Successful treatment of acyclovir-resistant herpes simplex virus infection with amenamevir in a patient who received umbilical cord blood transplantation for T-cell prolymphocytic leukemia.

A 34-year-old woman received umbilical cord blood transplantation for refractory T-cell prolymphocytic leukemia after salvage therapy with alemtuzumab. She developed right angular cheilitis on the 46th day after transplantation, which worsened after receiving systemic steroid therapy for extensive chronic graft versus host disease. The treatment dosage of acyclovir (ACV), ganciclovir, and vidarabine ointment was not effective due to ACV-resistant mutations of the herpes simplex virus type 1 (HSV-1) in the thymidine kinase domain. Foscarnet is expected to be effective against ACV-resistant HSV-1 infection. However, it could not be used because the patient developed renal dysfunction. Several viral thymidine kinase mutations related to ACV resistance were found in the patient's sample. Nevertheless, amenamevir, a helicase-primase complex inhibitor, was effective in our patient who was significantly immunocompromised after allogeneic hematopoietic stem cell transplantation (allo-HSCT). ACV-resistant HSV infection after allo-HSCT is an rare but important complication in the era of low-dose long-term ACV prophylaxis. To date, there is no established treatment against ACV-resistant HSV infection. This case report showed that amenamevir could be a promising treatment option for ACV-resistant HSV infection in patients with renal failure after allo-HSCT.

HIV estimation using population-based surveys with non-response: A partial identification approach.

HIV estimation using data from the demographic and health surveys (DHS) is limited by the presence of non-response and test refusals. Conventional adjustments such as imputation require the data to be missing at random. Methods that use instrumental variables allow the possibility that prevalence is different between the respondents and non-respondents, but their performance depends critically on the validity of the instrument. Using Manski's partial identification approach, we form instrumental variable bounds for HIV prevalence from a pool of candidate instruments. Our method does not require all candidate instruments to be valid. We use a simulation study to evaluate and compare our method against its competitors. We illustrate the proposed method using DHS data from Zambia, Malawi and Kenya. Our simulations show that imputation leads to seriously biased results even under mild violations of non-random missingness. Using worst case identification bounds that do not make assumptions about the non-response mechanism is robust but not informative. By taking the union of instrumental variable bounds balances informativeness of the bounds and robustness to inclusion of some invalid instruments. Non-response and refusals are ubiquitous in population based HIV data such as those collected under the DHS. Partial identification bounds provide a robust solution to HIV prevalence estimation without strong assumptions. Union bounds are significantly more informative than the worst case bounds without sacrificing credibility.

Daratumumab­resistant multiple myeloma with extramedullary disease successfully treated with combination elotuzumab, pomalidomide and dexamethasone: A case report.

Despite the emergence of monoclonal antibodies, the prognosis of patients with multiple myeloma (MM) with extramedullary disease remains poor. The present report describes a rare case of daratumumab-refractory MM that was successfully treated with elotuzumab, pomalidomide and dexamethasone. A 66-year-old male patient diagnosed with MM was treated with bortezomib, lenalidomide and dexamethasone, followed by high-dose chemotherapy and autologous stem cell transplantation. Thereafter, the patient was treated with lenalidomide and dexamethasone as maintenance therapy. This was changed to daratumumab, bortezomib and dexamethasone when new paraskeletal lesions were identified, resulting in marked tumor shrinkage. After 15 months, an increase in serum monoclonal protein levels, development of a skeletal lesion in the right second rib and extramedullary disease of the right thoracic mediastinal lymph nodes were noted. Treatment with elotuzumab, pomalidomide and dexamethasone (EPd) resulted in expeditious symptomatic improvement and regression of the lesions. Notably, during daratumumab, bortezomib and dexamethasone treatment, lymphocyte counts gradually increased to a level at which elotuzumab was sufficiently effective. EPd might be a promising strategy for the treatment of patients with relapsed extramedullary MM while on daratumumab treatment.

Clonal hematopoiesis of a novel dic(18;20) clone following allogeneic hematopoietic stem cell transplantation.

