Robert A. Hart

Background: Tranexamic acid (TXA) is commonly utilized to reduce blood loss in adult spinal deformity (ASD) surgery. Despite its widespread use, there is a lack of consensus regarding the optimal dosing regimen. The aim of this study was to assess differences in blood loss and complications between high, medium, and low-dose TXA regimens among patients undergoing surgery for complex ASD. Methods: A multicenter database was retrospectively analyzed to identify 265 patients with complex ASD. Patients were separated into 3 groups by TXA regimen: (1) low dose (50-mg/kg loading dose with ≥5-mg/kg/hr maintenance dose). The measured outcomes included blood loss, complications, and red blood cell (RBC) units transfused intraoperatively and perioperatively. The multivariable analysis controlled for TXA dosing regimen, levels fused, operating room time, preoperative hemoglobin, 3-column osteotomy, and posterior interbody fusion. Results: The cohort was predominantly White (91.3%) and female (69.1%) and had a mean age of 61.6 years. Of the 265 patients, 54 (20.4%) received low-dose, 131 (49.4%) received medium-dose, and 80 (30.2%) received high-dose TXA. The median blood loss was 1,200 mL (interquartile range [IQR], 750 to 2,000). The median RBC units transfused intraoperatively was 1.0 (IQR, 0.0 to 2.0), and the median RBC units transfused perioperatively was 2.0 (IQR, 1.0 to 4.0). Compared with the high-dose group, the low-dose group had increased blood loss (by 513.0 mL; p = 0.022) as well as increased RBC units transfused intraoperatively (by 0.6 units; p < 0.001) and perioperatively (by 0.3 units; p = 0.024). The medium-dose group had increased blood loss (by 491.8 mL; p = 0.006) as well as increased RBC units transfused intraoperatively (by 0.7 units; p < 0.001) and perioperatively (by 0.5 units; p < 0.001) compared with the high-dose group. Conclusions: Patients with ASD who received high-dose intraoperative TXA had fewer RBC transfusions intraoperatively, fewer RBC transfusions perioperatively, and less blood loss than those who received low or medium-dose TXA, with no differences in the rates of seizure or thromboembolic complications. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Skin is a major site of cortisol bioconversion by 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) enzymes which catalyze intracellular inactive cortisone into physiologically active cortisol. 11β‐HSD1 is highly expressed in skin, especially in dermal fibroblasts, epidermal keratinocytes, melanocytes, and hair follicles, and plays important roles in regulating keratinocytes, fibroblast proliferation, and has roles in skin aging. Inhibition of 11β‐HSD1 may reverse decreased collagen levels observed in extrinsically and intrinsically aged skin. Inhibitors of 11β‐HSD1 may also have the potential to reverse decreased collagen observed in skin atrophy induced by glucocorticoid treatment. This systematic review aimed to summarize the current knowledge of roles for 11β‐HSD1 inhibitor in skin physiology and potential for future use in medications. Studies have demonstrated that immediately following experimental insult in an animal model, there is increased expression of 11β‐HSD1, and that topical application of an 11β‐HSD1 inhibitor increases the rate of healing, increases skin collagen content, increases dermal fibroblasts, and increases dermal thickness. Furthermore, in patients with type 2 diabetes mellitus, 11β‐HSD1 inhibitors reduce wound diameter after injury. Further development of 11β‐HSD1 inhibitors appears to be a promising area for treating aging skin, aiding wound healing, and mitigating effects of systemic glucocorticoid use. Both topically and orally administered 11β‐HSD1 inhibitors appear to be viable avenues for future research.

Growth differentiation factor 15 (GDF15) is a peptide hormone, and a divergent member of the transforming growth factor beta (TGFβ) superfamily. In normal physiology, GDF15 is expressed in multiple tissues at a low concentration. GDF15 is overexpressed during and following many pathological conditions such as tissue injury and inflammation in order to play a protective role. However, GDF15 appears to promote tumour growth in the later stages of malignant cancer. The recently identified endogenous receptor for GDF15, GDNF family receptor a-like (GFRAL), has allowed elucidation of a physiological pathway in which GDF15 regulates energy homeostasis and body weight, primarily via appetite suppression. The anorectic effect of GDF15 provides some therapeutic potential in management of cancer-related anorexia/cachexia and obesity. Despite the identification of GFRAL as a GDF15 receptor, there appears to be other signalling mechanisms utilized by GDF15 that further increase the possibility of development of therapeutic treatments, should these pathways be fully characterized. In this review, GDF15 function in both physiological and pathological conditions in various tissues will be discussed.

