Improved risk stratification of nasopharyngeal cancer by targeted sequencing of Epstein-Barr virus DNA in post-treatment plasma.

BACKGROUND: Quantitative measurement of plasma Epstein-Barr virus (EBV) DNA by real-time PCR at the end of primary treatment is a robust prognostic marker for nasopharyngeal carcinoma (NPC) patients. However, up to 40% of patients who would later develop disease recurrence had undetectable post-treatment plasma EBV DNA. Targeted sequencing for the entire EBV genome potentially allows a more comprehensive and unbiased detection of plasma EBV DNA and enables the use of other parameters such as fragment size as biomarkers. Hence, we explored if plasma EBV DNA sequencing might allow more accurate prognostication of NPC patients. PATIENTS AND METHODS: Plasma samples collected from 769 patients with stage IIB-IVB NPC at 6-8 weeks after radiotherapy were analysed using targeted sequencing for EBV DNA. RESULTS: The sensitivities of the PCR-based analysis, at a cut-off of any detectable levels of plasma EBV DNA, for prediction of local and distant recurrences were 42.3% and 85.3%, respectively. The sequencing-based analysis (involving quantitation and size profiling) achieved better performance for both local and distant recurrences than PCR. Using a cut-off of the proportion of plasma EBV DNA deduced by sequencing at 0.01%, the sensitivities of the sequencing-based analysis for local and distant recurrences were 88.5% and 97.1%, with the resultant negative predictive values of 99.1% and 99.4%, respectively. Among patients with undetectable EBV DNA on quantitative PCR, sequencing could further define a subgroup that enjoyed superior survival outcomes based on the proportion of plasma EBV DNA, with a 5-year progression-free survival (PFS) approaching 90%. On multivariate analysis, sequencing-based quantitative level of plasma EBV DNA was the independent prognostic factor with the highest hazard ratio for prediction of overall survival and PFS. CONCLUSION: NPC prognostication using post-treatment plasma EBV DNA could be enhanced through sequencing.

Comparison of antral follicle count and serum anti Müllerian hormone level for determination of gonadotropin dosing in in-vitro fertilization: randomized trial.