A 55-year-old man in first complete remission of acute myeloid leukemia with a normal karyotype underwent allogeneic hematopoietic stem cell transplantation from a human-leukocyte-antigen-matched sibling. Bone marrow examination on day 28 confirmed complete remission, but G-banding analysis revealed a novel chromosomal abnormality, including dic(18;20)(p11.2;q11.2). The patient developed moderate chronic graft-versus-host disease on day 174, and the abnormal clones identified by dic(18;20) significantly increased after that point. Chimerism testing repeatedly confirmed complete donor type. Although next-generation sequencing showed no clonal hematopoiesis-related gene mutations, copy number analysis of the donor and the recipient revealed copy number deletion of 18p, 18q, and 20q. The patient has maintained remission for more than 2 years to date without developing a hematologic neoplasm or cytopenia. The distinctive clonal hematopoiesis with a dicentric chromosome seemed to have undergone the breakage-fusion-bridge cycle, which could cause the complex events of deletion, amplification, and inversion. These copy number alterations might have increased the number of clones with growth advantage, and the highly inflammatory environment in the recipient due to graft-versus-host disease might have contributed to the clonal selection.

Three cases of suspected pleuroparenchymal fibroelastosis after allogeneic hematopoietic cell transplantation.

This article reports the clinical course and imaging findings of three cases of suspected pleuroparenchymal fibroelastosis (PPFE) after allogeneic hematopoietic cell transplantation (HCT). All patients complained of dyspnea more than 5 years after HCT, had progressive restrictive deficits on respiratory function tests, and presented with pneumothorax, pleural thickening, or exacerbation of consolidation in the upper lobe of the lung. Though lung biopsy was not done in all three cases, the clinical findings and results of spirometry were compatible with those of PPFE. PPFE has been sporadically reported as a pulmonary complication of allogeneic HCT; however, clinical diagnostic criteria other than histological diagnosis and treatment methods have not yet been established. The accumulation of more cases is necessary to improve the prognosis of PPFE complications.

Thoracic Aortic Volume as a Predictor of Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: It is unclear whether thoracic aortic volume (TAV) is useful for cardiovascular (CV) disease prognosis and risk assessment. PURPOSE: This study evaluated cross-sectional associations of TAV with CV risk factors, and longitudinal association with incident CV events in the multiethnic study of atherosclerosis. STUDY TYPE: Retrospective cohort analysis of prospective data. POPULATION: 1182 participants (69 ± 9 years, 54% female, 37% Caucasian, 18% Chinese, 31% African American, 14% Hispanic, 60% hypertensive, and 20% diabetic) without prior CV disease. FIELD STRENGTH AND SEQUENCES: Axial black-blood turbo spin echo or bright blood steady-state free precession images on 1.5T scanners. ASSESSMENT: TAV was calculated using Simpson's method from axial images, and included the ascending arch and descending segments. Traditional CV risk factors were assessed at the time of MRI. CV outcomes over a 9-year follow-up period were recorded and represented a composite of stroke, stroke death, coronary heart disease (CHD), CHD death, atherosclerotic death, and CVD death. STATISTICAL TESTS: Multivariable linear regression models adjusted for height and weight were used to determine the relationship (ß coefficient) between TAV and CV risk factors. Cox regression models assessed the association of TAV and incident CV events. A P-value of <0.05 was deemed statistically significant. RESULTS: Mean TAV was = 139 ± 41 mL. In multivariable regression, TAV was directly associated with age (ß = 1.6), male gender (ß = 23.9), systolic blood pressure (ß = 0.1), and hypertension medication use (ß = 7.9); and inversely associated with lipid medication use (ß = -5.3) and treated diabetes (ß = -8.9). Compared to Caucasians, Chinese Americans had higher TAV (ß = 11.4), while African Americans had lower TAV (ß = -7.0). Higher TAV was independently associated with incident CV events (HR: 1.057 per 10 mL). CONCLUSION: Greater TAV is associated with incident CV events, increased age, and hypertension in a large multiethnic population while treated diabetes and lipid medication use were associated with lower TAV. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Analysis of applicator displacement in accelerated partial breast irradiation using a strut-based design brachytherapy applicator.