Research indicates that some adult diseases including reproductive pathologies are programmed in utero during foetal development. In particular, maternal low dietary protein, during the most critical developmental periods of male foetal development, may have a detrimental impact on male fertility through direct and epigenetic mechanisms. The aim of our study was to evaluate the impact of a gestational low protein diet on fertility markers in male offspring in rats through a systematic review and meta‐analysis. A systematic search using PubMed, and EMBASE databases was performed and two investigators independently screened the 1,703 prospective articles. Eleven articles met the eligibility criteria. Outcome measures were pooled using random‐effects models and expressed as mean differences (MDs) at 95% CIs for each study. The results reveal significant reduction in testis weight (MD (mean difference) −0.08 g; −0.12, −0.42; p = .0001), epididymal sperm count (MD −35.34 × 10⁶ cells; −52.15, −18.53; p = .0001), number of Sertoli cells (MD −7.27 × 10⁶ (−13.92, −0.62; p = .03), testosterone (T) concentration (MD −0.29 ng/ml; −0.48, −0.09; p = .004) and luteinising hormone (LH) concentration (MD of −0.24 ng/ml; −0.45, 0.04; p = .02) in comparison with controls. In contrast, follicle‐stimulating hormone (FSH) concentration (MD of 0.07 ng/ml; −0.16, 0.29; p = .56) was not significantly different from controls. We conclude that low gestational dietary protein maternal intake potentially negatively impacts fertility in male progeny later in life. The mechanisms of action responsible for these phenomena remain unclear.

Studies have shown that the amount of protein in the diet affects the hypothalamic-pituitary-testis axis and sub-optimal quantity reduces male fertility potential in both animals and humans. However, individual research reports on the factors associated with male infertility are collectively uncharacterized. We systematically reviewed, and meta-analysed animal (rats) studies on the effect of low protein diet on factors associated with male infertility. PubMed Central, EMBASE and Scopus databases were searched from inception to 30 March 2019 for the study concepts and related keywords in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. Data on the outcome measures were extracted and pooled across trials using random-effects model and expressed as mean differences (MD) at a 95% confidence interval (CI). Twelve trials identified from 3327 studies, met our inclusion criteria in the comparison of a low protein diet (2–10% protein) vs control protein diet (17–23% protein). The results showed that a low protein diet caused a significant reduction in the body weight (P = 0.0001) testis weight (P = 0.0001), seminal vesicle weight (P = 0.0003), epididymis weight P = 0.02), serum testosterone (P = 0.001) and follicle-stimulating hormone (FSH) concentrations (P = 0.04) compared with the control treatments. No effect on luteinizing hormone (LH) plasma concentration (P = 0.13) was observed. This study revealed that low protein diet caused significant reductions in body weight, testis, epididymis and seminal vesicle weights, serum testosterone and FSH concentration in rats. We infer that sub-optimal protein consumption reduces the gonadal and endocrine function, and consequently male infertility.

Leptin is a hormone secreted mainly by the adipocytes with an essential role in the regulation of body weight. It acts on the reproductive axis at different sites, with stimulatory effects at the hypothalamus and pituitary and inhibitory interactions at the gonads. To investigate the influence of leptin on pregnancy outcomes in women undergoing IVF, we undertook a systematic review. A search of PubMed from 1966 to 2018 identified ten studies meeting the inclusion criteria. Outcomes were BMI, serum leptin level at hCG injection, serum and follicular fluid leptin level at the oocyte pick up, and serum 17β-oestradiol level at oocyte pick up time, oocytes retrieved and embryo transfer number. Results indicated that follicular fluid leptin concentrations at the oocyte pick up were significantly lower in women who became pregnant compared to those who did not (MD = −4.53 (ng/ml); 95% CI: −7.78, −1.78; p value < 0.006). In conclusion, elevated leptin concentrations in follicular fluid at oocyte pick up time is significantly associated with an adverse pregnancy outcome in women undergoing an IVF programme.

