First in Human Subjects Testing of the UroMonitor: A Catheter-free Wireless Ambulatory Bladder Pressure Monitor.

PURPOSE: Urodynamics is the standard method of diagnosing bladder dysfunction, but involves catheters and retrograde bladder filling. With these artificial conditions, urodynamics cannot always reproduce patient complaints. We have developed a wireless, catheter-free intravesical pressure sensor, the UroMonitor, which enables catheter-free telemetric ambulatory bladder monitoring. The purpose of this study was twofold: to evaluate accuracy of UroMonitor pressure data, and assess safety and feasibility of use in humans. MATERIALS AND METHODS: Eleven adult female patients undergoing urodynamics for overactive bladder symptoms were enrolled. After baseline urodynamics, the UroMonitor was transurethrally inserted into the bladder and position was confirmed cystoscopically. A second urodynamics was then performed with the UroMonitor simultaneously transmitting bladder pressure. Following removal of urodynamics catheters, the UroMonitor transmitted bladder pressure during ambulation and voiding in private. Visual analogue pain scales (0-5) were used to assess patient discomfort. RESULTS: The UroMonitor did not significantly alter capacity, sensation, or flow during urodynamics. The UroMonitor was also easily inserted and removed in all subjects. The UroMonitor reproduced bladder pressure, capturing 98% (85/87) of voiding and nonvoiding urodynamic events. All subjects voided with only the UroMonitor in place with low post-void residual volume. Median ambulatory pain score with the UroMonitor was rated 0 (0-2). There were no post-procedural infections or changes to voiding behavior. CONCLUSIONS: The UroMonitor is the first device to enable catheter-free telemetric ambulatory bladder pressure monitoring in humans. The UroMonitor appears safe and well tolerated, does not impede lower urinary tract function, and can reliably identify bladder events compared to urodynamics.

Chemopreventive Effect of Statin on Hepatocellular Carcinoma in Patients With Nonalcoholic Steatohepatitis Cirrhosis.

INTRODUCTION: To estimate the annual incidence of hepatocellular carcinoma (HCC) in patients with nonalcoholic steatohepatitis (NASH) with advanced liver fibrosis, to determine the risk factors for the development of HCC, and to evaluate the chemoprotective effect of statin use stratified by fibrosis stage. METHODS: We conducted a retrospective study at 2 US tertiary academic centers, including patients with NASH-related advanced liver fibrosis (bridging fibrosis [F3] and cirrhosis [F4]) followed between July 2002 and June 2016. Patients were followed from the date of diagnosis to the time of last abdominal imaging, liver transplantation, or HCC diagnosis. Multivariable Cox regression analysis was performed to evaluate the risk factors associated with HCC development, stratified by fibrosis stage. RESULTS: A total of 1,072 patients were included: 122 patients with F3 fibrosis and 950 patients with cirrhosis. No HCC was observed during 602 person-year follow-up among F3 patients. Among patients with cirrhosis, HCC developed in 82 patients with the annual incidence rate of 1.90 per 100 person-years (95% confidence interval [CI], 1.53-2.35). Multivariable analysis in patients with cirrhosis demonstrated that HCC development was associated with male sex (hazard ratio [HR] 4.06, 95% CI, 2.54-6.51, P < 0.001), older age (HR, 1.05, 95% CI, 1.03-1.08, P < 0.001), and CTP score (HR, 1.38, 95% CI, 1.18-1.60, P < 0.001). Statin use was associated with a lower risk of developing HCC (HR, 0.40, 95% CI, 0.24-0.67, P = 0.001). Each 365 increment in cumulative defined daily dose of statin use reduced HCC risk by 23.6%. DISCUSSION: Our findings suggest that patients with NASH and bridging fibrosis have a low risk of HCC. Dose-dependent statin use reduced HCC risk significantly in patients with NASH cirrhosis.

Per oral endoscopic pyloromyotomy for refractory gastroparesis: initial results from a single institution.

