A case-control study of phosphodiesterase-5 inhibitor use and Alzheimer's disease and related dementias among male and female patients aged 65 years and older supporting the need for a phase III clinical trial.

BACKGROUND: Phosphodiesterase-5 inhibitors (PDE5i) have been evaluated as a novel treatment for Alzheimer's disease and related dementias (ADRD), but two recent cohort studies have offered opposing conclusions. METHODS: We performed an unmatched case-control study using electronic medical records from a large healthcare system to evaluate the association of PDE5i use and ADRD in patients ≥65 years old. RESULTS: Odds of PDE5i exposure were 64.2%, 55.7%, and 54.0% lower in patients with ADRD than controls among populations with erectile dysfunction, benign prostatic hyperplasia, and pulmonary hypertension, respectively. We observed odds ratios less than unity among males and females and with exposure to the PDE5i sildenafil (Viagra®) and tadalafil (Cialis®). We also evaluated the odds of exposure to two other common treatments for pulmonary hypertension: endothelin receptor antagonists (ERA) and calcium channel blockers (CCB). The odds of ERA exposure were 63.2% lower, but the odds of CCB exposure were 30.7% higher, in patients with ADRD than controls among the population with pulmonary hypertension. CONCLUSIONS: Our results reconcile the opposing conclusions from the previous observational studies and support further research into using PDE5i for prevention and treatment of ADRD.

Predictors and Impact of Postoperative 30-Day Readmission in Glioblastoma.

BACKGROUND: Postoperative 30-day readmissions have been shown to negatively affect survival and other important outcomes in patients with glioblastoma (GBM). OBJECTIVE: To further investigate patient readmission risk factors of primary and recurrent patients with GBM. METHODS: The authors retrospectively reviewed records of 418 adult patients undergoing 575 craniotomies for histologically confirmed GBM at an academic medical center. Patient demographics, comorbidities, and clinical characteristics were collected and compared by patient readmission status using chi-square and Mann-Whitney U testing. Multivariable logistic regression was performed to identify risk factors that predicted 30-day readmissions. RESULTS: The cohort included 69 (12%) 30-day readmissions after 575 operations. Readmitted patients experienced significantly lower median overall survival (11.3 vs 16.4 months, P = .014), had a lower mean Karnofsky Performance Scale score (66.9 vs 74.2, P = .005), and had a longer initial length of stay (6.1 vs 5.3 days, P = .007) relative to their nonreadmitted counterparts. Readmitted patients experienced more postoperative deep vein thromboses or pulmonary embolisms (12% vs 4%, P = .006), new motor deficits (29% vs 14%, P = .002), and nonhome discharges (39% vs 22%, P = .005) relative to their nonreadmitted counterparts. Multivariable analysis demonstrated increased odds of 30-day readmission with each 10-point decrease in Karnofsky Performance Scale score (odds ratio [OR] 1.32, P = .002), each single-point increase in 5-factor modified frailty index (OR 1.51, P = .016), and initial presentation with cognitive deficits (OR 2.11, P = .013). CONCLUSION: Preoperatively available clinical characteristics strongly predicted 30-day readmissions in patients undergoing surgery for GBM. Opportunities may exist to optimize preoperative and postoperative management of at-risk patients with GBM, with downstream improvements in clinical outcomes.

Intradiscal thermal therapy using interstitial ultrasound: an in vivo investigation in ovine cervical spine.

