Showing papers by "Rush University Medical Center published in 1989"

Sepsis syndrome: a valid clinical entity. Methylprednisolone Severe Sepsis Study Group.

Abstract: The sepsis syndrome represents a systemic response to infection and is defined as hypothermia (temperature less than 96 degrees F) or hyperthermia (greater than 101 degrees F), tachycardia (greater than 90 beat/min), tachypnea (greater than 20 breath/min), clinical evidence of an infection site and with at least one end-organ demonstrating inadequate perfusion or dysfunction expressed as poor or altered cerebral function, hypoxemia (PaO2 less than 75 torr), elevated plasma lactate, or oliguria (urine output less than 30 ml/h or 0.5 ml/kg body weight.h without corrective therapy). One hundred ninety-one patients with the sepsis syndrome were evaluated prospectively and comprised the placebo group of a multicenter trial of methylprednisolone in sepsis syndrome and septic shock. Forty-five percent of the patients were found to be bacteremic. Thirty-six percent of the patients were in septic shock (sepsis syndrome plus a systolic BP less than 90 mm Hg or a decrease from baseline in systolic BP greater than 40 mm Hg) on study entry. An additional 23% of the patients developed shock after admission with 70% doing so within 24 h of study entry. Shock reversal occurred with a 73% frequency. Twenty-five percent of the patients developed the adult respiratory distress syndrome (ARDS). Mortality for the patients with sepsis syndrome who did not develop shock was 13%. Mortality for the groups of patients with shock on admission and shock postadmission was 27.5% and 43.2%, respectively. Forty-seven percent of the bacteremic patients developed shock after study admission compared to 29.6% of the nonbacteremic patients (p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Intrathecal Baclofen for Severe Spinal Spasticity

Abstract: We studied the effect of the intrathecal infusion of baclofen, an agonist of gamma-aminobutyric acid, on abnormal muscle tone and spasms associated with spinal spasticity, in a randomized double-blind crossover study. Twenty patients with spinal spasticity caused by multiple sclerosis or spinal-cord injury who had had no response to treatment with oral baclofen received an intrathecal infusion of baclofen or saline for three days. The infusions were administered by means of a programmable pump implanted in the lumbar subarachnoid space. Muscle tone decreased in all 20 patients (mean [+/- SD] Ashworth score for rigidity, from 4.0 +/- 1.0 to 1.2 +/- 0.4; P less than 0.0001), and spasms were decreased in 18 of the 19 patients who had spasms (mean [+/- SD] score for spasm frequency, from 3.3 +/- 1.2 to 0.4 +/- 0.8; P less than 0.0005). Tests for motor function, neurologic examination, and assessments by the patients correctly indicated when baclofen was being infused in all cases. All patients were then entered in an open long-term trial of continuous infusion of intrathecal baclofen. During a mean follow-up period of 19.2 months (range, 10 to 33), muscle tone has been maintained within the normal range (mean Ashworth score, 1.0 +/- 0.1) and spasms have been reduced to a level that does not interfere with activities of daily living (mean spasm score, 0.3 +/- 0.6). No drowsiness or confusion occurred, one pump failed, and two catheters became dislodged and had to be replaced. No infections were observed. Our observations suggest that intrathecal baclofen is an effective long-term treatment for spinal spasticity that has not responded to oral baclofen.

Strategies for the control of voluntary movements with one mechanical degree of freedom

Abstract: A theory is presented to explain how accurate, single-joint movements are controlled. The theory applies to movements across different distances, with different inertial loads, toward targets of different widths over a wide range of experimentally manipulated velocities. The theory is based on three propositions. (1) Movements are planned according to “strategies” of which there are at least two: a speed-insensitive (SI) and a speed-sensitive (SS) one. (2) These strategies can be equated with sets of rules for performing diverse movement tasks. The choice between SI and SS depends on whether movement speed and/or movement time (and hence appropriate muscle forces) must be constrained to meet task requirements. (3) The electromyogram can be interpreted as a low-pass filtered version of the controlling signal to the motoneuron pools. This controlling signal can be modelled as a rectangular excitation pulse in which modulation occurs in either pulse amplitude or pulse width. Movements to different distances and with loads are controlled by the SI strategy, which modulates pulse width. Movements in which speed must be explicitly regulated are controlled by the SS strategy, which modulates pulse amplitude. The distinction between the two movement strategies reconciles many apparent conflicts in the motor control literature.

