Inferior orbital fissure release to access the inferolateral orbital apex.

OBJECTIVE: To describe release of the inferior orbital fissure (IOF) as a novel surgical technique that will improve access to the inferior and inferolateral orbital apex. DESIGN: Laboratory investigation. PARTICIPANTS: Human cadaver heads. METHODS: Cadaveric dissection study whereby the technique of an IOF release was performed. A swinging eyelid preseptal approach was used to enable a subperiosteal dissection to the orbital floor without obstruction from orbital fat prolapse. A plane was dissected between periorbita and Muller's muscle, the smooth muscle that overlies the entire length of the IOF. Measurements were taken in the sagittal plane from a point on the inferior orbital rim directly above the infraorbital foramen to the most posterior aspect of the orbital floor. RESULTS: Fifteen orbits from 8 cadaver heads were dissected with the aid of a rigid 0-degree endoscope and microsurgical instruments. This study demonstrated that an additional 10.93 ± 2.10 mm of access to the orbital apex was gained after the release of periorbita from the IOF. CONCLUSION: We propose that the IOF release can be adopted as an adjunctive technique to orbital surgery of the inferior and inferolateral orbital apex.

Transorbital Endoscopic Approach to the Foramen Rotundum for Infraorbital Nerve Stripping.

PURPOSE: To develop and evaluate a transorbital endoscopic approach to the foramen rotundum to excise the maxillary nerve and infraorbital nerve branch. METHODS: Cadaveric dissection study of 10 cadaver heads (20 orbits). This technique is predicated upon 1) an inferior orbital fissure release to facilitate access to the orbital apex and 2) the removal of the posterior maxillary wall to enter the pterygopalatine fossa (PPF). Angulations along the infraorbital nerve were quantified as follows: the first angulation was measured between the orbitomaxillary segment within the orbital floor and the pterygopalatine segment suspended within the PPF, while the second angulation was taken between the pterygopalatine segment and maxillary nerve as it exited the foramen rotundum. With refinement of the technique, the minimum amount of posterior maxillary wall removal was quantified in the final 5 cadaver heads (10 orbits). RESULTS: The mean distance from the inferior orbital rim to the foramen rotundum was 45.55 ± 3.24 mm. The first angulation of the infraorbital nerve was 133.10 ± 16.28 degrees, and the second angulation was 124.95 ± 18.01 degrees. The minimum posterior maxillary wall removal to reach the PPF was 11.10 ± 2.56 mm (vertical) and 11.10 ± 2.08 mm (horizontal). CONCLUSIONS: The transorbital endoscopic approach to an en bloc resection of the infraorbital nerve branch up to its maxillary nerve origin provides a pathway to the PPF. This is relevant for nerve stripping in the context of perineural spread. Other applications include access to the superior portion of the PPF in selective biopsy cases or in concurrent orbital pathology.

ACR Appropriateness Criteria® Sudden Onset of Cold, Painful Leg: 2023 Update.

Acute onset of a cold, painful leg, also known as acute limb ischemia, describes the sudden loss of perfusion to the lower extremity and carries significant risk of morbidity and mortality. Acute limb ischemia requires rapid identification and the management of suspected vascular compromise and is inherently driven by clinical considerations. The objectives of initial imaging include confirmation of diagnosis, identifying the location and extent of vascular occlusion, and preprocedural/presurgical planning. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Systematic Review of Use of Patient-Reported Outcomes in Interventional Radiology.

INTRODUCTION: A patient-reported outcome (PRO) is any outcome reported directly by the patient, in contradistinction to a clinician-reported outcomes, which have dominated clinical research. This systematic review evaluates the ways in which PROs have been used in the interventional radiology literature. METHODS: Systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was designed and conducted by a medical librarian. Studies were screened for inclusion by two independent members, with a third member as a conflict resolver. The data were extracted from each study in a consistent and structured manner. RESULTS: In all, 354 studies met criteria for full-text analysis; 218 of 354 (62%) used a prospective design and most frequently provided level III (249 of 354, 70%) or level I (68 of 354, 19%) evidence. The manner in which PROs were obtained was reported in 125 of 354 (35%) of studies. Questionnaire response rate was documented in 51 of 354 (14%) studies, and questionnaire completion rate was documented in 49 of 354 (14%) studies. Of 354 studies, 281 (79%) studies used at least one independently validated questionnaire. The disease domains most commonly assessed via PRO were women's health (62 of 354, 18%) and men's health (60 of 354, 17%). DISCUSSION: Wider development, validation, and systematic use of PROs in IR would enable more informed patient-centered decision making. A greater focus on PROs in clinical trials would elucidate expected outcomes from the patient's perspective, simplifying comparisons with therapeutic alternatives. To produce more convincing evidence, trials must apply validated PROs rigorously and report possible confounding factors consistently.

