Skeletal Muscle Mitochondrial Morphology Negatively Affected in Mice Lacking Xin.

Altered mitochondrial structure and function are implicated in the functional decline of skeletal muscle. Numerous cytoskeletal proteins are known to affect mitochondrial homeostasis, but this complex network is still being unraveled. Here, we investigated mitochondrial alterations in mice lacking the cytoskeletal adapter protein, XIN (XIN-/-). XIN-/- and wild-type littermate male and female mice were fed a chow or high-fat diet (HFD; 60% kcal fat) for 8 weeks before analyses of their skeletal muscles was conducted. Immuno-electron microscopy (EM) and immunofluorescence staining revealed XIN in the mitochondria and peri-mitochondrial areas, as well as the myoplasm. Intermyofibrillar mitochondria in chow-fed XIN-/- mice were notably different from wild-type (large, and/or swollen in appearance). Succinate Dehydrogenase and Cytochrome Oxidase IV staining indicated greater evidence of mitochondrial enzyme activity in XIN-/- mice. No difference in body mass gains or glucose handling was observed between cohorts with HFD. However, EM revealed significantly greater mitochondrial density with evident structural abnormalities (swelling, reduced cristae density) in XIN-/- mice. Absolute Complex I and II-supported respiration was not different between groups, but relative to mitochondrial density, was significantly lower in XIN-/-. These results provide the first evidence for a role of XIN in maintaining mitochondrial morphology and function.

Adrenal insufficiency is common amongst kidney transplant recipients receiving maintenance prednisolone and can be predicted using morning cortisol.

BACKGROUND: Long-term glucocorticoid therapy is a key component of immunosuppression for kidney transplant recipients (KTRs), leading to significant cumulative glucocorticoid exposure. The aims of this study are to investigate the prevalence of adrenal insufficiency (AI) in KTRs taking prednisolone and to develop a screening algorithm to identify patients at the highest risk of AI. METHODS: In this cross-sectional cohort study, 67 KTRs receiving prednisolone underwent a short synacthen test (SST) and measurement of cumulative glucocorticoid exposure. RESULTS: A total of 72% (n = 48) of participants failed the SST. Participants with AI had a higher daily prednisolone dose (4.9 versus 4.2 mg/day; P = .002) and greater cumulative glucocorticoid exposure (289 versus 111 mg/kg; P = .03) than those with intact adrenal function. Participants with AI had lower baseline cortisol than participants with intact adrenal function (143 versus 303 nmol/L; P < .001). Morning cortisol of >288 nmol/L predicted a normal SST with 100% specificity [95% confidence interval (CI) 92-100] and 70% sensitivity (95% CI 56-78%), therefore excluding AI. CONCLUSIONS: Our results suggest KTRs are at a higher risk for AI than previously reported. A morning serum cortisol measurement is a useful screening tool in this cohort, reducing the need for stimulatory testing by 44%. KTRs with AI need education regarding glucocorticoid sick rules, similar to patients with other forms of AI.

Incidence of breakthrough fungal infections on isavuconazole prophylaxis compared to posaconazole and voriconazole.

BACKGROUND: Invasive fungal infections (IFIs) are a common infectious complication during the treatment of acute myeloid leukemia (AML), high-risk myelodysplastic syndrome (MDS) or post hematopoietic cell transplantation (HCT). For these patients, the National Comprehensive Cancer Network recommends posaconazole or voriconazole for IFI prophylaxis. In clinical practice, however, there has been increased use of isavuconazole due to favorable pharmacokinetic and pharmacodynamic parameters despite limited data for this indication. The comparative prophylactic efficacy of antifungals in this patient population has not been reported, and an analysis is warranted. METHODS: This retrospective, matched cohort, single-center study, included AML, MDS, or HCT patients who began treatment or underwent transplant between January 1, 2015 and July 31, 2021. Isavuconazole patients were matched 1:2 with patients receiving posaconazole or voriconazole prophylaxis. RESULTS: A total of 126 patients were included, 42 received isavuconazole, 81 received posaconazole, and three received voriconazole. The majority of patients were male receiving secondary IFI prophylaxis while receiving steroids for treatment of GVHD. The incidence of possible, probable or proven IFI was 16.7% in the isavuconazole group compared to 10.7% in the posaconazole and voriconazole group (OR 1.28, 95% CI -0.9-1.4; p = .67). Hepatotoxicity occurred in 16 total patients, 14 receiving posaconazole and two receiving isavuconazole. CONCLUSION: Patients who received isavuconazole prophylaxis during AML induction therapy or post-HCT experienced a similar incidence of breakthrough fungal infections compared to those who received posaconazole or voriconazole. These results suggest no difference in antifungal prophylactic efficacy; however larger prospective comparative studies are needed.

