IL7 in combination with radiotherapy stimulates a memory T-cell response to improve outcomes in HNSCC models.

Clinically approved head and neck squamous cell carcinoma (HNSCC) immunotherapies manipulate the immune checkpoint blockade (ICB) axis but have had limited success outside of recurrent/metastatic disease. Interleukin-7 (IL7) has been shown to be essential for effector T-cell survival, activation, and proliferation. Here, we show that IL7 in combination with radiotherapy (RT) is effective in activating CD8 + T-cells for reducing tumor growth. Our studies were conducted using both human papillomavirus related and unrelated orthotopic HNSCC murine models. Immune populations from the tumor, draining lymph nodes, and blood were compared between treatment groups and controls using flow cytometry, proteomics, immunofluorescence staining, and RNA sequencing. Treatment with RT and IL7 (RT + IL7) resulted in significant tumor growth reduction, high CD8 T-cell tumor infiltration, and increased proliferation of T-cell progenitors in the bone marrow. IL7 also expanded a memory-like subpopulation of CD8 T-cells. These results indicate that IL7 in combination with RT can serve as an effective immunotherapy strategy outside of the conventional ICB axis to drive the antitumor activity of CD8 T-cells.

Adjuvant Chemotherapy With or Without Radiotherapy for Resected Pancreatic Cancer After Multiagent Neoadjuvant Chemotherapy.

BACKGROUND: Adjuvant therapy is associated with improved pancreatic cancer survival after neoadjuvant chemotherapy and surgery. However, whether adjuvant treatment should include radiotherapy is unclear in this setting. METHODS: This study queried the National Cancer Database for pancreatic adenocarcinoma patients who underwent curative resection after multiagent neoadjuvant chemotherapy between 2010 and 2019 and received adjuvant treatment. Adjuvant chemotherapy plus radiotherapy (external beam, 45-50.4 gray) was compared with adjuvant chemotherapy alone. Uni- and multivariable Cox regression was used to assess survival associations. Analyses were repeated in a propensity score-matched subgroup. RESULTS: Of 1983 patients who received adjuvant treatment after multiagent neoadjuvant chemotherapy and resection, 1502 (75.7%) received adjuvant chemotherapy alone and 481 (24.3%) received concomitant adjuvant radiotherapy (chemoradiotherapy). The patients treated with adjuvant chemoradiotherapy were younger, were treated at non-academic facilities more often, and had higher rates of lymph node metastasis (ypN1-2), positive resection margins (R1), and lymphovascular invasion (LVI+). The median survival was shorter for the chemoradiotherapy-treated patients according to the unadjusted analysis (26.8 vs 33.2 months; p = 0.0017). After adjustment for confounders, chemoradiotherapy was associated with better outcomes in the multivariable model (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.61-0.93; p = 0.008). The association between chemoradiotherapy and improved outcomes was stronger for the patients with grade III tumors (HR, 0.53; 95% CI, 0.37-0.74) or LVI+ tumors (HR, 0.58; 95% CI, 0.44-0.75). In a subgroup of 396 propensity-matched patients, chemoradiotherapy was associated with a survival benefit only for the patients with LVI+ or grade III tumors. CONCLUSION: After multiagent neoadjuvant chemotherapy and resection for pancreatic cancer, additional adjuvant chemoradiotherapy versus adjuvant chemotherapy alone is associated with improved survival for patients with LVI+ or grade III tumors.

Can AI Answer My Questions? Utilizing Artificial Intelligence in the Perioperative Assessment for Abdominoplasty Patients.

