Neurological complications of rotavirus infection in children: A systematic review and meta-analysis.

AIM: To systematically review the clinical features and outcomes of paediatric patients developing neurological complications associated with a rotavirus infection. METHODS: A systematic literature review and meta-analysis was performed, including articles published from 1984 to 2020. Neurological complications were classified into four groups: encephalitis, cerebellitis, encephalo-cerebellitis and benign convulsions with mild gastroenteritis (CwG). RESULTS: Out of 68 reports that fulfilled the research criteria, 99 cases of CwG, 39 cases of encephalitis, 18 cases of encephalo-cerebellitis and five cases of cerebellitis were collected. Ninety-five patients were from Asia. Median age was 22 (IQR 14-29) months, and the children who developed CwG were significantly younger (19, IQR 12-24 months, p < 0.0001) than the others. Status epilepticus was observed in 23% and 5% of the encephalitis and CwG groups respectively. The most frequently described neuroimaging finding were lesions of the splenium of corpus callosum. Four deaths were reported in the encephalitis group, whereas no fatal events were described in the other groups. Among the surviving children, the encephalo-cerebellitis group showed the most severe long-term outcome. All cases of CwG recovered completely. CONCLUSION: Older age at diagnosis and the development of encephalo-cerebellitis are associated with a higher risk of long-term complications.

Prospective observational study on the complications and tolerability of a peripherally inserted central catheter (PICC) in neuro-oncological patients.

PURPOSE: The use of central venous catheters with peripheral insertion (PICC) has increased rapidly in recent years, particularly in cancer patients. The benefits provided may occasionally be affected by relevant complications, such as infections and thrombotic events, especially in neuro-oncological patients. To date, the risk of PICC-related complications in this subset of patients is unknown, as is tolerability. As a primary objective, this study aimed to collect complications related to PICCs in primary neuro-oncological patients. As a secondary objective, the study aimed to evaluate PICC tolerability. METHODS: Neuro-oncological patients with PICCs that were placed as part of normal clinical practice at IRCCS Neurologico C. Besta were consecutively enrolled in the study. PICC-related complications were recorded immediately (during the procedure), early (within 1 week after PICC insertion), and late (1-3-5 months after PICC placement). At the same time points, all patients were also evaluated for tolerability through interviews with semi-structured, open-ended questions. RESULTS: Sixty patients were enrolled (41 males and 19 females, with a median age of 56.2 years). Excluding loss to follow-up, 33/49 patients developed at least one complication related to the PICC. Immediate complications mainly included hematoma (8), accidental arterial puncture (4), and primary malpositioning (3). Regarding early and late complications, 3 device-related infections, 8 thrombotic events, and 20 mechanical complications were registered. Semi-structured interviews revealed an overall positive experience with the device. The most negative impact was on hygiene habits, with 34 patients becoming caregiver-dependent. Over time, almost all patients became used to the device and perceived greater security during chemotherapy. A strongly negative issue was the difficulty of relying on competently trained healthcare personnel in outpatient setting. CONCLUSION: The results showed a nonnegligible increased thromboembolic risk in neuro-oncological patients with PICCs, almost double that in historical oncological populations. It is essential to extend the study to a greater number of patients to achieve reliable results and to identify patients at high risk. The device seems to be positively accepted by the majority of patients, without affecting activities of daily living.

Extra central nervous system metastases from glioblastoma: a new possible trigger event?

Extra-cranial metastases of glioblastoma (GBM) represent a rare event, and the biological-genetic mechanisms involved in the pathogenesis have not yet been determined. We report the case of a young patient with multiple visceral and osseous metastases occurred after 4 years after first diagnosis of GBM. The strangeness as well as the rarity of this event does not allow to identify an effective treatment for GBM metastases, making the management of this ominous tumor an even greater challenge.

Safety and efficacy of primary central nervous system lymphoma treatment in elderly population.