Survey of Patient Knowledge and Awareness of "Sick Day Rules" in Rheumatology Patients on Long Term Glucocorticoid Therapy.

Aims Rheumatic disease (RMD) patients treated with long-term glucocorticoids (GC) are at risk of developing tertiary adrenal insufficiency. With this survey we aimed to assess the knowledge of RMD patients taking long-term glucocorticoid therapy regarding risk of adrenal insufficiency and understanding of the "steroid sick day rules". Methods RMD patients taking ≥2.5 mg prednisolone daily for ≥3 months were recruited from the Rheumatology outpatient department in Beaumont Hospital, Dublin. Patient knowledge and previous counselling of steroid sick day rules was determined using an 8-point questionnaire carried out face-to-face or via phone call. Results 51 RMD patients on GC therapy were recruited. 3/51 (5.9%) of patients reported that they had been counselled on the Sick Day Rules. 2/51 (3.9%) carried a steroid emergency card or MedicAlert bracelet. Few patients would increase their steroid dose appropriately in response to infection, vomiting or peri-procedure [14/51 (27.5%); 9/51 (17.7%) and 5/51 (7.2%), respectively]. Conclusion We demonstrate a significant deficit of patient knowledge around the precautions for long-term GC use in rheumatic diseases. We suspect that our results may be generalisable to many other RMD units. We are currently reviewing our procedures around healthcare professional and patient education, issuing of information leaflets, emergency cards or MedicAlert bracelets etc. to at risk patients.

Intraperitoneal paclitaxel and cisplatin compared with dose-dense paclitaxel and carboplatin for patients with stage III ovarian cancer.

INTRODUCTION: Patients diagnosed with stage III ovarian cancer are at high risk of recurrence and optimal adjuvant therapy is often debated. There is limited literature that directly compares intraperitoneal paclitaxel and cisplatin with dose-dense paclitaxel and carboplatin. OBJECTIVES: The primary objective was to compare progression-free survival, overall survival, and tolerability of adjuvant intraperitoneal paclitaxel and cisplatin to dose-dense paclitaxel and carboplatin in stage III ovarian cancer patients. METHODS: A retrospective, IRB-approved, single center chart review was conducted reviewing adult patients with stage III ovarian cancer undergoing adjuvant intraperitoneal therapy or dose-dense therapy between 2010 and 2018. RESULTS: Eighty-two patients were included in the final analysis; 44 in the intraperitoneal group and 38 in the dose-dense group. Intraperitoneal therapy was not associated with a longer progression-free survival (35.4 vs. 31.1 months; P = 0.97). The duration of overall survival did not differ between intraperitoneal and dose-dense (56.3 vs. 54.5 months; P = 0.55). Dose reductions were less frequent with intraperitoneal than dose-dense (11.36% vs. 31.58%; P = 0.02). No difference in treatment delays (45.5% vs. 65.8%; P = 0.07), dose cancellations (59.1% vs. 57.9%; P = 0.91), supportive care additions (95.5% vs. 84.2%; P = 0.09), or therapy discontinuation (59.1% vs. 39.5%; P = 0.07) between groups was noted. CONCLUSIONS: Intraperitoneal therapy with paclitaxel and cisplatin, as compared with dose-dense paclitaxel and carboplatin, did not prolong progression-free or overall survival in the adjuvant setting among stage III ovarian cancer patients. A trend towards decreased tolerability was noted with intraperitoneal therapy.

Identifying the need to refine the potential patient risk factors for niraparib-induced thrombocytopenia.

