Surgical treatment of cystic pituitary adenomas: literature-based definitions and postoperative outcomes.

BACKGROUND AND OBJECTIVES: To survey the applied definitions of 'cystic' among pituitary adenomas and evaluate whether postoperative outcomes differ relative to non-cystic counterparts. METHODS: A literature search and meta-analysis was performed using PRISMA guidelines. Studies were eligible if novel data were reported regarding the applied definition of 'cystic' and postoperative outcomes among cases of surgically treated pituitary adenomas. Data were pooled with random effects meta-analysis models into cohorts based on the applied definition of 'cystic'. Categorical meta-regressions were used to investigate differences between cohorts. Among studies comparing cystic and non-cystic pituitary adenomas, meta-analysis models were applied to determine the Odds Ratio [95% Confidence Interval]. Statistical analyses were performed using Comprehensive Meta-Analysis (CMA, 4.0), with a priori significance defined as P < 0.05. RESULTS: Ten studies were eligible yielding 283 patients with cystic pituitary adenomas. The definitions of 'cystic' mainly varied between the visual appearance of cystic components on preoperative magnetic resonance imaging and a volumetric definition requiring 50% or greater of tumor volume exhibiting cystic components. Tumor diameter was seldom reported with an associated standard deviation/error, limiting meta-analyses. When the data were pooled in accordance with the definition applied, there were no significant differences in the rates of gross total resection (P = 0.830), endocrinologic remission (P = 0.563), and tumor recurrence (P = 0.320). Meta-analyses on studies comparing cystic versus non-cystic pituitary adenomas indicated no significant difference in the rates of gross total resection (P = 0.729), endocrinologic remission (P = 0.857), and tumor recurrence (P = 0.465). CONCLUSION: Despite some individual studies describing a significant influence of pituitary adenoma texture on postoperative outcomes, meta-analyses revealed no such differences between cystic and non-cystic pituitary adenomas. This discrepancy may be explained in part by the inconsistent definition of 'cystic' and between-group differences in tumor size. A notion of a field-standard definition of 'cystic' among pituitary adenomas should be established to facilitate inter-study comparisons.

Physiologic validation of the compensatory reserve metric obtained from pulse oximetry: A step towards advanced medical monitoring on the battlefield.

BACKGROUND: The Compensatory Reserve Metric (CRM) provides a time sensitive indicator of hemodynamic decompensation. However, its in-field utility is limited due to the size and cost-intensive nature of standard vital sign monitors or photoplethysmographic volume-clamp (PPGVC) devices used to measure arterial waveforms. In this regard, photoplethysmographic measurements obtained from pulse oximetry (PPGPO) may serve as a useful, portable alternative. This study aimed to validate CRM values obtained using PPGPO. METHODS: Forty-nine healthy adults (25 females) underwent a graded lower body negative pressure (LBNP) protocol to simulate hemorrhage. Arterial waveforms were sampled using PPGPO and PPGVC. The CRM was calculated using a one-dimensional convolutional neural network. Cardiac output and stroke volume were measured using PPGVC. A brachial artery catheter was used to measure intraarterial pressure. A 3-lead ECG was used to measure heart rate. Fixed-effect linear mixed models with repeated measures were used to examine the association between CRM values and physiologic variables. Log-rank analyses were used to examine differences in shock determination during LBNP between monitored hemodynamic parameters. RESULTS: The median LBNP stage reached was 70 mmHg (Range: 45-100 mmHg). Relative to baseline, at tolerance there was a 47±12% reduction in stroke volume, 64±27% increase in heart rate, and 21±7% reduction in systolic blood pressure (P<0.001 for all). CRM values obtained with both PPGPO and PPGVC were associated with changes in heart rate (P<0.001), stroke volume (P<0.001), and pulse pressure (P<0.001). Furthermore, they provided an earlier detection of hemodynamic shock relative to the traditional metrics of shock index (P<0.001 for both), systolic blood pressure (P<0.001 for both), and heart rate (P=0.001 for both). CONCLUSION: The CRM obtained from PPGPO provides a valid, time-sensitized prediction of hemodynamic decompensation, opening the door to provide military medical personnel noninvasive in-field advanced capability for early detection of hemorrhage and imminent onset of shock. LEVEL OF EVIDENCE: Diagnostic Tests or Criteria, Level IV.

