Acute hepatomegaly with severe liver toxicity due to all-trans-retinoic acid.
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Acute Disease↗
Biomedical subjects
S Brunet
Publications and source records attributed to S Brunet.
Relevance of presenting white blood cell count and kinetics of molecular remission in the prognosis of acute myeloid leukemia with CBFbeta/MYH11 rearrangement.
BACKGROUND AND OBJECTIVES: The detection of CBFbeta/MYH11 transcripts by RT-PCR has became a valuable and widely used technique in the accurate cytogenetic and molecular classification of acute myeloid leukemia (AML), but the clinical value of RT-PCR for monitoring minimal residual disease (MRD) during follow-up remains unclear. DESIGN AND METHODS: We analyzed the factors predicting relapse and the value of MRD monitoring by RT-PCR in a series of 16 patients with CBFb/MYH11-positive AML (15 M4Eo; 1 M4). Fifteen were newly diagnosed cases (CR1) and one was studied after first relapse (CR2). Eight patients had clinical relapse at 6 to 19 months from the achievement of CR. RESULTS: Presenting WBC count had a significant prognostic influence on disease-free survival (p=0.001). All four patients with a WBC count >100x10(9)/L relapsed, while only four additional relapses occurred among the eleven patients who had an initial WBC count below 100x10(9)/L. With regards to molecular monitoring, all relapses but one occurred in patients who showed persistent RT-PCR positivity during hematologic remission. By contrast, conversion to a repeatedly PCR-negative status was observed in the seven patients who remained in CR1 after a median follow-up of 48 months (range 31-79 months), as well as in the transplanted patient who was monitored in CR2. In these patients a PCR-positivity could be detected up to 24 months after diagnosis (median time to conversion to PCR-negative: 8 months). INTERPRETATION AND CONCLUSIONS: In conclusion, marked hyperleukocytosis (>100x10(9)/L) confers poor prognosis to the patient with CBFbeta/MYH11-positive AML. In addition, slow kinetics of molecular remission was observed in this subset of AML, but the CBFb/MYH11 fusion transcript is no longer detectable in long-term survivors, indicating that molecular remission is an important therapeutic goal.
Acute Disease↗
Combined use of reverse transcriptase polymerase chain reaction and flow cytometry to study minimal residual disease in Philadelphia positive acute lymphoblastic leukemia.
BACKGROUND AND OBJECTIVES: The Philadelphia chromosome in acute lymphoblastic leukemia (Ph+ ALL) is associated with a poor prognosis given the high frequency of chemoresistance and leukemia relapse. Minimal residual disease (MRD) detection before cytogenetic and hematologic relapse could be useful in early therapy. The most suitable methods for detecting MRD in Ph+ ALL are flow cytometry (FC) and reverse transcriptase polymerase chain reaction (RT-PCR). However, since both techniques carry the risk of false-negative results the combined use of these two techniques could overcome this problem. DESIGN AND METHODS: We report our experience using this approach in 47 bone marrow samples obtained from 10 Ph+ ALL patients. Twenty-seven marrow aspirates were taken from patients in clinical remission (CR). The samples were considered positive for MRD by FC when two conditions were met: 1) detection of an abnormal B-cell differentiation pattern and 2) presence of more than 1x10(-3) cells coexpressing CD22/CD34/CD45 or CD66/CD34/CD10. After FC analysis, RNA was purified using standard methods. RESULTS: FC was positive in 23/27 samples in CR (sensitivity 85%). RT-PCR was successfully performed in 23 samples in CR. RT-PCR was positive in 18/23 samples (sensitivity 78%). There were 5 samples with discordant results. FC was positive in 3 samples with a negative RT-PCR and FC was negative in 2 samples with a positive RT. All the 10 patients relapsed and only 1 is currently alive after an allogeneic stem cell transplantation (alloSCT). The median (range) time from MRD detection to relapse in patients treated with chemotherapy was 42 (39-71) days. INTERPRETATION AND CONCLUSIONS: These data suggest that RT-PCR may be negative despite the presence of neoplastic cells identified by their immunophenotypic traits. We conclude that immunologic and molecular techniques can be used in tandem for monitoring MRD in Ph+ ALL.
Adolescent↗
Allogeneic peripheral blood stem cell transplantation with CD34+-cell selection and delayed T-cell add-back in adults. Results of a single center pilot study.