BACKGROUND: Abdominoplasty is a common operation, used for a range of cosmetic and functional issues, often in the context of divarication of recti, significant weight loss, and after pregnancy. Despite this, patient-surgeon communication gaps can hinder informed decision-making. The integration of large language models (LLMs) in healthcare offers potential for enhancing patient information. This study evaluated the feasibility of using LLMs for answering perioperative queries. METHODS: This study assessed the efficacy of four leading LLMs-OpenAI's ChatGPT-3.5, Anthropic's Claude, Google's Gemini, and Bing's CoPilot-using fifteen unique prompts. All outputs were evaluated using the Flesch-Kincaid, Flesch Reading Ease score, and Coleman-Liau index for readability assessment. The DISCERN score and a Likert scale were utilized to evaluate quality. Scores were assigned by two plastic surgical residents and then reviewed and discussed until a consensus was reached by five plastic surgeon specialists. RESULTS: ChatGPT-3.5 required the highest level for comprehension, followed by Gemini, Claude, then CoPilot. Claude provided the most appropriate and actionable advice. In terms of patient-friendliness, CoPilot outperformed the rest, enhancing engagement and information comprehensiveness. ChatGPT-3.5 and Gemini offered adequate, though unremarkable, advice, employing more professional language. CoPilot uniquely included visual aids and was the only model to use hyperlinks, although they were not very helpful and acceptable, and it faced limitations in responding to certain queries. CONCLUSION: ChatGPT-3.5, Gemini, Claude, and Bing's CoPilot showcased differences in readability and reliability. LLMs offer unique advantages for patient care but require careful selection. Future research should integrate LLM strengths and address weaknesses for optimal patient education. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Developing oral chronotherapy for cortisol replacement in congenital adrenal hyperplasia.

The sun imposes a 24-h periodicity to life and circadian rhythms have evolved to maintain homoeostasis through the day/night cycle. In humans, there is a central clock that controls the sleep/wake cycle which is paralleled metabolically by a fast/feed cycle. The clock maintains homoeostasis by synchronising metabolism to the time of feeding. Loss of synchrony between the clock and hormonal rhythms results in loss of homoeostasis as evidenced by obesity, depression, and diabetes in people undertaking shift work. Cortisol has a distinct circadian rhythm; peaking on waking and low at sleep onset. Loss of this rhythm in adrenal insufficiency is associated with a poor quality of life and increased mortality. To replace the cortisol rhythm requires chronotherapy and for this you need to define the key parameters of the target rhythm, create a formulation to replicate that rhythm, and then prove clinical benefit. The physiology of hormones is more complex than that of nonnative drugs. Hormones are secreted with varied rhythms, bound to multiple cognate binding proteins, and actively transported and cleared through enzymatic pathways in multiple organs. We have examined the diurnal rhythm of cortisol in healthy volunteers, created physiologically-based pharmacokinetic models, and tested various oral delayed and sustained formulations of hydrocortisone (development name, Chronocort) in clinical trials. The outcome from this work was the manufacture of modified-release hydrocortisone hard capsules (tradename Efmody, Diurnal Ltd), that replicate the cortisol diurnal rhythm and improve the disease control of congenital adrenal hyperplasia the commonest hereditary form of adrenal insufficiency.

Real world evidence supports waking salivary cortisone as a screening test for adrenal insufficiency.

OBJECTIVE: Worldwide, adults and children are at risk of adrenal insufficiency largely due to infectious diseases and adrenal suppression from use of anti-inflammatory glucocorticoids. Home waking salivary cortisone is an accurate screening test for adrenal insufficiency, it has potential to reduce costs, and patients prefer it to the adrenocorticotropin (ACTH) (synacthen) stimulation test. We carried out a service evaluation of home waking salivary cortisone in clinical care to identify implementation barriers. DESIGN, PATIENTS AND MEASUREMENTS: Service evaluation in a centre where 212 patients referred for adrenal insufficiency had a waking salivary cortisone. Problems encountered during testing were recorded and patient feedback, via focus groups, collected. RESULTS: From all patients providing a waking salivary cortisone 55% had a normal test, 23% adrenal suppression, and 22% an equivocal result requiring a clinical centre ACTH stimulation test. The median (interquartile range [IQR]) for the time of the saliva sample was 07:40 (07:00-08:40). The median (IQR) days between collection and (i) delivery to local laboratory was 1 (0.25-2) day; (ii) reporting by local laboratory was 13 (11-18) days. Patients considered the test is "easy to do" and preferred it to the inpatient ACTH stimulation test. The principal challenge to clinical implementation was results reporting to clinicians due to delays at the local laboratory. CONCLUSIONS: This service evaluation provides real-world evidence that home waking salivary cortisone is an effective, practical screening test for adrenal insufficiency. It identified key barriers to testing implementation that need to be addressed when introducing the test to a health service.

Aesthetic Surgery Advice and Counseling from Artificial Intelligence: A Rhinoplasty Consultation with ChatGPT.

