Microstructural and functional alterations of the ventral pallidum are associated with levodopa-induced dyskinesia in Parkinson's disease.

BACKGROUND AND PURPOSE: The ventral pallidum (VP) regulates involuntary movements, but it is unclear whether the VP regulates the abnormal involuntary movements in Parkinson's disease (PD) patients who have levodopa-induced dyskinesia (LID). To further understand the role of the VP in PD patients with LID (PD-LID), we explored the structural and functional characteristics of the VP in such patients using multimodal magnetic resonance imaging (MRI). METHODS: Thirty-one PD-LID patients, 39 PD patients without LID (PD-nLID), and 28 healthy controls (HCs) underwent T1-weighted MRI, quantitative susceptibility mapping, multi-shell diffusion MRI, and resting-state functional MRI (rs-fMRI). Different measures characterizing the VP were obtained using a region-of-interest-based approach. RESULTS: The left VP in the PD-LID group showed significantly higher intracellular volume fraction (ICVF) and isotropic volume fraction (IsoVF) compared with the PD-nLID and HC groups. Rs-MRI revealed that, compared with the PD-nLID group, the PD-LID group in the medication 'off' state had higher functional connectivity (FC) between the left VP and the left anterior caudate, left middle frontal gyrus and left precentral gyrus, as well as between the right VP and the right posterior ventral putamen and right mediodorsal thalamus. In addition, the ICVF values of the left VP, the FC between the left VP and the left anterior caudate and left middle frontal gyrus were positively correlated with Unified Dyskinesia Rating Scale scores. CONCLUSION: Our multimodal imaging findings show that the microstructural changes of the VP (i.e., the higher ICVF and IsoVF) and the functional change in the ventral striatum-VP-mediodorsal thalamus-cortex network may be associated with pathophysiological mechanisms of PD-LID.

Feasibility and acceptability of electronic EQ-5D-5L for routine measurement of HRQOL in patients with chronic musculoskeletal problems in Hong Kong primary care.

BACKGROUND: Information on HRQOL can enhance patient diagnosis and management but it is rarely available in routine clinical practice. This mixed-method study evaluated the feasibility and acceptability of the electronic EQ-5D-5L measurement of HRQOL in patients with chronic musculoskeletal problems in primary care. METHODS: In three primary care clinics, 665 patients with musculoskeletal problems completed the electronic EQ-5D-5L and Visual Analogue Scale (e-EQ-5D-5L/VAS), and a questionnaire on socio-demographics, perceived ease of use (PEOU), and perceived usefulness (PU) at baseline and two follow-ups. Patient completion and response rates, and time to complete the e-EQ-5D-5L/VAS were measured. During the same consultations, 49 doctors reviewed the e-EQ-5D-5L/VAS reports and completed a clinician questionnaire on PEOU, PU, and time spent to address each report. Individual interviews along with focus group discussions were conducted on patients, doctors, and research assistants for further exploration. RESULTS: Mean completion time reduced from baseline to first and second follow-up (120.66, 83.99, and 105.22 s, respectively). Completion and response rates were high at each follow-up visit (> 99.8% and > 91.11%, respectively). Doctors needed less than 2 min to read the report but felt the time required to address the report was a significant barrier. Some patients had difficulties using e-platforms, in understanding or answering questions; but, PEOU improved with time (p < 0.001). Most patients found the e-platforms useful (> 85.3%). Clinicians agreed a great majority of the reports were easy to use (76.0-85.1%) and useful (69.2-72.0%), particularly aiding with a holistic view of the patient's musculoskeletal problem. CONCLUSION: The e-EQ-5D-5L/VAS is a feasible and acceptable measurement of HRQOL of patients with chronic musculoskeletal problems in routine primary care in Hong Kong which can assist real-time management decisions. TRIAL REGISTRATION: NCT03609762.

Clinical and health-related quality of life outcomes of transfusion-dependent thalassaemia patients in Singapore.