BACKGROUND AND OBJECTIVES: Allogeneic peripheral blood stem cell transplantation with CD34+ cell-selection (CD34+-PBSCT) allows rapid hematologic engraftment with a reduction in graft-versus-host disease (GVHD), although concerns exist regarding the increased risk of tumor relapse associated with T-cell depletion of the graft. Delayed T-cell add-back (TCAB) after such transplants may restore the graft-versus-tumor effect while achieving a reduced early transplant-related mortality due to less GVHD in a group of patients at high risk of early death (i.e., age >= 45 years). DESIGN AND METHODS: Ten patients 45 years of age or older with hematologic malignancies received a CD34+-PBSCT and cyclosporin A (CyA) to prevent acute GVHD, followed by a planned delayed donor TCAB of 107 T-cells/kg to restore the graft-versus-tumor effect. The infused graft included a median of 6.3x106 CD34+ cells/kg and 4.4x104 CD3+ cells/kg. RESULTS: Engraftment was prompt in all cases. Four patients developed acute GVHD after the CD34+-PBSCT and/or chronic GVHD after CyA withdrawal and did not proceed to TCAB, and two patients died early before the planned TCAB. Four patients proceeded to TCAB at a median of day +104 after CD34+-PBSCT (+92 to +150). Two of these patients developed acute GVHD grades I-II (IBMTR Index B) after TCAB and all four developed chronic GVHD, which was extensive in two. With a median follow-up of 611 days (range 499-847) after transplant in the seven survivors, there have been no disease progressions, and all patients show a pattern of complete donor chimerism in bone marrow and peripheral blood. INTERPRETATIONS AND CONCLUSIONS: The results of our pilot study suggest that this protocol produces an acceptable transplant-related morbidity and mortality in patients 45 years and older. However, there may be benefit in infusing CD34+-selected PBSCT with even lower T-cell contents and further delaying the TCAB.
Antigens, CD34↗
Attenuation of the slow component of delayed rectification, action potential prolongation, and triggered activity in mice expressing a dominant-negative Kv2 alpha subunit.
An in vivo experimental strategy, involving cardiac-specific expression of a mutant Kv 2.1 subunit that functions as a dominant negative, was exploited in studies focused on exploring the role of members of the Kv2 subfamily of pore-forming (alpha) subunits in the generation of functional voltage-gated K(+) channels in the mammalian heart. A mutant Kv2.1 alpha subunit (Kv2.1N216) was designed to produce a truncated protein containing the intracellular N terminus, the S1 membrane-spanning domain, and a portion of the S1/S2 loop. The truncated Kv2.1N216 was epitope tagged at the C terminus with the 8-amino acid FLAG peptide to generate Kv2. 1N216FLAG. No ionic currents are detected on expression of Kv2. 1N216FLAG in HEK-293 cells, although coexpression of this construct with wild-type Kv2.1 markedly reduced the amplitudes of Kv2. 1-induced currents. Using the alpha-myosin heavy chain promoter to direct cardiac specific expression of the transgene, 2 lines of Kv2. 1N216FLAG-expressing transgenic mice were generated. Electrophysiological recordings from ventricular myocytes isolated from these animals revealed that I(K, slow) is selectively reduced. The attenuation of I(K, slow) is accompanied by marked action potential prolongation, and, occasionally, spontaneous triggered activity (apparently induced by early afterdepolarizations) is observed. The time constant of inactivation of I(K, slow) in Kv2. 1N216FLAG-expressing cells (mean+/-SEM=830+/-103 ms; n=17) is accelerated compared with the time constant of I(K, slow) inactivation (mean+/-SEM=1147+/-57 ms; n=25) in nontransgenic cells. In addition, unlike I(K, slow) in wild-type cells, the component of I(K, slow) remaining in the Kv2.1N216FLAG-expressing cells is insensitive to 25 mmol/L tetraethylammonium. Taken together, these observations suggest that there are 2 distinct components of I(K, slow) in mouse ventricular myocytes and that Kv2 alpha subunits underlie the more slowly inactivating, tetraethylammonium-sensitive component of I(K, slow). In vivo telemetric recordings also reveal marked QT prolongation, consistent with a defect in ventricular repolarization, in Kv2.1N216FLAG-expressing transgenic mice.