BACKGROUND: ChatGPT is an open-source artificial large language model that uses deep learning to produce human-like text dialogue. This observational study evaluated the ability of ChatGPT to provide informative and accurate responses to a set of hypothetical questions designed to simulate an initial consultation about rhinoplasty. METHODS: Nine questions were prompted to ChatGPT on rhinoplasty. The questions were sourced from a checklist published by the American Society of Plastic Surgeons, and the responses were assessed for accessibility, informativeness, and accuracy by Specialist Plastic Surgeons with extensive experience in rhinoplasty. RESULTS: ChatGPT was able to provide coherent and easily comprehensible answers to the questions posed, demonstrating its understanding of natural language in a health-specific context. The responses emphasized the importance of an individualized approach, particularly in aesthetic plastic surgery. However, the study also highlighted ChatGPT's limitations in providing more detailed or personalized advice. CONCLUSION: Overall, the results suggest that ChatGPT has the potential to provide valuable information to patients in a medical context, particularly in situations where patients may be hesitant to seek advice from medical professionals or where access to medical advice is limited. However, further research is needed to determine the scope and limitations of AI language models in this domain and to assess the potential benefits and risks associated with their use. LEVEL OF EVIDENCE V: Observational study under respected authorities. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Evaluating Chatbot Efficacy for Answering Frequently Asked Questions in Plastic Surgery: A ChatGPT Case Study Focused on Breast Augmentation.

BACKGROUND: The integration of artificial intelligence (AI) and machine learning (ML) technologies into healthcare is transforming patient-practitioner interaction and could offer an additional platform for patient education and support. OBJECTIVES: This study investigated whether ChatGPT-4 could provide safe and up-to-date medical information about breast augmentation that is comparable to other patient information sources. METHODS: ChatGPT-4 was asked to generate 6 commonly asked questions regarding breast augmentation and respond to them. Its responses were qualitatively evaluated by a panel of specialist plastic and reconstructive surgeons and reconciled with a literature search of 2 large medical databases for accuracy, informativeness, and accessibility. RESULTS: ChatGPT-4 provided well-structured, grammatically accurate, and comprehensive responses to the questions posed; however, it was limited in providing personalized advice and sometimes generated inappropriate or outdated references. ChatGPT consistently encouraged engagement with a specialist for specific information. CONCLUSIONS: Although ChatGPT-4 showed promise as an adjunct tool in patient education regarding breast augmentation, there are areas requiring improvement. Additional advancements and software engineering are needed to enhance the reliability and applicability of AI-driven chatbots in patient education and support systems.

Patient Safety Outcomes under Flexible and Standard Resident Duty-Hour Rules.

BACKGROUND: Concern persists that extended shifts in medical residency programs may adversely affect patient safety. METHODS: We conducted a cluster-randomized noninferiority trial in 63 internal-medicine residency programs during the 2015-2016 academic year. Programs underwent randomization to a group with standard duty hours, as adopted by the Accreditation Council for Graduate Medical Education (ACGME) in July 2011, or to a group with more flexible duty-hour rules that did not specify limits on shift length or mandatory time off between shifts. The primary outcome for each program was the change in unadjusted 30-day mortality from the pretrial year to the trial year, as ascertained from Medicare claims. We hypothesized that the change in 30-day mortality in the flexible programs would not be worse than the change in the standard programs (difference-in-difference analysis) by more than 1 percentage point (noninferiority margin). Secondary outcomes were changes in five other patient safety measures and risk-adjusted outcomes for all measures. RESULTS: The change in 30-day mortality (primary outcome) among the patients in the flexible programs (12.5% in the trial year vs. 12.6% in the pretrial year) was noninferior to that in the standard programs (12.2% in the trial year vs. 12.7% in the pretrial year). The test for noninferiority was significant (P = 0.03), with an estimate of the upper limit of the one-sided 95% confidence interval (0.93%) for a between-group difference in the change in mortality that was less than the prespecified noninferiority margin of 1 percentage point. Differences in changes between the flexible programs and the standard programs in the unadjusted rate of readmission at 7 days, patient safety indicators, and Medicare payments were also below 1 percentage point; the noninferiority criterion was not met for 30-day readmissions or prolonged length of hospital stay. Risk-adjusted measures generally showed similar findings. CONCLUSIONS: Allowing program directors flexibility in adjusting duty-hour schedules for trainees did not adversely affect 30-day mortality or several other measured outcomes of patient safety. (Funded by the National Heart, Lung, and Blood Institute and Accreditation Council for Graduate Medical Education; iCOMPARE ClinicalTrials.gov number, NCT02274818.).