INTRODUCTION: Transfusion-dependent thalassaemia is associated with complications related to iron overload from frequent red cell transfusions which affect quality of life. We collected data on the clinical outcomes, complications, socioeconomic status and health-related quality of life (HRQoL) of transfusion-dependent thalassaemia patients in Singapore, and analysed the associations between clinical and socioeconomic factors with development of transfusion-related complications and HRQoL scores. MATERIALS AND METHODS: This was a cross-sectional study of transfusion-dependent thalassaemia patients treated at four major public hospitals in Singapore. Clinical information was obtained from retrospective reviews of medical records. Socioeconomic data and patient-reported compliance to iron chelators were obtained from prospective interviews of patients or caregivers using a questionnaire. A validated, disease-specific HRQoL instrument, the TranQOL, was administered to patients and caregivers during a routine clinic or transfusion visit. RESULTS: Liver iron loading was the most common transfusion-related complication and occurred in 79% of patients. Cardiac iron loading was noted in 28.3% and endocrine complications were present in 34.2%. Liver iron loading was significantly associated with higher mean ferritin level. Cardiac iron loading was significantly associated with increasing age, higher mean ferritin level and type of iron chelator. Endocrine complications were associated with increasing age, higher mean ferritin level, type of iron chelator and poorer patient-reported compliance to iron chelators. The lowest TranQOL scores were reported by caregiver parents of patients aged less than 18 years. Lower TranQOL scores were significantly associated with increasing age, especially in the 31-50 age cohort, and with reception of social assistance. CONCLUSION: The main morbidities noted in transfusion-dependent thalassaemia patients in Singapore are from complications associated with iron loading. The cohort of older thalassaemia patients aged 31-50 experienced significantly higher rates of cardiac iron loading, endocrine complications and lower TranQOL scores compared to younger age cohorts.

Non-transfusion dependent thalassemia is independently associated with higher alloimmunization risk than transfusion dependent thalassemia and would benefit the most from extended red cell antigen-matching.

BACKGROUND: Alloimmunization prevalence is conventionally used to identify RBCs alloimmunization risk factors among thalassemia patients, but it may be confounded by differences in transfusion exposure especially between non-transfusion dependent thalassemia (NTDT) and transfusion dependent thalassemia (TDT) patients. To better identify thalassemia patients with high alloimmunization risks, we used cumulative incidence of first alloimmunization as a function of RBCs transfused to compare alloimmunization risks between TDT and NTDT and to evaluate other risk factors. We also proposed practical strategies to prevent alloimmunization in thalassemia. STUDY DESIGN AND METHODS: Adult TDT and NTDT patients who had received ≥2 transfusions and no alloimmunization before their first transfusion were included. Alloimmunization was defined as the development of clinically significant alloantibodies. We estimated the first alloimmunization incidence from transfusion by Kaplan-Meier analysis with the horizontal axis expressed as cumulative non-antigen-matched RBC units transfused. We compared this incidence between TDT and NTDT, and analyzed for other alloimmunization risk factors and the alloantibody specificities/frequencies. RESULTS: The alloimmunization prevalence was similar between TDT and NTDT (27% vs. 30% respectively, p = .726). However, for the same transfusion exposure, NTDT had higher alloimmunization incidence than TDT (hazard ratio 8.59, 95% confidence interval [2.25-32.74], p = .002), independent of age at first transfusion and last follow-up, gender, and splenectomy. Anti-E, anti-c, anti-Mia , and anti-Jka were most frequent. DISCUSSION: NTDT has the highest alloimmunization risk and would benefit the most from extended RBC antigen-matching, especially C, c, E, and e. Other blood group antigen-matching should be guided by the patient/donor disparities and alloantibody frequencies in different populations.

Pediatric resident knowledge of transfusion medicine: Results from the BEST-TEST3 international education needs assessment.

BACKGROUND: Transfusions are a common intervention within pediatrics and require unique considerations to optimize patient care. Poor knowledge of evidence-based transfusion practice can lead to misuse of transfusion therapy and harm. While there have been assessments of transfusion medicine knowledge of physicians caring for adult patients, there is little data regarding pediatricians. STUDY DESIGN AND METHODS: Using a published transfusion medicine knowledge exam for internal medicine physicians as a backbone, pediatric transfusion medicine experts, using an iterative process, developed a pediatric-specific examination. Pilot testing and Rasch analysis, a method used in high-stakes testing, was used to validate the exam. The exam and a previously validated survey on transfusion medicine training, attitudes, and perceived ability were administered to pediatric residents. Analysis consisted of descriptive statistics as well as comparisons of exam scores based on survey responses. RESULTS: 330 pediatric residents from 19 sites in 6 countries participated in the study. The vast majority (91%) of residents had obtained blood product consent. The mean exam score was 37.1% (range 9.5%-71.4%) with no statistical differences based on amount or perceived quality of transfusion medicine education or perceived ability. DISCUSSION: A rigorously validated exam has now been developed that can be used to assess pediatric transfusion medicine knowledge. A large international group of pediatric residents performed poorly on the exam demonstrating a pressing need for improved transfusion medicine education to ensure safe and appropriate administration of blood components to infants and children.

