Crystalloid volume versus catecholamines for management of hemorrhagic shock during esophagectomy - assessment of microcirculatory tissue oxygenation of the gastric conduit in a porcine model using hyperspectral imaging - an experimental study.

INTRODUCTION: Oncologic esophagectomy is a two-cavity procedure with considerable morbidity and mortality. Complex anatomy and the proximity to major vessels constitute a risk for massive intraoperative hemorrhage. Currently, there is no conclusive consensus on the ideal anesthesiologic countermeasure in case of such immense blood loss. The objective of this work was to identify the most promising anesthesiologic management in case of intraoperative hemorrhage with regards to tissue perfusion of the gastric conduit during esophagectomy using hyperspectral imaging (HSI). MATERIAL AND METHODS: An established live porcine model (n=32) for esophagectomy was used with gastric conduit formation and simulation of a linear stapled side-to-side esophagogastrostomy. After a standardized procedure of controlled blood loss of about 1 L per pig, the four experimental groups (n=8 each) differed in anesthesiologic intervention i.e. (I) permissive hypotension, (II) catecholamine therapy using noradrenaline, (III) crystalloid volume supplementation and (IV) combined crystalloid volume supplementation with noradrenaline therapy. HSI tissue oxygenation (StO2) of the gastric conduit was evaluated and correlated with systemic perfusion parameters. Measurements were conducted before (T0) and after (T1) laparotomy, after hemorrhage (T2) and 60 minutes (T3) and 120 minutes (T4) after anesthesiologic intervention. RESULTS: StO2 values of the gastric conduit showed significantly different results between the four experimental groups with 63.3% (±7.6%) after permissive hypotension (I), 45.9% (±6.4%) after catecholamine therapy (II), 70.5% (±6.1%) after crystalloid volume supplementation (III) and 69.0% (±3.7%) after combined therapy (IV). StO2 values correlated strongly with systemic lactate values (r=-0.67; CI -0.77 to -0.54), which is an established prognostic factor. CONCLUSION: Crystalloid volume supplementation (III) yields the highest StO2 values and lowest systemic lactate values and therefore appears to be the superior primary treatment strategy after hemorrhage during esophagectomy with regards to microcirculatory tissue oxygenation of the gastric conduit.

Evaluation of high dose N- Acetylcysteine on airway inflammation and quality of life outcomes in adults with bronchiectasis: A randomised placebo-controlled pilot study.

BACKGROUND: High dose N acetylcysteine (NAC), a mucolytic, anti-inflammatory and antioxidant agent has been shown to significantly reduce exacerbations, and improve quality of life in placebo controlled, double blind randomised (RCT) studies in patients with COPD, and in an open, randomised study in bronchiectasis. In this pilot, randomised, double-blind, placebo-controlled study, we wished to investigate the feasibility of a larger clinical trial, and the anti-inflammatory and clinical benefits of high dose NAC in bronchiectasis. AIMS: Primary outcome: to assess the efficacy of NAC 2400 mg/day at 6 weeks on sputum neutrophil elastase (NE), a surrogate marker for exacerbations. Secondary aims included assessing the efficacy of NAC on sputum MUC5B, IL-8, lung function, quality of life, and adverse effects. METHODS: Participants were randomised to receive 2400 mg or placebo for 6 weeks. They underwent 3 visits: at baseline, week 3 and week 6 where clinical and sputum measurements were assessed. RESULTS: The study was stopped early due to the COVID pandemic. In total 24/30 patients were recruited, of which 17 completed all aspects of the study. Given this, a per protocol analysis was undertaken: NAC (n = 9) vs placebo (n = 8): mean age 72 vs 62 years; male gender: 44% vs 50%; baseline median FEV11.56 L (mean 71.5 % predicted) vs 2.29L (mean 82.2% predicted). At 6 weeks, sputum NE fell by 47% in the NAC group relative to placebo (mean fold difference (95%CI: 0.53 (0.12,2.42); MUC5B increased by 48% with NAC compared with placebo. Lung function, FVC improved significantly with NAC compared with placebo at 6 weeks (mean fold difference (95%CI): 1.10 (1.00, 1.20), p = 0.045. Bronchiectasis Quality of life measures within the respiratory and social functioning domains demonstrated clinically meaningful improvements, with social functioning reaching statistical significance. Adverse effects were similar in both groups. CONCLUSION: High dose NAC exhibits anti-inflammatory benefits, and improvements in aspects of quality of life and lung function measures. It is safe and well tolerated. Further larger placebo controlled RCT's are now warranted examining its role in reducing exacerbations.