PURPOSE: This study aimed to identify factors associated with strut-adjusted volume implant (SAVI) displacement in accelerated partial breast irradiation (APBI) using a SAVI device. METHODS AND MATERIALS: We retrospectively analyzed computed tomography scans taken at the time of treatment planning and immediately before treatment in 61 patients (median age; 55 years, range; 40-85) treated with SAVI and determined the amount of SAVI displacement that occurred between the time from planning to the treatment. The displacement was calculated for the CT axis and SAVI axis, which is related to the SAVI structure. To investigate the cause of the displacement, multivariate analysis was performed on the calculated standard deviation and the insertion angle of SAVI with respect to the sternum in each cross-section, breast density, amount of air around the SAVI, and SAVI length inside the patient to obtain the ß coefficient (p-value). RESULTS: On the CT coordinate system, positive correlations were observed between the SAVI insertion angle and air volume in the lateral (ß coefficient:0.255-0.483) and rotational directions (ß coefficient:0.341). On the SAVI coordinate system, positive correlations were observed between the SAVI insertion angle and air volume in all lateral (ß coefficient:0.270-0.354) and rotational directions (ß coefficient:0.294). A negative correlation was observed between the SAVI length inside the patient and the rotational direction (ß coefficient: -0.262). CONCLUSION: SAVI insertion angle, the amount of the air outside SAVI and SAVI insertion length are factors which affect the displacement of the applicator. From the results, the applicator displacement and rotation must be <3 mm and 10o in order to meet all the dose criteria. Thus, we should be aware of these factors during insertion of the device to avoid the problem in treatment delivery for the APBI.

[Intestinal pneumatosis developed during the treatment of severe gastrointestinal graft-versus-host disease after cord blood transplantation].

A 62-year-old female developed stage4 gastrointestinal graft-versus-host disease (GVHD) on day 109 following an allogeneic cord blood transplant for relapsed refractory angioimmunoblastic T-cell lymphoma. GVHD went into remission 4 weeks after receiving the steroid (mPSL 1 mg/kg), but abdominal bloating started to emerge at the same time. A diagnosis of intestinal pneumatosis was made on day 158 after a CT scan revealed submucosal and serosal pneumatosis in the entire colon, and intestinal pneumatosis was identified as the cause. Fasting and reducing steroid use have helped. the abdominal symptoms, and the pneumatosis disappeared on day 175. No more flare-ups occurred, and the steroid was successfully stopped. After allogeneic transplantation, intestinal pneumatosis is a rather uncommon complications. Its pathogenesis is thought to be influenced by GVHD or steroids. Treatments for the disease may be incompatible with one another, and the response in individual cases needs to be studied in detail.

[Acquired thrombotic thrombocytopenic purpura following COVID-19].

COVID-19 often contributes to thrombus formation in microvessels, resulting in damaged vital organs. In this study, we report a case of COVID-19 associated with acquired thrombotic thrombocytopenic purpura (TTP). A 44-year-old man with a history of systemic lupus erythematosus presented with COVID-19 and concomitant hemolytic anemia and a marked thrombocytopenia. The patient was diagnosed with acquired TTP because ADAMTS13 inhibitor was detected and ADAMTS13 activity below the sensitivity level. The patient developed agitated neuropsychiatric symptoms, such as aphasia, disorientation, and delirium, which improved after a plasma exchange, prednisolone, and rituximab administration. Only a few reports have revealed COVID-19 with TTP, and this is the first case in Japan. Although acquired TTP rarely develops, it is an important complication of COVID-19, and thus, it should be promptly diagnosed and treated as soon as possible.

Anti-inflammatory effects of ruxolitinib on chronic neutrophilic leukemia harboring CSF3R-T618I mutation with bilateral renal abscesses.

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) characterized by sustained mature neutrophilic leukocytosis. Recently, presence of colony-stimulating factor 3 receptor (CSF3R) mutations has been added to the diagnostic criteria for CNL. Anti-inflammatory effects of the JAK1/2 inhibitor ruxolitinib relieve constitutional symptoms associated with MPN, such as fatigue, night sweats, and fever. We present a case of CNL harboring CSF3R-T618I mutation exacerbated by concomitant bilateral renal abscesses, which was refractory to antibiotics, at the time of initial diagnosis. In this case, ruxolitinib rapidly improved not only CNL but the infection, due to its anti-inflammatory potency.