OBJECTIVE: Niraparib is a poly (ADP-ribose) polymerase inhibitor (PARP) approved for use in maintenance therapy for ovarian cancer that is associated with the unpredictable grade 3/4 thrombocytopenia. This study was conducted to refine patient dosing recommendations for niraparib based upon clinical practice observations of grade 3/4 thrombocytopenia. METHODS AND MATERIALS: Six patient cases were reviewed to identify similarities in patient factors. An in vitro study was conducted using healthy volunteer blood spiked with Niraparib concentrations ranging from 0 ng/mL to 5000 ng/mL. Manual platelet counts were evaluated at different time intervals for each concentration and compared to untreated controls. Data was then analyzed based on percent change in platelet count versus untreated control for each concentration/time point. RESULTS: In three patients with body weight > 80 kg and platelet count >200 × 109/L, decreased creatinine clearance (CrCl) <60 mL/min was identified as potential signal. An additional three patients with weights below 77 kg and/or baseline platelet counts <150 × 109/L were re-evaluated, and it was observed that all had decreased CrCl of <60 mL/min. Albumin <3.5 g/dL was also observed in some patients with thrombocytopenia. The in vitro study, observed a direct concentration-dependent relationship between niraparib and thrombocytopenia. CONCLUSION: The data suggests that renal insufficiency and hypoalbuminemia may be associated with the development of niraparib-induced thrombocytopenia. Moreover, the preliminary in vitro studies also demonstrated a concentration-dependent relationship between niraparib and direct toxicity to platelets.

Lower Extremity Duplex Ultrasound Screening Protocol for Moderate- and High-Risk Trauma Patients.

BACKGROUND: Deep vein thrombosis (DVT) remains a significant cause of morbidity after injury. Lower extremity duplex ultrasound screening (LEDUS) is designed to identify early, asymptomatic DVTs in moderate and high risk patients. We sought to describe when thrombus is detected and identify which trauma patients benefit from LEDUS. MATERIALS AND METHODS: A retrospective review was conducted on trauma patients who were moderate or high risk for venous thromboembolism based on risk assessment profile (RAP) scoring. Patients with RAP scores ≥5 underwent LEDUS on hospital Day 4 and then weekly. We defined moderate venous thromboembolism risk as an RAP score of 5-9 and high risk as an RAP score of ≥10. Demographics, injury characteristics, and chemoprophylaxis type and timing were analyzed. RESULTS: A total of 579 trauma patients underwent a total of 820 ultrasounds in 1 y. Eighty-eight acute DVTs were identified. There was only one progression of a below- to above-the-knee DVT. Patients with RAP scores ≥10 had significantly higher rates of DVTs compared with patients with lower RAP scores in addition to longer lengths of stay and time to DVT prophylaxis. Moderate- and high-risk patients had similar rates of pulmonary embolism. Two-thirds of all DVTs were diagnosed on the first screening examination. The rate of DVTs in patients with RAP scores 7-9 was 15.4% compared with 6.1% of those with RAP scores of 5-6. CONCLUSIONS: LEDUS allows for early identification of asymptomatic DVTs. Moderate-risk patients with RAP scores of ≥7 should be considered for LEDUS, given higher rates of DVT.

Congenital hypophosphataemia in adults: determinants of bone turnover markers and amelioration of renal phosphate wasting following total parathyroidectomy.

Congenital hypophosphataemia (CH) is a collection of disorders that cause defective bone mineralisation manifesting with rickets in childhood and osteomalacia in adulthood. Bone turnover markers (BTMs) are surrogate measures of metabolic bone disease severity. We explored the utility of BTMs in 27 adults with CH: 23 had X-linked hypophosphataemia (XLH), of whom 2 were hypoparathyroid post-total parathyroidectomy (PTx); 2 had autosomal dominant hypophosphataemic rickets (ADHR), and 2 had none of the known mutations. We measured the renal tubular maximum reabsorption rate of phosphate (TmP/GFR), C-terminal fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), ionised calcium, 1,25-dihydroxyvitamin D [1,25(OH)2D], and a panel of BTMs: serum bone-specific alkaline phosphatase (bone ALP), osteocalcin (Oc), total procollagen type I amino-terminal propeptide (PINP), and carboxy-terminal telopeptide of type I collagen (CTX); and urine amino-terminal telopeptides of type I collagen (uNTX). After excluding 2 patients with XLH and PTx, the frequency of abnormal elevation in BTMs was: bone ALP (96%); CTX (72%); PINP (52%); uNTX (48%); Oc (28%). The strongest association with bone ALP was TmP/GFR. Those patients receiving phosphate supplements and alfacalcidol had significant elevation in CTX. The 2 patients with XLH and PTx had normalisation of TmP/GFR and near normalisation of BTMs post-operatively, despite marked elevation in both C-terminal and intact FGF23. In conclusion, BTMs in our CH patients indicated that most have abnormalities consistent with osteomalacia and many have mild secondary hyperparathyroidism; and the normalisation of TmP/GFR after total PTx in 2 cases of XLH remains unexplained, but possible causes are speculated.