Elderly patients represent an important subgroup in primary central nervous system lymphoma (PCNSL) that accounts for approximately half the cases. Furthermore age represents one of the heaviest prognostic factors and in some cases it has more effect on survival than therapies. We performed a retrospective analysis to assess the toxicity and the efficacy of high-dose methotrexate (HDMTX) chemotherapy in a PCNSL population older than 70 years. Seventeen consecutive immunocompetent patients older than 70 years, with histologically confirmed PCNSL, without systemic involvement, treated with HDMTX at our institution between May 2005 and April 2013, were retrospectively evaluated. Main outcome measures were acute toxicity and tumour response. No evidence of haematological toxicity was recorded in 47 % of patients and no deaths related to toxicity grade were reported. Patients achieved a partial response after 3 cycles of chemotherapy in 53 % of cases. The median overall survival (m-OS) from diagnosis was 20.9 months (range 5.2-34 months), with OS-12 of 58.8 % and an OS-24 of 45.4 %. Since there is no standard of care in the treatment of PCNSL in elderly population, it should be taken into account that elderly patients not always can be considered "fragile" and the general tendency to less treat to avoid severe toxicity should not be the rule.

A case of medulloblastoma in adult patient affected by anaplastic oligoastrocytoma.

Medulloblastomas and high-grade gliomas (HGG) are two distinct brain tumor, with different peculiarities in terms of age of onset, localizations and prognosis. The coexistence of the two neoplasms in the same adult patient is an extremely rare event. We present the case of a woman treated with radio-chemotherapy for an HGG, who developed a cerebellar medulloblastoma 7 years later. Considering the poor prognosis of these tumors, the lack of knowledge about the mechanisms of onset as well as effective therapies, it is necessary to determine the exact role of irradiation and the presence of any potential molecular genetic abnormalities in the developing of the two tumors.

Isthmocele in a retroflexed uterus: a report of an unrecognized case.

The term "isthmocele" refers to a niche on the anterior wall of the uterine isthmus or of the cervical canal at the site of a previous cesarean delivery scar. Such anatomic defect can cause many gynecologic sequelae that only recently have being identified and described. Hysteroscopy is commonly considered the gold standard for the diagnosis and also for the treatment, at least in the case of defects of small size. The authors described the case of a 37-year-old woman who underwent a cesarean section (CS) seven years before, with a long lasting history of menstrual irregularities, and pelvic pain increasing during menstruation at the hypogastric level. Magnetic resonance imaging (MRI) showed an exceptionally large isthmocele on the anterior wall of a retroflexed uterus which was otherwise misinterpreted as the uterine cavity filled with menstrual blood during a previous hysteroscopy (HSC). Although exceptional, this case highlights the possibility that a large sized isthmocele in a retroflexed uterus could be misinterpreted as the uterine cavity filled by menstrual blood at HSC. In this case MRI definitely clarified the diagnosis.

MRI in the assessment of prolapsed pedunculated submucous leiomyomas: two case reports.

Uterine leiomyomas are the most common benign gynecological tumors affecting 20-30% of women in reproductive age. Despite their benignity, in some cases several symptoms may require surgical intervention. Submucosal leiomyomas are less frequent (5-10%), but are usually symptomatic. Approximately 2.5% of the myomas are pedunculated and can protrude in the cervical canal. Symptomatic leiomyomas can be treated either by hysterectomy or myomectomy, and these procedures can be performed with several techniques. Whenever possible, hysteroscopic myomectomy is better because it has many advantages, as it also preserves future fertility. Two interesting cases of prolapsed pedunculated submucous leiomyomas are reported in order to prove that magnetic resonance imaging (MRI) is essential to choose the most appropriate treatment and to perform an adequate presurgical planning, which must be based on an overall assessment of the leiomyoma's characteristics (number, location, size and presence or absence of a stalk) and the patient's characteristics.

Update on treatment strategies for anaplastic glioma: a review of literature.

Anaplastic gliomas (AG) include 6-10% of all newly diagnoses of primary brain tumors. They have an unfavourable prognosis and, to date, there is not an established treatment universally recognized. Four recent randomized clinical trials were identified for a total of 1,170 patients (anaplastic-astrocytomas, anaplasticoligoastrocytoma, anaplastic-oligodendroglioma), in order to define the better sequence and timing of chemo-radiotherapy, Three studies compared radiotherapy (RT) treatment vs. radio-chemotherapy with procarbazine-lomustine-vincristine (PCV) or temozolomide (TMZ) or dibromodulcitol and bichloroethylnitrosurea (DBD/BCNU) and only one compared RT vs chemotherapy (CT) with PCV or TMZ. Results show no significant differences in terms of PFS/OS between RT/CT alone or combined treatment although a trend toward an improvement of OS was observed after RT + CT treatment (m-OS in RT + adjuvant PCV was 42.3 vs. 30.6 months in RT alone p=0.0003). Grade 3-4 mielotoxicity has been observed in almost all cases of patients treated with PCV + RT. None of four studies reviewed conducted a head to head comparison between PCV vs. TMZ. Only a study randomized patients to PCV/TMZ without however providing data in terms of PSF and OS between the two treatments. It found no significant differences in PFS from initial RT and adjuvant CT (PCV-TMZ) at progression compared to initial CT followed by RT at progression. The optimal treatment of AG should reasonably consider not only the histology as well as the molecular markers of the tumor, but also clinical conditions, age of patients, life expectancy, Karnofsky-performance-status and tumor resection to achieve in future the personalization of care.