Multiple subpial transection: a new approach to the surgical treatment of focal epilepsy

Abstract: A new operative approach has been designed for the relief of medically intractable focal epilepsy. It is intended particularly to be used in those cases where the epileptogenic lesion lies in "unresectable" cortex; that is, those cerebral regions subserving speech, memory, and primary motor and sensory function. The procedure is based upon experimental evidence indicating 1) that epileptogenic discharge requires substantial side-to-side or horizontal interaction of cortical neurons, and 2) that the major functional properties of cortical tissue depend upon the vertical fiber connections of the columnar units. The technique requires severing of tangential intracortical fibers while preserving the vertical fiber connections of both incoming and outgoing nerve pathways and of the penetrating blood vessels which also have a vertical orientation. In this study, the effect of multiple subpial transection was assessed on both function and seizure control. The effect on function was reviewed in 32 cases; only 20 cases were evaluated with respect to seizure control, since a follow-up period of 5 years or more (5 to 22 years) is required before conclusions can be drawn. Multiple subpial transection was applied to the precentral gyrus in 16 cases, the postcentral gyrus in six, Broca's area in five, and Wernicke's area in five. With respect to function, the major finding was that none of the 32 patients has suffered a clinically significant behavioral deficit (although subtle deficits could be detected by careful neurological examination). Complete control of seizures has been obtained in 11 (55%) of the 20 cases evaluated. Nine patients developed recurrent seizures consequent to progressive disease unsuspected before operation (Rasmussen's encephalitis in five, tumor in three, and subacute sclerosing panencephalitis in one). In none of these cases, however, did the recurrent seizures arise in the transected zone. Thus, the results indicate that multiple subpial transection is about as effective as standard excisional therapy, and can be successfully employed when epileptogenic lesions encroach upon cortical territories, the removal of which would be functionally incapacitating.

Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small-cell lung cancer: a study of the Eastern Cooperative Oncology Group.

Abstract: During the last decade, the Eastern Cooperative Oncology Group (ECOG) has studied a series of combination chemotherapy regimens in metastatic (stage IV) non-small-cell lung cancer (NSCLC). In January 1984, the ECOG activated a randomized study, EST 1583, which concluded the evaluation of combination regimens in phase III trials and initiated the evaluation of single agents exclusively in previously untreated patients. The treatment regimens in EST 1583 consisted of: (1) mitomycin, vinblastine, and cisplatin (MVP); (2) vinblastine and cisplatin (VP); (3) MVP alternating with the regimen cyclophosphamide, doxorubicin, methotrexate, and procarbazine (CAMP); (4) carboplatin followed by the MVP regimen at the time of progression; and (5) iproplatin followed by MVP at the time of progression. From January 1984 to July 1985, 743 patients were entered on this trial and 699 fulfilled the eligibility requirements. The following objective response rates (complete plus partial remissions) were observed: first-line MV...

Multicenter Study of Autologous Adrenal Medullary Transplantation to the Corpus Striatum in Patients with Advanced Parkinson's Disease

Abstract: In 19 patients with severe Parkinson's disease, we replicated the surgical procedures developed by Madrazo et al. for transplantation of the adrenal medulla to the striatum, and followed them for six months after operation. We monitored their motor function with the use of standardized scales and determined the amount and quality of "on" and "off" time (the hours of the waking day when the anti-parkinsonism medications were effective and ineffective, respectively). We found significant improvement in focal areas of motor function. The mean percentage of on time during the day increased from 47.6 percent to 75.0 percent (P = 0.012); the mean percentage of on time without chorea increased from 26.6 percent to 59.2 percent (P = 0.006); the mean severity of off time decreased as assessed by both the Activities of Daily Living subscale of the Unified Parkinson's Disease Scale (P = 0.002) and the Schwab and England scale (P = 0.037). In contrast to the finding of Madrazo et al., however, the dosages of...

Effect of pulmonary artery catheterization on outcome in patients undergoing coronary artery surgery.