Comparing the compensatory reserve metric obtained from invasive arterial measurements and photoplethysmographic volume-clamp during simulated hemorrhage.

PURPOSE: The compensatory reserve metric (CRM) is a novel tool to predict cardiovascular decompensation during hemorrhage. The CRM is traditionally computed using waveforms obtained from photoplethysmographic volume-clamp (PPGVC), yet invasive arterial pressures may be uniquely available. We aimed to examine the level of agreement of CRM values computed from invasive arterial-derived waveforms and values computed from PPGVC-derived waveforms. METHODS: Sixty-nine participants underwent graded lower body negative pressure to simulate hemorrhage. Waveform measurements from a brachial arterial catheter and PPGVC finger-cuff were collected. A PPGVC brachial waveform was reconstructed from the PPGVC finger waveform. Thereafter, CRM values were computed using a deep one-dimensional convolutional neural network for each of the following source waveforms; (1) invasive arterial, (2) PPGVC brachial, and (3) PPGVC finger. Bland-Altman analyses were used to determine the level of agreement between invasive arterial CRM values and PPGVC CRM values, with results presented as the Mean Bias [95% Limits of Agreement]. RESULTS: The mean bias between invasive arterial- and PPGVC brachial CRM values at rest, an applied pressure of -45mmHg, and at tolerance was 6% [-17%, 29%], 1% [-28%, 30%], and 0% [-25%, 25%], respectively. Additionally, the mean bias between invasive arterial- and PPGVC finger CRM values at rest, applied pressure of -45mmHg, and tolerance was 2% [-22%, 26%], 8% [-19%, 35%], and 5% [-15%, 25%], respectively. CONCLUSION: There is generally good agreement between CRM values obtained from invasive arterial waveforms and values obtained from PPGVC waveforms. Invasive arterial waveforms may serve as an alternative for computation of the CRM.

Inferior Petrosal Sinus Sampling Tumor Lateralization and the Surgical Treatment of Cushing Disease: A Meta-Analysis and Systematic Review.

OBJECTIVE: To determine whether accurate inferior petrosal sinus sampling (IPSS) tumor lateralization is associated with improved clinical outcomes following the surgical treatment of Cushing disease. METHODS: The presented study was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data regarding patient demographics, IPSS tumor lateralization, and postoperative endocrinologic outcomes were abstracted and pooled with random effects meta-analysis models. Additional meta-regression models were used to examine the association between the accuracy of IPSS tumor lateralization and postoperative outcomes (recurrence/persistence or remission/cure). Statistical analyses were performed using the Comprehensive Meta-Analysis software (significance of P < 0.05). RESULTS: Seventeen eligible articles were identified, yielding data on 461 patients. Within average follow-up duration (∼59 months), the rate of correct IPSS tumor lateralization was 69% [95% confidence interval: 61%, 76%], and the rate of postoperative remission/cure was 78% [67%, 86%]. Preoperative IPSS tumor lateralization was concordant with magnetic resonance imaging lateralization for 53% of patients [40%, 66%]. There was no significant association between the rate of correct IPSS tumor lateralization and postoperative remission/cure among study-level data (P = 0.735). Additionally, there was no association among subgroup analyses for studies using stimulatory agents during IPSS (corticotropin-releasing hormone or desmopressin, P = 0.635), nor among subgroup analyses for adult (P = 0.363) and pediatric (P = 0.931) patients. CONCLUSIONS: Limited data suggest that the rate of correct IPSS tumor lateralization may not be positively associated with postoperative remission or cure in patients with Cushing disease. These findings bring into question the utility of IPSS tumor lateralization in the context of preoperative planning and surgical approach rather than confirming a pituitary source.

The relationship between hemoglobin and [Formula: see text]: A systematic review and meta-analysis.

