3G testing in a contact investigation in Osaka City in 2011-2012. For index cases, sputum smears were tested, and the infecting organism was identified. For the contacts, the following information was collected: age, results of 3G testing, presence or absence of latent tuberculosis infection (LTBI) treatment, and onset of tuberculosis disease within 2 years of follow-up from the last contact with the index cases. RESULTS: (1) There were 830 index cases, including 774 subjects with pulmonary tuberculosis (93.3%) and 3 with laryngeal tuberculosis (0.4%). From sputum smear tests, 726 patients (87.5%) were determined to be 3G positive, and 83 (10.0%) were determined to be 3G negative. (2) In total, 2,644 contacts were subjected to 3G testing. Of these, 2,072 patients (78.4%) tested negative, 196 (7.4%) showed an equivocal result, and 375 (14.2%) tested positive. Their mean ages were 33.7, 38.0, and 38.8 years, respectively, showing significant differences in tuberculosis status according to age (P < 0.001). (3) Among the 2,072 3G-negative contacts, tuberculosis developed in 2 (0.1%) of 2063. None of these contacts was treated for LTBI. Among the 375 3G-positive contacts, tuberculosis developed in 36 (36.0%) of 100 subjects that were not LTBI treated, while tuberculosis developed in 3 (1.1 %) of 275 subjects that were LTBI treated. A significant difference in the incidence of tuberculosis between treated and untreated 3G-positive contacts was observed (P < 0.001). DISCUSSION: Tuberculosis developed in a high proportion of 3G-positive contacts that were not LTBI treated, suggesting the need for preventive management of 3G-positive contacts.

A theoretical investigation of symmetry-origin unidirectional energy gradient in light-harvesting dendrimers.

We theoretically investigate a possibility that the symmetry of the repetitively branched structure of light-harvesting dendrimers creates the energy gradient descending toward inner generations (layers of pigment molecules) of the dendrimers. In the first half of this paper, we define a model system using the Frenkel exciton Hamiltonian that focuses only on the topology of dendrimers and numerically show that excitation energy tends to gather at inner generations of the model system at a thermal equilibrium state. This indicates that an energy gradient is formed in the model system. In the last half, we attribute this result to the symmetry of the model system and propose two symmetry-origin mechanisms creating the energy gradient. The present analysis and proposition are based on the theory of the linear chain (LC) decomposition [S. Koda, J. Chem. Phys. 142, 204112 (2015)], which equivalently transforms the model system into a set of one-dimensional systems on the basis of the symmetry of dendrimers. In the picture of the LC decomposition, we find that energy gradient is formed both in each linear chain and among linear chains, and these two mechanisms explain the numerical results well.

[PULMONARY TUBERCULOSIS TREATMENT OUTCOME AMONG FOREIGN NATIONALS RESIDING IN OSAKA CITY].

UNLABELLED: Abstract PURPOSE: In this study, we analyzed pulmonary tuberculosis treatment outcomes among foreign nationals of different backgrounds. METHODS: The research was conducted between January 2006 and December 2011. One hundred fifty nine foreign nationals residing in Osaka city had pulmonary tuberculosis during this period. Patients were grouped according to treatment outcomes. We conducted three different types of comparisons. First, we compared backgrounds of patients with treatment success or default. Second, backgrounds of patients who continued treatment in Japan or who moved overseas (transfer out) were compared. Third, treatment outcomes of foreign nationals between 20 and 39 years of age were compared with those of age-matched Japanese patients registered between 2010 and 2011. RESULTS: (1) The treatment outcomes were as follows: cured, 53 cases (33.3%); treatment completed, 55 cases (34.6 %); treatment failure, 0 cases (0.0%); treatment default, 14 cases (8.8%); moved overseas, 17 cases (10.7%); moved to another location inside Japan, 13 cases (8.2%); died, 6 cases (3.8%); and under treatment, 1 case (0.6%). (2) Comparison of treatment success and default among foreign nationals with pulmonary tuberculosis revealed a default rate among smear-negative cases of 14.5%, significantly higher than in smear-positive cases (2.1%; P < 0.05). (3) We compared backgrounds between foreign nationals with pulmonary tuberculosis who continued taking treatment in Japan and those who moved abroad (transfer out). The rate of overseas transfer out (44.4%) was higher among patients not covered by health insurance. This was significantly higher than among patients covered by public insurance or assistance (9.0%; P < 0.01). (4) Comparison of foreign and Japanese nationals between 20 and 39 years of age revealed a default rate in foreign nationals with pulmonary tuberculosis of 13.6%. This was significantly higher than that of Japanese patients (4.0%; P < 0.01). The rate of transfer out among foreign nationals with pulmonary tuberculosis was 19.1%, also significantly higher than that of Japanese patients (5.3%; P < 0.001). DISCUSSION: The rates of treatment default and transfer out among patients between 20 to 39 years of age were significantly higher among foreign nationals than in Japanese patients. Lack of knowledge about treatment and language problems may contribute to this finding. This suggests that adequate support and definitive directly observed treatment short-course programs are needed for foreign nationals. Patients who moved abroad (overseas transfer out) may also be ultimately categorized as treatment default. However, it is difficult to determine final treatment outcomes of patients who moved abroad. Further measures are needed to ensure that foreign nationals continue to receive treatment when they transfer overseas.