PARAGON II - A single arm multicentre phase II study of neoadjuvant therapy using irinotecan bead in patients with resectable liver metastases from colorectal cancer.

PURPOSE: Perioperative chemotherapy confers a 3-year progression free survival advantage following resection of colorectal liver metastases (CRLM), but is associated with significant toxicity. Chemoembolisation using drug eluting PVA microspheres loaded with irinotecan (DEBIRI) allows sustained delivery of drug directly to tumour, maximising response whilst minimising systemic exposure. This phase II single arm study examined the safety and feasibility of DEBIRI before resection of CRLM. METHODS: Patients with resectable CRLM received lobar DEBIRI 1 month prior to surgery, with a radiological endpoint of near stasis. The trial had a primary end-point of tumour resectability (R0 resection). Secondary end-points included safety, pathologic tumour response and overall survival. RESULTS: 40 patients received DEBIRI, with a median dose of 103 mg irinotecan (range 64-175 mg). Morbidity was low (2.5%, CTCAE grade 2) with no evidence of systemic chemotoxicity. All patients proceeded to surgery, with 38 undergoing resection (95%, R0 resection rate 74%). 30-day post-operative mortality was 5% (n = 2), with neither death TACE related. 66 lesions were resected, with histologic major or complete pathologic response seen in 77.3% of targeted lesions. At median follow up of 40.6 months, 12 patients (34.3%) had died of recurrent disease with a median overall survival of 50.9 months. Nominal 1, 3 and 5-year OS was 93, 78 & 49% respectively. CONCLUSIONS: Resection after neoadjuvant DEBIRI for CRLM is feasible and safe. Single treatment with DEBIRI resulted in tumour pathologic response and median overall survival comparable to that seen after systemic neoadjuvant chemotherapy. Registered at clinicaltrials.gov (NCT00844233).

Propensity score-matched outcomes analysis of the liver-first approach for synchronous colorectal liver metastases.

BACKGROUND: Liver resection before primary cancer resection is a novel strategy advocated for selected patients with synchronous colorectal liver metastases (sCRLM). This study measured outcomes in patients with sCRLM following a liver-first or classical approach, and used a validated propensity score. METHODS: Clinical, pathological and follow-up data were collected prospectively from consecutive patients undergoing hepatic resection for sCRLM at a single centre (2004-2014). Cumulative disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) were calculated by means of Kaplan-Meier analysis. Survival differences were analysed in the whole cohort and in subgroups matched according to Basingstoke Predictive Index (BPI). RESULTS: Of 582 patients, 98 had a liver-first and 467 a classical approach to treatment; 17 patients undergoing simultaneous bowel and liver resection were excluded. The median (i.q.r.) BPI was significantly higher in the liver-first compared with the classical group: 8·5 (5-10) versus 8 (4-9) (P = 0·030). Median follow-up was 34 months. The 5-year DFS rate was lower in the liver-first group than in the classical group (23 versus 45·6 per cent; P = 0·001), but there was no difference in 5-year CSS (51 versus 53·8 per cent; P = 0·379) or OS (44 versus 49·6 per cent; P = 0·305). After matching for preoperative BPI, there was no difference in 5-year DFS (37 versus 41·2 per cent for liver-first versus classical approach; P = 0·083), CSS (51 versus 53·2 per cent; P = 0·616) or OS (47 versus 49·1 per cent; P = 0·846) rates. CONCLUSION: Patients with sCRLM selected for a liver-first approach had more oncologically advanced disease and a poorer prognosis. They had inferior cumulative DFS than those undergoing a classical approach, a difference negated by matching preoperative BPI.

Localized melanoma in older patients, the impact of increasing age and comorbid medical conditions.