Safety of bevacizumab in patients with malignant gliomas: a systematic review.

Angiogenesis has recently become a major target for the development of new antineoplastic drugs. The most serious adverse events linked to angiogenesis inhibitors are venous or arterial thromboembolism and haemorrhage. Thus, there is need to define with more certainty the impact of these new drugs in terms of adverse effects in neurological patients. The aim of the study is to assess the risk of venous thromboembolism (VTE) and bleeding in patients with malignant gliomas treated with bevacizumab with or without concomitant anticoagulant therapy. A review of published literature was performed in Medline, from which 476 records were identified. A total of 27 full-text articles, including retrospective analyses, retrospective reviews, and open label trials, were assessed for eligibility. The investigated drugs included bevacizumab alone, bevacizumab plus chemotherapy with/without concomitant radiation therapy; only two articles dealt with bevacizumab in association with anticoagulant treatment. A total of 2,208 patients with malignant gliomas, were identified and included in the analysis. From data it appears that patients receiving bevacizumab had a major risk of developing VTE that increased when bevacizumab is associated with radio-chemotherapy (4.27 vs 7.46 %). Regarding bleeding, data showed that patients treated with anticoagulant had a significantly increased risk of severe central nervous system (CNS) bleeding compared to patients not receiving anticoagulant therapy (0.6 vs 8.2 %). The use of bevacizumab combined with chemo-radiotherapy seems to be associated with a higher risk for VTE compared to patients receiving antiangiogenic therapy alone. The associated use of anticoagulants and bevacizumab far increases the risk of developing CNS and non-CNS bleeding higher than grade 3, compared to patients receiving bevacizumab alone.

Accuracy of tympanic and forehead thermometers in private paediatric practice.

AIM: To compare infrared tympanic and infrared contact forehead thermometer measurements with traditional rectal digital thermometers. METHODS: A total of 254 children (137 girls) aged one to 24 months (median 7 months) consulting a private paediatric practice because of fever were prospectively recruited. Body temperature was measured using the three different devices. RESULTS: The median and interquartile range for rectal, tympanic and forehead thermometers were 37.6 (37.1-38.4)°C, 37.5 (37.0-38.1)°C and 37.5 (37.1-37.9)°C, respectively (p < 0.01). The limits of agreement in the Bland-Altman plots were -0.73 to +1.04°C for the tympanic thermometer and -1.18 to +1.64°C for the forehead thermometer. The specificity of both the tympanic and forehead thermometers for detecting fever above 38°C was good, but sensitivity was low. Forehead measurements were susceptible to the use of a radiant warmer. CONCLUSION: Both the tympanic and forehead devices recorded lower temperatures than the rectal thermometers. The limits of agreement were particularly wide for the forehead thermometer and considerable for the tympanic thermometer. In the absence of valid alternatives, because of the ease to use and little degree of discomfort, tympanic thermometers can still be used with some reservations. Forehead thermometers should not be used in paediatric practice.

Juvenile spring eruption: an outbreak report and systematic review of the literature.