INTRODUCTION: Gastroparesis is a debilitating disease characterized by delayed gastric emptying in the absence of mechanical obstruction. A new intramural technique, per oral endoscopic pyloromyotomy (POP), has been proposed as an alternative to surgical pyloroplasty for the management of medical refractory gastroparesis. Herein, we detail the short-term results of POP at our institution. METHODS: POP was first performed at our institution in January 2016. All patients undergoing POP for management of gastroparesis from January 2016 through January 2017 were prospectively followed. All patients underwent a 4-h, non-extrapolated gastric emptying scintigraphy study and were asked to rate their symptoms using the Gastroparesis Cardinal Symptom Index (GCSI) at their pre-procedure visit and at 3 months post-procedure. RESULTS: A total of 47 patients underwent POP during the defined study period. Twenty-seven (57.4%) patients had idiopathic gastroparesis, 12 (25.6%) had diabetic gastroparesis, and eight (17.0%) had post-surgical gastroparesis. Forty-one (87.2%) patients had at least one previous intervention (i.e., enteral feeding tube, gastric pacer, botox injection) for their gastroparesis symptoms. All patients had evidence of gastroparesis on pre-procedure gastric emptying studies. The average length of hospital stay was 1 day. One patient died within 30-days of their index procedure which was unrelated to the procedure itself. The average pre-procedure percentage of retained food at 4 h was 37% compared to an average post-procedure percentage of 20% (p < 0.03). The average pre-procedure GCSI score was 4.6 compared to an average post-procedure GCSI of 3.3 (p < 0.001). CONCLUSIONS: POP is a safe and feasible endoscopic intervention for medical refractory gastroparesis. Additional follow-up is required to determine the long-term success of this approach in alleviating gastroparesis symptoms.

Vascular access complications during outpatient parenteral antimicrobial therapy at home: a retrospective cohort study.

OBJECTIVES: The need for indwelling vascular access for outpatient parenteral antimicrobial therapy (OPAT) places patients at risk of vascular access complications. The purpose of this study was to describe vascular access complications during OPAT at home, and identify factors associated with their occurrence. METHODS: All OPAT courses carried out at home for patients at Cleveland Clinic in 2013 were identified from the institution's OPAT registry. The first OPAT course per patient was included. Vascular access complications that occurred during the treatment course were abstracted from the electronic medical record. Only complications that triggered a clinical intervention were included. RESULTS: The 1461 included OPAT courses encompassed 33,579 OPAT days of treatment. One-hundred-and-forty-four vascular access complications occurred in 131 OPAT courses (9% of OPAT courses, 4.29 complications per 1000 OPAT days). The most common complication was occlusion (53% of all complications). Hickman catheters [incidence rate ratio (IRR) 0.20, 95% CI 0.03-0.63] and indwelling ports (IRR 0.25, 95% CI 0.04-0.78) were associated with lower complication rates than peripherally inserted central catheters, as was increasing age (IRR 0.99, 95% CI 0.98-1.00). Log OPAT duration (IRR 1.60, 95% CI 1.28-2.03), female sex (IRR 1.62, 95% CI 1.16-2.28) and injection drug use (IRR 3.32, 1.16-7.46) were associated with increased risk of vascular access complications. CONCLUSIONS: Nine percent of OPAT courses at home have at least one vascular access complication requiring clinical intervention. Longer OPAT duration, younger age, female sex and injection drug use are associated with increased risk of vascular access complications.

Impact of Alzheimer's Disease, Lewy Body and Vascular Co-Pathologies on Clinical Transition to Dementia in a National Autopsy Cohort.

AIMS: We examined the effect of vascular or Lewy body co-pathologies in subjects with autopsy-confirmed Alzheimer's disease (AD) on the rate of cognitive and functional decline and transition to dementia. METHODS: In an autopsy sample of prospectively characterized subjects from the National Alzheimer's Coordinating Center database, neuropathology diagnosis was used to define the groups of pure AD (pAD, n = 84), mixed vascular and AD (ADV, n = 54), and mixed Lewy body disease and AD (ADLBD, n = 31). Subjects had an initial Clinical Dementia Rating-Global (CDR-G) score <1, Mini-Mental State Examination ≥15, a final visit CDR-G >1, ≥3 evaluations, and Braak tangle stage ≥III. We compared the rate of cognitive and functional decline between the groups. RESULTS: The rate of functional and cognitive decline was lower for ADV, and ADV patients had less severe deficits on CDR-G and the CDR-Sum of Boxes scores at the last visit than pAD and ADLBD patients. No significant differences were noted between ADLBD and pAD patients. After controlling for age at death, the odds of reaching CDR ≥1 at the last visit were lower in the ADV subjects compared to the pAD subjects. CONCLUSIONS: The mean rate of functional and cognitive decline among ADV subjects was slower than among either pAD or ADLBD patients. Vascular pathology did not increase the odds of attaining CDR ≥1 when occurring with AD in this national cohort.