External Fixator Usage and Delayed MRI Scans: A National Survey Study.

OBJECTIVE: To report the current state of institutional protocols regarding the use of MRI in patients with external fixation devices (EFDs) in the United States. DESIGN: National Survey Study. PARTICIPANTS: Practicing orthopaedic surgeons frequenting the Orthopaedic Trauma Association website were invited to participate in this study. RESULTS: Sixty-two eligible orthopaedic surgeons completed the survey. No respondents reported any known harmful complications of MRI use with an EFD. Eight respondents (13%) reported at least one early scan termination because of mild warmth or vibration without any lasting complications. Fifty-six respondents (90%) reported delays to care related to MRI-EFD compatibility labeling, and 27 respondents (48%) reported delayed MRI scans in every patient with an EFD who needed one. Twenty-six surgeons (42%) had modified their practice in some way in response to these barriers. Examples include delaying EFD placement until after MRI, relying on CT arthrograms over MRI for surgical planning, and taking patients to the operating room to remove EFDs temporarily and then replace them. Nineteen respondents (31%) had developed formal protocols to address this issue, but having a written protocol was not associated with any decrease in delays ( P = 0.119). Eighty-nine percent of respondents thought there was a need for a national consensus guideline on this issue. CONCLUSION: Despite no previous reports of harmful complications, MRI utilization is frequently delayed or prevented in patients with EFDs in place. This is a pervasive problem nationally, which persists despite the implementation of written institutional protocols. Additional research is needed, potentially at the national level, to address this common issue. LEVEL OF EVIDENCE: V.

Regional Anesthesia as an Alternative to Moderate Sedation for Perioperative Pain Control for Percutaneous Gastrostomy Tube Placement.

Percutaneous gastrostomy tube placement is typically performed under moderate sedation. However, some patients are not ideal candidates for moderate sedation because of respiratory compromise, difficult airways, or other factors. The purpose of this study was to evaluate regional anesthesia as an alternative to moderate sedation. A retrospective review of patients who underwent percutaneous gastrostomy tube placement between March 2014 and September 2020 was performed. Data on patient demographics, anesthesia type, pain scores, and opiate usage were collected. A total of 189 patients were included in the study; 35 (18.5%) received regional anesthesia and 154 received moderate sedation. Patients in the regional anesthesia group tolerated the procedure well, with lower mean immediate postprocedural and maximal pain scores of 0.7 vs 2.2 (P = .011) and 4.3 vs 6.5 (P = .003), respectively. Regional anesthesia is effective at controlling perioperative pain and is an alternative with a low complication rate for patients who cannot tolerate moderate sedation.

New clinic workflow improves compliance for routine PCN exchanges.

PURPOSE: To examine the effect of a clinic workflow intervention on follow-up for routine ercutaneous nephrostomy tube (PCN) exchanges. METHODS: An intervention consisting of automated electronic tracking for all PCN placements and exchanges followed by phone call reminders to schedule a follow-up exchange 60 days post-procedure was introduced on March 19, 2019. All PCN exchanges performed from March 19, 2018 to September 18, 2019 were identified through a local electronic database search to assess the impact of intervention as a quality improvement project. Basic demographic information and procedure details were collected. Routine follow-up at our institution is recommended every 90 days. The exchange rates within 90 days were compared between groups using a Chi-squared test. RESULTS: A total of 160 PCN placements or exchanges were performed pre-intervention and 69 PCN exchanges were performed post-intervention. Pre-intervention, 75/160 (46.3%) were exchanged within 90 days compared to 47/69 (68.1%) exchanged within 90 days post-intervention. The remainder had delayed follow-up due to loss to follow-up or scheduling delays. Post-intervention, there was a significantly improved rate of compliance for PCN exchanges within the recommended 90 days at our institution (p-value = 0.002). CONCLUSION: Automated tracking and phone call follow-up at 60 days post-procedure is a simple and effective intervention that can improve compliance for routine PCN exchanges and reduce the number of patients that are lost to follow-up.