Action Potentials↗
Kinetochore fibers are not involved in the formation of the first meiotic spindle in mouse oocytes, but control the exit from the first meiotic M phase.
During meiosis, two successive divisions occur without any intermediate S phase to produce haploid gametes. The first meiotic division is unique in that homologous chromosomes are segregated while the cohesion between sister chromatids is maintained, resulting in a reductional division. Moreover, the duration of the first meiotic M phase is usually prolonged when compared with mitotic M phases lasting 8 h in mouse oocytes.We investigated the spindle assembly pathway and its role in the progression of the first meiotic M phase in mouse oocytes. During the first 4 h, a bipolar spindle forms and the chromosomes congress near the equatorial plane of the spindle without stable kinetochore- microtubule end interactions. This late prometaphase spindle is then maintained for 4 h with chromosomes oscillating in the central region of the spindle. The kinetochore-microtubule end interactions are set up at the end of the first meiotic M phase (8 h after entry into M phase). This event allows the final alignment of the chromosomes and exit from metaphase. The continuous presence of the prometaphase spindle is not required for progression of the first meiotic M phase. Finally, the ability of kinetochores to interact with microtubules is acquired at the end of the first meiotic M phase and determines the timing of polar body extrusion.
Animals↗
Dietary iron overload and induced lipid peroxidation are associated with impaired plasma lipid transport and hepatic sterol metabolism in rats.
Although hemochromatosis is characterized by dramatic morphological and functional alterations in the liver, little is known about the effects of an excess of iron on lipid metabolism. Therefore, we determined the effect of chronic iron overload on plasma lipid profile and lipoprotein composition, as well as on hepatic cholesterol metabolism and biliary sterol output. Rats administered a diet enriched with 3% iron carbonyl for 12 weeks displayed a 30-fold increase in iron (P <.0001) and a 5-fold rise in malondialdehyde (P <.001) in the liver. When compared with pair-fed controls, iron-overload rats showed a significant increase in triglycerides (P <.005), free cholesterol (P <.006), cholesteryl ester (P <.007), and high-density lipoprotein (HDL)-cholesterol (P <. 003). Triglyceride and cholesteryl ester enrichment, protein depletion, size increase, and apolipoprotein composition alterations characterized the very low density lipoprotein (VLDL) and HDL particles of iron-overload rats. Assessment of the activity of intracellular key enzymes for cholesterol homeostasis in these rats disclosed a reduction in 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (66%, P <.005) and cholesterol 7alpha-hydroxylase (58%, P <.0004) with an increment of acyl-CoA: cholesterol acyltransferase (62%, P <.002). The lack of optimal enzymatic activity may be a result of marked membrane lipid peroxidation that brings about fluidity drop (P <.029) in microsomes of iron-overload rats (5.00 +/- 0.013) versus controls (8.20 +/- 0. 03), reflected by polarization. A decline of the pool size of cholesterol and bile acids was noted in iron-overload rats during a 6-hour bile drainage. Our results show that experimental iron overload causes marked perturbations in plasma lipid transport and hepatobiliary sterol metabolism. Given the positive correlation of malondialdehyde with most of the altered parameters, iron-catalyzed lipid peroxidation may well be one of the involved mechanisms.
Alanine Transaminase↗
Chlorambucil-induced inappropriate antidiuresis in a man with chronic lymphocytic leukemia.
The syndrome of inappropriate antidiuretic hormone (SIADH) has been described in patients suffering from leukemia or lymphoma involving the central nervous system. Several alkylating agents have also been associated with this syndrome. We describe a patient with chronic lymphocytic leukemia, without evidence of central nervous system involvement, who suffered from SIADH presumably caused by small doses of chlorambucil.
Antineoplastic Agents, Alkylating↗
Exuberant granulation tissue associated with chronic graft-versus-host disease after transplantation of peripheral blood progenitor cells.
Angiomatous lesions appearing in chronic graft versus host disease (cGVHD) has been reported previously. We report a case of a patient in whom cutaneous exuberant granulation tissue developed in the course of a cGVHD after allo-peripheral blood progenitor cells transplantation.
Chronic Disease↗
Diffusive and convective solute clearances during continuous renal replacement therapy at various dialysate and ultrafiltration flow rates.