[RATES OF COMPLETION AND TREATMENT OUTCOMES FOR TYPE OF COMMUNITY DOTS].

AIM: To investigate the relationship between completion rates for community directly observed treatment short-course (DOTS) and treatment outcomes, according to implementation tactics, to improve the treatment outcomes. METHODS AND SUBJECTS: We evaluated 529 newly registered patients with smear-positive pulmonary tuberculosis who underwent community DOTS (checking medication at least once per week) during 2010 and 2011 in Osaka City. DOTS completion was defined as checking medication 3 times or more per month, with checking medication missed less than 3 consecutive times. DOTS was implemented using the following 4 tactics: healthcare staff visited the patients' home or workplace (visiting type), the patients visited a health and welfare center (HWC type), the patients visited a pharmacy (P type), or the patients visited an outpatient department at a medical center (MC type). Regarding treatment outcomes, resolution of the tuberculosis or treatment completion was defined as "successful treatment", and treatment failure or default was defined as "unsuccessful treatment". We then analyzed the DOTS completion rate for each DOTS implementation tactic. RESULTS: DOTS was completed in 417 (78.8%) of the 529 patients. The completion rates were 79.7%, 75.4%, 75.9%, and 81.3% for patients who underwent visiting (n= 394), HWC (n = 61), P (n = 58), and MC (n = 16) DOTS, respectively; no significant difference was observed. The mean ages for each group were 62.8 years, 53.6 years, 45.0 years, and 56.6 years for patients who underwent visiting, HWC, P, and MC DOTS, respectively; patients who underwent P DOTS were significantly younger (P < 0.001). Among the 4 groups, the visiting DOTS group had the lowest percentage of full-time employees (16.2%) and the highest percentage of unemployed individuals (67.3%). In contrast, the percentage of full-time employees was 63.8% and 50.0% in the P and MC DOTS groups, respectively. The P DOTS group had the lowest unemployment percentage (19.0%) among the 4 groups. Thus, a significant correlation existed between the DOTS implementation tactics and the presence/ absence of the patients' occupations (P < 0.001). Among the 417 patients who completed DOTS, 99.8% achieved successful treatment. Among the 112 patients who did not complete DOTS, 89.3% achieved successful treatment, and this success rate was significantly lower than that for the group who completed DOTS (P < 0.00 1). Among the visiting, HWC, and P DOTS groups, the completion of DOTS resulted in a high treatment success rate. DISCUSSION: Patients who completed DOTS achieved better treatment outcomes; therefore, it is important to provide patients with medication support until their tuberculosis is resolved. The P DOTS group contained a higher percentage of full-time employees and had a significantly lower mean age; this was likely because pharmacies are accessible at night and during the weekend. There was no significant difference in the DOTS completion rates according to implementation tactic, which suggests that it is important to assist patients with their medication according to their needs.

[EXAMINATION OF TUBERCULOSIS OUTBREAK INDEX CASES IN OSAKA CITY].