[Extranodal NK/T cell lymphoma, nasal type with local recurrence in the contralateral nasal cavity 15 years after initial sequential chemoradiotherapy].

A 72-year-old woman was diagnosed with extranodal NK/T cell lymphoma of the right nasal cavity and received sequential radiochemotherapy comprising focal radiotherapy and THP-COP chemotherapy. Showed a complete tumor response to the treatment; however, the tumor recurred in the contralateral right nasal cavity 15 years after the initial treatment. This was judged to be a marginal recurrence in the radiation field. After four cycles of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy, a second complete response was achieved. It is possible that another recurrence occurs in the future, and if the lesion is localized at the time of recurrence, it may be possible to control the disease again. Careful follow-up is considered necessary.

[Listeria meningitis during daratumumab/bortezomib/dexamethasone therapy in a patient with multiple myeloma].

An 88-year-old woman was diagnosed with multiple myeloma received third-line chemotherapy, including DBd (daratumumab [DARA], bortezomib, and dexamethasone [Dex]), and the myeloma was in remission. Sulfamethoxazole/trimethoprim (ST) prophylaxis was discontinued because the dose of Dex was reduced to 20 mg every 4 weeks after 21 cycles of DBd. After 28 cycles of DBd, altered consciousness with fever ensued, and she was referred to the emergency department where Listeria monocytogenes (LM) meningitis was diagnosed. CD38 inactivation is associated with increased LM susceptibility. In patients on Dara-based chemotherapy, antibiotic prophylaxis should be considered using ST, which has activity against Listeria.

[Successful treatment with imatinib for a patient with myeloid neoplasms with eosinophilia and abnormalities of PDGFRB due to t (5;14)(q33;q22)].

A 50-year old man with a 1-year history of eosinophilia presented with an eosinophil count exceeding 13,800/mm3 in the peripheral blood at the first visit. Bone marrow examination revealed that eosinophils accounted for 30% of the nucleated cell count, and G-band karyotyping analysis detected t (5;14)(q33;q22). Using peripheral blood FISH test, he was found to have platelet-derived growth factor receptor ß (PDGFRB) locus rearrangement at 5q32-33. The level of eosinophils in the peripheral blood reduced markedly 3 days after the initiation of Imatinib mesylate, 400 mg daily. This treatment was administered for 2 years, after which the peripheral blood FISH test was negative for PDGFRB. In this disease, although most cases are with t (5;12), those with t (5;14) are relatively rare, and the long-term course of this translocation is unknown.

Right ventricular function as assessed by cardiac magnetic resonance imaging-derived strain parameters compared to high-fidelity micromanometer catheter measurements.

Right ventricular function has prognostic significance in patients with pulmonary hypertension. We evaluated whether cardiac magnetic resonance-derived strain and strain rate parameters could reliably reflect right ventricular systolic and diastolic function in precapillary pulmonary hypertension. End-systolic elastance and the time constant of right ventricular relaxation tau, both derived from invasive high-fidelity micromanometer catheter measurements, were used as gold standards for assessing systolic and diastolic right ventricular function, respectively. Nineteen consecutive precapillary pulmonary hypertension patients underwent cardiac magnetic resonance and right heart catheterization prospectively. Cardiac magnetic resonance data were compared with those of 19 control subjects. In pulmonary hypertension patients, associations between strain- and strain rate-related parameters and invasive hemodynamic parameters were evaluated. Longitudinal peak systolic strain, strain rate, and early diastolic strain rate were lower in PAH patients than in controls; peak atrial-diastolic strain rate was higher in pulmonary hypertension patients. Similarly, circumferential peak systolic strain rate was lower and peak atrial-diastolic strain rate was higher in pulmonary hypertension. In pulmonary hypertension, no correlations existed between cardiac magnetic resonance-derived and hemodynamically derived measures of systolic right ventricular function. Regarding diastolic parameters, tau was significantly correlated with peak longitudinal atrial-diastolic strain rate (r = -0.61), deceleration time (r = 0.75), longitudinal systolic to diastolic time ratio (r = 0.59), early diastolic strain rate (r = -0.5), circumferential peak atrial-diastolic strain rate (r = -0.52), and deceleration time (r = 0.62). Strain analysis of the right ventricular diastolic phase is a reliable non-invasive method for detecting right ventricular diastolic dysfunction in PAH.