Relationship of Coagulopathy and Platelet Dysfunction to Transfusion Needs After Traumatic Brain Injury.

BACKGROUND: Coagulopathy and platelet dysfunction commonly develop after traumatic brain injury (TBI). Thromboelastography (TEG) and platelet function assays (PFAs) are often performed at the time of admission; however, their roles in assessing post-TBI coagulopathy have not been investigated. We hypothesized that compared to blunt TBI, penetrating TBI would (1) demonstrate greater coagulopathy by TEG, (2) be associated with abnormal PFA results, and (3) require more blood product transfusions. METHODS: We performed a retrospective study of patients admitted to the neuroscience intensive care unit of a level 1 trauma center from 2013 to 2015 with head Abbreviated Injury Scale ≥3. Patients were compared by mechanism of injury (blunt vs. penetrating). Admission demographics, injury characteristics, and laboratory parameters were evaluated. VerifyNow® Aspirin and P2Y12 tests were used for platelet function analysis. RESULTS: Five hundred and thirty-four patients were included in the analysis. There were no differences between groups in platelet count or international normalized ratio; however, patients with penetrating TBI were more coagulopathic by TEG, with all of the TEG parameters being significantly different except for R time. Patients with penetrating head trauma were not more likely than their blunt counterparts to have abnormal PFA results, and PFA results did not correlate with any TEG parameter in either group. The penetrating cohort received more units of blood products in the first 4 and 24 h than the blunt cohort. CONCLUSIONS: Patients presenting with penetrating TBI demonstrated increased coagulopathy compared to those with blunt TBI as measured by TEG and need for transfusion. PFA results did not correlate with TEG findings in this population.

Laparoscopic subtotal cholecystectomy compared to total cholecystectomy: a matched national analysis.

BACKGROUND: Laparoscopic subtotal cholecystectomy (LSC) is considered a safe alternative to laparoscopic cholecystectomy (LC) if biliary anatomy is obscured by inflammation. While case series studies have observed low morbidity rates with LSC, the impact of operative conversion on patient outcomes is poorly understood. METHODS: A national analysis of all patients who underwent LC or LSC from 2009 to 2013 was performed using the University HealthSystem Consortium database. A 1:1 propensity score match was used to compare procedural outcomes accounting for clinical and demographic factors. Matched samples had <10% standardized differences of each baseline covariate. RESULTS: A total of 131,082 LC and 487 LSC were performed during the study period. Compared with LC, patients undergoing LSC were more likely to be older (56 versus 48 years), male (54.2% versus 32.3%), and have higher severity of illness scores on admission (9.2% versus 3.5% extreme severity of illness; P < 0.001 each). LSC patients had a prolonged hospital length of stay (LOS, 4 versus 3 days), greater total direct cost ($9053 versus $6398), higher readmission rates (11.9% versus 7.0%), and higher mortality rates (0.82% versus 0.28%, P < 0.05 each). After matching, the difference in total direct cost persisted ($9053 versus $7,581, P < 0.001), but there were no differences in hospital LOS, readmission rates, or overall mortality. CONCLUSIONS: LSC is an important alternative to LC for the difficult gallbladder. Conversion to LSC is associated with increased patient morbidity and resource utilization leading to perceived poor outcomes, but this is due to patient factors at initial presentation. Health care providers should consider LSC if the patient may be at risk for iatrogenic injury to the biliary tract.

Perception Is Reality: quality metrics in pancreas surgery - a Central Pancreas Consortium (CPC) analysis of 1399 patients.