BACKGROUND: Elderly patients experience a different spectrum of disease and poorer outcomes than younger patients. This study investigated the impact of age and medical comorbidities on the management and outcome of patients ≥65 years. METHODS: A retrospective review of all patients ≥65 years (481 patients with 525 primary melanomas) presenting with AJCC clinical stage I-II melanoma to an Australian cancer centre between 2000 and 2008. RESULT: The median age was 74 years (65-94) with a male predominance (313 males, 65.0%) and median tumour thickness of 1.90 mm (IQR = 0.40-2.90, T1 = 33%, T2 = 20%, T3 = 24%, T4 = 23%). Inadequate surgical margins of excision (<10 mm) were common in older patients independent of site, thickness and ulceration (OR = 1.04, 95%CI = 1.00-1.07, p = 0.038). Inadequate excision margins were strongly associated with time to local recurrence, independent of age, thickness, ulceration and mitotic rate (HR = 3.00, 95%CI = 1.49-6.03, p = 0.0021), but not time to progression (p = 0.10) or disease specific survival (DSS, p = 0.27). Overall survival (OS) was strongly related to increasing age (HR = 1.04, 95%CI = 1.01-1.07, p = 0.015) and comorbid medical conditions (HR = 1.26, 95%CI = 1.12-1.42, p < 0.001), as assessed by the Charlson comorbidity index (CCI). DSS was significantly related to CCI (HR = 1.20, 95%CI = 1.01-1.42, p = 0.041) and not age (p = 0.46), when adjusting for thickness, ulceration and mitotic rate on multivariate analysis. CONCLUSION: Older patients present with poor prognosis melanomas yet are less likely to receive adequate surgical excision margins resulting in higher rates of local recurrence. In melanoma patients ≥65 years, the increasing number of medical comorbidities explains much of the age related variations in OS and DSS and should be considered when planning treatment.

Patient-reported outcomes in long-term survivors of metastatic colorectal cancer needing liver resection.

BACKGROUND: Five-year survival after hepatic resection for colorectal cancer (CRC) liver metastases is good, but data on patient-reported outcomes are lacking. This study describes the long-term impact of liver surgery for CRC metastases on patient-reported outcomes. METHODS: The study used the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 and the disease-specific module, EORTC QLQ-LMC21. For functional scales, mean scores out of 100 with 95 per cent c.i. were calculated; differences of 10 points or more were considered clinically significant. Responses to symptom scales and items were categorized as 'minimal' or 'severe'. Proportions and 95 per cent c.i. for symptoms were calculated. RESULTS: A total of 241 patients were recruited; nine (3·7 per cent) had unresectable disease and were excluded. Some 68 (42 men) of 80 long-term survivors participated; their mean age was 69·5 years and median follow-up was 8·0 (range 6·9-9·2) years. Values for baseline and 1-year patient-reported outcome data were similar. Scores for functional scales were excellent (emotional function: 92, 95 per cent c.i. 87 to 96; social function: 94, 89 to 99; role function: 94, 90 to 98), reflecting clinically significant improvements from baseline values of 17 (10 to 24), 12 (3 to 21) and 12 (3 to 20) respectively. Severe symptoms were uncommon (affected less than 5 per cent of patients) for most patient-reported outcome scales or items, but persistent severe symptoms were noted for sexual function (2 per cent increase from baseline), peripheral neuropathy (2 per cent increase), constipation (10 per cent increase) and diarrhoea (5 per cent increase). CONCLUSION: Long-term survivors of metastatic colorectal cancer who have undergone liver surgery have excellent global quality of life, high levels of function and few symptoms.

Flow-induced ATP release in patient-specific arterial geometries--a comparative study of computational models.

The importance of the endothelium in the local regulation of blood flow is reflected by its influence on vascular tone by means of vasodilatory responses to many physiological stimuli. Regulatory pathways are affected by mass transport and wall shear stress (WSS), via mechanotransduction mechanisms. In the present work, we review the most relevant computational models that have been proposed to date, and introduce a general framework for modelling the responses of the endothelium to alteration in the flow, with a view to understanding the biomechanical processes involved in the pathways to endothelial dysfunction. Simulations are performed on two different patient-specific stenosed carotid artery geometries to investigate the influence of WSS and mass transport phenomena upon the agonist coupling response at the endothelium. In particular, results presented for two different models of WSS-dependent adenosine-5'-triphosphate (ATP) release reveal that existing paradigms may not account for the conditions encountered in vivo and may therefore not be adequate to model the kinetics of ATP at the endothelium.