Clearances of several solutes (urea, creatinine, phosphate, urates, beta(2)-microglobulin [beta(2)-M]) were measured during venovenous continuous renal replacement therapy (CRRT) at various ultrafiltration (Q(UF); 0 to 2 L/h) and dialysate flow rates (Q(D); 0 to 2.5 L/h). Preset Multiflow-60 and Multiflow-100 hollow-fiber dialysers (M-60 and M-100; Hospal-Gambro, St-Leonard, Canada) were compared (five patients for each type). First, we evaluated the impact of predilution on convective clearances: a progressive decrease in patient clearances, similar for both filters, was observed, reaching a maximum of 15%, 18%, and 19% for urea, urates, and creatinine, respectively, with predilution at a Q(UF) of 2 L/h. Second, we compared convective and diffusive clearances. Because effluent to plasma ratio (E/P) remained at 1 for small solutes (urea, creatinine, phosphate, urates) during convection, clearances were equal to the effluent rate for both dialyzers. However, we observed greater diffusive clearances for small molecules with M-100 than with M-60 at a Q(D) of 1.5 to 2.5 L/h, the difference being more significant as molecular weight increased. For beta(2)-M, diffusive clearance was very low and rapidly reached a plateau of 8 and 12 mL/min for M-60 and M-100, respectively, at a Q(D) greater than 1.5 L/h. Convective clearances for beta(2)-M increased nonlinearly up to 20 +/- 2 mL/min at a progressively greater Q(UF) (from 0.5 to 2 L/h) for both M-60 and M-100. This nonlinear increase was attributed to an increase of almost 40% in E/P for beta(2)-M from a Q(UF) of 0.5 to 2 L/h. Third, the interaction between convection and diffusion was assessed by measuring solute clearances at a fixed Q(UF) (1 and 2 L/h) and variable Q(D) (0.5 to 2.5 L/h). For small molecules, no significant interaction between convection and diffusion was noticed with M-100, whereas only a small interaction was noticed with M-60. However, for beta(2)-M, the addition of diffusion (Q(D), 0.5 to 2.5 L/h) did not result in any significant increase in total clearances over convective clearances for M-60 and M-100. This observation suggests that the diffusive clearances for beta(2)-M observed with M-60 and M-100 at a Q(UF) of 0 L/h and at various Q(D) probably occurs by convective fluxes across the membrane. These results demonstrate that convection is more efficient than diffusion in removing mixed-molecular-weight solutes during CRRT.
Acute Kidney Injury↗
Pulmonary enterovirus infections in stem cell transplant recipients.
In recent years, it has been recognised that the community respiratory viruses are a frequent cause of upper and lower respiratory tract infections in immunocompromised hosts such as bone marrow transplant recipients. By contrast, infections by non-polio enteroviruses have rarely been reported after stem cell transplantation. We present four cases of acute respiratory illness with enterovirus isolated as the sole pathogen from bronchoalveolar lavage. All four patients developed pneumonia and three died of progressive pneumonia, which reflects the severity of this complication. We conclude that enteroviral pulmonary infections may be a cause of severe pneumonia in immunocompromised hosts.
Adolescent↗
Immunomagnetic bone marrow (BM) and peripheral blood progenitor cell (PBPC) purging in follicular lymphoma (FL).
Twenty-nine B cell follicular lymphoma (FL) patients had their BM (n = 12) or PBPC (n = 17) purged using a panel of monoclonal antibodies and immunomagnetic beads (IMB). The median recovery of nucleated cells (NC) and CD34+ cells was 59.3% (40.5-74) and 56.1% (30.8-82.9) in BM and 77.2% (64.7-88.3) and 73.5% (61.5-98.6) in PBPC (P<0.0005). A median of >1.62 and >1.02 log of target cell depletion was achieved as judged by flow cytometry analysis in BM and PBPC, respectively. Of 29% of initial harvests that had a bcl2 PCR-amplified signal, 37.5% became PCR negative in the final purged products. Absorbed cells containing IMB-target cell complexes gave bcl2 rearrangement signal in 20% of samples in which the start and final purged components were negative. Twenty-three of 26 patients receiving an autologous purged product are evaluable for engraftment. Median time to reach an ANC >0.5x10(9)/l and platelet count >20x10(9)/l was 21 (11-43) and 41 days (13-70) for BM (n = 9) and 14 (10-31) and 14 (8-37) for PBPC (n = 14) autografted patients (P = 0.01 and 0.001). One patient did not engraft and was rescued with a back-up BM. These data demonstrate that this indirect immunomagnetic technique is able to achieve a high grade of lymphoma cell depletion in BM and PBPC and that these purged products are capable of rapid engraftment after autologous transplantation.