Abstract: Previous studies have suggested that low-risk cardiac surgical patients may be safely managed without pulmonary artery catheterization (PAC). However, no prospective studies have determined whether PAC improves outcome in higher risk patients compared with that following central venous pressure (CVP) monitoring alone. The authors prospectively examined the incidence of and factors related to perioperative morbidity and mortality in 1094 consecutive patients undergoing coronary artery surgery managed with elective PAC (n = 537) or with CVP (n = 557). Perioperative risk factors and demographics that predict morbidity and mortality after cardiac surgery were used to quantify risk classification. Outcome was judged by length of ICU stay, occurrence of postoperative myocardial infarction, in-hospital death, major hemodynamic aberrations, and significant noncardiac systemic complications. No significant differences in any outcome variables were noted in any group of patients with similar quantitative risk classification managed with or without PAC, including those in the highest risk class. In addition, there were no significant differences in outcome among the 39 patients who would have been managed with CVP monitoring only, but who subsequently developed a clinical need for PAC based on the occurrence of serious hemodynamic events compared to patients who had PAC performed electively. This study suggests that PAC does not play a major role in influencing outcome after cardiac surgery, that even high-risk cardiac surgical patients may be safely managed without routine PAC, and that delaying PAC until a clinical need develops does not significantly alter outcome, but may have an important impact on cost savings.

Effect of helium‐neon and infrared laser irradiation on wound healing in rabbits

Abstract: We examined the biostimulating effects of helium-neon laser radiation (HeNe; 632.8 nm), pulsed infrared laser radiation (IR; 904 nm), and the two combined on skin wound healing in New Zealand white rabbits. Seventy-two rabbits received either (1) no exposure, (2) 1.65 J/cm2 HeNe, (3) 8.25 J/cm2 pulsed IR, or (4) both HeNe and IR together to one of two dorsal full-thickness skin wounds, daily, for 21 days. Wound areas were measured photographically at periodic intervals. Tissue samples were analyzed for tensile strength, and histology was done to measure epidermal thickness and cross-sectional collagen area. Significant differences were found in the tensile strength of all laser-treated groups (both the irradiated and nonirradiated lesion) compared to group 1. No differences were found in the rate of wound healing or collagen area. Epidermal growth was greater in the HeNe-lased area compared to unexposed tissue, but the difference was not significant. Thus, laser irradiation at 632.8 nm and 904 nm alone or in combination increased tensile strength during wound healing and may have released tissue factors into the systemic circulation that increased tensile strength on the opposite side as well.

Environmental factors and Parkinson's disease: a case-control study in China.

Abstract: We studied the role of environment in the development of Parkinson9s disease (PD) in China, where industrialization is relatively recent and the population geographically stable. Using a case-control method, we investigated the relationship between PD and exposure to the following factors before disease onset: place of residence, source of drinking water, environmental and occupational exposure to various agricultural and industrial processes. Occupational or residential exposure to industrial chemicals, printing plants, or quarries was associated with an increased risk of developing PD. In contrast, living in villages and exposure to the common accompaniments of village life, wheat growing and pig raising, were associated with a decreased risk for PD. PD cases and controls did not differ with respect to other factors investigated. These findings are consistent with the hypothesis that environmental exposure to certain industrial chemicals may be related to the development of PD.

Clinical impact of rapid identification and susceptibility testing of bacterial blood culture isolates.

Abstract: Two hundred twenty-six patients with bacteremia were prospectively enrolled in a randomized trial that was performed to determine the clinical impact of the receipt of in vitro microbiological data by the physician soon after organism detection as opposed to having the physicians wait until similar data were available by routine methods. Identification and antibiotic susceptibility patterns of 110 isolates were determined by direct inoculation of the Vitek AutoMicrobic system (Vitek Systems, Inc., Hazelwood, Mo.) with a sample from a positive blood culture vial. One hundred sixteen isolates were processed by routine methods. Microbiological results were available within an average of 8.8 h by the direct method versus an average of 48 h by the routine method. In both groups an infectious disease fellow used the information to make therapeutic recommendations to the responsible physician. When compared with that provided by the routine method, the information provided by the direct method was significantly more likely to result in an initiation of antibiotic therapy, a change to more effective therapy, or a change to less expensive therapy. Recommendations were significantly more likely to be followed in patients whose isolates were processed by the direct method versus the routine method. A projected savings of $158 per patient was estimated for the patients who were changed to less expensive therapy or in whom antibiotics were discontinued because results were available sooner. These cost savings, coupled with changes in therapy made for reasons of efficacy, support the usefulness of the earlier reporting of the identity and antibiotic susceptibility patterns of bacterial blood culture isolates.