OBJECTIVE: To analyze tuberculosis outbreak index cases in order to improve preventative measures. METHODS: Outbreaks reported in Osaka City between 2008 and 2014 were investigated. The index cases were examined according to category group, sex, age, chest radiograph findings, sputum smear examination, patient delay, doctor delay, total delay in case finding, and adherence to regular health examinations. As controls, 467 patients in Osaka City with newly registered sputum smear-positive pulmonary tuberculosis in 2011 were included. RESULTS: Thirteen outbreaks occurred. The group categories included enterprises (9 outbreaks), preparatory schools (2), a junior high school (1), and other (1). The group of index cases consisted of 12 men (92.3%) and one woman (7.7%), with a mean age of 39.1 years; 11 (84.6%) were 30 to 50 years of age. Their ages ranged from 15 to 54 years. Of the control group of patients with sputum smear-positive pulmonary tuberculosis, 69.2% were 60 years or older, with a mean age of 65.4 years. These results suggest that the index case group was significantly younger (p < 0.001). There were ten cases (76.9%) of patient delay (initial visit 2 months or more after onset), and 8 (61.5%) of total delay (diagnosed 3 months or more after onset). These rates were significantly higher than those in the control group (p < 0.001). There were regular health examinations in four cases; among those, one did not see a doctor and another did not receive further examination. Chest radiographs revealed cavities in 12 cases (92.3%). All sputum smears were positive, with grades of 1 + in one case (7.7%), 2 + in two cases (15.4%), and 3 + in 10 cases (76.9%). These cases had a significantly higher rate of smear positivity than those in the control group (p < 0.001). DISCUSSION: The index cases were predominantly male, in their prime, and had higher infectivity rates. These findings suggest the importance of preventing delays in case findings and receiving regular and adequate health examinations.

Equivalence between a generalized dendritic network and a set of one-dimensional networks as a ground of linear dynamics.

It has been shown by some existing studies that some linear dynamical systems defined on a dendritic network are equivalent to those defined on a set of one-dimensional networks in special cases and this transformation to the simple picture, which we call linear chain (LC) decomposition, has a significant advantage in understanding properties of dendrimers. In this paper, we expand the class of LC decomposable system with some generalizations. In addition, we propose two general sufficient conditions for LC decomposability with a procedure to systematically realize the LC decomposition. Some examples of LC decomposable linear dynamical systems are also presented with their graphs. The generalization of the LC decomposition is implemented in the following three aspects: (i) the type of linear operators; (ii) the shape of dendritic networks on which linear operators are defined; and (iii) the type of symmetry operations representing the symmetry of the systems. In the generalization (iii), symmetry groups that represent the symmetry of dendritic systems are defined. The LC decomposition is realized by changing the basis of a linear operator defined on a dendritic network into bases of irreducible representations of the symmetry group. The achievement of this paper makes it easier to utilize the LC decomposition in various cases. This may lead to a further understanding of the relation between structure and functions of dendrimers in future studies.

Initial-value semiclassical propagators for the Wigner phase space representation: Formulation based on the interpretation of the Moyal equation as a Schrödinger equation.

We formulate various semiclassical propagators for the Wigner phase space representation from a unified point of view. As is shown in several studies, the Moyal equation, which is an equation of motion for the Wigner distribution function, can be regarded as the Schrödinger equation of an extended Hamiltonian system where its "position" and "momentum" correspond to the middle point of two points of the original phase space and the difference between them, respectively. Then we show that various phase-space semiclassical propagators can be formulated just by applying existing semiclassical propagators to the extended system. As a result, a phase space version of the Van Vleck propagator, the initial-value Van Vleck propagator, the Herman-Kluk propagator, and the thawed Gaussian approximation are obtained. In addition, we numerically compare the initial-value phase-space Van Vleck propagator, the phase-space Herman-Kluk propagator, and the classical mechanical propagation as approximation methods for the time propagation of the Wigner distribution function in terms of both accuracy and convergence speed. As a result, we find that the convergence speed of the Van Vleck propagator is far slower than others as is the case of the Hilbert space, and the Herman-Kluk propagator keeps its accuracy for a long period compared with the classical mechanical propagation while the convergence speed of the latter is faster than the former.

[Evaluation of risk factors for failed/defaulted on treatment outcomes of pulmonary tuberculosis in Osaka City].