INTRODUCTION: Several groups have defined pancreatic surgery quality metrics that identify centers delivering quality care. Although these metrics are perceived to be associated with good outcomes, their relationship with actual outcomes has not been established. METHODS: A national cadre of pancreatic surgeons was surveyed regarding perceived quality metrics, which were evaluated against the Central Pancreas Consortium (CPC) database to determine actual performance and relationships with long-term outcomes. RESULTS: The most important metrics were perceived to be participation in clinical trials, appropriate clinical staging, perioperative mortality, and documentation of receipt of adjuvant therapy. Subsequent analysis of 1399 patients in the CPC dataset demonstrated that a R0 retroperitoneal and neck margin was obtained in 79% (n = 1109) and 91.4% (n = 1278) of cases, respectively. 74% of patients (n = 1041) had >10 lymph nodes harvested, and LN positivity was 65% (n = 903). 76% (n = 960) of eligible patients (surgery first approach) received adjuvant therapy within 60 days of surgery. Multivariate analysis demonstrated margin status, identification of >10 lymph nodes, nodal status, tumor grade and delivery of adjuvant therapy within 60 days to be associated with improved overall survival. CONCLUSIONS: These analyses demonstrate that systematic monitoring of surgeons' perceived quality metrics provides critical prognostic information, which is associated with patient survival.

Iatrogenic adrenal insufficiency in adults.

Iatrogenic adrenal insufficiency (IAI) is the most common form of adrenal insufficiency in adult patients, although its overall exact prevalence remains unclear. IAI is associated with adverse clinical outcomes, including adrenal crisis, impaired quality of life and increased mortality; therefore, it is imperative that clinicians maintain a high index of suspicion in patients at risk of IAI to facilitate timely diagnosis and appropriate management. Herein, we review the major causes, clinical consequences, diagnosis and care of patients with IAI. The management of IAI, particularly glucocorticoid-induced (or tertiary) adrenal insufficiency, can be particularly challenging, and the provision of adequate glucocorticoid replacement must be balanced against minimizing the cardiometabolic effects of excess glucocorticoid exposure and optimizing recovery of the hypothalamic-pituitary-adrenal axis. We review current treatment strategies and their limitations and discuss developments in optimizing treatment of IAI. This comprehensive Review aims to aid clinicians in identifying who is at risk of IAI, how to approach screening of at-risk populations and how to treat patients with IAI, with a focus on emergency management and prevention of an adrenal crisis.

Systematic review of health related-quality of life in adults with osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare, connective tissue disorder characterised by bone fragility, resulting in recurrent fractures and skeletal deformities. Extra-skeletal manifestations include dentinogenesis imperfecta, hearing abnormalities and lung disease. These co-morbidities combined with recurrent fractures can exert a significant impact on health-related quality of life (HR-QOL). It is important to assess HR-QOL throughout adulthood because the prevalence of some OI-specific complications increases with age. METHODS: PubMed, EMBASE and CENTRAL databases were searched on 2nd February 2022 to identify studies reporting quantitative assessments of HR-QOL in adults with OI. The primary endpoint was to determine the impact of an OI diagnosis on adult's HR-QOL. Secondary endpoints were to (i) examine how frequently various HR-QOL assessment tools were used (ii) identify differences in HR-QOL between OI types and (iii) investigate the determinants of HR-QOL in adults with OI. Search results were exported to Endnote where two reviewers independently conducted title/abstract and full-text reviews. Data from accepted studies were extracted into Microsoft Excel. A narrative synthesis was then undertaken. RESULTS: The review identified 17 studies with a total of 1,648 adults. The Short Form-36 (SF-36) was the most frequently reported HR-QOL assessment tool and was used in nine studies. Physical HR-QOL was reduced in adults with OI. Physical component scores (PCS) or individual physical domains of the SF-36 were lower in eight of nine studies. Mental component scores (MCS) were preserved in all six studies, however individual mental health domains of the SF-36 were reduced in some studies. The prevalence of anxiety/depression was relatively low in adults with OI. Those with type III OI had lower physical and respiratory HR-QOL but preserved mental HR-QOL compared with type I. The prevalence of fatigue and pain was higher in adults with OI compared with reference populations. Age and cardio-pulmonary co-morbidities were associated with lower HR-QOL. CONCLUSION: OI in adulthood has a wide-ranging negative impact on HR-QOL. Physical and respiratory HR-QOL were lower, while the prevalence of pain and fatigue were higher than in reference populations. Mental HR-QOL was relatively preserved, although some deficits were identified. Age and cardio-pulmonary co-morbidities were associated with lower HR-QOL.

Management of chronic pain secondary to temporomandibular disorders: a systematic review and network meta-analysis of randomised trials.