Close collaboration between local and specialist multidisciplinary teams allows 'fast-tracking' of patients with colorectal liver metastases.

AIM: The ongoing evolution of treatment strategies for colorectal liver metastases necessarily requires all patients to be reviewed at some point by the specialist hepatobiliary unit. This process can be streamlined through close collaboration with the local colorectal multidisciplinary team (MDT). The study was performed to see if a local colorectal MDT was able to make a correct decision regarding potential operability of liver metastases, by comparing its decision with that of two hepatobiliary surgeons in our referral centre. METHOD: CT scans of 38 patients found to have liver metastases from colorectal cancer were anonymized and sent to two hepatobiliary surgeons in our cancer network. They classified them into three categories: R, resectable; C, chemotherapy to downsize then consider resection; U, unresectable. The results were then compared with the opinion of our colorectal MDT, made before the referral to the hepatobiliary surgeons. RESULTS: The two independent hepatobiliary surgeons agreed with each other on 35/38 (92%) of CT scans. Our colorectal MDT agreed with the hepatobiliary surgeons in 36/38 (95%) of cases. Only 9 (32%) of the 28 patients deemed suitable on the CT scan by the hepatobiliary surgeons actually had a liver resection. CONCLUSION: The results show that a local colorectal MDT is able to make an accurate assessment of the operability of liver metastases. Patients deemed to be inoperable by the colorectal MDT could be 'fast-tracked' to the hepatobiliary MDT with review of imaging only, saving time and resources by avoiding referral of patients who are not suitable for liver resection.

Global consensus statement on menopausal hormone therapy.

The following Consensus Statement is endorsed by The American Society for Reproductive Medicine, The Asia Pacific Menopause Federation, The Endocrine Society, The European Menopause and Andropause Society, The International Menopause Society, The International Osteoporosis Foundation and The North American Menopause Society.

Osteoarthritis in temporomandibular joint of Col2a1 mutant mice.

OBJECTIVE: Col2a1 gene mutations cause premature degeneration of knee articular cartilage in disproportionate micromelia (Dmm) and spondyloepiphesial dysplasia congenita (sedc) mice. The present study analyses the temporomandibular joint (TMJ) in Col2a1 mutant mice in order to provide an animal model of TMJ osteoarthritis (OA) that may offer better understanding of the progression of this disease in humans. DESIGN: Dmm/+ mice and controls were compared at two, six, nine and 12 months. Craniums were fixed, processed to paraffin sections, stained with Safranin-O/Fast Green, and analysed with light microscopy. OA was quantified using a Mankin scoring procedure. Unfolded protein response (UPR) assay was performed and immunohistochemistry (IHC) was used to assay for known OA biomarkers. RESULTS: Dmm/+ TMJs showed fissuring of condylar cartilage as early as 6 months of age. Chondrocytes were clustered, leaving acellular regions in the matrix. Significant staining of HtrA1, Ddr2 and Mmp-13 was observed in Dmm/+ mice (p<0.01). We detected upregulation of the UPR in knee but not TMJ. CONCLUSIONS: Dmm/+ mice are subject to early-onset OA in the TMJ. We observed upregulation of biomarkers and condylar cartilage degradation concomitant with OA. An upregulated UPR may exacerbate the onset of OA. The Dmm/+ mouse TMJ is a viable model for the study of the progression of OA in humans.

Fatty liver disease as a predictor of local recurrence following resection of colorectal liver metastases.