Survival Analysis Using Albumin-Bilirubin (ALBI) Grade for Patients Treated with Drug-Eluting Embolic Transarterial Chemoembolization for Hepatocellular Carcinoma.

PURPOSE: The albumin-bilirubin (ALBI) grade has been established as an improved predictor of survival in patients with hepatocellular carcinoma (HCC) treated with conventional transarterial chemoembolization and yttrium-90 radioembolization. The purpose of the study was to investigate the utility of ALBI grade in prognosticating outcomes in patients with HCC treated with drug-eluting embolic (DEE) transarterial chemoembolization (TACE). MATERIALS AND METHODS: A single-center retrospective review was performed to compare the efficacy of ALBI grade and Child-Pugh (CP) classification in predicting the survival of patients with HCC receiving DEE-TACE. A total of 303 patients with HCC were identified who had received DEE-TACE without concomitant locoregional therapy within 30 days. Survival analysis was performed using Kaplan-Meier methods and censored for curative therapy. Survival curves were stratified based on the ALBI grade, CP class, Barcelona Clinic Liver Cancer (BCLC) stage, Eastern Cooperative Oncology Group performance status, and presence of ascites. The discriminatory ability of survival curves was calculated by C-Index. RESULTS: Kaplan-Meier survival curves stratified by the ALBI grade produced distinct, nonoverlapping curves (P < .001), showing greater discriminatory ability than the CP classification (C-index = 0.568 and 0.545, respectively). The substratification of the BCLC stage by the ALBI grade yielded greater discriminatory ability than the substratification by the CP classification (C-index = 0.573 and 0.565, respectively). For patients with BCLC stage B, the substratification by the ALBI grade yielded distinct curves, whereas the substratification by the CP classification did not (P = .011 and P = .379, respectively). CONCLUSIONS: ALBI grade showed improved discriminatory ability compared with CP classification in differentiating overall survival among patients with HCC receiving DEE-TACE. Furthermore, ALBI grade was effective in substratifying survival among patients categorized as CP class A and patients with BCLC stage B, whereas CP classification was not effective.

What is "safety"?: Lethal means counseling as a cross-cultural communication.

U.S. suicide rates have risen every year over the past two decades with self-directed firearm use as the method accounting for the highest proportion of deaths. This pattern is particularly pronounced among veterans and members of the U.S. Armed Forces. The numerical burden of firearm-related suicide accompanied by characteristics of self-directed firearm injury have motivated the development of lethal means safety initiatives focused on firearms. Simultaneously, research has sought to characterize patterns of firearm ownership and use among veterans as well as optimal strategies for clinicians to deliver suicide prevention messages to firearm owners. Increasingly, findings from research have been understood as cultural factors that warrant greater attention to improve the quality of lethal means counseling. Here, we review and interpret selected research on cultural aspects of firearm ownership and suggest that cultural differences between health care practitioners and firearm owners may result in health care practitioners delivering clinical interventions that are broadly divergent from perspectives within the cultural frameworks of firearm owners. We follow by organizing these cultural factors into existing frameworks of cultural competency training as a basis for developing curriculum for health care practitioners to improve clinical care.

Systematic Reviews and Meta-Analyses of Portal Vein Embolization, Associated Liver Partition and Portal Vein Ligation, and Radiation Lobectomy Outcomes in Hepatocellular Carcinoma Patients.