OBJECTIVE: There is widespread agreement about the key role of hemoglobin for oxygen transport. Both observational and interventional studies have examined the relationship between hemoglobin levels and maximal oxygen uptake ([Formula: see text]) in humans. However, there exists considerable variability in the scientific literature regarding the potential relationship between hemoglobin and [Formula: see text]. Thus, we aimed to provide a comprehensive analysis of the diverse literature and examine the relationship between hemoglobin levels (hemoglobin concentration and mass) and [Formula: see text] (absolute and relative [Formula: see text]) among both observational and interventional studies. METHODS: A systematic search was performed on December 6th, 2021. The study procedures and reporting of findings followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Article selection and data abstraction were performed in duplicate by two independent reviewers. Primary outcomes were hemoglobin levels and [Formula: see text] values (absolute and relative). For observational studies, meta-regression models were performed to examine the relationship between hemoglobin levels and [Formula: see text] values. For interventional studies, meta-analysis models were performed to determine the change in [Formula: see text] values (standard paired difference) associated with interventions designed to modify hemoglobin levels or [Formula: see text]. Meta-regression models were then performed to determine the relationship between a change in hemoglobin levels and the change in [Formula: see text] values. RESULTS: Data from 384 studies (226 observational studies and 158 interventional studies) were examined. For observational data, there was a positive association between absolute [Formula: see text] and hemoglobin levels (hemoglobin concentration, hemoglobin mass, and hematocrit (P<0.001 for all)). Prespecified subgroup analyses demonstrated no apparent sex-related differences among these relationships. For interventional data, there was a positive association between the change of absolute [Formula: see text] (standard paired difference) and the change in hemoglobin levels (hemoglobin concentration (P<0.0001) and hemoglobin mass (P = 0.006)). CONCLUSION: These findings suggest that [Formula: see text] values are closely associated with hemoglobin levels among both observational and interventional studies. Although our findings suggest a lack of sex differences in these relationships, there were limited studies incorporating females or stratifying results by biological sex.

The dependence of maximum oxygen uptake and utilization (V̇O2 max) on hemoglobin-oxygen affinity and altitude.

Oxygen transport from the lungs to peripheral tissue is dependent on the affinity of hemoglobin for oxygen. Recent experimental data have suggested that the maximum human capacity for oxygen uptake and utilization (V̇O2 max) at sea level and altitude (~3000 m) is sensitive to alterations in hemoglobin-oxygen affinity. However, the effect of such alterations on V̇O2 max at extreme altitudes remains largely unknown due to the rarity of mutations affecting hemoglobin-oxygen affinity. This work uses a mathematical model that couples pulmonary oxygen uptake with systemic oxygen utilization under conditions of high metabolic demand to investigate the effect of hemoglobin-oxygen affinity on V̇O2 max as a function of altitude. The model includes the effects of both diffusive and convective limitations on oxygen transport. Pulmonary oxygen uptake is calculated using a spatially-distributed model that accounts for the effects of hematocrit and hemoglobin-oxygen affinity. Systemic oxygen utilization is calculated assuming Michaelis-Menten kinetics. The pulmonary and systemic model components are solved iteratively to compute predicted arterial and venous oxygen levels. Values of V̇O2 max are predicted for several values of hemoglobin-oxygen affinity and hemoglobin concentration based on data from humans with hemoglobin mutations. The model predicts that increased hemoglobin-oxygen affinity leads to increased V̇O2 max at altitudes above ~4500 m.

At-Home High-Intensity Interval Training for Individuals with Paraplegia Following Spinal Cord Injury: A Pilot Study.

Objective: This pilot study aimed to assess the efficacy of a 16-week at-home high-intensity interval training (HIIT) program among individuals with spinal cord injury (SCI). Methods: Eight individuals (age: 47±11 (SD) years, 3 females) with SCI below the sixth thoracic vertebrae participated in a 16-week at-home HIIT program using an arm ergometer. Participants completed baseline graded exercise tests to determine target heart rate zones. HIIT was prescribed thrice per week. Each training session consisted of six one-minute bouts with a target heart rate ~80% heart rate reserve (HRR), interspersed with two minutes of recovery at ~30% HRR. A portable heart rate monitor and phone application provided visual feedback during training and allowed for measurements of adherence and compliance. Graded exercise tests were completed after 8 and 16 weeks of HIIT. Surveys were administered to assess participation, self-efficacy, and satisfaction. Results: Participants demonstrated a decrease in submaximal cardiac output (P=0.028) and an increase in exercise capacity (peak power output, P=0.027) following HIIT, indicative of improved exercise economy and maximal work capacity. An 87% adherence rate was achieved during the HIIT program. Participants reached a high intensity of 70% HRR or greater during ~80% of intervals. The recovery HRR target was reached during only ~35% of intervals. Self-reported metrics of satisfaction and self-efficacy with at-home HIIT scored moderate to high. Conclusion: Participants demonstrated an improvement in exercise economy and maximal work capacity following at-home HIIT. Additionally, participant adherence, compliance, satisfaction, and self-efficacy metrics suggest that at-home HIIT was easily implemented and enjoyable.