BACKGROUND: Obesity and tissue adiposity constitute a risk factor for several cancers. Whether tissue adiposity increases the risk of cancer recurrence after curative resection is not clear. The present study analysed the influence of hepatic steatosis on recurrence following resection of colorectal liver metastases. METHODS: A prospective cohort of patients who had primary resection of colorectal liver metastases in two major hepatobiliary units between 1987 and 2010 was studied. Hepatic steatosis was assessed in non-cancerous resected liver tissue. Patients were divided into two groups based on the presence of hepatic steatosis. The association between hepatic steatosis and local recurrence was analysed, adjusting for relevant patient, pathological and surgical factors using Cox regression and propensity score case-match analysis. RESULTS: A total of 2715 patients were included. The cumulative local (liver) disease-free survival rate was significantly better in the group without steatosis (hazard ratio (HR) 1·32, 95 per cent confidence interval 1·16 to 1·51; P < 0·001). On multivariable analysis, hepatic steatosis was an independent risk factor for local liver recurrence (HR 1·28, 1·11 to 1·47; P = 0·005). After one-to-one matching of cases (steatotic, 902) with controls (non-steatotic, 902), local (liver) disease-free survival remained significantly better in the group without steatosis (HR 1·27, 1·09 to 1·48; P = 0·002). Patients with steatosis had a greater risk of developing postoperative liver failure (P = 0·001). CONCLUSION: Hepatic steatosis was an independent predictor of local hepatic recurrence following resection with curative intent of colorectal liver metastases.

Effect of specialist decision-making on treatment strategies for colorectal liver metastases.

BACKGROUND: One hundred and ten patients were treated with palliative chemotherapy, of whom 53 had liver-only disease and had not been reviewed by a specialist liver surgeon. One scan was excluded as all reviewers felt it to be of insufficient quality to assess. Improved surgical technique and better chemotherapeutic manipulation of metastatic disease has increased the number of patients eligible for potentially curative resection of colorectal liver metastases. The rapid evolution in this field suggests that non-specialist decision-making may lead to inappropriate management. This study aimed to assess the management of colorectal liver metastases by non-liver surgeons. METHODS: All patients who underwent chemotherapy with palliative intent for metastatic colorectal cancer at a regional oncology centre between 1 January and 31 December 2009 were identified from a prospectively maintained local database. Six resectional liver surgeons blinded to patient management and outcome reviewed pretreatment imaging and assigned each scan a score based on their own management choice. A consensus decision was reached on the appropriateness of palliative chemotherapy. RESULTS: One hundred and ten patients were treated with palliative chemotherapy, of whom 53 had liver-only disease and had not been reviewed by a specialist liver surgeon. One scan was excluded as all reviewers felt it to be of insufficient quality to assess [corrected]. Tumours in 33 patients (63 per cent) were considered potentially resectable, with a high level of interobserver agreement (κ = 0 · 577). When individual approach to management was considered, interobserver agreement was less marked (κ = 0 · 378). CONCLUSION: Management of patients with colorectal liver metastases without the involvement of a specialist liver multidisciplinary team can lead to patients being denied potentially curative treatments. Management of these patients must involve a specialist liver surgeon to ensure appropriate management.

Resection of colorectal liver metastases in the elderly: does age matter?

AIM: Despite the incidence of colorectal cancer increasing with age the proportion of patients undergoing surgery for colorectal liver metastases decreases dramatically in the elderly. Is this referral or selection bias justified? METHOD: A prospective database of resection for colorectal liver metastases at a single centre was retrospectively analysed to compare the outcome in patients aged ≥75 years (group E) with those aged <75 years (group Y). Data were analysed using the Kaplan-Meier method with Cox regression modelling. RESULTS: Of 1443 resections, 151 (10.5%) in group E were compared with 1292 (89.5%) in group Y. The two groups were matched apart from higher American Society of Anesthesiology scores (P=0.001) and less use of chemotherapy (P=0.01) in the elderly. Perioperative morbidity and 90-day mortality were higher in the elderly compared with the younger group (32.5%vs 21.2%, P=0.02, and 7.3%vs 1.3%, P=0.001). In the last 5 years, mortality in the elderly improved and was no longer significantly different from that of the younger patients [n=2/76 (2.6%) vs n=9/559 (1.6%); P=0.063]. The 5-year survival was similar in groups E and Y for cancer-specific (41.4%vs 41.6%, P=0.917), overall (37.0%vs 38.2%) and median (44.1 months vs 43.6 months, P=0.697) survival respectively. CONCLUSION: In the elderly liver resection for metastatic disease can be performed with acceptable mortality and morbidity with as good a prospect of survival as for younger patients.