OBJECTIVE: We explored the comparative effectiveness of available therapies for chronic pain associated with temporomandibular disorders (TMD). DESIGN: Systematic review and network meta-analysis of randomised clinical trials (RCTs). DATA SOURCES: MEDLINE, EMBASE, CINAHL, CENTRAL, and SCOPUS were searched to May 2021, and again in January 2023. STUDY SELECTION: Interventional RCTs that enrolled patients presenting with chronic pain associated with TMD. DATA EXTRACTION AND SYNTHESIS: Pairs of reviewers independently identified eligible studies, extracted data, and assessed risk of bias. We captured all reported patient-important outcomes, including pain relief, physical functioning, emotional functioning, role functioning, social functioning, sleep quality, and adverse events. We conducted frequentist network meta-analyses to summarise the evidence and used the GRADE approach to rate the certainty of evidence and categorise interventions from most to least beneficial. RESULTS: 233 trials proved eligible for review, of which 153-enrolling 8713 participants and exploring 59 interventions or combinations of interventions-were included in network meta-analyses. All subsequent effects refer to comparisons with placebo or sham procedures. Effects on pain for eight interventions were supported by high to moderate certainty evidence. The three therapies probably most effective for pain relief were cognitive behavioural therapy (CBT) augmented with biofeedback or relaxation therapy (risk difference (RD) for achieving the minimally important difference (MID) in pain relief of 1 cm on a 10 cm visual analogue scale: 36% (95% CI 33 to 39)), therapist-assisted jaw mobilisation (RD 36% (95% CI 31 to 40)), and manual trigger point therapy (RD 32% (29 to 34)). Five interventions were less effective, yet more effective than placebo, showing RDs ranging between 23% and 30%: CBT, supervised postural exercise, supervised jaw exercise and stretching, supervised jaw exercise and stretching with manual trigger point therapy, and usual care (such as home exercises, self stretching, reassurance).Moderate certainty evidence showed four interventions probably improved physical functioning: supervised jaw exercise and stretching (RD for achieving the MID of 5 points on the short form-36 physical component summary score: 43% (95% CI 33 to 51)), manipulation (RD 43% (25 to 56)), acupuncture (RD 42% (33 to 50)), and supervised jaw exercise and mobilisation (RD 36% (19 to 51)). The evidence for pain relief or physical functioning among other interventions, and all evidence for adverse events, was low or very low certainty. CONCLUSION: When restricted to moderate or high certainty evidence, interventions that promote coping and encourage movement and activity were found to be most effective for reducing chronic TMD pain. REGISTRATION: PROSPERO (CRD42021258567).

Tissue Glucocorticoid Metabolism in Adrenal Insufficiency: A Prospective Study of Dual-release Hydrocortisone Therapy.

BACKGROUND: Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11ß-hydroxysteroid dehydrogenase (11ß-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI because of the nonphysiological pattern of current immediate release hydrocortisone (IR-HC) replacement therapy. The use of a once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may alter corticosteroid metabolism in vivo. STUDY DESIGN AND METHODS: Prospective crossover study assessing the impact of 12 weeks of DR-HC on systemic GC metabolism (urinary steroid metabolome profiling), cortisol activation in the liver (cortisone acetate challenge test), and subcutaneous adipose tissue (microdialysis, biopsy for gene expression analysis) in 51 patients with AI (primary and secondary) in comparison to IR-HC treatment and age- and BMI-matched controls. RESULTS: Patients with AI receiving IR-HC had a higher median 24-hour urinary excretion of cortisol compared with healthy controls (72.1 µg/24 hours [IQR 43.6-124.2] vs 51.9 µg/24 hours [35.5-72.3], P = .02), with lower global activity of 11ß-HSD2 and higher 5-alpha reductase activity. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary cortisol and total GC metabolite excretion, which was most significant in the evening. There was an increase in 11ß-HSD2 activity. Hepatic 11ß-HSD1 activity was not significantly altered after switching to DR-HC, but there was a significant reduction in the expression and activity of 11ß-HSD1 in subcutaneous adipose tissue. CONCLUSION: Using comprehensive in vivo techniques, we have demonstrated abnormalities in corticosteroid metabolism in patients with primary and secondary AI receiving IR-HC. This dysregulation of pre-receptor glucocorticoid metabolism results in enhanced glucocorticoid activation in adipose tissue, which was ameliorated by treatment with DR-HC.