Inhibition, Binding of Organometallics, and Thermally Induced CO Release in an MFU-4-Type Metal-Organic Framework Scaffold with Open Bidentate Bibenzimidazole Coordination Sites.

Triazolate-based MFU-4-type metal-organic frameworks are promising candidates for various applications, of which heterogeneous catalysis has emerged as a hot topic owing to the facile post-synthetic metal and ligand exchange in Kuratowski secondary building units (SBUs). Herein, we present the largest non-interpenetrated isoreticular MFU-4-type framework CFA-19 ([Co5IICl4(H2-bibt)3]; H4-bibt = 1,1',5,5'-tetrahydro-6,6'-biimidazo[4,5-f]benzotriazole; CFA-19 = Coordination Framework Augsburg University-19) and the CFA-19-Tp derivative featuring trispyrazolylborate inhibited SBUs as a scaffold with open bibenzimidazole coordination sites at the backbone of the H4-bibt linker. The proof-of-principle incorporation of accessible MIBr(CO)3 (M = Re, Mn) sites in CFA-19-Tp was revealed by single-crystal X-ray diffraction, and a thermally induced CO release was observed for MnBr(CO)3. Deprotonation of bibenzimidazole was also achieved by the reaction with ZnEt2.

Sex differences in stress-induced sleep deficits.

Sleep disruptions are hallmarks in the pathophysiology of several stress-related disorders, including Major Depressive Disorder (MDD) and Post-Traumatic Stress Disorder (PTSD), both known to disproportionately affect female populations. Although previous studies have attempted to investigate disordered sleep in women, few studies have explored and compared how repeated stress affects sleep in both sexes in either human or animal models. We have previously shown that male rats exhibit behavioral and neuroendocrine habituation to 5 days of repeated restraint, whereas females do not; additional days of stress exposure are required to observe habituation in females. This study examined sex differences in sleep measures prior to, during, and after repeated restraint stress in adult male and female rats. Our data reveal that repeated stress increased time spent awake and decreased slow-wave sleep (SWS) and REM sleep (REMS) in females, and these effects persisted over 2 days of recovery. In contrast, the effects of stress on males were transient. These insomnia-like symptoms were accompanied by a greater number of exaggerated motor responses to waking from REMS in females, a phenotype similar to trauma-related nightmares. In sum, these data demonstrate that repeated stress produces disruptions in sleep that persist days after the stress is terminated in female rats. These disruptions in sleep produced by 5 days of repeated restraint may be due to their lack of habituation.

Hypophosphatemia and FGF23 tumor-induced osteomalacia in two cases of metastatic breast cancer.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by factor-induced dysregulation of phosphate and vitamin D metabolism resulting in alterations in bone formation, leading to bone pain and fractures. While the true incidence is likely underestimated, less than 500 cases of TIO have been reported since initial description in 1947. TIO cases have classically been associated with mesenchymal tumors of bone and soft tissue, but have also rarely been linked to malignant tumors, with scant reports implicating non-mesenchymal tumors. TIO is mediated through inappropriate tumor overproduction of fibroblast growth factor 23 (FGF23). Increased FGF23 secretion leads to hypophosphatemia by (1) reduced phosphate reabsorption via activation of the proximal renal tubular epithelial cells to internalize sodium phosphate cotransporters and (2) reduced activation of vitamin D3 via inhibition of the renal enzyme 1-α hydroxylase. Low circulating levels of active vitamin D lead to reduced intestinal phosphate absorption and impaired mineralization of osteoid matrix. TIO in breast cancer poses a distinct diagnostic challenge due to the common adjunct oncologic management with bone protection therapy such as denosumab or bisphosphonates. These agents can be culprits of hypophosphatemia and hypocalcemia, rendering timely diagnosis of TIO difficult. Delay of diagnosis of TIO can result in worsening functional status, and early morbidity and mortality. To date, there has been one prior case report of TIO in breast cancer, and herein we describe two additional cases of TIO in this setting.

Surgically treated acromegaly patients have a similar quality of life whether controlled by surgery or requiring additional medical therapy (QuaLAT Study).