The incidence and outcome of brain metastases after liver resection for colorectal cancer metastases.

AIM: Brain metastases from colorectal cancer are rare, with an incidence of 0.6-4%. The risk and outcome of brain metastases after hepatic and pulmonary metastasectomy have not been previously described. This study aimed to determine the incidence, predictive factors, treatment and survival of patients developing colorectal brain metastases, who had previously undergone resection of hepatic metastases. METHOD: A retrospective review was carried out of a prospectively maintained database of patients undergoing liver resection for colorectal metastases. RESULTS: Fifty-two (4.0%) of 1304 patients were diagnosed with brain metastases. The annual incidence rate was 1.03% per person-year. In the majority of cases brain metastases were found as part of multifocal disease. Median survival was 3.2 months (95% CI: 2.3-4.1), but was best for six patients treated with potentially curative resection [median survival = 13.2 (range, 4.9-32.1) months]. Multivariate analysis showed that a lymph node-positive primary tumour [hazard ratio (HR) = 2.7, 95% CI: 1.8-6.19; P = 0.019], large liver metastases (> 6 cm) [HR = 2.23, 95% CI: 1.19-2.33; P = 0.012] and recurrent intrahepatic and extrahepatic disease [HR = 2.11, 95% CI: 1.2-4.62; P = 0.013] were independent predictors for the development of brain metastases. CONCLUSION: The annual risk of developing brain metastases following liver resection for colorectal metastases is low, but highest for patients presenting with a Dukes' C primary tumour, large liver metastases or who subsequently develop disseminated disease. The overall survival from colorectal brain metastases is poor, but resection with curative intent offers patients their best chance of medium-term survival.

Long-term survival following delayed presentation and resection of colorectal liver metastases.

BACKGROUND: Long-term survival from metastatic colorectal cancer is partly dependent on favourable tumour biology. Large case series have shown improved survival following hepatectomy for colorectal liver metastases (CRLM) in patients diagnosed with metastases more than 12 months after index colorectal surgery (metachronous), compared with those with synchronous metastases. This study investigated whether delayed hepatic resection for CRLM affects long-term survival. METHODS: Consecutive patients undergoing hepatic resection for CRLM in a single centre (1987-2007) were grouped according to the timing of hepatectomy relative to index bowel surgery: less than 12 months (synchronous; group 1), 12-36 months (group 2) and more than 36 months (group 3). Cancer-specific survival was calculated using Kaplan-Meier analysis. RESULTS: There were 577 patients (48·0 per cent) in group 1, 467 (38·9 per cent) in group 2 and 158 (13·1 per cent) in group 3. The overall 5-year cancer-specific survival rate after liver surgery was 42·3 per cent, with no difference between groups. However, when measured from the time of primary colorectal surgery, group 3 showed a survival advantage at both 5 and 10 years (94·1 and 47·6 per cent respectively) compared with groups 1 (46·3 and 24·9 per cent) and 2 (57·1 and 35·0 per cent) (P = 0·003). Survival graphs showed a steeper negative gradient from 5 to 10 years for group 3 compared with groups 1 and 2 (-0·80 versus - 0·34 and - 0·37), indicating an accelerated mortality rate. CONCLUSION: Patients undergoing delayed liver resection for CRLM have a survival advantage that is lost during long-term follow-up.

Optimized sample preparation for high-resolution AFM characterization of fixed human cells.