Effectiveness of Interprofessional Consultation-Based Interventions for Delirium: A Scoping Review.

BACKGROUND: Interprofessional geriatric consultation teams and multicomponent interventions are established models for delirium care. They are combined in interprofessional consultative delirium team interventions; however, insight into this novel approach is lacking. OBJECTIVE: To describe the effectiveness and core components of consultation-based interventions for delirium. METHOD: Ovid MEDLINE, EMBASE, PsycINFO, CINAHL, and ProQuest. Data on core intervention components, outcomes, facilitators, and barriers were extracted. RESULTS: 10 studies were included. Core intervention components were systematic delirium screening, ongoing consultation, implementation of non-pharmacologic and pharmacological interventions, and staff education. Of the included studies, 1/6 found a significant reduction in delirium incidence, 1/2 a reduction in delirium duration, and 2/3 found a reduction in falls. Facilitators and barriers to implementation were discussed. CONCLUSION: There was consistency in team structure and core components, however intervention operationalization and effectiveness varied widely. There is some evidence that this model is effective for reducing delirium and its sequelae.

Approach to the Patient: Hyponatremia and the Syndrome of Inappropriate Antidiuresis (SIAD).

Hyponatremia is the most common electrolyte disturbance seen in clinical practice, affecting up to 30% of acute hospital admissions, and is associated with significant adverse clinical outcomes. Acute or severe symptomatic hyponatremia carries a high risk of neurological morbidity and mortality. In contrast, chronic hyponatremia is associated with significant morbidity including increased risk of falls, osteoporosis, fractures, gait instability, and cognitive decline; prolonged hospital admissions; and etiology-specific increase in mortality. In this Approach to the Patient, we review and compare the current recommendations, guidelines, and literature for diagnosis and treatment options for both acute and chronic hyponatremia, illustrated by 2 case studies. Particular focus is concentrated on the diagnosis and management of the syndrome of inappropriate antidiuresis. An understanding of the pathophysiology of hyponatremia, along with a synthesis of the duration of hyponatremia, biochemical severity, symptomatology, and blood volume status, forms the structure to guide the appropriate and timely management of hyponatremia. We present 2 illustrative cases that represent common presentations with hyponatremia and discuss the approach to management of these and other causes of hyponatremia.

Diagnosis and Management of Central Diabetes Insipidus in Adults.

Central diabetes insipidus (CDI) is a clinical syndrome which results from loss or impaired function of vasopressinergic neurons in the hypothalamus/posterior pituitary, resulting in impaired synthesis and/or secretion of arginine vasopressin (AVP). AVP deficiency leads to the inability to concentrate urine and excessive renal water losses, resulting in a clinical syndrome of hypotonic polyuria with compensatory thirst. CDI is caused by diverse etiologies, although it typically develops due to neoplastic, traumatic, or autoimmune destruction of AVP-synthesizing/secreting neurons. This review focuses on the diagnosis and management of CDI, providing insights into the physiological disturbances underpinning the syndrome. Recent developments in diagnostic techniques, particularly the development of the copeptin assay, have improved accuracy and acceptability of the diagnostic approach to the hypotonic polyuria syndrome. We discuss the management of CDI with particular emphasis on management of fluid intake and pharmacological replacement of AVP. Specific clinical syndromes such as adipsic diabetes insipidus and diabetes insipidus in pregnancy as well as management of the perioperative patient with diabetes insipidus are also discussed.

Contemporary management of paragangliomas of the head and neck.

Head and neck paragangliomas (HNPGLs) are rare neuroendocrine tumors typically arising from nonsecretory head and neck parasympathetic ganglia. Historically thought of as aggressive tumors that warranted equally aggressive surgical intervention, evidence has emerged demonstrating that the vast majority of HNPGLs are slow growing and indolent. It is also now recognized that a large proportion of HNPGLs are hereditary with succinate dehydrogenase gene mutations typically implicated. These recent advances have led to significant changes in the way in which clinicians investigate and treat HNPGLs with most now opting for more conservative treatment strategies. However, a proportion of patients present with more aggressive disease and still require nonconservative treatment strategies. Recent studies have sought to determine in which groups of patients the morbidity associated with treatment is justified. We summarize the recent advances in the understanding and management of these tumors and we provide our recommendations regarding the management of HNPGLs.