Adult↗
Allogeneic bone marrow transplantation for advanced Waldenstrom's macroglobulinemia.
Waldenstrom's disease is a lymphoproliferative disorder that is typically treated with plasmapheresis and/or alkylating agents. In young patients, other lymphoproliferative disorders have been treated with allogeneic transplantation. Two patients with aggressive Waldenstrom's disease, who progressed in spite of multi-agent chemotherapy and autologous stem cell transplantation, in one case, underwent allogeneic transplantation from their HLA-identical donors. Both remain alive with event-free survivals of more than 3, and more than 9 years, respectively. Allogeneic transplantation should be considered for young patients with Waldenstrom's disease.
Adult↗
Comparison of the classic Glucksberg criteria and the IBMTR Severity Index for grading acute graft-versus-host disease following HLA-identical sibling stem cell transplantation. International Bone Marrow Transplant Registry.
Acute graft-versus-host disease (AGVHD) severity is usually graded (grades 0-IV) by the pattern of organ involvement using the classic Glucksberg-Seattle criteria (GSC). Recently, the International Bone Marrow Transplant Registry (IBMTR) developed a new Severity Index by regrouping the patterns of organ involvement into five Indexes (0-D) that appeared more predictive of transplant-related mortality (TRM) and transplant failure (TF, relapse or TRM). We studied the predictive value of both grading systems of TRM, TF and GVHD-related mortality (GTRM) in a series of 114 consecutive patients > or = 12 years old allografted from a histocompatible sibling at our institution, 100 of whom were evaluable for AGVHD. The IBMTR Severity Index showed better incremental prediction of TRM (relative risks (RR) of 1, 1.5, 1.4, 2 and 2.5 for Indexes 0, A, B, C and D), TF (RRs of 1, 1.6, 1.6, 2 and 2.3, respectively) and GTRM (RRs of 1, 2.2 and 4.8 for Indexes B, C and D) than the GSC. With the GSC different outcomes for TRM and TF were found only from grade 0 to I-II and 0 to IV or I-III to IV, but not from I-II to III. The GSC also appeared less predictive of GTRM (RRs of 1, 0.4 and 2.9 for grades II, III and IV). In our relatively small patient sample, the new IBMTR Severity Index appeared more predictive of transplant outcome than the GSC, especially between no AGVHD, early Indexes (A-B) and advanced Indexes (C-D).
Adolescent↗
Autologous bone marrow transplantation for high risk acute lymphoblastic leukemia: clinical relevance of ex vivo bone marrow purging with monoclonal antibodies and complement.
Herein we describe our experience with 75 consecutive autologous BM transplants for patients with high-risk ALL, with special attention to the clinical impact of BM purging. Fifty-two patients received purged BM using monoclonal antibody (MoAb) cocktails and complement, and 23 patients received untreated BM. The distribution of prognostic factors was similar in both groups. Hemopoietic reconstitution was adequate and did not differ in the two groups. Transplant-related mortality was 9.6% and 13% in 'purged' and 'unpurged' groups. Median follow up was 11 months (2-71) and overall actuarial probability of disease-free survival (DFS) at 5 years was 40% (53% relapse probability). We found a beneficial effect of purging in patients over 15 years of age and in patients needing more than 1 month to reach CR1. Patients in CR1 receiving purged marrow had a longer DFS and a lower relapse probability (52% vs 12%, P = 0.02 and 35% vs 86%, P = 0.005, respectively) which were related to the efficacy of the purging procedure (more or less than one log of depletion). In further CR, no advantage of purging has been found. Our data strongly suggest the clinical relevance of BM purging in autologous BMT in high-risk ALL patients and support the need for prospective randomized studies.
Adult↗
Administration of recombinant human granulocyte colony-stimulating factor to normal donors: results of the Spanish National Donor Registry. Spanish Group of Allo-PBT.