Sural sensory nerve action potential, epidermal nerve fiber density, and quantitative sudomotor axon reflex in the healthy elderly.

INTRODUCTION: Polyneuropathy evaluation in older patients is often challenging due to conflicting data regarding normative values for peripheral nerve testing. METHODS: We characterized the results of sural nerve conduction studies, intraepidermal nerve fiber density (IENFD), and quantitative sudomotor axon reflex testing (QSART) in a prospective study of 50 healthy subjects aged ≥60 years. RESULTS: Of the 50 subjects, 48 (96%) had an obtainable sural sensory nerve action potential (SNAP). Using quantile regression, we estimated the lower limit of normal (LLN) for sural amplitudes to be 3 µV for patients 60-70 years, 1 µV for those 70-74 years, and <1 µV (absent) for those ≥75 years of age. IENFD and QSART volume were reduced with advancing age, although IENFD was lower in men and QSART volume was lower in women. CONCLUSIONS: We propose that an absent sural SNAP in patients up to 75 years of age should be considered abnormal. Our findings also support age- and gender-stratified normative data for IENFD and QSART.

Physicians caring for physicians: the perspective of the primary care physician.

OBJECTIVES: How physicians provide longitudinal primary care to physician-patients (ie, physicians as patients) has not been well studied. The potential challenges of providing care to physician-patients include maintaining professional boundaries and adhering to practice guidelines. The objective was to explore the differences in identifying how physicians perceive caring for physicians-patients in the longitudinal setting versus caring for other patients in the general population. METHODS: The study consisted of focus groups, followed by quantitative survey. Participants were primary care physicians (internal medicine and family medicine) at an academic multispecialty group practice. Thematic analysis of focus groups informed the development of the survey. RESULTS: In focus groups, participants identified several benefits, challenges, and differences in caring for physician-patients versus the general population. When these findings were explored further by quantitative survey, participants noted differences in care regarding chart documentation protocols, communication of results, and accommodation of schedules. They agreed that there were benefits to providing care to physician-patients, such as believing their work was valued and discussing complex issues with greater ease. There also were challenges, including anxiety or self-doubt. Participants also agreed on the following strategies when caring for this population: make recommendations based on evidence-based medicine, follow routine assessment and examination protocols, follow routine scheduling and communication protocols, recommend the same follow-up visit schedule, and define boundaries of the relationship. CONCLUSIONS: Physicians perceive caring for physician-patients as different and rewarding, although some find that it provokes anxiety. Many are willing to make concessions regarding scheduling and testing. With increasing experience, the anxiety decreased as did the need to follow protocols and maintain boundaries. Further investigation is needed to determine the impact of physician experience and training on the quality of care for physician-patients.

Effects of passive cycling on cerebrovascular reactivity in acute brain injured patients: A pilot study.