PURPOSE OF REVIEW: To understand portal vein embolization (PVE), associated liver partition and portal vein ligation (ALPPS) and radiation lobectomy (RL) outcomes in hepatocellular carcinoma (HCC) patients. Systematic reviews of future liver remnant (FLR) percent hypertrophy, proportion undergoing hepatectomy and proportion with major complications following PVE, ALPPS, and RL were performed by searching Ovid MEDLINE, Ovid EMBASE, The Cochrane Library, and Web of Science. Separate meta-analyses using random-effects models with assessment of study heterogeneity and publication bias were performed whenever allowable by available data. RECENT FINDINGS: Of the 10,616 articles screened, 21 articles with 636 subjects, 4 articles with 65 subjects, and 4 articles with 195 subjects met the inclusion criteria for systematic reviews and meta-analyses for PVE, ALPPS, and RL, respectively. The pooled estimate of mean percent FLR hypertrophy was 30.9% (95%CI: 22-39%, Q = 4034.8, p < 0.0001) over 40.3 +/- 26.3 days for PVE, 54.9% (95%CI: 36-74%, Q = 73.8, p < 0.0001) over 11.1 +/- 3.1 days for ALPPS, and 29.0% (95%CI: 23-35%, Q = 56.2, p < 0.0001) over 138.5 +/- 56.5 days for RL. The pooled proportion undergoing hepatectomy was 91% (95%CI: 83-95%, Q = 43.9, p = 0.002) following PVE and 98% (95%CI: 50-100%, Q = 0.0, p = 1.0) following ALPPS. The pooled proportion with major complications was 5% (95%CI: 2-10%, Q = 7.3, p = 0.887) following PVE and 38% (95%CI: 18-63%, Q = 10.0, p = 0.019) following ALPPS. Though liver hypertrophy occurs following all three treatments in HCC patients, PVE balances effective hypertrophy with a short time frame and low major complication rate.

Intermittent Projectile Urethraggia: An Unusual Sequela of a Skateboarding Accident in an Adolescent Male.

Our patient suffered a perineal straddle injury, resulting in right cavernosal artery pseudoaneurysm in combination with a cavernosal-urethral fistula. The urethra failed to heal after several weeks, and the patient presented with severe intermittent urethral bleeding. The pseudoaneurysm was successfully treated by coil embolization, with resolution of the bleeding. The patient recovered completely, with normal erectile and voiding function. This type of injury is very rare in the literature: traumatic cavernosal arterial pseudoaneurysm is known to cause high flow priapism, but in this case additional cavernosal-urethral fistula resulted in a severe urethraggia. This is the only case, to our knowledge, of delayed urethral bleeding from cavernosal artery pseudoaneursym in combination with a cavernosal-urethral fistula.

Percutaneous treatment of hepatocellular carcinoma in patients with cirrhosis: a comparison of the safety of cryoablation and radiofrequency ablation.

PURPOSE: To compare the safety of image-guided percutaneous cryoablation and radiofrequency ablation in the treatment of hepatocellular carcinoma in patients with cirrhosis. MATERIALS AND METHODS: This retrospective HIPAA-compliant study received institutional review board approval. Forty-two adult patients with cirrhosis underwent image-guided percutaneous ablation of hepatocellular carcinoma from 2003 to 2011. Twenty-five patients underwent 33 cryoablation procedures to treat 39 tumors, and 22 underwent 30 radiofrequency ablation procedures to treat 39 tumors. Five patients underwent both cryoablation and radiofrequency ablation procedures. Complication rates and severity per procedure were compared between the ablation groups. Potential confounding patient, procedure, and tumor-related variables were also compared. Statistical analyses included Kruskal-Wallis, Wilcoxon rank sum, and Fisher's exact tests. Two-sided P-values <0.05 were considered significant. RESULTS: The overall complication rates, 13 (39.4%) of 33 cryoablation procedures versus eight (26.7%) of 30 radiofrequency ablation procedures and severe/fatal complication rates, two (6.1%) of 33 cryoablation procedures versus one (3.3%) of 30 radiofrequency ablation procedures, were not significantly different between the ablation groups (both P=0.26). Severe complications included pneumothoraces requiring chest tube insertion during two cryoablation procedures. One death occurred within 90 days of a radiofrequency ablation procedure; all other complications were managed successfully. CONCLUSION: No significant difference was seen in the overall safety of image-guided percutaneous cryoablation and radiofrequency ablation in the treatment of hepatocellular carcinoma in patients with cirrhosis.

The effects of electronic polarization on water adsorption in metal-organic frameworks: H2O in MIL-53(Cr).