A pilot study on the validity and psychometric properties of the electronic EQ-5D-5L in routine clinical practice.

BACKGROUND: Electronic measurement of health-related quality of life (HRQOL) may facilitate timely and regular assessments in routine clinical practice. This study evaluated the validity and psychometric properties of an electronic version of the EQ-5D-5L (e-EQ-5D-5L) in Chinese patients with chronic knee and/or back problems. METHODS: 151 Chinese subjects completed an electronic version of the Chinese (Hong Kong) EQ-5D-5L when they attended a primary care or orthopedics specialist out-patient clinic in Hong Kong. They also completed the Chinese Western Ontario and McMaster University Osteoarthritis Index (WOMAC), a Pain Rating Scale, and a structured questionnaire on socio-demographics, co-morbidities and health service utilization. 32 subjects repeated the e-EQ-5D-5L two weeks after the baseline. 102 subjects completed e-EQ-5D-5L and 99 completed the Global Rating on Change Scale at three-month clinic follow up. Construct validity was assessed by the association of EQ-5D-5L scores with external criterion of WOMAC scores. We tested mean differences of WOMAC scores between adjacent response levels of the EQ-5D-5L dimensions by one-way ANOVA, test-retest reliability by intra-class correlation, sensitivity by known group comparisons and responsiveness by changes in EQ-5D-5L scores over 3 months. RESULTS: There was an association between EQ-5D-5L and WOMAC scores. Mean WOMAC scores increased with the increase in adjacent response levels of EQ-5D-5L dimensions. Test-retest intraclass correlation coefficient (ICC) of EQ-5D-5L utility and EQ-VAS scores were 0.76 and 0.83, respectively, indicating good reliability. There were significant differences in the proportions reporting limitations in the EQ-5D-5L dimensions, the utility and VAS scores between the mild and severe pain groups (utility = 0.28, p = 0.001; VAS = 11.46, p < 0.001), and between primary care and specialist out-patient clinic patients (utility = 0.15, p = 0.001; VAS = 10.21, p < 0.001), supporting sensitivity. Among those reporting 'better' global health at three-months, their EQ-5D-5L utility and EQ-VAS scores were significantly increased from baseline (utility = 0.18, p < 0.001; VAS = 10.75, p = 0.005). CONCLUSIONS: The electronic version of the EQ-5D-5L is valid, reliable, sensitive and responsive in the measurement of HRQOL in Chinese patients with chronic knee or back pain in routine clinical practice.

Bleeder With a Clot: Thrombosis Following Treatment of Bleeding in a Child With Severe Hemophilia B.

A 16-year-old boy with severe hemophilia B and minimal bleeding manifestations in his early childhood presented with gastrointestinal bleeding at 11 years of age. Following administration of prothrombin complex concentrate, he developed peripheral venous thrombosis and cerebral sinovenous thrombosis, posing a management dilemma. His cerebral sinovenous thrombosis resolved spontaneously, proving watchful waiting to be a useful strategy. He developed spontaneous intracranial bleed at 14 years of age for which he was treated with factor IX concentrate and commenced on prophylaxis. We discuss the factors contributing to genotype-phenotype dissonance in severe hemophilia and considerations before commencing prophylaxis in such cases.

Gastrointestinal and oncologic outcomes of pediatric gastrointestinal lymphoma following upfront resection or biopsy of bowel masses.