INTRODUCTION: Early mobilization benefits critically ill patients, but concerns persist, especially in neurologic intensive care unit patients with acute brain injuries. This study assesses early mobility's impact on cerebrovascular autoregulation (CA) and systemic hemodynamics. METHODS: This single-center retrospective study focused on adult neurologic intensive care unit patients undergoing passive cycle ergometry. Data were collected from December 2020 to April 2022. Physical therapists conducted sessions using a standardized protocol, monitoring mean arterial blood pressure (MAP) and intracranial pressure (ICP). The Pressure Reactivity Index (PRx) was calculated as a measure of CA. Statistical analysis included mixed models and repeated measures ANOVA. RESULTS: Eleven patients undergoing continuous physiologic monitoring and early mobility were included, primarily with subarachnoid hemorrhage or intracranial hemorrhage. Median time to protocol initiation was 4 days, with two patients discontinuing due to hemodynamic disturbances. Over a total of 11-hours of neuromonitoring data, passive cycling demonstrated a significant reduction in heart rate (HR), MAP, and ICP across different rotations per minute (RPM) settings compared to baseline. No significant alterations in PRx or cerebral perfusion pressure (CPP) were noted at various RPM levels. However, a significant difference in PRx emerged between patients who completed the protocol and those who did not, particularly at 10 RPM. DISCUSSION: This study offers preliminary insights into the impact of early mobility on CA in acute brain injured patients. While passive cycling demonstrates promise in preserving cerebral hemodynamics, its tolerability may not be uniform across all brain-injured patients. These findings highlight the need to determine optimal early mobilization timing and intensity in this population, emphasizing the necessity for larger prospective studies to validate these findings and inform clinical practice. DETAILS: This manuscript complies with all instructions to the authors. All coauthors meet the authorship requirements and have reviewed and approved the contents of the manuscript. The manuscript has not been published totally or partly, accepted for publication, or under editorial review for publication elsewhere. We have no conflicts of interest to disclose. STROBE checklist was reviewed prior to the submission of this paper. The manuscript adheres to ethical guidelines and was approved by Cleveland Clinic's institutional research board for retrospective study. There is no funding to disclose for this study.

Impact of parturition on chemokine homing factor expression in the vaginal distention model of stress urinary incontinence.

PURPOSE: Human childbirth simulated by vaginal distention is known to increase the expression of chemokines and receptors involved in stem cell homing and tissue repair. We hypothesized that pregnancy and parturition in rats contributes to the expression of chemokines and receptors after vaginal distention. MATERIALS AND METHODS: We used 72 age matched female Lewis rats, including virgin rats with and without vaginal distention, and delivered rats with and without vaginal distention. Each rat was sacrificed immediately, or 3 or 7 days after vaginal distention and/or parturition, and the urethra was harvested. Relative expression of chemokines and receptors was determined by real-time polymerase chain reaction. Mixed models were used with the Bonferroni correction for multiple comparisons. RESULTS: Vaginal distention up-regulated urethral expression of CCL7 immediately after injury in virgin and postpartum rats. Hypoxia inducible factor-1α and vascular endothelial growth factor were up-regulated only in virgin rats immediately after vaginal distention. CD191 expression was immediately up-regulated in postpartum rats without vaginal distention compared to virgin rats without vaginal distention. CD195 was up-regulated in virgin rats 3 days after vaginal distention compared to virgin rats without vaginal distention. CD193 and CXCR4 showed delayed up-regulation in virgin rats 7 days after vaginal distention. CXCL12 was up-regulated in virgin rats 3 days after vaginal distention compared to immediately after vaginal distention. Interleukin-8 and CD192 showed no differential expression. CONCLUSIONS: Vaginal distention results in up-regulation of the chemokines and receptors expressed during tissue injury, which may facilitate the spontaneous functional recovery previously noted. Pregnancy and delivery up-regulated CD191 and attenuated the expression of hypoxia inducible factor-1α and vascular endothelial growth factor in the setting of vaginal distention, likely by decreasing hypoxia.

Biological and biomechanical responses to traditional epithelium-off and transepithelial riboflavin-UVA CXL techniques in rabbits.