Comparison of viscoelastic measures of coagulation after cardiopulmonary bypass.

Abstract: Postoperative hemorrhage remains a major cause of morbidity after cardiopulmonary bypass (CPB). Treatment remains empiric because of the need for immediate correction and the lack of availability of rapid intraoperative coagulation monitoring (except for ACT) at most institutions. Thrombelastography (TEG) and Sonoclot analysis (SCT) are measures of viscoelastic properties of blood which allow rapid intraoperative evaluation of coagulation factor and platelet activity as well as overall clot integrity from a single blood sample. Routine coagulation tests (RCT) including activated clotting time (ACT), prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen level (FIB), and platelet count (PLT) were determined and compared to TEG and SCT to assess which best predicted clinical hemostasis after CPB. Forty-two patients prospectively felt to be at high risk for excessive post-CPB bleeding had blood obtained for RCT, TEG, and SCT analysis before systemic heparinization and 30 min after protamine administration. Nine of 42 patients had excessive chest tube drainage, but no reoperations were required. After CPB, mean values for RCT were normal, but there were abnormalities in TEG and SCT parameters that reflect platelet-fibrin interaction. Both TEG and SCT were 100% accurate in predicting bleeding in these nine patients and, overall, both tests were significantly better predictors of postoperative hemorrhage than RCT. We conclude that viscoelastic determinants of clot strength may be abnormal after CPB and that SCT and TEG are, therefore, more useful than RCT for the detection and management of coagulation defects associated with CPB.

Does choice of anesthetic agent significantly affect outcome after coronary artery surgery

Abstract: A prospective study of 1094 consecutive adult patients undergoing coronary revascularization was undertaken to determine the effect of anesthetic technique on outcome. Patients received one of five primary techniques: high-dose fentanyl (greater than 50 micrograms/kg), moderate-dose fentanyl (less than 50 micrograms/kg), sufentanil (3-8 micrograms/kg), diazepam (0.4-1 mg/kg) with ketamine (3-6 mg/kg) or halothane (0.5-2.5% inspired concentration after thiopental induction). Supplemental inhalation anesthesia (enflurane, halothane, or isoflurane) was used in 60% of cases where the primary technique was intravenous based. Patients in the above anesthetic groupings had similar perioperative demographic and risk classifications. The overall incidence of postoperative myocardial infarction, postoperative low cardiac output state, and in-hospital death were 4.1, 5.6, and 3.1%, respectively. There were no significant differences in the incidence of these occurrences or in the incidence of serious pulmonary, renal, or neurologic morbidity or length of ICU stay among primary anesthetic techniques nor among supplemental inhalation agent groups. Multivariate discriminant analysis of this data suggests that a multitude of factors are significantly more important than anesthetic technique as determinants of outcome after coronary artery surgery.

The role and regulation of tumour-associated hyaluronan.

Abstract: Significantly increased levels of the glycosaminoglycan hyaluronan are often associated with human and animal tumours. In the rabbit V2 carcinoma elevated levels of tumour-associated hyaluronan are also closely correlated with invasiveness. We have therefore initiated studies to better define the role and regulation of hyaluronan synthesis in tumour tissues. In cell culture many tumour cell types have reduced capacities to synthesize hyaluronan even when derived from tumours enriched in hyaluronan. We showed that several of these same cells can nevertheless stimulate hyaluronan synthesis by normal fibroblasts. In the LX-1 human lung carcinoma cell line this stimulatory potential resides in a membrane-bound, heat-sensitive, lipophilic, cell surface glycoprotein. These data suggest that production of tumour-associated hyaluronan occurs via tumour-stromal cell interactions. We recently demonstrated that some human tumour cells also possess unoccupied, high affinity, cell surface binding sites for hyaluronan which may allow tumour cells to interact directly with hyaluronan-enriched extracellular matrices. This interaction may in turn allow tumour cells to use hyaluronan as a support for adhesion and locomotion. The spatial organization of hyaluronan could then function to guide tumour cells into surrounding stroma. We attempted to visualize this spatial deposition of hyaluronan in situ within frozen sections of human tumour tissue using a morphological probe that specifically recognizes hyaluronan. Hyaluronan appears most prominently in the partially degraded connective tissue.