OBJECTIVE: To compare the proportion of women achieving a desired ovarian response following ovarian stimulation when gonadotropin dosing was determined based on antral follicle count (AFC) vs serum anti-Müllerian hormone (AMH) level, in women undergoing in-vitro fertilization (IVF) using the gonadotropin-releasing hormone (GnRH) antagonist protocol. METHODS: This was a randomized double-blind trial carried out in a university-affiliated assisted reproduction unit. A total of 200 women undergoing their first IVF cycle using the GnRH-antagonist protocol between April 2016 and February 2018 were randomized to determination of gonadotropin dosing based on either AFC or serum AMH level measured in the pretreatment cycle 1 month before the IVF cycle. Patients underwent IVF as per our center's standard protocol. The proportion of subjects achieving a desired ovarian response, defined as retrieval of six to 14 oocytes, was compared between the two study arms. Subgroup analysis of patients with baseline AFC > 5 and those with baseline AFC ≤ 5 was performed. Concordance in AFC and AMH categorization between the pretreatment cycle and the ovarian-stimulation cycle was assessed using Cohen's kappa (κ). RESULTS: There was no significant difference in the proportion of patients achieving a desired ovarian response between the AFC (54%) and AMH (49%) groups (P = 0.479). The median number of oocytes retrieved was nine vs seven (P = 0.070), and the median follicular output rate was 0.54 vs 0.55 (P = 0.764) in the AFC and AMH groups, respectively. Similar findings were observed on subgroup analysis of subjects with AFC ≤ 5 and AFC > 5 at the start of ovarian stimulation (P > 0.05 for all comparisons). There was moderate concordance between AFC and AMH measured in the pretreatment cycle and the stimulation cycle (κ = 0.478 and 0.587, respectively). CONCLUSION: The proportion of women achieving a desired ovarian response following ovarian stimulation using the GnRH-antagonist protocol is similar when the gonadotropin-dosing algorithm used is based on AFC or serum AMH level. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Comparación del recuento de folículos sinusales y el nivel de la hormona antimulleriana en el suero para la determinación de la dosis de gonadotrofina en la fecundación in vitro: ensayo aleatorizado OBJETIVO: Comparar la proporción de mujeres que logran una respuesta ovárica deseada tras la estimulación del ovario cuando se determinó la dosis de gonadotrofina en función del recuento de folículos sinusales (AFC, por sus siglas en inglés) frente al nivel de la hormona antimulleriana (HAM) en el suero, en mujeres que se sometieron a una fecundación in vitro (FIV) mediante el protocolo de antagonistas de la hormona liberadora de gonadotropina (GnRH, por sus siglas en inglés). MÉTODOS: Se trata de un ensayo aleatorizado doble ciego realizado en una unidad de reproducción asistida afiliada a una universidad. Un total de 200 mujeres que se sometieron a su primer ciclo de FIV y utilizaron el protocolo de antagonistas de la GnRH entre abril de 2016 y febrero de 2018 fueron asignadas al azar a la determinación de la dosis de gonadotrofina basada en el nivel de AFC o de HAM en suero, medidos en el ciclo de pretratamiento un mes antes del ciclo de FIV. Las pacientes se sometieron a una FIV según el protocolo estándar de nuestro centro. La proporción de mujeres que lograron una respuesta ovárica deseada, definida como la recuperación de seis a 14 ovocitos, se comparó entre las dos ramas del estudio. Se realizó un análisis de subgrupos de las pacientes con AFC de base >5 y de aquellas con AFC de base ≤5. La concordancia en la categorización del AFC y la HAM entre el ciclo de pretratamiento y el ciclo de estimulación ovárica se evaluó utilizando la medida estadística kappa de Cohen (κ). RESULTADOS: No hubo diferencias significativas en la proporción de pacientes que lograron una respuesta ovárica deseada entre los grupos de AFC (54%) y HAM (49%) (P=0,479). La mediana del número de ovocitos recuperados fue de nueve frente a siete (P=0,070), y la mediana de la tasa de producción folicular fue de 0,54 frente a 0,55 (P=0,764) en los grupos AFC y HAM, respectivamente. Se observaron hallazgos similares en el análisis de subgrupos de pacientes con AFC ≤5 y AFC >5 al comienzo de la estimulación ovárica (P>0,05 para todas las comparaciones). Se observó una concordancia moderada entre el AFC y la HAM medidos en el ciclo de pretratamiento y el ciclo de estimulación (κ=0,478 y 0,587, respectivamente). CONCLUSIÓN: La proporción de mujeres que logran una respuesta ovárica deseada después de la estimulación ovárica utilizando el protocolo de antagonistas de la GnRH es similar cuando el algoritmo de dosificación de gonadotrofina utilizado se basa en el nivel del AFC o de la HAM en suero.

Pathway to mental health recovery: a qualitative and quantitative study on the needs of Chinese psychiatric inpatients.

