Publications by Year: 2023

INTRODUCTION: A consolidated sleep-wake pattern is essential for maintaining healthy cognition in older individuals, but many suffer from sleep fragmentation that exacerbates age-related cognitive decline and worsens overall mental and physical health. Timed light exposure (light therapy) has been explored as a countermeasure, but mixed results have been obtained. To determine whether the timing of light exposure is important for sleep-wake consolidation, we analyzed the natural light diets of a cohort of community-dwelling older men.

METHODS: The degree of sleep-wake fragmentation and light exposure patterns were obtained over a week using wrist actigraphy. Correlations between fragmentation, light patterns, and various physical and mental health measures were examined (n = 877).

RESULTS: Our findings revealed that higher sleep-wake fragmentation correlated with poorer physical and mental health and reduced cognition. Moreover, reduced daytime light exposure was associated with increased sleep-wake fragmentation. Interestingly, morning and evening light exposure (>1,000 lux) were not useful in distinguishing between low and high sleep-wake fragmentation scores, while increased afternoon light exposure showed much better discrimination. Specifically, optimal discrimination between low and high fragmentation occurred 6.7 h after habitual sleep offset. This suggests that afternoon light therapy might be more efficient in consolidating sleep and wake in older adults, particularly in those with low-amplitude circadian rhythms.

DISCUSSION: This study highlights the significance of properly-timed light exposure in promoting consolidated sleep and cognitive health among older individuals. Tailored light-based strategies may have the potential to enhance physical, mental, and cognitive well-being in the aging population.

The pathophysiology of sleep apnea goes beyond anatomic predisposition to airway collapse and includes additional factors such as arousal threshold and loop gain. High loop gain is a prominent feature in central and complex sleep apnea (with a mixture of obstructive and central features) where relative hypocapnia can lead to respiratory instability and periodic breathing. Existing therapies, including continuous positive airway pressure (CPAP) and adaptive servo-ventilators, often inadequately treat sleep apnea with high loop gain features. Enhanced expiratory rebreathing space (EERS) targets prevention of the hypocapnia that triggers central events in sleep by increasing dead space in amounts less than typical tidal volumes. This is accomplished by covering traditional exhalation ports on positive airway pressure masks and adding small additional tubing with distal exhalation and safety valves. This technique reduces carbon dioxide (CO2) blow-off during arousals and the associated large recovery breaths, typically producing a maximal increase in resting CO2 by 1-2 mmHg, thus increasing the CO2 reserve and making it less likely to encounter the hypocapnic apneic threshold. Typically, the amount of EERS is titrated in response to central events and periodic breathing rather than aiming for a goal CO2 level. Ideally CO2 monitoring is used during titration of EERS and the technique is avoided in the setting of baseline hypercapnia. This method has been used in clinical practice at our sleep center for over 15 years, and retrospective data suggests an excellent safety profile and high rates of successful therapy including in patients who have previously failed CPAP therapy. Limitations include decreased effectiveness in the setting of leak and decreased tolerance of the bulkier circuit. EERS represents a simple, affordable modification of existing positive airway pressure modalities for treatment of central and complex sleep apnea. Areas of future study include randomized controlled trials of the technique and study of use of EERS in combination with adaptive ventilation, and pharmacologic adjuncts targeting high loop gain physiology.

Obstructive sleep apnea (OSA) is a common disorder characterized by recurrent upper airway obstruction during sleep. Despite the availability of continuous positive airway pressure (CPAP) as the gold standard treatment, it is not well tolerated by all patients. Accordingly, research has increasingly focused on developing methods for OSA endotyping, which aims to identify underlying pathophysiological mechanisms of the disorder to help guide treatment for CPAP-intolerant individuals. Four key endotypic traits have been identified, namely: collapsibility, upper airway muscle compensation, arousal threshold and loop gain. However, most methods for extracting these traits require specialized training and equipment not available in a standard sleep clinic, which has hampered the ability to assess the full impact of these traits on OSA outcomes. This paper aims to provide an overview of current methods for OSA endotyping, focusing on the Endo-Phenotyping Using Polysomnography (PUP) method and its cloud-based extension, PUPpy, which offer scalable and accessible ways to estimate endotypic traits from standard polysomnography. We discuss the potential for these methods to facilitate precision medicine for OSA patients and the challenges that need to be addressed for their translation into clinical practice.

Sleep-disordered breathing (obstructive and central sleep apnea) are common in patients with heart failure with reduced ejection fraction. Herein, we report a 69-year-old patient with a history of severe heart failure and refractory ventricular arrhythmia who was diagnosed with a moderate degree of obstructive and central sleep apnea with Cheyne Stokes breathing. He underwent a successful implantation of left ventricular assist device. Our patient had a complete resolution of both obstructive and central sleep apnea 60 days post-LVAD implantation as confirmed by home sleep apnea test.

BACKGROUND: The neuroinflammatory response to surgery can be characterized by peripheral acute plasma protein changes in blood, but corresponding, persisting alterations in cerebrospinal fluid (CSF) proteins remain mostly unknown. Using the SOMAscan assay, we define acute and longer-term proteome changes associated with surgery in plasma and CSF. We hypothesized that biological pathways identified by these proteins would be in the categories of neuroinflammation and neuronal function and define neuroinflammatory proteome changes associated with surgery in older patients.