OBJECTIVE: In this study, we analyzed the relationship between the risk of discontinuing medication and patient outcomes. METHODS: Newly registered patients with pulmonary tuberculosis from Osaka City who required outpatient treatment in 2011 were included in the study. We assessed the number of patient cures and the number of patients who completed medication as outcomes for successful treatment and the number of failed treatments and the number of treatments that were discontinued by patients as outcomes for failed and discontinued treatments. As related factors, we examined the risk of discontinuing medication, implementation of directly observed treatments, short course (DOTS), and planned duration of treatment. To assess the risk of discontinuing medication, we examined the following medical risk factors: (1) drug resistance to isoniazid or rifampicin, (2) diabetes, (3) use of immunosuppressive/anticancer drugs, (4) use of adrenal corticosteroid, (5) artificial dialysis, (6) human immunodeficiency virus infection/acquired immunodeficiency syndrome, (7) liver damage, and (8) side effects. The social risk factors were (1) being without a fixed address at the time of registration, (2) a history of discontinuing treatment, (3) lack of assistance with medication, (4) being elderly and requiring nursing care, (5) alcohol/drug dependence, (6) serious mental disease, (7) financial problems, (8) lack of the awareness of being ill, (9) keeping irregular hours, and (10) others. RESULTS: We identified 568 cases of successful treatment and 41 cases of failed and discontinued treatment. Multiple logistic regression analysis was performed, with successful treatment considered as the dependent variable 0 and failed and discontinued treatment considered as the dependent variable 1. The medical/social risk factors, positive/negative sputum smear test results, the planned duration of treatment (6 months/9 months or more), and the implementation of B type or higher DOTS were included as independent variables. The significant medical risk factors were drug resistance to isoniazid or rifampicin, the use of immunosuppressive/anticancer drugs, and side effects, with odds ratios of 4.55, 4.68, and 2.68, respectively. Further, a planned duration of treatment of 9 months or more and the implementation of B type or higher DOTS were associated with odd ratios of 4.51 and 0.35, respectively. CONCLUSION: These results highlight the need to assess risk factors for discontinuing treatment and to adopt measures to overcome these factors, such as the type of DOTS being implemented, in each case.

[Tuberculosis contact investigation in hospitals].

OBJECTIVE: To contribute to measures against hospital-acquired infections by analyzing and evaluating tuberculosis contact investigations in hospitals. METHODS: This study included 202 tuberculosis cases between January 2010 and September 2011 in which contact investigations were requested from the Public Health Office in Osaka City. RESULTS: 1) To assess the necessity for contact investigation and the demographics of index cases, contact investigations were conducted for 66 of the 202 cases. Index cases with higher rates of contact investigation included those with "higher degree of sputum smear positivity," "respiratory symptoms," "period from hospitalization to tuberculosis diagnosis of 8 days or longer," and "high-risk procedures (including endotracheal intubation, endotracheal aspiration, and bronchofiberscopy)." 2) A total of 632 contact persons from the following professions underwent QuantiFERON-TB (QFT) testing: 59 doctors, 492 nurses, 60 other hospital staff members, and 21 patients, and the positive QFT rates were 18.6, 10.8, 13.3, and 14.3%, respectively. 3) Among the 66 index cases for which contact investigations were conducted, there were 0 QFT-positive contact persons in 37 cases (56.1%), 1 or more in 29 (43.9%), and 2 or more in 18 cases (27.3%). Assuming the dependent variable to be 0 and 1, respectively, for index cases with 0 and 2 or more QFT-positive contact persons, we performed a multiple logistic regression analysis with independent variables that included the presence or absence of high-risk procedures, period from hospitalization to diagnosis either within 7 days or 8 or more days, presence or absence of cough and cavity, and the degree of sputum smear positivity (1+/2+/3+). Among these variables, those significantly associated with cases with 1 and 2 or more QFT-positive persons included the "presence of high-risk procedures" and "period from hospitalization to diagnosis of 8 days or longer" (P < 0.05). DISCUSSION: Our results suggest that early diagnosis and appropriate responses during high-risk procedures may be necessary measures to prevent hospital-acquired infections.

[Medication support and treatment outcome in homeless patients with tuberculosis].