A Spanish National PBPC Donor Registry has recently been established for short- and long-term safety data collection in normal donors receiving rhG-CSF. To date, 466 donors have been included in the Registry. Median (range) dose and duration of rhG-CSF administration was 10 microg/kg/day (4-20) and 5 days (4-8), respectively. Donors underwent a median of two aphereses (range, 1-5). Adverse effects consisted mainly of bone pain (90.2%), headache (16.9%) and fever (6. 1%), but no donor discontinued rhG-CSF prematurely due to toxicity. Side-effects were more frequent in donors receiving >10 microg/kg/day than in those with lower doses (82.8% vs 61.8%; P = 0. 004). A significant decrease between baseline and post-apheresis platelet counts was the most important analytical finding (229 x 10(9)/l vs 140 x 10(9)/l; P < 0.0001), with a progressive reduction in platelet count with each apheresis procedure. One donor developed pneumothorax that required hospitalization due to central venous line placement. The mean CD34+ cell dose collected was 6.9 x 10(6)/kg (range, 1.3-36), with only 14 donors (2.9%) not achieving a minimum target of CD34+ cells of 2 x 10(6)/kg. No definitive information about potential long-term side effects is yet available. However, we hope this National Registry will serve as a useful basis for better monitoring of the efficiency and side-effects of cytokine administration in healthy people.
Adolescent↗
Mini-ICE regimen as mobilization therapy for chronic myelogenous leukaemia patients at diagnosis.
Between April 1996 and May 1998, 20 consecutive patients with Ph chromosome-positive CML in first chronic phase without an HLA-identical sibling received the mini-ICE regimen shortly after diagnosis to mobilize progenitor cells into the peripheral blood (PBPCs). The sex distribution was 12 males and eight females and the median (range) age 48.5 (22-62) years. The time interval between diagnosis and mobilization was a median (range) of 2 (0-5) months. Leukaphereses were initiated during recovery from chemotherapy-induced aplasia. A median number of 3 (1-7) aphereses per patient were performed to collect >/=2.0 x 106 CD34+cells/kg. Cytogenetic analysis was performed on the aphereses products of 18 patients. Complete cytogenetic Ph chromosome negativity was observed in four patients, nine had a partial negativity, three a minimal negativity and two no negative cells. Southern blot for bcr-abl was negative in the remaining two patients but the polymerase chain reaction analysis was positive. Following reinfusion, severe neutropenia was present for a median of 8.5 (3-19) days and severe thrombocytopenia lasted a median of 8 (3-18) days. Ten patients did not develop febrile neutropenia with four of them being treated on an outpatient basis. Treatment-related mortality was not observed. In conclusion, our experience demonstrates the feasibility of mobilizing PBPCs shortly after the diagnosis of CML with a safe regimen. Of note, mini-ICE allowed the collection of apheresis products with at least a major component of Ph-negative cells in almost 75% of the patients.
Adult↗
Intensified prophylaxis of febrile neutropenia with ofloxacin plus rifampin during severe short-duration neutropenia in patients with lymphoma.
To analyse the impact of intensified prophylaxis with ofloxacin plus rifampin (O+R) in neutropenic patients we used this combination in 40 consecutive cycles of ifosfamide, cytarabine, prednisolone and etoposide (IAPVP-16). This salvage chemotherapy regimen for lymphoma usually produces four to six days of severe neutropenia without significant extrahematologic toxicities. We compared the infectious morbidity during neutropenia under O+R with 58 consecutives cycles using either norfloxacin or no prophylaxis (control group). Fifty-three percent of control group patients and 20% of the O+R group developed febrile neutropenia that required hospital admission (p<0.001, 95% CI for the difference between both proportions of 16% to 51%). Bacteremia was documented in two patients in the O+R group and six in the control group (p=0.08). Gram-positive cocci (GPC) accounted for all six bacteremias in the control group, while both cases in O+R group were due to a quinolone-resistant gram-negative bacteria (GNB) (p<0.01 for GPC). Five patients (13%) who received O+R and 23 (40%) in control group developed fever of unknown origin, p<0.001, while the total duration of hospitalization due to febril neutropenia was 42 days and 158 days, respectively (p<0.001). In conclusion, intensified prophylaxis with O+R appears to reduce the rate of febrile neutropenia and GPC bacteremia in patients with short and severe neutropenia, which translates into a reduction in the need for hospitalization.
Adolescent↗