[Case of Primary Mediastinal Non-Seminomatous Germ Cell Tumor with Pathological Complete Response after Induction Chemotherapy and Residual Tumor Resection Accompanied by Late-Onset Bilateral Pneumothorax].

A man in his late teens presented to our hospital with left-sided chest pain. CT showed a 12 cm sized anterior mediastinal tumor and tiny nodules in the bilateral lower lobe of the lungs. The patient also had elevated serum AFP and hCG levels. Pathological findings of the CT-guided biopsy specimen suggested a yolk sac tumor, and no testicular abnormality was seen on ultrasound. Following whole body examination, he was diagnosed with primary mediastinal non-seminomatous germ cell tumor. After sperm cryopreservation, 4 courses of BEP(bleomycin[BLM]plus etoposide[ETP]plus cisplatin[CDDP]) chemotherapy were administered to normalize the tumor markers. The mediastinal tumor shrank but was still widely in contact with the left pulmonary artery. He underwent mediastinal tumor resection and segmentectomy of the left upper lobe via a median sternotomy. The maximum tumor size was 9 cm in diameter, and pathological examination of the specimen revealed only an immature teratoma with no malignant findings. At the same time, both the lower lung nodules were resected and pathologically identified as intrapulmonary lymph nodes. No recurrence was observed, but 6 months after surgery, he made an emergency visit to our department due to dyspnea. Bilateral pneumothorax was detected, and chest tube insertion was rapidly performed that improved with only right chest drainage. Cytology of the right hemorrhagic pleural effusion showed no evidence of malignancy. It was possible that a postoperative right-to-left shunt of the anterior mediastinum was present, leading to bilateral pneumothorax.

[A Case of Philadelphia Chromosome-Positive Acute Myeloid Leukemia Extramedullary Recurrence in a Patient Undergoing Thoracoscopy for Massive Pleural Effusion].

A man in his early 70s visited a previous hospital because of pancytopenia and was diagnosed with acute myeloid leukemia based on a bone marrowexamination. The karyotype was 46,XY, t(9;22)(q34;q11.2)[2/20], and real-time polymerase chain reaction(PCR)revealed minor bcr-abl chimeric mRNA. Finally, the patient was judged as having Philadelphia chromosome- positive acute myeloid leukemia, and remission induction chemotherapy with the JALSG AML 201 protocol was initiated in combination with dasatinib to achieve complete remission. After 3 courses of consolidation chemotherapy, the anticancer drugs were discontinued because of deterioration of his general condition and renal insufficiency. Six months after the initial treatment, he was referred to our department, and no evidence of recurrence was confirmed on bone marrow examination. However, 2 months later, right massive pleural effusion was detected, and he was admitted to the department of pneumology at our hospital. Thoracoscopic pleural biopsy was performed at the time of chest tube insertion, and he was diagnosed with acute myeloid leukemia extramedullary recurrence. Peripheral myeloblasts appeared and increased rapidly, accompanied by further exacerbation of renal function; thus, he received palliative care at the department of hematology and oncology.

Refusal bias in HIV data from the Demographic and Health Surveys: Evaluation, critique and recommendations.

Non-response is a commonly encountered problem in many population-based surveys. Broadly speaking, non-response can be due to refusal or failure to contact the sample units. Although both types of non-response may lead to bias, there is much evidence to indicate that it is much easier to reduce the proportion of non-contacts than to do the same with refusals. In this article, we use data collected from a nationally representative survey under the Demographic and Health Surveys program to study non-response due to refusals to HIV testing in Malawi. We review existing estimation methods and propose novel approaches to the estimation of HIV prevalence that adjust for refusal behaviour. We then explain the data requirement and practical implications of the conventional and proposed approaches. Finally, we provide some general recommendations for handling non-response due to refusals and we highlight the challenges in working with Demographic and Health Surveys and explore different approaches to statistical estimation in the presence of refusals. Our results show that variation in the estimated HIV prevalence across different estimators is due largely to those who already know their HIV test results. In the case of Malawi, variations in the prevalence estimates due to refusals for women are larger than those for men.