PURPOSE: We conducted a study on factors related to treatment outcome and medication support in homeless patients with tuberculosis. METHODS: Participants were 433 homeless patients with tuberculosis newly registered in Osaka City between 2007 and 2009. We investigated factors related to treatment outcome (e.g., length of hospital stay, scheduled duration of outpatient treatment, and type of DOTS). Controls were 3,047 non-homeless patients with pulmonary tuberculosis newly registered in Osaka City during the same period. RESULTS: Regarding medication support, 219 (70.4%) of the 311 patients with successful treatment received DOTS and completed the treatment during their hospital stay. Thirty-five (72.9%) of the forty-eight patients who did not complete treatment left the hospital at their own discretion, resulting in treatment failure/default. The rate of treatment failure/default in the homeless patients with pulmonary tuberculosis was 11.0%, significantly higher than that of non-homeless patients with pulmonary tuberculosis (6.5%; P < 0.001). Among the 102 patients receiving community DOTS, medication compliance occurred at least 5 days a week in 66 patients (64.7%) and treatments failed or were interrupted in 10 patients (9.8%). The mean hospital stay was 2.0 +/- 1.6 months in patients with failed/defaulted treatment and 4.4 +/- 2.5 months in those with successful treatment. The scheduled duration of outpatient treatment was 7.9 +/- 2.7 months in patients with failed/defaulted treatment and 3.6 +/- 2.1 months in those with successful treatment. Shorter length of hospital stay and longer scheduled duration of outpatient treatment were associated with a higher rate of treatment failure/default (P < 0.01). CONCLUSION: Homeless patients with tuberculosis had a higher rate of treatment failure/default, most likely due to leaving the hospital at their own discretion. Patients with successful treatment generally completed treatment during their hospital stay. In contrast, patients who received community DOTS after discharge from the hospital had a higher rate of treatment failure/default, despite receiving medication at least 5 days a week. This suggests the need for adequate support, particularly in patients with a shorter hospital stay and those with a longer scheduled duration of outpatient treatment.

[Interpreting "equivocal" results obtained from the QuantiFERON-TB Gold In-Tube test in contact investigations].

OBJECTIVE: In this study, we demonstrate the interpretation of "equivocal" results by the QuantiFERON"-TB Gold In-Tube (QFT-GIT) test in contact investigations. METHODS: The participants of the contact examinations were assessed by the QFT-GIT test after 2 to 4 months from the last contact with smear-positive tuberculosis patients. The study was conducted between April 2011 and March 2012. We enrolled 79 contact participants whose QFT-GIT tests produced equivocal results. RESULTS: The average age of the enrolled contacts was 35.9 years and the average interval from the last contact to the first QFT-GIT test was 85.4 days (range 62-118 days). The second QFT-GIT test produced negative results in 42 (53%) participants, equivocal results in 28 (35%), and positive results in 9 (11%). These 9 positive contacts belonged to the group of contacts with an index case whose QFT-GIT positive rate was more than 15%. The contacts belonging to groups with a QFT positive rate higher than 15% in the initial test had significantly higher QFT positive rates in the follow-up test than those belonging to groups with lower initial QFT positive rates (p=0.011). CONCLUSIONS: After retesting contacts with initially equivocal QFT results, 65% demonstrated either negative or positive results. If a contact's second QFT-GIT test is positive, it is highly probable that he/she is infected with tuberculosis and adequate treatment for latent TB infection is indicated. Thus far, no guidelines have been established for the management of contacts with equivocal results by the QFT-GIT test; therefore, further investigations and discussions are mandatory.

Influence of the 2009 financial crisis on detection of advanced pulmonary tuberculosis in Osaka city, Japan: a cross-sectional study.

OBJECTIVE: To investigate the association between the economic recession and the detection of advanced cases of pulmonary tuberculosis in Osaka city from 2007 to 2009. DESIGN: A repeated cross-sectional study. SETTING: Osaka city has been the highest tuberculosis burden area in Japan. After the previous global financial crisis, the unemployment rate in Osaka prefecture has deteriorated from 5.3% in 2008 to 6.6% in 2009. PARTICIPANTS: During the study period, 3406 pulmonary tuberculosis cases were enrolled: 2530 males and 876 females; 1546 elderly cases (65 years and above) and 1860 young cases (under 65 years); 417 homeless cases and 2989 non-homeless cases. OUTCOME MEASURES: Patients' information included the sex, age, registry, health insurances, places of detection, sputum smear test results, patients' delay, doctors' delay and the grade of chest x-ray findings. They were statistically analysed between 2007 and 2008, two years before and just before the financial crisis, and between 2008 and 2009, just before and after the financial crisis. RESULTS: The total numbers of pulmonary tuberculosis cases were 1172 in 2007, 1083 in 2008 and 1151 in 2009. In health examinations for non-homeless people, higher number of cases in 2009 were sputum smear positive, had respiratory symptoms and showed advanced disease in chest x-rays than those in 2008, with a longer patients' delay. On the contrary, in health examination for homeless people, fewer cases of advanced pulmonary tuberculosis were found in 2009 than in 2008, with a shorter patients' delay. In clinical examinations, there was no trend towards a difference between non-homeless and homeless people. CONCLUSIONS: Although homeless people might be protected by public assistance, tuberculosis prevention and control need to be reinforced for the non-homeless population after the financial crisis.