Studies with animal models have consistently demonstrated adverse health outcomes in offspring born following nutritional manipulation during gestation. However, the effects of gestational dietary protein modification on reproductive outcomes at birth are less clear. We, therefore, conducted a systematic review and meta-analysis of controlled trials to determine whether high- or low-protein diets are associated with altered reproductive outcomes in a commonly studied species, the rat. Included studies were identified through a systematic search using electronic databases and manual literature review to identify randomized studies published between June 1972 and March 2019. Thirty-two studies were identified and used to analyze the effects of low- and high-protein gestational diets on litter size, litter weight, gestational weight gain, and gestational feed intake. The results indicate that low-protein diets significantly reduced litter weight (P < 0.00001) and gestational weight gain (P < 0.0006), but did not influence litter size (P = 0.62) or gestational feed intake (P = 0.25). In contrast, high-protein diets were found to reduce gestational feed intake (P = 0.004) but did not influence litter size (P = 0.56), litter weight (P = 0.22), or gestational weight gain (P = 0.35). The results suggest that low but not high-protein gestational diets alter reproductive outcomes at birth in rats.

Gut microbiome diversity has been strongly associated with mood-relating behaviours, including major depressive disorder (MDD). This association stems from the recently characterised bi-directional communication system between the gut and the brain, mediated by neuroimmune, neuroendocrine and sensory neural pathways. While the link between gut microbiome and depression is well supported by research, a major question needing to be addressed is the causality in the connection between the two, which will support the understanding of the role that the gut microbiota play in depression. In this article, we address this question by examining a theoretical ‘chronology’, reviewing the evidence supporting two possible sequences of events. First, we discuss that alterations in the gut microbiota populations of specific species might contribute to depression, and secondly, that depressive states might induce modification of specific gut microbiota species and eventually contribute to more severe depression. The feasibility of both sequences is supported by pre-clinical trials. For instance, research in rodents has shown an onset of depressive behaviour following faecal transplantations from patients with MDD. On the other hand, mental induction of stress and depressive behaviour in rodents resulted in reduced gut microbiota richness and diversity. Synthesis of these chronology dynamics raises important research directions to further understand the role that gut microbiota play in mood-relating behaviours, which holds substantial potential clinical outcomes for persons who experience MDD or related depressive disorders.

Pharmacokinetics of leptin in mammals has not been studied in detail and only one study has examined more than one time point in non-mutant mice and this was in female mice. This is the first study to describe leptin distribution over a detailed time course in normal male mice. A physiologic dose (12 ng) of radiolabelled leptin was injected in adult male mice via the lateral tail vein and tissues were dissected out and measured for radioactivity over a time course of up to two hours. Major targets were the digestive tract, kidneys, skin and lungs. The brain was not a major target, 0.15 % of the total dose was recovered from the brain 5 min after administration. Major differences appear to exist between the distribution of leptin in male and female mice, indicating a high degree of sexual dimorphism. Although the half-lives were similar between male and female mice, almost twice the proportion of leptin was recovered from the digestive tract of male mice in comparison to that reported previously for females. This would seem to indicate a major difference in leptin distribution and possibly function between males and females.

Pharmacokinetics of leptin in mammals has received limited attention and only one study has examined more than two time points and this was in ob/ob mice. This study is the first to observe the distribution of leptin over a time course in female mice. A physiologic dose (12 ng) of radiolabelled leptin was injected in adult female mice via the lateral tail vein and tissues were dissected out and measured for radioactivity over a time course up to two hours. Major targets for administered leptin included the liver, kidneys, gastrointestinal tract and the skin while the lungs had high concentrations of administered leptin per gram of tissue. Leptin was also found to enter the lumen of the digestive tract intact from the plasma. Very little of the dose (<1 %) was recovered from the brain at any time. Consequently we confirm that the brain is not a major target for leptin from the periphery, although it may be very sensitive to leptin that does get to the hypothalamus. Several of the major targets (GI tract, skin and lungs) for leptin form the interface for the body with the environment, and given the ability of leptin to modulate immune function, this may represent a priming effect for tissues to respond to damage and infection.