PURPOSE: To compare the biological effects of riboflavin-ultraviolet A (UVA) corneal cross-linking (CXL) performed with a traditional epithelium-off method to several transepithelial methods in a rabbit model. Preliminary experiments on biomechanical rigidity were also performed. METHODS: Four treatment groups were included: (1) standard epithelium-off, (2) tetracaine transepithelial, (3) benzal-konium chloride-ethylenediaminetetraacetic acid (BKC-EDTA) transepithelial, and (4) femtosecond laser-assisted transepithelial riboflavin-UVA CXL. Six eyes from each treatment group and the untreated control group were analyzed at 24 hours and 2 months after treatment in wound healing studies. The TUNEL assay was performed to detect the extent of stromal cell death. Optical density was measured with a Scheimpflug analyzer. The corneal stiffening effect was quantitated in three eyes from each group using optical coherence elastography performed 2 months after treatments. RESULTS: Twenty-four hours after CXL, stromal cell death extended full corneal thickness with both standard epithelium-off CXL and femtosecond laser-assisted CXL, but only approximately one-third stromal depth after BKC-EDTA transepithelial CXL. Negligible stromal cell death was detected with tetracaine transepithelial CXL. Cell death results were statistically different between the BKC-EDTA transepithelial CXL and standard epithelium-off CXL groups (P < .0001). Significant corneal opacity differences were noted. Standard epithelium-off CXL had the greatest density and tetracaine transepithelial CXL had the least density compared to the control group after treatment. As measured with optical coherence elastography, a trend toward greater mean stiffening was observed with BKC-EDTA transepithelial CXL than with epithelium-off CXL, femtosecond laser-assisted CXL, or tetracaine transepithelial CXL, but the result did not reach statistical significance. All of the CXL treatment groups exhibited significantly smaller variance of stiffness compared to the control group. CONCLUSION: In the rabbit model, BKC-EDTA transepithelial CXL produced less stromal cell death and less risk of endothelial cell damage than standard epithelium-off CXL or femtosecond laser-assisted CXL. Additional study is needed to determine whether biomechanical stiffness is significantly different between the epithelium-off CXL and transepithelial CXL groups.

Phencyclidine Positivity on Urine Drug Screening in Patients Treated for Alcohol Withdrawal on a Dual-diagnosis Medically Assisted Withdrawal Unit.

OBJECTIVES: Little contemporary research has explored phencyclidine (PCP) use in people with alcohol use disorder. Therefore, we sought to determine the prevalence of PCP positivity on urine toxicology screening among patients admitted for alcohol withdrawal, identify correlates of PCP positivity, and investigate PCP positivity's relationship to length of stay (LOS) and risk of facility readmission. METHODS: This was a retrospective study of patients admitted to a dual-diagnosis medically assisted withdrawal unit for alcohol withdrawal from 2014 to 2019. Univariate tests and logistic regression were used to investigate potential correlates of PCP positivity on admission toxicology screening (primary outcome). Multivariable linear regression models and survival analyses analyzing LOS and risk of readmission (secondary outcomes) were also developed. RESULTS: Ninety of 3731 patients (2.4%) screened positive for PCP. There were significant associations on univariate testing between PCP positivity and age, race, homeless status, and urine toxicology positivity for amphetamines, benzodiazepines, barbiturates, cocaine, tetrahydrocannabinol, and oxycodone. On multivariate logistic regression, only tetrahydrocannabinol, barbiturates, and cocaine positivity were associated with PCP positivity. Multivariate logistic regression and survival analysis found no statistically significant associations between PCP positivity and LOS or risk of readmission. CONCLUSIONS: This study provides rare analysis of contemporary data on PCP use among patients undergoing medically assisted alcohol withdrawal. Phencyclidine positivity was uncommon, but use appears considerably higher among this patient population than the general population. There was no significant association between PCP positivity and LOS or readmission risk.

Antemortem Health System Utilization in People Experiencing Homelessness Who Died in the Emergency Department.

People experiencing homelessness (PEH) have high rates of mortality, medical and psychiatric comorbidities, and emergency department utilization. In this study, a health system's emergency department encounters were evaluated to identify PEH who died in the emergency department. Patient demographics, medical history, prehospital and emergency department characteristics, and health care utilization patterns were collected. Descriptive statistics were calculated. We identified 48 PEH pronounced dead in the emergency department; mean age at death was 46.5. Forty-four (92%) decedents presented in cardiac arrest, 12 (25%) of which were substance use-related; 4 (8%) presented with trauma. Out of 44 patients presenting in cardiac arrest, (20.5%) had bystander cardiopulmonary resuscitation (CPR) performed before arrival of emergency medical services. In the year prior to death, 15 (32%) decedents had no documented health care utilization, while 16 (33%) had 10 or more emergency department/outpatient visits. Our study is the first to characterize PEH who died in the emergency department, analyzing the pre-hospital and in-hospital characteristics and antemortem health system utilization in this population. A sizeable proportion of deceased PEH had no health system contact in the 12 months prior to death, suggesting that those with high mortality risk may underutilize health services. Conversely, a similar proportion of decedents had extensive (more than 10) health system utilization in the year prior to death, representing possible opportunities to reduce mortality.