STUDY DESIGN: In vivo investigation of intradiscal ultrasound thermal therapy in ovine cervical spine model. OBJECTIVE: To evaluate the potential of interstitial ultrasound for selective heating of intradiscal tissue in vivo. SUMMARY OF BACKGROUND DATA: Application of heat in the spine using resistive wire and radiofrequency current heating devices is currently being used clinically for minimally invasive treatment of discogenic low back pain. Treatment temperatures are representative of those required for thermal necrosis of ingrowing nociceptor nerve fibers and disc cellularity alone, or with coagulation and restructuring of anular collagen in the high temperature case. METHODS: Two interstitial ultrasound applicator design configurations with directional heating patterns were evaluated in vivo in ovine cervical intervertebral discs (n = 62), with up to 45-day survival periods. Two heating protocols were employed in which the temperature measured 5 mm away from the applicator was controlled to either <54 C (capable of nerve and cellular necrosis) or >70 C (for coagulation of collagen) for a 10-minute treatment period. Transient and steady state temperature maps, calculated thermal doses (t43), and histology were used to assess the thermal treatments. RESULTS: These studies demonstrated the capability to control spatial temperature distributions within selected regions of the in vivo intervertebral disc and anular wall using interstitial ultrasound. CONCLUSIONS: Ultrasound energy is capable of penetrating within the highly attenuating disc tissue to produce more extensive radial thermal penetration, lower maximum intradiscal temperature, and shorter treatment times than can be achieved with current clinical intradiscal heating technology. Thus, interstitial ultrasound offers potential as a more precise and faster heating modality for the clinical management of low back pain and studies of thermal effects on disc tissue in animal models.

Intradiscal thermal therapy does not stimulate biologic remodeling in an in vivo sheep model.

STUDY DESIGN: Thermal energy was delivered in vivo to ovine cervical discs and the postheating response was monitored over time. OBJECTIVES: To determine the effects of two distinctly different thermal exposures on biologic remodeling: a "high-dose" regimen intended to produce both cellular necrosis and collagen denaturation and a "low-dose" regimen intended only to kill cells. SUMMARY OF BACKGROUND DATA: Thermal therapy is a minimally invasive technique that may ameliorate discogenic back pain. Potential therapeutic mechanisms include shrinkage of collagenous tissues, stimulation of biologic remodeling, and ablation of cytokine-producing cells and nociceptive fibers. METHODS: Intradiscal heating was performed using directional interstitial ultrasound applicators. Temperature and thermal dose distributions were characterized. The effects of high (>70 C, 10 minutes) and low (52 C-54 C, 10 minutes) temperature treatments on chronic biomechanical and architectural changes were compared with sham-treated and control discs at 7, 45, and 180 days. RESULTS: The high-dose treatment caused both an acute and chronic loss of proteoglycan staining and a degradation of biomechanical properties compared with low-dose and sham groups. Similar amounts of degradation were observed in the low-dose and sham-treated discs relative to the control discs at 180 days after treatment. CONCLUSIONS: While a high temperature thermal protocol had a detrimental effect on the disc, the effects of low temperature treatment were relatively minor. Thermal therapy did not stimulate significant biologic remodeling. Future studies should focus on the effects of low-dose therapy on tissue innervation and pro-inflammatory factor production.

Heat-induced changes in porcine annulus fibrosus biomechanics.

The intervertebral disc is implicated as the source of low-back pain in a substantial number of patients. Because thermal therapy has been thought to have a therapeutic effect on collagenous tissues, this technique has recently been incorporated into several minimally invasive back pain treatments. However, patient selection criteria and precise definition of optimum dose are hindered by uncertainty of treatment mechanisms. The purpose of this study was to quantify acute changes in annulus fibrosus biomechanics after a range of thermal exposures, and to correlate these results with tissue denaturation. Intact annulus fibrosus (attached to adjacent vertebrae) from porcine lumbar spines was tested ex vivo. Biomechanical behavior, microstructure, peak of denaturation endotherm, and enthalpy of denaturation (mDSC) were determined before and after hydrothermal heat treatment at 37 degrees C, 50 degrees C, 60 degrees C, 65 degrees C, 70 degrees C, 75 degrees C, 80 degrees C, and 85 degrees C. Shrinkage of excised annular tissue (removed from adjacent vertebrae) was also measured after treatment at 85 degrees C. Significant differences in intact annulus biomechanics were observed after treatment, but the effects were much smaller in magnitude than those observed in excised annulus and those reported previously for other tissues. Consistent with this, intact tissue was only minimally denatured by treatment at 85 degrees C for 15 min, whereas excised tissue was completely denatured by this protocol. Our data suggest that in situ constraint imposed by the joint structure significantly retards annular thermal denaturation. These findings should aid the interpretation of clinical outcomes and provide a basis for the future design of optimum dosing regimens.