Improvements in the Endoscopic Transsphenoidal Resection of Craniopharyngiomas: A Global Learning Curve.

BACKGROUND: Surgical management of craniopharyngiomas is nuanced and has varied in terms of the selected approach and aggressiveness of resection over time. In the past several decades, the endoscopic transsphenoidal approach has become commonly used for craniopharyngioma resection. There is a well characterized institutional 'learning curve' regarding endoscopic transsphenoidal approaches for craniopharyngiomas at specialized centers; however, the broader global learning curve remains to be characterized. METHODS: Clinical outcome data following endoscopic transsphenoidal craniopharyngioma resection were obtained from a previously published meta-analysis, including data published during or after the year 1990. Additionally, the year of publication, the country where procedures were performed, and the human development index of the country at time of publication were abstracted. Meta-regressional analyses were used to determine the significance of year and human development index as a covariate of the logit event rate of clinical outcomes. Statistical analyses were performed using the Comprehensive Meta-Analysis with a priori significance set as P < 0.05. RESULTS: A total of 100 studies (8230 patients) were examined, representing data from 19 countries. There was a significant increase in the achieved gross total resection rate (P = 0.0002) and a decrease in the achieved partial resection rate (P < 0.0001) across the time studied. Additionally, the rate of visual worsening (P = 0.025), postoperative cerebrospinal fluid leaks (P = 0.007), and development of meningitis (P = 0.032) decreased across time. CONCLUSIONS: This work suggests the existence of a global learning curve when examining clinical outcomes following endoscopic transsphenoidal craniopharyngioma resection. Globally, these findings highlight a general improvement in clinical outcomes across time.

Comparing Surgical Approaches for Craniopharyngioma Resection Among Adults and Children: A Meta-analysis and Systematic Review.

BACKGROUND: Craniopharyngioma treatment often necessitates surgical resection. Conventional approaches, such as transcranial and transsphenoidal approaches, are predominantly used. However, a recently adopted supraorbital approach may be more efficacious. Thus, this meta-analysis and systematic review aimed to compare the efficacy of the transcranial, transsphenoidal, and supraorbital approaches for resection and treatment of craniopharyngiomas. METHODS: This study was performed following PRISMA guidelines. Analyses were performed according to study design: (1) analyses for studies comparing several surgical approaches; and (2) analyses of all included studies. Random effects meta-analysis models were used to pool odds ratios among studies comparing several approaches. Similarly, categorical meta-regression models were used to examine the effect of surgical approach as a covariate of outcome data for all studies. Statistics were performed using Comprehensive Meta-Analysis software (CMA 3.3, Biostat, Englewood, NJ) (significance set at P < 0.05). RESULTS: Patients were well-matched for age, sex, and preoperative comorbidities between groups stratified by surgical approach. Analyses including 22 studies that compared several approaches demonstrated that the transsphenoidal group had a greater occurrence of postoperative visual improvement (P < 0.0001), lesser occurrence of visual deterioration (P < 0.0001), and lower tumor recurrence rate (P = 0.015) compared with the transcranial group. Only 2 studies compared the supraorbital approach to another approach, limiting analyses. Analyses including all studies demonstrated that the supraorbital group did not differ to either the transcranial or transsphenoidal group for any examined variables. CONCLUSIONS: The present study suggests that the transsphenoidal approach is associated with improved clinical outcomes for craniopharyngioma resection. There are limited data regarding the supraorbital approach, warranting future investigation.

CTB-targeted protocells enhance ability of lanthionine ketenamine analogs to induce autophagy in motor neuron-like cells.