Human liver plasma membranes contain receptors for the hepatitis B virus pre-S1 region and, via polymerized human serum albumin, for the pre-S2 region.

Abstract: Hepatitis B virus particles contain three related viral envelope proteins, the small, middle, and large S (surface) proteins All three proteins contain the small S amino acid sequence at their carboxyl terminus It is not clear which of these S proteins functions as the viral attachment protein, binding to a target cell receptor and initiating infection In this report, recombinant hepatitis B surface antigen (rHBsAg) particles, which contain only virus envelope proteins, were radioactively labeled, and their attachment to human liver membranes was examined Only the rHBsAg particles containing the large S protein were capable of directly attaching to liver plasma membranes The attachment was saturable and could be prevented by competition with unlabeled particles or by a monoclonal antibody specific for the large S protein In the presence of polymerized human serum albumin, both large and middle S protein-containing rHBsAg particles were capable of attaching to the liver plasma membranes Small S protein-containing rHBsAg particles were not able to attach even in the presence of polymerized human serum albumin These results indicate that the large S protein may be the viral attachment protein for hepatocytes, binding directly to liver plasma membranes by its unique amino-terminal (pre-S1) sequence These results also indicate that polymerized human serum albumin or a similar molecule could act as an intermediate receptor, attaching to liver plasma membranes and to the amino acid sequence (pre-S2) shared by the middle and large S proteins but not contained in the small S protein

Femoral capital osteonecrosis: MR finding of diffuse marrow abnormalities without focal lesions.

Abstract: Six painful hips in five patients were examined with magnetic resonance (MR) imaging and were found to have diffuse signal abnormalities in the marrow of the femoral head and neck, which extended into the intertrochanteric area in five cases. The abnormal regions were low in signal intensity on images obtained with a short repetition time (TR) and a short echo time (TE) and were isointense or hyperintense on long TR/TE images--findings that have been attributed by others to bone marrow edema. Edema was also seen in marrow just above the acetabulum in two cases. No focal abnormalities characteristic of osteonecrosis were seen. Osteonecrosis was subsequently shown to be present in all six femoral heads at core biopsy (three cases) or by subsequent development of focal MR abnormalities reported to be highly specific for osteonecrosis (three cases). The affected hips had been radiographically normal or subtly osteopenic and had shown intense radionuclide uptake in the femoral head at scintigraphy, with lesser abnormality in the neck and intertrochanteric region. Follow-up MR examinations of five of the six femoral heads showed the diffuse abnormalities to have been transient. Although diffuse MR abnormalities in the proximal femur are not specific, they may indicate the presence of osteonecrosis of the femoral head.

A simple, clinical assay to evaluate the acrosin activity of human spermatozoa.

Abstract: Acrosin, a sperm-specific acrosomal proteinase, has an essential role in the fertilization process. Low levels of acrosin appear to be associated with subfertility and infertility, and the acrosin activity of spermatozoa may potentially be a useful indicator of semen quality. The standard acrosin tests employed by research laboratories are too complicated and/or time consuming for clinical use; therefore, a simple assay has been developed to assess total acrosin activity (acrosin and activatable proacrosin). To perform the test, liquefied semen is centrifuged over Ficoll, the washed sperm pellet is suspended in a detergent (Triton X-100)-substrate (N-alpha-benzoyl-DL-arginine p-nitroanilide) buffer, pH. 8.0, and the amidase activity is determined spectrophotometrically after a 3-hour incubation period. Amidase activity can be inhibited with benzamidine, indicating that the activity is primarily or entirely due to acrosin. The absence of detergent in the incubation medium results in greatly reduced activity. The assay is repeatable, linear with increasing sperm concentration, sensitive to a lower limit of 2 x 10(6) spermatozoa, and the results correspond to those obtained with a standard acrosin extraction and assay technique. Storage of ejaculates at 3 to 6 C or at 22 to 24 C for 24 hours does not affect the acrosin activity significantly but much higher temperatures can cause a loss of activity. Freezing ejaculates results in a large decrease in sperm acrosin activity. Leukocytes show minimal activity in the assay. Sperm populations prepared by a swim-up procedure average approximately a 2-fold higher acrosin activity than the original ejaculates. Preliminary experiments indicate that the average sperm acrosin activity of ejaculates whose spermatozoa successfully fertilize human eggs in vitro is significantly higher than those that do not fertilize eggs.