Intravenous hemostatic nanoparticles increase survival following blunt trauma injury.

Trauma is the leading cause of death for people ages 1-44, with blood loss comprising 60-70% of mortality in the absence of lethal CNS or cardiac injury. Immediate intervention is critical to improving chances of survival. While there are several products to control bleeding for external and compressible wounds, including pressure dressings, tourniquets, or topical materials (e.g., QuikClot, HemCon), there are no products that can be administered in the field for internal bleeding. There is a tremendous unmet need for a hemostatic agent to address internal bleeding in the field. We have developed hemostatic nanoparticles (GRGDS-NPs) that reduce bleeding times by ~50% in a rat femoral artery injury model. Here, we investigated their impact on survival following administration in a lethal liver resection injury in rats. Administration of these hemostatic nanoparticles reduced blood loss following the liver injury and dramatically and significantly increased 1 h survival from 40 and 47% in controls (inactive nanoparticles and saline, respectively) to 80%. Furthermore, we saw no complications following administration of these nanoparticles. We further characterized the nanoparticles' effect on clotting time (CT) and maximum clot firmness (MCF) using rotational thromboelastometry (ROTEM), a clinical measurement of whole-blood coagulation. Clotting time is significantly reduced, with no change in MCF. Administration of these hemostatic nanoparticles after massive trauma may help staunch bleeding and improve survival in the critical window following injury, and this could fundamentally change trauma care.

Electrical stimulation of anal sphincter or pudendal nerve improves anal sphincter pressure.

OBJECTIVE: Stimulation of the pudendal nerve or the anal sphincter could provide therapeutic options for fecal incontinence with little involvement of other organs. The goal of this project was to assess the effects of pudendal nerve and anal sphincter stimulation on bladder and anal pressures. DESIGN: Ten virgin female Sprague Dawley rats were randomly allocated to control (n = 2), perianal stimulation (n = 4), and pudendal nerve stimulation (n = 4) groups. A monopolar electrode was hooked to the pudendal nerve or placed on the anal sphincter. Aballoon catheter was inserted into the anus to measure anal pressure, and a catheter was inserted into the bladder via the urethra to measure bladder pressure. Bladder and anal pressures were measured with different electrical stimulation parameters and different timing of electrical stimulation relative to spontaneous anal sphincter contractions. RESULTS: Increasing stimulation current had the most dramatic effect on both anal and bladder pressures. An immediate increase in anal pressure was observed when stimulating either the anal sphincter or the pudendal nerve at stimulation values of 1 mA or 2 mA. No increase in anal pressure was observed for lower current values. Bladder pressure increased at high current during anal sphincter stimulation, but not as much as during pudendal nerve stimulation. Increased bladder pressure during anal sphincter stimulation was due to contraction of the abdominal muscles. CONCLUSION: Electrical stimulation caused an increase in anal pressures with bladder involvement only at high current. These initial results suggest that electrical stimulation can increase anal sphincter pressure, enhancing continence control.

Reported firearm access among patients admitted to a dual diagnosis medically-assisted withdrawal unit over five years.

Background: Up to one-third of firearm-related suicides were carried out by individuals who had consumed alcohol shortly before their death. Despite the critical role of firearm access screening in suicide risk assessment, few studies have examined firearm access among patients with substance use disorders. This study examines the rates of firearm access among those admitted to a co-occurring diagnosis unit over a five year period. Methods: All patients admitted to a co-occurring disorders inpatient unit from 2014 to mid-2020 were included. An analysis contrasting the differences among patients reporting firearms was performed. A multivariable logistic regression model using factors from initial admission were chosen based on clinical relevance, past firearms research, and statistical significance on bivariate analysis was used. Results: Over the study period there were 7332 admissions representing 4055 patients. Documentation of firearm access was completed in 83.6% of admissions. Firearm access was reported in 9.4% of admissions. Patients reporting firearm access were more likely to report never having suicidal ideation (p = 0.001), be married (p = <0.001), and report no past history of suicide attempts (p = <0.001). The full logistic regression model revealed that being married (OR: 2.29 and p < 0.0001) and employed (OR: 1.51 and p = 0.024) were factors associated with firearms access. Conclusions: This is one of the largest reports assessing factors associated with firearm access among those admitted to a co-occurring disorders unit. Firearm access rates in this population appear lower than rates in the general population. The roles employment and marital status play in firearm access deserve future attention.