BACKGROUND: Juvenile spring eruption of the helices of the ears is a distinctive sun-induced condition appearing on the light-exposed skin of the ears, typically in boys and young men in early spring. OBJECTIVES: To determine clinical features and outcome of juvenile spring eruption of the ears. METHODS: We report a new outbreak in 14 Swiss-Italian children. A systematic search of the literature was also performed. RESULTS: Five outbreaks in children involved a total of 203 cases (boys, 72%), and three outbreaks in young adults involved 223 male subjects. A further 54 sporadic cases were found: 41 among children (boys, 97%) and 13 among young adult males. The typical presentation included itching and diffuse erythema of both ears starting in the evening after exposure to bright sunlight during cold weather, followed within 24-48 h by papules or blisters. No other organ system was involved. The subjects recovered spontaneously without sequelae within 1-2 weeks. In New Zealand, among 162 school-aged boys, 20 developed the condition. CONCLUSIONS: A limitation is that the analysis was based upon the scanty available literature. Juvenile spring eruption is a self-limiting and generally easy recognizable variant of polymorphic light eruption. Outbreaks tend to appear on sunny and cold spring days. Paediatricians and general practitioners might rapidly develop the skills necessary to clinically appreciate this condition.

Combined use of percutaneous cryoablation and vertebroplasty with 3D rotational angiograph in treatment of single vertebral metastasis: comparison with vertebroplasty.

INTRODUCTION: This study aims to assess the effectiveness of combined procedure of cryoablation and vertebroplasty (CVT) for reduction of pain and improvement of the quality of life in patients with single painful metastatic vertebral fractures. METHODS: We retrospectively analyzed data from 23 patients with single vertebral metastasis treated with combined procedure of CVT, compared with those obtained in 23 patients treated by vertebroplasty. Pain intensity was evaluated by a visual analog scale (VAS) score administered before and 1 day, 1 week, and 1, 3, and 6 months after procedure. Quality of life was evaluated by an Oswestry Disability Index (ODI) score administered before and at 3 and 6 months after procedure. RESULTS: Procedural success was achieved in all patients without any complications. The VAS and ODI scores showed a reduction in both groups during follow-up (VAS score, p < 0.05 and p < 0.001, respectively; ODI score, p < 0.0001). No difference of the VAS and ODI scores were observed before treatment (p = 0.33 and 0.78, respectively). VAS score showed a difference at 1 week and 1, 3, and 6 months after treatment (p < 0.001). ODI score showed a difference at 3 and 6 months after treatment (p < 0.001). CONCLUSION: Our findings suggested that combined procedure of CVT is safe and effective for pain relief in single metastatic vertebral fractures, especially when other standard palliative treatments have failed, and improves disability. Careful needle positioning and accurate fluoroscopic and CT guidance are mandatory for a complication-free treatment.

Static and dynamic evaluation of pelvic floor disorders with an open low-field tilting magnet.

AIM: To assess the feasibility of magnetic resonance defaecography (MRD) in pelvic floor disorders using an open tilting magnet with a 0.25 T static field and to compare the results obtained from the same patient both in supine and orthostatic positions. MATERIALS AND METHODS: From May 2010 to November 2011, 49 symptomatic female subjects (mean age 43.5 years) were enrolled. All the patients underwent MRD in the supine and orthostatic positions using three-dimensional (3D) hybrid contrast-enhanced (HYCE) sequences and dynamic gradient echo (GE) T1-weighted sequences. All the patients underwent conventional defaecography (CD) to correlate both results. Two radiologists evaluated the examinations; inter and intra-observer concordance was measured. The results obtained in the two positions were compared between them and with CD. RESULTS: The comparison between CD and MRD found statistically significant differences in the evaluation of anterior and posterior rectocoele during defaecation in both positions and of rectal prolapse under the pubo-coccygeal line (PCL) during evacuation, only in the supine position (versus MRD orthostatic: rectal prolapse p < 0.0001; anterior rectocoele p < 0.001; posterior rectocoele p = 0.008; versus CD: rectal prolapse p < 0.0001; anterior rectocoele p < 0.001; posterior rectocoele p = 0.01). The value of intra-observer intra-class correlation coefficient (ICC) ranged from good to excellent; the interobserver ICC from moderate to excellent. CONCLUSION: MRD is feasible with an open low-field tilting magnet, and it is more accurate in the orthostatic position than in the supine position to evaluate pelvic floor disorders.

Breast MRI artefacts: evaluation and solutions in 630 consecutive patients.