PURPOSE: Complete upfront resection of pediatric gastrointestinal lymphomas is recommended over biopsy whenever feasible, but either approach may have adverse sequelae. We sought to compare gastrointestinal and oncological outcomes of pediatric gastrointestinal lymphomas who underwent attempted upfront resection or biopsy of the presenting bowel mass. METHODS: We retrospectively reviewed charts of children with gastrointestinal lymphomas treated on LMB89 and LMB96 protocols from 2000 to 2019 who underwent upfront gastrointestinal surgery, and compared resection and biopsy groups. RESULTS: Of 33 children with abdominal lymphomas, 20 had upfront gastrointestinal surgery-10 each had resection or biopsy. Patients with attempted upfront resections had fewer postoperative gastrointestinal complications compared to biopsies (10% vs. 60%, p = 0.057), but longer time to chemotherapy initiation (median 11.5 vs. 4.5 days, p < 0.001). Three resection patients were surgically down-staged. Second surgeries were required in 30% and 40% of resected and biopsied patients, respectively, at median 4.6 months. Survival was similar in both groups, but better in patients on LMB96 protocol and stage II/III disease. CONCLUSIONS: Children with upfront attempted resection had low rates of surgical down-staging, greater delay in chemotherapy initiation, but fewer gastrointestinal complications and subsequent surgeries than biopsies. Survival was similar regardless of upfront surgery, likely reflecting beneficial effects of newer protocols.

Neuroblastoma patient-derived cultures are enriched for a mesenchymal gene signature and reflect individual drug response.

Ex vivo evaluation of personalized models can facilitate individualized treatment selection for patients, and advance the discovery of novel therapeutic options. However, for embryonal malignancies, representative primary cultures have been difficult to establish. We developed patient-derived cell cultures (PDCs) from chemo-naïve and post-treatment neuroblastoma tumors in a consistent and efficient manner, and characterized their in vitro growth dynamics, histomorphology, gene expression, and functional chemo-response. From 34 neuroblastoma tumors, 22 engrafted in vitro to generate 31 individual PDC lines, with higher engraftment seen with metastatic tumors. PDCs displayed characteristic immunohistochemical staining patterns of PHOX2B, TH, and GD2 synthase. Concordance of MYCN amplification, 1p and 11q deletion between PDCs and patient tumors was 83.3%, 72.7%, and 80.0% respectively. PDCs displayed a predominantly mesenchymal-type gene expression signature and showed upregulation of pro-angiogenic factors that were similarly enriched in culture medium and paired patient serum samples. When tested with standard-of-care cytotoxics at human Cmax -equivalent concentrations, MYCN-amplified and non-MYCN-amplified PDCs showed a differential response to cyclophosphamide and topotecan, which mirrored the corresponding patients' responses, and correlated with gene signatures of chemosensitivity. In this translational proof-of-concept study, early-phase neuroblastoma PDCs enriched for the mesenchymal cell subpopulation recapitulated the individual molecular and phenotypic profile of patient tumors, and highlighted their potential as a platform for individualized ex vivo drug-response testing.

Clinical Predictors for Unsafe Direct Discharge Home Patients From Intensive Care Units.

PURPOSE: To describe factors (demographics and clinical characteristics) that predict patients who are at an increased risk of adverse events or unplanned return visits to a health-care facility following discharge direct to home (DDH) from intensive care units (ICUs). METHODS: Prospective cohort study of all adult patients who survived their stay in our medical-surgical-trauma ICU between February 2016 and 2017 and were discharged directly home. Patients were followed for 8 weeks postdischarge. Univariable and multivariable logistic regression analyses were performed to identify factors associated with adverse events or unplanned return visits to a health-care facility following DDH from ICU. RESULTS: A total of 129 DDH patients were enrolled and completed the 8-week follow-up. We identified 39 unplanned return visits (URVs). There was 0% mortality at 8 weeks postdischarge. Eight potential predictors of hospital URVs (P < .2) were identified in the univariable analysis: prior substance abuse (odds ratio [OR] of URV of 2.50 [95% confidence interval: 1.08-5.80], hepatitis (OR: 6.92 [1.68-28.48]), sepsis (OR: 11.03 [1.19-102.29]), admission nine equivalents of nursing manpower score (NEMS) <24 (OR: 2.28 [1.03-5.04], no fixed address (OR: 22.9 [1.2-437.3]), ICU length of stay (LOS) <2 days (OR: 2.95 [1.28-6.78]), home discharge within London, Ontario (OR: 2.44 [1.00-5.92]), and left against medical advice (AMA; OR: 6.06 [2.04-17.98]). CONCLUSIONS: Our study identified 8 covariates that were potential predictors of URV: prior substance abuse, hepatitis, sepsis, admission NEMS <24, no fixed address, ICU LOS <2 days, home discharge within London, Ontario, and left AMA. The practice of direct discharges home from the ICU would benefit from adequately powered multicenter study in order to construct a clinical prediction model (that would require further testing and validation).