PURPOSE: There is no consensus on quality of life (QOL) in patients with acromegaly requiring medical treatment after surgery compared with those achieving remission by surgery alone. METHODS: QuaLAT is a cross-sectional study comparing QOL in surgery-only treated acromegaly patients versus those requiring medical treatment post-surgery. Patients attending clinics were identified and divided into-Group 1: patients who had surgery only and were in biochemical remission, Group 2: all patients on medical treatment post-surgery, Group 3: patients from Group 2 with biochemical control. Participants were asked to fill three questionnaires; Acromegaly Quality of Life Questionnaire (ACROQOL), 36-Item Short Form Survey (SF36), and Fatigue Severity Scale (FSS). RESULTS: There were 32 patients in Group 1 and 25 in Group 2. There was no difference in QOL scores between groups 1 and 2, as measured by ACROQOL (mean difference [MD] = - 2.5, 95% CI - 16.6 to 11.6; p = 0.72), SF36v2 [Physical component score (PCS) MD = - 4.9, 95% CI - 10.9 to 1.2; p = 0.12; mental component score MD = - 3.0, 95% CI - 10.5 to 4.4; p = 0.44], or FSS (MD = - 0.004, 95% CI - 1.14 to 1.33; p = 0.1). Comparison between groups 1 and 3 however showed that PCS (and 3 subdomains) was significantly better in group 3 (MD = - 8.3, 95% CI - 14.8 to -1.8; p = 0.01). All three QOL scores were lower when compared with healthy controls. CONCLUSIONS: Medical treatment not only achieves a QOL comparable to surgery, it may also be associated with better QOL in physical subdomains. When compared with healthy controls, QOL remains worse in treated acromegaly patients compared to controls.

Lucid Dreams in Veterans With Posttraumatic Stress Disorder Include Nightmares.

A previous study in military veterans with posttraumatic stress disorder (PTSD) and recurrent nightmares found a high prevalence of lucid dreaming (LD), the awareness while a dream continues that one is dreaming, and an "LD profile" characterized by frequent dream awareness and rare dream content control. Given the importance of the nightmare disturbance in PTSD, this study assessed with questionnaires the prevalence and characteristics of lucid nightmares, specifically, in a sample of 54 veterans with PTSD. Over half the sample endorsed experiencing LD, with nearly all of these individuals explicitly reporting lucidity in nightmares. The lucid nightmare profile was characterized by high awareness and low content control. Veterans reported feeling stuck and anxious, trying unsuccessfully to awaken from lucid nightmares. We conclude that lucid nightmares may occur commonly in veterans with PTSD, with a profile resembling that previously reported for LD experiences generally in this group.

Comparing Outcomes and Costs of Surgical Patients Treated at Major Teaching and Nonteaching Hospitals: A National Matched Analysis.

OBJECTIVE: To compare outcomes and costs between major teaching and nonteaching hospitals on a national scale by closely matching on patient procedures and characteristics. BACKGROUND: Teaching hospitals have been shown to often have better quality than nonteaching hospitals, but cost and value associated with teaching hospitals remains unclear. METHODS: A study of Medicare patients at 340 teaching hospitals (resident-to-bed ratios ≥ 0.25) and matched patient controls from 2444 nonteaching hospitals (resident-to-bed ratios < 0.05).We studied 86,751 pairs admitted for general surgery (GS), 214,302 pairs of patients admitted for orthopedic surgery, and 52,025 pairs of patients admitted for vascular surgery. RESULTS: In GS, mortality was 4.62% in teaching hospitals versus 5.57%, (a difference of -0.95%, <0.0001), and overall paired cost difference = $915 (P < 0.0001). For the GS quintile of pairs with highest risk on admission, mortality differences were larger (15.94% versus 18.18%, difference = -2.24%, P < 0.0001), and paired cost difference = $3773 (P < 0.0001), yielding $1682 per 1% mortality improvement at 30 days. Patterns for vascular surgery outcomes resembled general surgery; however, orthopedics outcomes did not show significant differences in mortality across teaching and nonteaching environments, though costs were higher at teaching hospitals. CONCLUSIONS: Among Medicare patients, as admission risk of mortality increased, the absolute mortality benefit of treatment at teaching hospitals also increased, though accompanied by marginally higher cost. Major teaching hospitals appear to return good value for the extra resources used in general surgery, and to some extent vascular surgery, but this was not apparent in orthopedic surgery.

Comparing Outcomes and Costs of Medical Patients Treated at Major Teaching and Non-teaching Hospitals: A National Matched Analysis.