Are There Differences in the Cranial Base of Humans and Apes?

PURPOSE: Differences in skull-base angles between humans, other hominid species and apes might account for the ability of humans to develop complex speech. This study compared midline skull base angles, and angles related to insertion of skull base musculature between these species. METHODS: 126 human adult, 29 adolescent, 19 children, and 13 fetus skulls were compared to 32 ape and a subset of non-human antiquity hominid casts of skulls (13). Cranial base measurements were taken using an eMicroscribe 3d G2 digitizer. Midline and muscle insertion measurements were obtained. RESULTS: There were statistical differences in both the midline angles of the skull base (humans, 119o; apes, 130o) and in the Skull base angles related to points of muscle insertion (humans, 113o; apes, 124o), with humans exhibiting a more acute angle than the apes and other non-human hominids. There were no differences between human adults and children CONCLUSION: Acute angle differentiation of the midline skull base between humans and apes was confirmed with an alternate measurement method. Whether these angular differences are the primary reason for the lower position of the larynx in humans and the potential for more complex speech is still in debate.

Assessment of L5-S1 anterior lumbar interbody fusion stability in the setting of lengthening posterior instrumentation constructs: a cadaveric biomechanical study.

OBJECTIVE: Excessive stress and motion at the L5-S1 level can lead to degenerative changes, especially in patients with posterior instrumentation suprajacent to L5. Attention has turned to utilization of L5-S1 anterior lumbar interbody fusion (ALIF) to stabilize the lumbosacral junction. However, questions remain regarding the effectiveness of stand-alone ALIF in the setting of prior posterior instrumented fusions terminating at L5. The purpose of this study was to assess the biomechanical stability of an L5-S1 ALIF with increasing lengths of posterior thoracolumbar constructs. METHODS: Seven human cadaveric spines (T9-sacrum) were instrumented with pedicle screws from T10 to L5 and mounted to a 6 degrees-of-freedom robot. Posterior fusion construct lengths (T10-L5, T12-L5, L2-5, and L4-5) were instrumented to each specimen, and torque-fusion level relationships were determined for each construct in flexion-extension, axial rotation, and lateral bending. A stand-alone L5-S1 ALIF was then instrumented, and L5-S1 motion was measured as increasing pure moments (2 to 12 Nm) were applied. Motion reduction was calculated by comparing L5-S1 motion across the ALIF and non-ALIF states. RESULTS: The average motion at L5-S1 in axial rotation, flexion-extension, and lateral bending was assessed for each fusion construct with and without ALIF. After adding ALIF to a posterior fusion, L5-S1 motion was significantly reduced relative to the non-ALIF state in all but one fused surgical condition (p < 0.05). Longer fusions with ALIF produced larger L5-S1 motions, and in some cases resulted in motions higher than native state motion. CONCLUSIONS: Posterior fusion constructs up to L4-5 could be appropriately stabilized by a stand-alone L5-S1 ALIF when using a nominal threshold of 80% reduction in native motion as a potential positive indicator of fusion. The results of this study allow conclusions to be drawn from a biomechanical standpoint; however, the clinical implications of these data are not well defined. These findings, when taken in appropriate clinical context, can be used to better guide clinicians seeking to treat L5-S1 pathology in patients with prior posterior thoracolumbar constructs.

Real-world experience of using combinatorial pharmacogenomic test in children and adolescents with depression and anxiety.