Patient, Family, and Physician Satisfaction With Planning for Direct Discharge to Home From Intensive Care Units: Direct From ICU Sent Home Study.

BACKGROUND: In the new era of decreasing hospital bed availability, there is an increasing rate of direct discharge to home (DDH) from intensive care units (ICUs), despite sparse literature informing this practice. OBJECTIVES: To evaluate patient, family, and ICU attending physician satisfaction with planning for DDH from the ICU and intensivists' current DDH practices and perceptions. METHODS: Prospective cohort study, using convenience sampling, of adult patients undergoing DDH from an ICU between February 2016 and February 2017 using a modified FS-ICU 24 satisfaction survey completed by patients, family members, and attending physicians at the time of patient discharge to home from the ICU. RESULTS: Seventy-two percent of patients, 37% of family members, and 100% of ICU physicians recruited completed the survey. A majority of patients (89%) and families (78%) were satisfied or very satisfied with DDH. Only 6% of patients and 8% of families were dissatisfied to very dissatisfied with DDH. Conversely, ICU physician satisfaction varied, with only 5% being very comfortable with DDH and the majority (50%) only somewhat comfortable. Twenty percent of staff consultants were uncomfortable to very uncomfortable with the practice of DDH. Thirty-one percent of staff physician respondents felt that patient and family discomfort would be barriers to DDH. Compared to physicians and other allied health professionals, nurses were identified as the most helpful members of the health-care team in preparation for DDH by 98% of patients and 92% of family members. The DDH rates have increased for the past 12 years in our ICUs but declined during the study period (February 2016 to February 2017). CONCLUSIONS: Patients and family members are satisfied with the practice of DDH from ICU, although ICU physician satisfaction is more variable. Physician comfort may be improved by data informing which patients may be safely DDH from the ICU.

Pericytoma With t(7;12): The First Ovarian Case Reported and a Review of the Literature.

We report the first case of an ovarian pericytoma with t(7;12). An 11-year-old child presented with abdominal pain and distension. A suprapubic mass was detected on examination and radiological investigations revealed a 16.5 cm solid-cystic ovarian mass. Histologically, the tumor was composed of spindle cells with S100-protein, Bcl-2, and CD10 reactivity on immunohistochemistry. Alpha fetoprotein, calretinin, alpha-inhibin, WT1, smooth muscle actin, caldesmon, desmin, cytokeratins, chromogranin, synaptophysin, EMA, Sox10, CD117, CD31, CD34, and CD68 were all negative. Molecular tests showed t(7;12)(p22;q13), resulting in the fusion of the ACTB with GLI1 genes and a diagnosis of pericytoma with t(7;12) of the ovary was made. We discuss the difficulties in diagnosing this lesion in the ovary and highlight the importance on molecular tests in characterizing challenging cases, especially primary ovarian spindle cell mesenchymal tumors.

Evaluation of a Novel Bony Landmark-Based Method for Teaching Percutaneous Insertion of Subclavian Venous Catheters in Pediatric Patients.

BACKGROUND: Surgical trainees performing subclavian vein (SCV) cannulation often incorrectly perceive needle trajectory and anatomical relations. As surface landmark-based methods derived from adult surgical practice may be less effective in younger patients, we developed and evaluated a novel bony landmark-based method for teaching SCV cannulation for central venous access device (CVAD) placement in children. METHODS: Over 2 sequential 3-year periods, pediatric surgical trainees were taught infraclavicular SCV cannulation via surface- and bony-landmark approaches, respectively. We prospectively recorded patient, surgeon and operative details on all Hickman line and port-a-cath insertions placed by trainees as the first surgeon via percutaneous infraclavicular SCV puncture and compared procedural outcomes and complications across both periods. RESULTS: Of 271 cases included in the study, trainees performed 52 (50.5%) and 92 (54.8%) procedures in the first and second periods, respectively. Patients in both periods did not differ by gender, disease, CVAD device, or prior CVAD, chemotherapy or infection status. In the second (bony landmark) period, although patients were younger (6.0 vs. 8.7 years, P = 0.003) mean procedural duration was shorter (42.5 vs. 58.3 min, P < 0.001). Also, cannulation attempts and complication rates did not differ significantly between study periods (P = 0.257 and 1.0, respectively). CONCLUSIONS: With the bony landmark approach, trainees could perform the procedures faster despite operating on younger patients, without impacting complication rates and cannulation attempts. Bony landmarks may better approximate SCV position across a range of ages, thus improving the consistency of SCV cannulation in CVAD placements in children.