METHODS: SOMAscan analyzed 1305 proteins in blood plasma (n = 14) and CSF (n = 15) samples from older patients enrolled in the Role of Inflammation after Surgery for Elders (RISE) study undergoing elective hip and knee replacement surgery with spinal anesthesia. Systems biology analysis identified biological pathways enriched among the surgery-associated differentially expressed proteins in plasma and CSF.

RESULTS: Comparison of postoperative day 1 (POD1) to preoperative (PREOP) plasma protein levels identified 343 proteins with postsurgical changes ( P < .05; absolute value of the fold change [|FC|] > 1.2). Comparing postoperative 1-month (PO1MO) plasma and CSF with PREOP identified 67 proteins in plasma and 79 proteins in CSF with altered levels ( P < .05; |FC| > 1.2). In plasma, 21 proteins, primarily linked to immune response and inflammation, were similarly changed at POD1 and PO1MO. Comparison of plasma to CSF at PO1MO identified 8 shared proteins. Comparison of plasma at POD1 to CSF at PO1MO identified a larger number, 15 proteins in common, most of which are regulated by interleukin-6 (IL-6) or transforming growth factor beta-1 (TGFB1) and linked to the inflammatory response. Of the 79 CSF PO1MO-specific proteins, many are involved in neuronal function and neuroinflammation.

CONCLUSIONS: SOMAscan can characterize both short- and long-term surgery-induced protein alterations in plasma and CSF. Acute plasma protein changes at POD1 parallel changes in PO1MO CSF and suggest 15 potential biomarkers for longer-term neuroinflammation that warrant further investigation.

BACKGROUND: Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (< 5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas.

QUESTIONS/PURPOSES: (1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What is the cumulative incidence of amputation after LSS for patients diagnosed with pediatric lower extremity sarcomas 25 years after diagnosis? (3) What are the factors associated with time to late amputation (≥ 5 years after diagnosis) in patients initially treated with LSS for lower extremity sarcomas in the CCSS? (4) What are the comparative social, physical, and emotional health-related quality of life (HRQOL) outcomes among patients with sarcoma treated with primary amputation, LSS without amputation, or LSS complicated by late amputation, as assessed by CCSS follow-up questionnaires, the SF-36, and the Brief Symptom Inventory-18 at 20 years after cancer diagnosis?

METHODS: The CCSS is a long-term follow-up study that began in 1994 and is coordinated through St. Jude Children's Research Hospital. It is a retrospective study with longitudinal follow-up of more than 38,000 participants treated for childhood cancer when younger than 21 years at one of 31 collaborating institutions between 1970 and 1999 in the United States and Canada. Participants were eligible for enrollment in the CCSS after they had survived 5 years from diagnosis. Within the CCSS cohort, we included participants who had a diagnosis of lower extremity sarcoma treated with primary amputation (547 patients with a mean age at diagnosis of 13 ± 4 years) or primary LSS (510 patients with a mean age 14 ± 4 years). The LSS cohort was subdivided into LSS without amputation, defined as primary LSS without amputation at the time of latest follow-up; LSS with early amputation, defined as LSS complicated by amputation occurring less than 5 years from diagnosis; or LSS with late amputation, defined as primary LSS in study patients who subsequently underwent amputation 5 years or more from cancer diagnosis. The cumulative incidence of late amputation after primary LSS was estimated. Cox proportional hazards regression with time-varying covariates identified factors associated with late amputation. Modified Poisson regression models were used to compare psychosocial, physical, and HRQOL outcomes among patients treated with primary amputation, LSS without amputation, or LSS complicated by late amputation using validated surveys.

RESULTS: More study participants were treated with LSS than with primary amputation in more recent decades. The overall survival at 25 years in this population who survived 5 years from diagnosis was not different between those treated with primary amputation (87% [95% confidence interval [CI] 82% to 91%]) compared with LSS (88% [95% CI 85% to 91%]; p = 0.31). The cumulative incidence of amputation at 25 years after cancer diagnosis and primary LSS was 18% (95% CI 14% to 21%). With the numbers available, the cumulative incidence of late amputation was not different among study patients treated in the 1970s (27% [95% CI 15% to 38%]) versus the 1980s and 1990s (19% [95% CI 13% to 25%] and 15% [95% CI 10% to 19%], respectively; p = 0.15). After controlling for gender, medical and surgical treatment variables, cancer recurrence, and chronic health conditions, gender (hazard ratio [HR] 2.02 [95% CI 1.07 to 3.82]; p = 0.03) and history of prosthetic joint reconstruction (HR 2.58 [95% CI 1.37 to 4.84]; p = 0.003) were associated with an increased likelihood of late amputation. Study patients treated with a primary amputation (relative risk [RR] 2.04 [95% CI 1.15 to 3.64]) and LSS complicated by late amputation (relative risk [RR] 3.85 [95% CI 1.66 to 8.92]) were more likely to be unemployed or unable to attend school than patients treated with LSS without amputation to date. The CCSS cohort treated with primary amputation and those with LSS complicated by late amputation reported worse physical health scores than those without amputation to date, although mental and emotional health outcomes did not differ between the groups.