[A Patient Surviving More Than Five Years Due to the Effect of Sequential Alternating Chemotherapy Administered to Metachronous Overlapping Cancer of Multiple Myeloma and Stageâ £ EGFR Positive Non-Small Cell Lung Cancer].

A woman in her late 50s visited our department because an abnormal shadow of her right lung was seen on her chest radiographs. She was diagnosed with Stage ⅠA primary lung adenocarcinoma with EGFR exon 19 deletion mutation by performing thoracoscopic middle lobe resection and lymph node dissection. After 1 and a half years, the lung metastasis recurred and she received gefitinib(GEF)monotherapy for 9 months and withdrew because of the sustained complete response(CR). Three years and 7 months after the first visit, she was diagnosed as having complication of revised international staging system(R-ISS)Ⅱ multiple myeloma with anemia, retinal vein occlusion, and M proteinemia. It was decided that treatment for myeloma should be given priority and hence, Bd, high dose chemotherapy with auto-peripheral blood stem cell transplantation(aPBSCT), Ld, ELd and Pd therapy were performed sequentially until progressive disease(PD)and survival benefit were evident. As lung metastasis of adenocarcinoma also progressed, myeloma treatment was terminated, GEF was administered intermittently and consequently, shrinkage of the lung metastasis was confirmed. Depending on sequential alternating chemotherapy for both malignancies, a relatively long survival time of 5.4 years from the initiation of treatment for myeloma and 7.5 years from the recurrence of lung adenocarcinoma was achieved.

[A Case of Synchronous Diffuse Large B-Cell Lymphoma of the Right Breast and Invasive Ductal Carcinoma of the Left Breast].

A woman in her early 60s noticed bilateral breast masses and visited a different hospital. Core needle biopsy showed diffuse large B-cell lymphoma of the right breast and invasive ductal carcinoma of the left breast. After referral to our department, PET-CT was performed. Compared with mild fluorodeoxyglucose accumulation in left breast cancer(BC), highly accumulated lesions were found on the right breast, left anterior chest wall, nasopharynx, and tonsil. The right breast lesion was the largest with a diameter of 30mm and was considered the primary lesion of malignant lymphoma(ML). The ML was classified as stage Ⅳ, pathologically proven with erythema of the left breast and nasopharynx. Three courses of R-CHOP were performed. However, due to suspicion of heart failure, chemotherapy was changed to R-CEOP(non-anthracycline-containing regimen)and 3 courses were additionally performed. The therapeutic effect of R-Chemo for ML was CR. Left BC showed a tendency of shrinkage. After intrathecal administration of anticancer drugs to prevent infiltration of ML into the central nervous system and preoperative endocrine therapy with aromatase inhibitor, left lumpectomy and sentinel lymph node biopsy were performed. BC was classified as clinical stage ⅠA and had an estrogen receptor score of 3b. Postoperative whole breast radiotherapy was completed, and the planned internal use of exemestane was more than 5 years. With multidisciplinary therapy, 3.5 years had passed since the initial treatment without recurrence.

[A Case of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Achieving Complete Molecular Response with Ponatinib Therapy despite the Development of Hemorrhagic Stroke during Remission Induction Chemotherapy].

A man in his late 50s had lumbago and thrombocytopenia. He was diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia(Ph plus ALL). Remission induction chemotherapy was initiated with JALSG Ph plus ALL 208 protocol, but cerebral infarction in the right occipital lobe developed on day 2 and, to make matters worse, was accompanied by hemorrhagic cerebral infarction in the left occipital lobe on day 9. We decided that chemotherapy with multiple drugs was difficult to continue, and it was stopped. After improvement of the general condition, dasatinib therapy was started on day 52. After about 5 months, Ph plus ALL relapsed. Although mild disorientation and visual field defects remained due to old cerebral infarction, organ function was maintained, and patient performance status(PS)was classified as 1. Introduction of ponatinib was considered feasible, and ponatinib was started from a dose of 15mg/day to prevent the occurrence of vaso- occlusive adverse events. It was gradually increased to 30mg /day and continued about 4 months without recurrence of cerebral infarction. Complete molecular response was achieved with ponatinib therapy. It was suggested that, in patients with Ph plus ALL with a history of cerebral infarction, ponatinib could be a treatment option under careful risk management.