Impaired autophagy, a cellular digestion process that eliminates proteins and damaged organelles, has been implicated in neurodegenerative diseases, including motor neuron disorders. Motor neuron targeted upregulation of autophagy may serve as a promising therapeutic approach. Lanthionine ketenamine (LK), an amino acid metabolite found in mammalian brain tissue, activates autophagy in neuronal cell lines. We hypothesized that analogs of LK can be targeted to motor neurons using nanoparticles to improve autophagy flux. Using a mouse motor neuron-like hybrid cell line (NSC-34), we tested the effect of three different LK analogs on autophagy modulation, either alone or loaded in nanoparticles. For fluorescence visualization of autophagy flux, we used a mCherry-GFP-LC3 plasmid reporter. We also evaluated protein expression changes in LC3-II/LC3-I ratio obtained by western blot, as well as presence of autophagic vacuoles per cell obtained by electron microscopy. Delivering LK analogs with targeted nanoparticles significantly enhanced autophagy flux in differentiated motor neuron-like cells compared to LK analogs alone, suggesting the need of a delivery vehicle to enhance their efficacy. In conclusion, LK analogs loaded in nanoparticles targeting motor neurons constitute a promising treatment option to induce autophagy flux, which may serve to mitigate motor neuron degeneration/loss and preserve motor function in motor neuron disease.

Muscle oxygenation during normoxic and hypoxic cycling exercise in humans with high-affinity haemoglobin.

NEW FINDINGS: What is the central question of this study? Do humans with high-affinity haemoglobin (HAH) demonstrate attenuated skeletal muscle deoxygenation during normoxic and hypoxic exercise? What is the main finding and its importance? Examination of near-infrared spectroscopy-derived muscle oxygenation profiles suggests that fractional oxygen extraction is blunted during hypoxic exercise in humans with HAH compared with control subjects. However, muscle tissue oxygen saturation levels were higher in humans with HAH during exercise in normoxia compared with control subjects. These alterations in fractional oxygen extraction in humans with HAH might influence blood flow regulation and exercise capacity during hypoxia. ABSTRACT: Recently, researchers in our laboratory have shown that humans with genetic mutations resulting in high-affinity haemoglobin (HAH) demonstrate better maintained aerobic capacity and peak power output during hypoxic exercise versus normoxic exercise in comparison to humans with normal-affinity haemoglobin. However, the influence of HAH on tissue oxygenation within exercising muscle during normoxia and hypoxia is unknown. Therefore, we examined near-infrared spectroscopy-derived oxygenation profiles of the vastus lateralis during graded cycling exercise in normoxia and hypoxia among humans with HAH (n = 5) and control subjects with normal-affinity haemoglobin (n = 12). The HAH group elicited a blunted increase of deoxygenated haemoglobin + myoglobin during hypoxic exercise compared with the control group (P = 0.03), suggesting reduced fractional oxygen extraction in the HAH group. In addition, the HAH group maintained a higher level of muscle tissue oxygen saturation during normoxic exercise (HAH, 75 ± 4% vs. controls, 65 ± 3%, P = 0.049) and there were no differences between groups in muscle tissue oxygen saturation during hypoxic exercise (HAH, 68 ± 3% vs. controls, 68 ± 2%, P = 0.943). Overall, our results suggest that humans with HAH might demonstrate divergent patterns of fractional oxygen extraction during hypoxic exercise and elevated muscle tissue oxygenation during normoxic exercise compared with control subjects.

Influence of High Hemoglobin-Oxygen Affinity on Humans During Hypoxia.

Humans elicit a robust series of physiological responses to maintain adequate oxygen delivery during hypoxia, including a transient reduction in hemoglobin-oxygen (Hb-O2) affinity. However, high Hb-O2 affinity has been identified as a beneficial adaptation in several species that have been exposed to high altitude for generations. The observed differences in Hb-O2 affinity between humans and species adapted to high altitude pose a central question: is higher or lower Hb-O2 affinity in humans more advantageous when O2 availability is limited? Humans with genetic mutations in hemoglobin structure resulting in high Hb-O2 affinity have shown attenuated cardiorespiratory adjustments during hypoxia both at rest and during exercise, providing unique insight into this central question. Therefore, the purpose of this review is to examine the influence of high Hb-O2 affinity during hypoxia through comparison of cardiovascular and respiratory adjustments elicited by humans with high Hb-O2 affinity compared to those with normal Hb-O2 affinity.