Atomic force microscopy enables the simultaneous acquisition of high-resolution topographical and biophysical data allowing integrated analysis of cell surfaces during development and pathogenesis, and, critically, can link molecular and biophysical events. Here we used atomic force microscopy to analyse endometrial epithelial cells and neuronally differentiated P19 cells. Optimized reproducible sample preparation techniques enabled micro- and nanoscale multi-parameter analysis. Comparative analysis using atomic force microscopy and scanning electron microscopy demonstrated the utility of atomic force microscopy for examining tissue morphology, and its ability to generate data allowing differentiation of cells from different origins to be monitored. At low resolution atomic force microscopy produced topographic data complementary to scanning electron microscopy images, whilst at high resolution atomic force microscopy captured novel cell surface structural detail for both epithelial and neuronal cell types. Analysis of surface roughness provided biophysical data which enabled qualitative and quantitative differences between samples to be measured. This study provides an important optimization of sample preparation enabling more generalized atomic force microscopy utilization for cellular analysis required for advanced cell surface morphological studies.

Testosterone treatment of HSDD in naturally menopausal women: the ADORE study.

OBJECTIVE: To evaluate the efficacy and safety of a transdermal testosterone patch (TTP, 300 microg/day) in naturally menopausal women with hypoactive sexual desire disorder (HSDD). METHODS: A total of 272 naturally menopausal women, predominantly not using hormone therapy, were randomized in this 6-month, placebo-controlled, double-blind, multicenter study to receive twice weekly either TTP or an identical placebo. Efficacy endpoints measured were the 4-week frequency of satisfying sexual episodes (SSE) using the Sexual Activity Log, the sexual desire domain of the Profile of Female Sexual Function and distress by the Personal Distress Scale. Safety was assessed by adverse events, laboratory parameters and hormone levels. RESULTS: The TTP group demonstrated significant improvements in SSE (p = 0.0089) as well as in sexual desire (p = 0.0007) and reduced personal distress (p = 0.0024) versus placebo at 6 months (intent-to-treat analysis, n = 247). The results were significant for all three endpoints in the subgroup (n = 199) not using hormone therapy. Similar numbers of women treated with placebo and TTP discontinued (n = 39, 27.5% vs. n = 26, 20%), reported adverse events (including application site reactions) (n = 101, 71.1% vs. n = 81, 62.3%) and withdrew due to adverse events (n = 20, 14.1% vs. n = 9, 6.9%). No clinically relevant changes were noted in laboratory parameters. Serum free and total testosterone levels increased from baseline in the TTP group (geometric means 5.65 pg/ml and 67.8 ng/dl, respectively, at week 24) within the physiological range; no changes were seen in estradiol and sex hormone binding globulin levels. CONCLUSIONS: TTP was effective in treating HSDD and improving sexual function in this study of naturally menopausal women with and without concurrent hormone therapy.

Posthumous diagnosis of long QT syndrome from neonatal screening cards.

BACKGROUND: Molecular autopsy in sudden unexplained death in the young (SUDY) victims cannot usually be performed if tissue suitable for DNA extraction is not retained at autopsy. OBJECTIVE: The purpose of this study was to assess the feasibility and clinical value of posthumous genetic testing for long QT syndrome (LQTS) using residual material from the neonatal screening (Guthrie) card in SUDY victims. METHODS: Twenty-one cases were investigated up to 13 years after death. Deaths occurred at <1 year in one, 1-18 years in 18, and 19-35 years in two patients. Guthrie cards were 3-39 years old. DNA was extracted, and amplicons corresponding to the coding regions of the LQTS genes 1, 2, 3, 5, and 6 underwent either denaturing high-performance liquid chromatography screening or direct DNA sequencing. RESULTS: Adequate DNA was extracted in every case, although repeated purification and amplification was often required. Rare variants were detected in six of 19 cases undergoing diagnostic screening. Four (21%) are considered to be pathological and have been used for family screening: R243C and H455Y in KCNQ1 in 12-year-old and 13-year-old boys, respectively, and Q81H and S621R in KCNH2 in 21-month and 28-year-old females, respectively. Variants of uncertain significance were R1047L in KCNH2 in a 2-year-old girl and S38G in KCNE1 in a 19-month-old boy. Point mutation tests for previously identified familial LQTS mutations revealed a positive result in both cases: E146K in KCNQ1 and exon 6-4del in KCNH2. CONCLUSION: Residual material from Guthrie cards collected for newborn metabolic screening can be used as a reliable source of DNA for the posthumous diagnosis of LQTS decades after SUDY, although purification and amplification of DNA is time intensive.