The effects of electronic polarization on the adsorption of water in the MIL-53(Cr) metal-organic framework are investigated using molecular dynamics simulations. For this purpose a fully polarizable force field for MIL-53(Cr) was developed which is compatible with the ab initio-based TTM3-F water model. The analysis of the spatial distributions of the water molecules within the MIL-53(Cr) nanopores calculated as a function of loading indicates that polarization effects play an important role in the formation of hydrogen bonds between the water molecules and the hydroxyl groups of the framework. As a result, large qualitative differences are found between the radial distribution functions calculated with non-polarizable and polarizable force fields. The present analysis suggests that polarization effects can significantly impact molecular adsorption in metal-organic frameworks under hydrated conditions.

Role of secondary sialic acid binding sites in influenza N1 neuraminidase.

Within influenza viral particles, the intricate balance between host cell binding and sialic acid receptor destruction is carefully maintained by the hemagglutinin (HA) and neuraminidase (NA) glycoproteins, respectively. A major outstanding question in influenza biology is the function of a secondary sialic acid binding site on the NA enzyme. Through a series of Brownian dynamics (BD) simulations of the avian N1, human pandemic N2, and currently circulating pandemic (H1)N1 enzymes, we have probed the role of this secondary sialic acid binding site in the avian N1 subtype. Our results suggest that electrostatic interactions at the secondary and primary sites in avian NA may play a key role in the recognition process of the sialic acid receptors and catalytic efficiency of NA. This secondary site appears to facilitate the formation of complexes with the NA protein and the sialic acid receptors, as well as provide HA activity to a lesser extent. Moreover, this site is able to steer inhibitor binding as well, albeit with reduced capacity in N1, and may have potential implications for drug resistance or optimal inhibitor design. Although the secondary sialic acid binding site has previously been shown to be nonconserved in swine NA strains, our investigations of the currently circulating pandemic H1N1 strain of swine origin appears to have retained some of the key features of the secondary sialic acid binding site. Our results indicate possible lowered HA activity for this secondary sialic acid site, which may be an important event in the emergence of the current pandemic strain.

Do nonspecific deep corticomedullary sutures performed during partial nephrectomy adequately control major vascular and collecting system injury?

OBJECTIVE: To critically evaluate the effectiveness of placing nonspecific deep corticomedullary sutures in the setting of major vascular and collecting system injury during laparoscopic partial nephrectomy (LPN). We also aimed to evaluate the incidence of ischaemic injury to the remaining renal remnant because of these sutures, as many laparoscopic centres have adopted this practice. MATERIALS AND METHODS: We performed open PN on eight porcine kidneys. Both the artery and vein were clamped. The ureter was transected and tied around an angiocatheter for evaluating collecting system integrity both before and after corticomedullary suturing. The renal artery was cannulated for angiography before and after the corticomedullary suturing. The rate of bleeding was also assessed before and after corticomedullary suturing. RESULTS: There was marked arterial bleeding and large collecting system injury induced in all kidneys. Two of the eight renal units continued to have significant arterial bleeding after the deep corticomedullary sutures were placed. All of the eight units had at least a small urinary leak after suturing, with three having medium-to-large leaks. In four of the renal units, there were major segmental vessels occluded by the sutures, as detected by angiography. CONCLUSIONS: The practice of placing nonspecific deep corticomedullary sutures, during PN, may not adequately control major vascular and collecting system injury. In addition, segmental vessels supplying remnant renal tissue are often affected; thereby further compromising function because of devascularization. The search for the best technique for LPN continues.

Outside CT imaging among emergency department transfer patients.