AIM: To evaluate the problems that may arise in breast magnetic resonance imaging (MRI) related to the presence of artefacts and pitfalls, in order to improve its accuracy, sensitivity, and specificity. MATERIALS AND METHODS: Six hundred and thirty breast MRI examinations performed using a 1.5 T magnet were analysed retrospectively. Each type of artefact that may have affected the correct interpretation of the acquired images was considered and analysed. In particular, the presence of technical artefacts, which are related to patient-dependent factors or to the examination itself, and non-technical artefacts, which are the result of inadequate and incorrect image interpretation occurring in absence of technical issues, were examined. In every case of suspicious findings, doubtful lesions were subjected to histological characterization for appropriate therapeutic planning. In the remainder of cases, patients underwent follow-up for at least 18 months. RESULTS: Artefacts were found in 33% of all examinations, among those 48.6% were caused by movement, 33.6% were due to non-homogeneous or failed fat saturation, 8.7% to incorrect positioning of the patient, 7.2% to metallic artefacts, 1.4% to aliasing, and 0.5% were "zebra artefacts". When the artefact was identified in a sequence, the sequence was performed a second time after corrective measures. No artefacts affected diagnostic interpretation of the obtained images. CONCLUSION: The present study provides a specific and precise review of the most frequent artefacts with a discussion of possible and practical solutions. A highly qualified team is required to perform accurate diagnostic tests and to limit or remove the possibility of misinterpretation.

Osteoporosis detection by 3T diffusion tensor imaging and MRI spectroscopy in women older than 60 years.

Aim of this study was to evaluate the cancellous bone quality of postmenopausal women (age >60 years) by diffusion tensor imaging (DTI) using mean diffusivity (MD) and fractional anisotropy (FA) in combination with proton magnetic resonance spectroscopy (1H-MRS). 20 postmenopausal women older than 60 years were introduced to dual-energy X-ray absorptiometry (DXA) examination in femoral neck and to an MRI spectroscopy and DTI evaluation at 3T. We observed that fat fraction (FF) can discriminate healthy and osteoporotic patients. Water mean diffusivity (MD) and FA can discriminate the healthy group from osteopenic and osteoporotic group. MD/FF vs FA/FF graph extracted from the femoral neck identifies all healthy individuals, according to DXA results. DTI and spectroscopy protocol performed in the femoral neck could be highly sensitive and specific in identifying healthy subjects.

3-Tesla MR spectroscopy in patients subjected to bone marrow transplantation: clinical correlations.

PURPOSE: This study evaluated the usefulness of 3-Tesla magnetic resonance (MR) spectroscopy in patients with non-Hodgkin's lymphoma (NHL) undergoing bone marrow transplantation (BMT). MATERIALS AND METHODS: Twelve NHL patients who were candidates for BMT underwent three MR examinations of the lumbosacral spine: before ablative therapy for BMT, 15±4 days and 54±24 days after BMT. The MR study was supplemented by spectroscopic analysis. The lipid content was calculated and expressed as a percentage of lipid signal intensity relative to total signal intensity [fat fraction (FF)]. RESULTS: In the first MR study, the FF was 62.5±7%, in the second it was 70.75±5% and in the third it was 75±1%. We observed a statistically significant difference between FF values calculated at the various MR studies (p=0.02) and between red blood cell count (p=0.017), platelet count (p=0.003) and haematocrit (p<0.001) at the three MR studies. FF had a statistically significant correlation with the number of circulating platelets (p<0.01) CONCLUSIONS: MR spectroscopy of the bone marrow of NHL patients undergoing BMT is noninvasive and highly sensitive for characterising and monitoring bone marrow after BMT.

Evidence for heavy hyperhydrogen (Λ)(6)h.

Evidence for the neutron-rich hypernucleus (Λ)(6)H is presented from the FINUDA experiment at DAΦNE, Frascati, studying (π+,π-) pairs in coincidence from the K(stop)(-) + (6)Li →(Λ)(6)H + π+ production reaction followed by (Λ)(6)H → (6)He + π- weak decay. The production rate of (Λ)(6) undergoing this two-body π- decay is determined to be (2.9 ± 2.0) × 10(-6)/K(stop)(-). Its binding energy, evaluated jointly from production and decay, is BΛ((Λ)(6)H) = (4.0 ± 1.1) MeV with respect to (5)H+Λ. A systematic difference of (0.98 ± 0.74) MeV between BΛ values derived separately from decay and from production is tentatively assigned to the (Λ)(6)H 0(g.s.)(+) → 1+ excitation.

Palatability of crushed ß-blockers, converting enzyme inhibitors and thiazides.