CONCLUSION: There is a substantial risk of late amputation after LSS, and both primary and late amputation status are associated with decreased physical HRQOL outcomes. Children treated for sarcoma who survive into adulthood after primary amputation and those who undergo late amputation after LSS may benefit from interventions focused on improving physical function and reaching educational and employment milestones. Efforts to improve the physical function of people who have undergone amputation either through prosthetic design or integration into the residuum should be supported. Understanding factors associated with late amputation in the setting of more modern surgical approaches and implants will help surgeons more effectively manage patient expectations and adjust practice to mitigate these risks over the life of the patient.

LEVEL OF EVIDENCE: Level III, therapeutic study.

INTRODUCTION: It is unclear whether the medial malleolus in unstable bi- and tri- malleolar ankle fractures without medial talar displacement should be addressed surgically. This study reviews a fixation protocol for the medial malleolar component of unstable bi- or tri- malleolar ankle fractures.

MATERIALS AND METHODS: Two hundred fifty-seven patients who sustained bi- (AO/OTA 44-B2) or tri- (AO/OTA 44-B3) malleolar ankle fractures between January 2005 and August 2019 at two Level 1 trauma centers were retrospectively identified. Medial malleolar fractures were defined as anterior, supra or intercollicular fractures based on the exit of the posterior fracture line. Fixation of the medial malleolar component was performed based on surgical algorithm. Only large or significantly displaced medial malleolar fractures were fixed if the soft tissues were amenable. Primary outcome measure was the presence of medial-sided ankle pain after operative or non-operative treatment of the medial malleolar fracture after a minimum follow up of 6 months. Presence of pain was defined by a pain score of 3 or higher on a 10-point VAS pain score at the site of the medial malleolar fracture.

RESULTS: Significantly more patients in the supracollicular group reported the presence of pain when this type was not fixed versus fixed (28 vs 14%, p = 0.0094). Significantly more patients in the anterior collicular subgroup reported the presence of pain when this type was fixed versus not fixed (40 vs 10%, p = 0.0438). There was no difference in the number of patients reporting pain in the intercollicular group when comparing those who were fixed versus not fixed, (21 vs 22%, p = 1.000).

CONCLUSIONS: When examining post-operative pain, not all medial malleolar fractures require fixation when appropriately selected based on fracture pattern. Only 10% of patients with anterior collicular fractures reported pain after non operative management. Unsurprisingly, more patients in the supracollicular fractures reported pain without surgery compared to with surgery. Fracture pattern should be considered in the treatment algorithm for the medial malleolar component in bi- and tri- malleolar fractures.

PURPOSE: Objectives are (1) to evaluate the biomechanical effect of isolated medial patellofemoral ligament (MPFL) reconstruction in the setting of increased tibial tuberosity-trochlear groove distance (TTTG), in terms of patella contact pressures, contact area and lateral displacement; (2) to describe the threshold of TTTG up to which MPFL reconstruction should be performed alone or in combination with tibial tuberosity transfer.

METHODS: A finite element model of the knee was developed and validated. The model was modified to simulate isolated MPFL reconstruction, tibial tuberosity transfer and MPFL reconstruction combined with tibial tuberosity transfer for patella malalignment. Two TT-TG distances (17 mm and 22 mm) were simulated. Patella contact pressure, contact area and lateral displacement were analysed.

RESULTS: Isolated MPFL reconstruction, at early degrees of flexion, restored normal patella contact pressure when TTTG was 17 mm, but not when TTTG was 22 mm. After 60° of flexion, the TTTG distance was the main factor influencing contact pressure. Isolated MPFL reconstruction for both TTTG 17 mm and 22 mm showed higher contact area and lower lateral displacement than normal throughout knee flexion. Tibial tuberosity transfer, at early degrees of flexion, reduced the contact pressure, but did not restore the normal contact pressure. After 60° of flexion, the TTTG distance was the main factor influencing contact pressure. Tibial tuberosity transfer maintained lower contact area than normal throughout knee flexion. The lateral displacement was higher than normal between 0° and 30° of flexion (< 0.5 mm). MPFL reconstruction combined with tibial tuberosity transfer produced the same contact mechanics and kinematics of the normal condition.

CONCLUSION: This study highlights the importance of considering to correct alignment in lateral tracking patella to avoid focal patella overload. Our results showed that isolated MPFL reconstruction corrects patella kinematics regardless of TTTG distance. However, isolated MPFL reconstruction would not restore normal patella contact pressure when TTTG is 22 mm. For TTTG 22 mm, the combined procedure of MPFL reconstruction and tibial tuberosity transfer provided an adequate patellofemoral contact mechanics and kinematics, restoring normal biomechanics. This data supports the use of MPFL reconstruction when the patient has normal alignment and the use of combined MPFL reconstruction and tibial tuberosity transfer in patients with elevated TT-TG distances to avoid focal overload.