Nonpalpable breast tumors: diagnosis with stereotaxic localization and fine-needle aspiration.

Abstract: Modern mammography is the most effective means of detecting nonpalpable breast cancers, but correct diagnosis for malignancy is made in only 20%-30% of the cases. The conventional method of lesion localization usually results in approximate placement of the hookwire in the breast. The authors report the results of stereotaxic localization, combined with fine-needle aspiration and cytologic study, performed in 528 cases. Clinically occult breast lesions were localized precisely (within 2 mm 96% of the time), sampled by means of a 23-gauge needle, and marked with either methylene blue or a hookwire for subsequent open excisional biopsy. The results indicate a sensitivity of 95%, specificity of 91%, and accuracy of 92% for the fine-needle aspiration procedure. This technique offers a significantly improved preoperative method of diagnosing small breast lesions with minimal pain, no complications, reduced cost, and no disfigurement or scar interfering with subsequent mammographic follow-up.

Imaging of abdominal aortic aneurysms.

Abstract: There is no single correct approach to evaluate aortic aneurysm. Variations in individual cases, equipment availability, technical expertise, and surgeons' preference frequently dictate the workup. Sonography is optimal for screening and follow-up in uncomplicated cases. CT is excellent in preoperative and postoperative evaluation of aneurysms and their potential complications. Angiography is used to determine visceral-branch involvement and define variations in vascular anatomy, although its routine preoperative use is controversial. MR imaging has emerged as a powerful tool to visualize and stage aneurysms.

The flow cytometric crossmatch. Dual-color analysis of T cell and B cell reactivities.

Abstract: The flow cytometric crossmatch (FCXM) has become an increasingly utilized method to detect low levels of anti-donor antibodies (e.g., anti-HLA) in potential renal allograft recipients. Anti-donor antibodies not apparent in the standard complement-dependent crossmatch, but detectable by the FCXM, are often associated with increased episodes of graft rejection and early graft failure. In this study we examined several parameters of the FCXM in order to establish a standardized methodology. First, we observed that optimal staining results were obtained when the secondary antibody was an Fc-specific F(ab'), anti-human IgG. In contrast to an anti-whole immunoglobulin antibody, the anti-Fc specific reagent did not react with surface immunoglobulin on B cells but was reactive with cytophilic immunoglobulin present on CD16+ cells. Next we determined that dualcolor analysis was superior to single-color analysis both for the evaluation of T cell reactivities and for the discrimination of T cell from B cell reactivities. Additionally, dual-color analysis revealed that the density of class I histocompatibility antigens on B cells is greater than on T cells, indicating that B cells may be a more sensitive target for detecting low levels of anti-class I antibodies. Finally, we determined that a shift in the mean fluorescence intensity of greater than 10 channels on a 256-channel, 3-decade log scale was indicative of a positive FCXM. The data presented in these studies provide the basis for performing standardized dual-color FCXM with increased sensitivity and specificity.

Combined simultaneous cisplatin/fluorouracil chemotherapy and split course radiation in head and neck cancer.

Abstract: Fifty-three patients with stage III (eight patients, 15%), stage IV (36 patients, 68%), or recurrent disease (nine patients, 17%) entered a study of simultaneous cisplatin, 60 mg/m2 day 1, fluorouracil (5-FU) infusion, 800 mg/m2 days 1 to 5, and radiation, 2 Gy days 1 to 5, every other week for a total of seven cycles (70 Gy in 13 weeks). Patient acceptance was high, with only two patients (4%) refusing to complete therapy. The median actual dose delivered was 88% of the planned dose for cisplatin, 78% for 5-FU, and 70 Gy for radiation. Weight loss of 10% or more and severe mucositis were the most common side effects (53% and 48% incidence, respectively). All patients were followed at least 1 year (median, 51 months). While the complete response rate (55%) seemed no better than that reported in other series, freedom of progression of regional disease (73%), and the survival of all patients (median, 37 months) were substantially improved. Only 33% of partial responders have failed regionally, while 15% of ...