PURPOSE: The aim of this study was to characterize the quantity and types of outside computed tomographic (CT) examinations submitted for reinterpretation among emergency department (ED) transfers to a tertiary care, level I trauma, academic medical center and the frequency of and reasons for repeat imaging. METHODS: Reinterpretation requests for outside CT studies accompanying ED transfer patients over a 4-month period were prospectively audited. Clinicians completed forms specifying type of CT study, outside report availability, interpretational discrepancies, repeat imaging requests, and reasons for repeat imaging. RESULTS: A total of 425 CT studies were reviewed among 255 transfer patients, with a mean of 2.8 examinations (range, 0-16) on 1.7 patients (range, 0-8) per day. The patients' mean age was 59 years, and 57% were male. The clinicians reported no outside verbal or written reports for 16% of patients. Interpretational discrepancies were noted in 12% of those with outside reports. Repeat scans might have been avoided in as many as 25% of rescanned patients (35% of repeat examinations) because they were performed solely for imaging or information technology reasons (inadequate imaging, compact disc inoperability, or unavailable images within the hospital's picture archiving and communication system). Rescanned trauma patients in particular had a high per patient rate (32%) of potentially avoidable reasons, with a lower rate (11%) in nontrauma patients. CONCLUSION: Outside CT imaging in ED transfers adds workload and resource requirements for receiving institutions. A communication gap exists between transferring and receiving institutions, and interpretational discrepancies are common. Process improvement measures are suggested that might reduce the substantial rates of potentially avoidable reimaging.

Geographic variations in the use of medical and surgical therapies for benign prostatic hyperplasia.

PURPOSE: Patients with BPH have several treatment options. Little is known about geographic variations in surgical rates for BPH and the market relationships to medical therapy, health resources and sociodemographic factors. MATERIALS AND METHODS: We conducted a cross-sectional study using administrative data from 5 states in 2000. Rates of surgical and medical therapy were calculated per 100,000 men 55 years old or older. Main outcome measures were county level weighted coefficient of variation and systematic component of variation in therapy rates, as well as surgery rates as a function of medication dispensing rates, health care resources and sociodemographic characteristics. RESULTS: North Carolina had the lowest surgery rates (26.3 minimally invasive procedures and 332.1 invasive surgeries per 100,000) and finasteride dispensing rates (503.5 per 100,000). Overall rates of medical therapy were 5 times higher than surgery rates. Geographic variations in surgical and medical therapy rates were significant for each state, and North Carolina had the greatest variation. An increase of 11.6 per 100,000 (95% CI, 6.5-55.8) in annual county level finasteride dispensing would be associated with a decrease in the surgery rate of 1 per 100,000, controlling for other variables. CONCLUSIONS: There is significant systematic variation in rates of surgical and medical therapy for BPH at county and state levels. The relationship between finasteride and surgery in randomized clinical trials is generalizable to the marketplace. Finasteride rates are inversely related to surgery rates, and tamsulosin rates are positively associated with surgery rates. Surgery rates are not significantly associated with urologists per capita.

Controlled survival study of the effects of Tisseel or a combination of FloSeal and Tisseel on major vascular injury and major collecting-system injury during partial nephrectomy in a porcine model.

PURPOSE: We report the results of a controlled survival study in a porcine model investigating Tisseel or a combination of FloSeal and Tisseel in dealing with vascular and collecting-system injury during partial nephrectomy. MATERIALS AND METHODS: We performed an open right lower-pole partial nephrectomy on 15 large female pigs. The defect was repaired using standard open techniques (N = 5; controls), Tisseel only (N = 6; group I), or FloSeal followed by Tisseel (N = 4; group II). A Jackson-Pratt drain was placed. Nephrectomy and retrograde pyelography were performed at 1 week. RESULTS: Operative times were shorter in both study groups, achieving statistical significance in group I (P = 0.008). Warm-ischemia times were significantly improved in both study groups (P = 0.029 and P = 0.00005 in groups I and II, respectively). Time to hemostasis was significantly shorter in group II only (P = 0.002) but approached significance in Group I as well (P = 0.09). Estimated blood loss was not significantly different from the controls in either group. When Tisseel was placed alone after hilar control, hematoma formation under the Tisseel was noted on release of the hilar clamp. After 1 week, there was one urinoma and three urine leaks in the control group. In group I, there was one urinoma and four urine leaks, and there was only one urine leak and no urinomas in group II. There were no hematomas in any of the groups. CONCLUSIONS: Tisseel alone is not adequate for either hemostasis or management of major collecting-system injury. FloSeal capped with Tisseel appears sufficient to control major vascular and collecting-system injuries without adjunctive surgical measures. A proposed technique for laparoscopic partial nephrectomy without reconstructive techniques is presented that warrants clinical study.