BACKGROUND: Teaching hospitals typically pioneer investment in new technology and cultivate workforce characteristics generally associated with better quality, but the value of this extra investment is unclear. OBJECTIVE: Compare outcomes and costs between major teaching and non-teaching hospitals by closely matching on patient characteristics. DESIGN: Medicare patients at 339 major teaching hospitals (resident-to-bed (RTB) ratios ≥ 0.25); matched patient controls from 2439 non-teaching hospitals (RTB ratios < 0.05). PARTICIPANTS: Forty-three thousand nine hundred ninety pairs of patients (one from a major teaching hospital and one from a non-teaching hospital) admitted for acute myocardial infarction (AMI), 84,985 pairs admitted for heart failure (HF), and 74,947 pairs admitted for pneumonia (PNA). EXPOSURE: Treatment at major teaching hospitals versus non-teaching hospitals. MAIN MEASURES: Thirty-day all-cause mortality, readmissions, ICU utilization, costs, payments, and value expressed as extra cost for a 1% improvement in survival. KEY RESULTS: Thirty-day mortality was lower in teaching than non-teaching hospitals (10.7% versus 12.0%, difference = - 1.3%, P < 0.0001). The paired cost difference (teaching - non-teaching) was $273 (P < 0.0001), yielding $211 per 1% mortality improvement. For the quintile of pairs with highest risk on admission, mortality differences were larger (24.6% versus 27.6%, difference = - 3.0%, P < 0.0001), and paired cost difference = $1289 (P < 0.0001), yielding $427 per 1% mortality improvement at 30 days. Readmissions and ICU utilization were lower in teaching hospitals (both P < 0.0001), but length of stay was longer (5.5 versus 5.1 days, P < 0.0001). Finally, individual results for AMI, HF, and PNA showed similar findings as in the combined results. CONCLUSIONS AND RELEVANCE: Among Medicare patients admitted for common medical conditions, as admission risk of mortality increased, the absolute mortality benefit of treatment at teaching hospitals also increased, though accompanied by marginally higher cost. Major teaching hospitals appear to return good value for the extra resources used.

Cooperative Large-Hysteresis Spin-Crossover Transition in the Iron(II) Triazolate [Fe(ta)2] Metal-Organic Framework.

The metal-organic framework [Fe(ta)2] (Hta = 1H-1,2,3-triazole) containing Fe(II) ions and 1,2,3-triazolate ligands shows a reversible phase transition while retaining the cubic crystal symmetry and space group Fd3m (no. 227). The phase transition between room temperature (RT-[Fe(ta)2]; a = 16.6315(2) Å, V = 4600.39(8) Å3) and high temperature (HT-[Fe(ta)2]; a = 17.7566(4) Å, V = 5598.6(1) Å3) phases occurs at a temperature above 290 °C, whereas the phase transition between HT- and RT-[Fe(ta)2] starts at a temperature below 210 °C. Both [Fe(ta)2] polymorphs have identical bond topologies, but they differ by a large increase of the unit cell's volume of 22% for HT-[Fe(ta)2]. The compounds are characterized by powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analyses. Additionally, Mössbauer spectroscopy, magnetic studies, and the electronic structure of both phases are discussed in detail with respect to the spin-crossover transition from the low-spin (RT-[Fe(ta)2]) to the high-spin phase (HT-[Fe(ta)2]).

Testosterone replacement in young male cancer survivors: A 6-month double-blind randomised placebo-controlled trial.

BACKGROUND: Young male cancer survivors have lower testosterone levels, higher fat mass, and worse quality of life (QoL) than age-matched healthy controls. Low testosterone in cancer survivors can be due to orchidectomy or effects of chemotherapy and radiotherapy. We have undertaken a double-blind, placebo-controlled, 6-month trial of testosterone replacement in young male cancer survivors with borderline low testosterone (7-12 nmol/l). METHODS AND FINDINGS: This was a multicentre United Kingdom study conducted in secondary care hospital outpatients. Male survivors of testicular cancer, lymphoma, and leukaemia aged 25-50 years with morning total serum testosterone 7-12 nmol/l were recruited. A total of 136 men were randomised between July 2012 and February 2015 (42.6% aged 25-37 years, 57.4% 38-50 years, 88% testicular cancer, 10% lymphoma, matched for body mass index [BMI]). Participants were randomised 1:1 to receive testosterone (Tostran 2% gel) or placebo for 26 weeks. A dose titration was performed after 2 weeks. The coprimary end points were trunk fat mass and SF36 Physical Functioning score (SF36-PF) at 26 weeks by intention to treat. At 26 weeks, testosterone treatment compared with placebo was associated with decreased trunk fat mass (-0.9 kg, 95% CI -1.6 to -0.3, p = 0.0073), decreased whole-body fat mass (-1.8 kg, 95% CI -2.9 to -0.7, p = 0.0016), and increased lean body mass (1.5 kg, 95% CI 0.9-2.1, p < 0.001). Decrease in fat mass was greatest in those with a high truncal fat mass at baseline. There was no treatment effect on SF36-PF or any other QoL scores. Testosterone treatment was well tolerated. The limitations of our study were as follows: a relatively short duration of treatment, only three cancer groups included, and no hard end point data such as cardiovascular events. CONCLUSIONS: In young male cancer survivors with low-normal morning total serum testosterone, replacement with testosterone is associated with an improvement in body composition. TRIAL REGISTRATION: ISRCTN: 70274195, EudraCT: 2011-000677-31.