Survival and Safety Outcomes of ICU Patients Discharged Directly Home-A Direct From ICU Sent Home Study.

OBJECTIVES: Evaluate outcomes (mortality, morbidity, unplanned return visits) of patients who are discharged directly to home from the ICU. DESIGN: Prospective cohort study. SETTING: Two tertiary care medical-surgical-trauma ICUs at Canadian hospitals over 1 year (February 2016-2017). SUBJECTS: All adult patients who were either discharged directly to home (Recruited and Nonrecruited cohorts) from ICU or discharged home within 24 hours after ward transfer (Ward Transfer cohort). INTERVENTIONS: Direct discharge home from ICU or discharge home within 24 hours of ward transfer from ICU. MEASUREMENTS AND MAIN RESULTS: One-hundred ninety-eight patients were in the study, 100 patients in the discharged directly to home Recruited arm, 37 patients in the discharged directly to home Nonrecruited arm, and 61 patients in the Ward cohort. All three patient cohorts had 0% mortality at 8 weeks post discharge. The unplanned return visit rate for the Recruited cohort was 24% (emergency department 18%, Ward 4%, ICU 1%), whereas the rate for the Nonrecruited cohort was 52% (emergency department 34%, Ward 14%, ICU 3%) and the Ward Transfer cohort was 46% (emergency department 17%, Ward 26%, ICU 3%) (p = 0.005). No home support was available for 7% of the discharged directly to home Recruited cohort. Twenty-four percent of patients had funded home care nursing, but the majority of patients (81%) relied on help from friends/family. CONCLUSIONS: Recruited discharged directly to home patients experienced very good 8-week postdischarge outcomes with 0% mortality and a low rate of ICU readmission (1%) or ward readmission (4%), but not an insignificant rate of emergency department visits (18%). Recruited discharged directly to home patients had better outcomes compared with nonrecruited discharged directly to home patients and patients transferred briefly to the ward prior to discharge home. Future work should include derivation of a clinical prediction tool to identify patient characteristics that make discharged directly to home safe and a randomized control trial to compare discharged directly to home with short stay ward transfers.

Factors Associated With the Increasing Rates of Discharges Directly Home From Intensive Care Units-A Direct From ICU Sent Home Study.

OBJECTIVES: To evaluate the relationship between rates of discharge directly to home (DDH) from the intensive care unit (ICU) and bed availability (ward and ICU). Also to identify patient characteristics that make them candidates for safe DDH and describe transfer delay impact on length of stay (LOS). METHODS: Retrospective cohort study of all adult patients who survived their stay in our medical-surgical-trauma ICU between April 2003 and March 2015. RESULTS: Median age was 49 years (interquartile range [IQR]: 33.5-60.4), and the majority of the patients were males (54.8%). Median number of preexisting comorbidities was 5 (IQR: 2-7) diagnoses. Discharge directly to home increased from 28 (3.1% of all survivors) patients in 2003 to 120 (12.5%) patients in 2014. The mean annual rate of DDH was between 11% and 12% over the last 6 years. Approximately 62% (n = 397) of patients waited longer than 4 hours for a ward bed, with a median delay of 2.0 days (IQR: 0.5-4.7) before being DDH. There was an inverse correlation between ICU occupancy and DDH rates ( rP = -.55, P < .0001, 95% confidence interval [CI] = -0.36 to -0.69, R2 = .29). There was no correlation with ward occupancy and DDH rates ( rs = -.055, P = .64, 95% CI = -0.25 to 0.21). CONCLUSIONS: The DDH rates have been increasing over time at our institution and were inversely correlated with ICU bed occupancy but were not associated with ward occupancy. The DDH patients are young, have few comorbidities on admission, and few discharge diagnoses, which are usually reversible single system problems with low disease burden. Transfers to the ward are delayed in a majority of cases, leading to increased ICU LOS and likely increased overall hospital LOS as well.