WHAT IS KNOWN AND OBJECTIVES: A problem that often affects antihypertensive drugs is the lack of formulations appropriate for childhood. Parents, therefore, crush tablets and administer the antihypertensive drug mixed with solid food or a palatable drink. Because palatability is a major modulator of adherence to prescribed medication, the palatability of crushed ß-blockers, converting enzyme inhibitors and thiazides was assessed among adult volunteers. METHODS: The palatability of crushed atenolol, bisoprolol, enalapril, lisinopril, ramipril, chlorthalidone and hydrochlorothiazide was evaluated by means of a facial hedonic scale among 20 volunteers. The calcium channel-blockers amlodipine and lercanidipine whose tastes are disliked and liked, respectively, by children were also tested. A concealed random allocation procedure was used. RESULTS: The palatability scores assigned to chlorthalidone, hydrochlorothiazide and lisinopril were superior (P < 0·002) to those assigned to atenolol, bisoprolol, enalapril and ramipril. As with children, the palatability score of lercanidipine was superior to that of amlodipine (P < 0·002). The scores assigned to the various agents were similar in women and in men and were age-independent. WHAT IS NEW AND CONCLUSION: Pulverized atenolol, bisoprolol, enalapril and ramipril are poor tasting. From the perspective of palatability, pulverized chlorthalidone, hydrochlorothiazide and lisinopril are preferable.

Optimisation of low-dose CT with adaptive statistical iterative reconstruction in total body examination.

PURPOSE: The aim of this study was to assess the feasibility of low-dose computed tomography (CT) with the adaptive statistical iterative reconstruction (ASIR) algorithm in whole-body imaging with low tube voltage and current. MATERIALS AND METHODS: Twenty-three patients underwent whole-body CT with 40% of ASIR and parameters modulated according to body mass index (BMI). All had previously undergone conventional-dose CT with 100% filtered back projection (FBP). Two radiologists jointly assessed image quality (sharpness, noise, artefacts) and diagnostic quality blinded to the scanning technique. The effective dose and image quality obtained with the ASIR protocol were compared with those obtained with the FBP algorithm. RESULTS: The mean effective dose achieved with ASIR was 15.6 ± 5 mSv versus 21.8 ± 5.3 mSv with the FBP protocol (p<0.0001). Image quality was good in all low-dose CT scans, and diagnostic quality was comparable with or superior to that of conventional-dose CT. CONCLUSIONS: Low-dose CT with the ASIR algorithm is feasible and ensures significant reduction in effective dose.

Role of [18F]-FDG-PET/MDCT in evaluating early response in patients with Hodgkin's lymphoma.

PURPOSE: The authors evaluated the prognostic role of 18-fluoro-fluorodeoxyglucose positron emission tomography/multidetector computed tomography ([(18)F]-FDG PET/MDCT) in treating patients with Hodgkin's lymphoma (HL). MATERIALS AND METHODS: We retrospectively evaluated 132 patients with HL studied with PET/MDCT before the start of chemotherapy (CTX) for staging purposes and again after two CTX cycles with [doxorubicin (Adriblastin), bleomycin, vinblastine, dacarbazine (ABVD_] (interim PET/MDCT), at least 30 days after the end of the last CTX cycle and/or 3 months after the end of radiotherapy, if delivered (final PET-MDCT). RESULTS: Interim PET-MDCT was negative in 104/132 patients (79%), and their final PET-MDCT showed complete remission in 102/104 (98%) of cases, with disease recurrence/persistence in two (2%). In the remaining 28 (21%) patients, interim PET-MDCT revealed an early response in 68% of cases and chemoresistance with disease progression in 32% of cases; in these 28 patients, final PET-MDCT showed a lack of response to treatment in 43% of cases (43%) and complete remission in 57% of cases. Statistical analysis of these data showed that interim PET-MDCT had a negative predictive value of 98% and a positive predictive value of 42%, with values of sensitivity, specificity and diagnostic accuracy of 85.7%, 86.4% and 86.4%, respectively. CONCLUSIONS: Interim PET-MDCT has a reliable prognostic role in diagnosis and treatment of patients with HL, as it helps predict which patients are more likely to achieve a complete response at the end of treatment. PET/MDCT may also lead to a change in treatment, with reduced treatment-related toxic effects and significantly reduced total costs.