Accuracy of hydrocortisone dose administration via nasogastric tube.

OBJECTIVE: Hydrocortisone via nasogastric (NG) tube is used in sick children with adrenal insufficiency; however, there is no licensed formulation for NG administration. METHODS: We investigated hydrocortisone recovery after passage through NG tubes in vitro for three formulations: liquid suspension, crushed tablets mixed with water, and hydrocortisone granules designed for oral administration to children. Cortisol was measured by LC-MS/MS. RESULTS: Hydrocortisone content was variable and recovery low after preparation in syringe and prior to passage through NG tubes. For doses, 0.5 and 2.0 mg mean percentage recovery was as follows: liquid suspension 57% and 58%; crushed tablets 46% and 30%; and hydrocortisone granules 78% and 71%. Flushing the administering syringe increased recovery. Hydrocortisone recovery after passage with flushing through 6-12Fr gauge NG tubes was variable: liquid suspension 61%-92%, crushed tablets 40%-174%, hydrocortisone granules 61%-92%. Administration of hydrocortisone granules occluded 6 and 8Fr NG tubes; however, administration using a sampling needle to prevent granules being administered gave a recovery of 74%-98%. CONCLUSIONS: The administration of hydrocortisone through NG tubes is possible; however, current methods deliver a variable dose of hydrocortisone, generally less than that prescribed. Attention should be placed on the technique used to optimize drug delivery such as flushing of the administering syringe. Hydrocortisone granules block small NG tubes but behaved as well as the commonly used liquid suspension when prepared with a filtering needle that filters out granules.

The circadian rhythm of corticosteroid-binding globulin has little impact on cortisol exposure after hydrocortisone dosing.

CONTEXT: Optimization of hydrocortisone replacement therapy is important to prevent under- and over dosing. Hydrocortisone pharmacokinetics is complex as circulating cortisol is protein bound mainly to corticosteroid-binding globulin (CBG) that has a circadian rhythm. OBJECTIVE: A detailed analysis of the CBG circadian rhythm and its impact on cortisol exposure after hydrocortisone administration. DESIGN AND METHODS: CBG was measured over 24 hours in 14 healthy individuals and, employing a modelling and simulation approach using a semi-mechanistic hydrocortisone pharmacokinetic model, we evaluated the impact on cortisol exposure (area under concentration-time curve and maximum concentration of total cortisol) of hydrocortisone administration at different clock times and of the changing CBG concentrations. RESULTS: The circadian rhythm of CBG was well described with two cosine terms added to the baseline of CBG: baseline CBG was 21.8 µg/mL and interindividual variability 11.9%; the amplitude for the 24 and 12 hours cosine functions were relatively small (24 hours: 5.53%, 12 hours: 2.87%) and highest and lowest CBG were measured at 18:00 and 02:00, respectively. In simulations, the lowest cortisol exposure was observed after administration of hydrocortisone at 23:00-02:00, whereas the highest was observed at 15:00-18:00. The differences between the highest and lowest exposure were minor (≤12.2%), also regarding the free cortisol concentration and free fraction (≤11.7%). CONCLUSIONS: Corticosteroid-binding globulin has a circadian rhythm but the difference in cortisol exposure is ≤12.2% between times of highest and lowest CBG concentrations; therefore, hydrocortisone dose adjustment based on time of dosing to adjust for the CBG concentrations is unlikely to be of clinical benefit.