OBJECTIVE: To evaluate the real-world impact of using a commercially available combinatorial pharmacogenomic (CPGx) test on medication management and clinical outcomes in children and adolescents treated at a tertiary care psychiatry practice. METHODS: A retrospective cohort study using our prospectively maintained database of patients undergoing CPGx testing was performed. Only patients with clinical data at the time of ordering CPGx test (pre-baseline), potential medication change visit (baseline) and 8-weeks follow-up (post-baseline) visit were included. Clinical Global Impression (CGI) scores for each visit were calculated. Appropriate statistical analysis, including one-sample t-test, paired t-test and Chi-square test was performed. RESULTS: Based on the inclusion criteria, 281 (75.9%) of the 370 patients with CPGx testing were included. Their mean age was 15.8 ± 4.5 years (111 females; 39.5%). The average number of medications significantly increased to 2.4 ± 1.2 on the post-baseline visit [t(280) = 8.34, p < 0.001). Medications were added in 123 (43.7%), replaced in 92 (32.7%) patients and remained unchanged in rest. There was no significant association between medication-related adverse effects and psychotropic medication change group (p = 0.27). The study population showed a significant improvement (p < 0.001) in the CGI severity, efficacy, and global improvement indices. CONCLUSION: In our experience of using CPGx test in a large cohort of children and adolescents during routine clinical practice, three-quarter of them underwent medication change. Additionally, we noted an improvement in clinical outcomes without impacting adverse effects. While the role of clinical judgement in medication changes in our cohort is likely, CPGx may supplement clinical decision making. However, the best use and benefit of CPGx in routine clinical practice needs further investigation.

Papillary Renal Cell Carcinoma With Microcystic Architecture Is Strongly Associated With Extrarenal Invasion and Metastatic Disease.

Papillary renal cell carcinoma (PRCC) is well-recognized as a morphologically and molecularly heterogenous group of kidney tumors with variable clinical behavior. Our goal was to analyze a unique histologic pattern of PRCC we have observed in routine practice to evaluate for potential clinical significance or distinct molecular signature. We identified 42 cases of PRCC showing a morphologically distinct architecture characterized by numerous epithelial-lined cysts containing the papillary tumor (herein called "microcysts"), which are typically separated by fibrous stroma. Of the initial 42 case test set with microcystic features, 23 (55%) were stage pT3a or higher. Most tumors had strong and diffuse cytoplasmic immunoreactivity for CK7 (93%, 37/40) and AMACR (100%, 40/40). Fumarate hydratase staining was retained in all cases tested (39/39). We performed next-generation sequencing on 15 of these cases with available tissue and identified chromosomal alterations commonly reported in historically "type 1" PRCC, notably multiple chromosomal gains, particularly of chromosomes 7 and 17, and MET alterations. However, alterations in pathways associated with more aggressive behavior (including SETD2, CDKN2A, and members of the NRF pathway) were also identified in 6 of 15 cases tested (40%). Given this molecular and immunophenotypic data, we subsequently reviewed an additional group of 60 consecutive pT2b-pT3 PRCCs to allow for comparisons between cases with and without microcysts, to assess for potential associations with other recently described histologic patterns (ie, "unfavorable architecture": micropapillary, solid, and hobnail), and to assess interobserver reproducibility for diagnosing architectural patterns and grade. Of the total combined 102 PRCCs, 67 (66%) had microcystic architecture within the intrarenal component but were commonly admixed with other patterns (39% had micropapillary, 31% solid, and 31% hobnail). Twenty-seven cases (26%) had metastatic disease, and 24 of these 27 (89%) had microcystic architecture in the intrarenal tumor. Within the pT3 subset, 21 of 22 cases with metastases (95%) had extrarenal invasion as either individual microcysts in renal sinus fat or aggregates of microcysts bulging beyond the confines of the capsule. Backward elimination and stepwise regression methods to detect features significantly associated with adverse outcome identified solid architecture (hazard ratio [HR]: 6.3; confidence interval [CI]: 2.1-18.8; P=0.001), hobnail architecture (HR: 5.3; CI: 1.7-16.7; P=0.004), and microcystic architecture at the tumor-stromal interface (HR: 4.2; CI: 1.1-16.7; P=0.036) as strongest. Of architectural patterns and grade, the microcystic pattern had a substantial interobserver agreement (κ score=0.795) that was highest among the 6 observers. In summary, PRCCs with microcystic architecture represents a subset of historically "type 1" PRCC with a predilection for morphologically distinctive extrarenal involvement and metastatic disease. Microcysts co-vary with other "unfavorable" architectural patterns also associated with higher risk for aggressive disease (ie, micropapillary, hobnail, and solid), but microcysts were more common and have superior interobserver reproducibility. These findings suggest that microcystic PRCC should be recognized as a potentially aggressive histologic pattern of growth in PRCC.