BACKGROUND: Exploration of the information and participation needs of psychiatric inpatients is an important step for the implementation of recovery-oriented mental health service. The objective of this study was to explore the information and participation needs of Chinese psychiatric inpatients in the largest psychiatric hospital in Hong Kong. METHODS: The study was divided into two parts. In the first part, eight focus groups with patients, patients' relatives and healthcare professionals were held to identify 22 items of information needs and 16 items of participation needs of Chinese psychiatric inpatients. Basing on the items identified in the first part of the study, a questionnaire was developed to survey on the importance of the different information and participation needs in the second part of the study. Participants were asked to rate in rank order their perceived importance of the items in the questionnaire survey. RESULTS: A hundred and eighty three Chinese psychiatric inpatients completed the questionnaire and the majority of them suffered from schizophrenia (68.3 %). For information needs, the top three needs rated by patients as the most important in descending order were: "Information on the classifications of mental illnesses, signs and symptoms and factors contributing to relapse", "Information on the criteria and arrangements for discharge", and "Information on the importance of psychiatric drug taking and its side effects". For participation needs, the top three needs rated by patients as the most important in descending order were: "Enquiring about personal needs and arrangements", "Keeping in touch with the outside world", and "Learning and practising self-management". CONCLUSIONS: This study reveals that Chinese psychiatric inpatients are concerned about information on their mental illness and its treatments as well as the criteria for discharge. On the other hand, patients are concerned about their personal needs, their self-management, as well as their keeping in touch with the outside world during their hospitalisation. Moreover, patients with different socio-demographic and clinical characteristics have different information and participation needs. The results of the present study serve as a reference for designing guidelines, strategies, and programmes to meet the information needs and participation needs of psychiatric inpatients in Hong Kong.

Randomized, controlled, double-blind trial of topical lidocaine gel and intrauterine lidocaine infusion for pain relief during saline contrast sonohysterography.

OBJECTIVES: To evaluate the efficacy of topical lidocaine gel and intrauterine lidocaine infusion administered prior to saline contrast sonohysterography (SCSH) in reducing pain level during the procedure. METHODS: This was a randomized, double-blind, placebo controlled trial. We recruited 120 women scheduled to undergo SCSH and randomized them into one of three groups according to administration of gel and intrauterine infusion immediately prior to the procedure: (1) the 'lidocaine gel' group received 3 mL 2% lidocaine gel applied to the cervix and intrauterine infusion, using an infant feeding tube without balloon, of 5 mL normal saline; (2) the 'lidocaine infusion' group received 3 mL gel lubricant applied to the cervix and intrauterine infusion of 5 mL 2% lidocaine; (3) the placebo group received 3 mL gel lubricant applied to the cervix and intrauterine infusion of 5 mL normal saline. The tube was left in place for the SCSH procedure. The primary outcome measure was the overall pain level (on a scale of 0-100) reported by the women during the SCSH procedure. Women also rated their pain levels at various other time points and an observer assessed visible signs of the women's discomfort during the procedure, producing a distress score. RESULTS: There were no significant differences among the three groups in baseline characteristics, volume of saline solution infused, tenaculum use and duration and difficulty level of the SCSH procedure. The median (range) pain scores during normal saline infusion for the SCSH procedure were 0 (0-65) in the placebo group, 2.5 (0-80) in the lidocaine gel group, and 0 (0-70) in the lidocaine infusion group. The pain scores at other time points, the overall pain score and the distress score were also comparable for the three groups. No significant adverse events were reported. CONCLUSIONS: SCSH performed with an infant feeding tube without balloon is associated with very low pain levels. Topical lidocaine gel application and intrauterine lidocaine infusion do not further reduce pain levels during SCSH.

Screening for dysglycaemia by oral glucose tolerance test should be recommended in all women with polycystic ovary syndrome.

STUDY QUESTION: Should fasting glucose (FG) or an oral glucose tolerance test (OGTT) be used to screen for dysglycaemia in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: A full OGTT should be recommended as the screening method for dysglycaemia in women with PCOS, regardless of BMI or family history of diabetes mellitus (DM). STUDY DESIGN, SIZE, DURATION: A cross-sectional study on 467 Chinese women diagnosed with PCOS by the Rotterdam criteria between January 2010 to December 2013. PARTICIPANTS, SETTING, METHODS: The study was done at a university hospital in Hong Kong. All subjects underwent a 75 g OGTT after overnight fasting. We evaluated the performance of FG alone, when compared with the full OGTT, in identifying subjects with dysglycaemia (prediabetes or DM, according to the 2010 diagnostic criteria of the American Diabetes Association). MAIN RESULTS AND THE ROLE OF CHANCE: Of the 467 subjects, 58 (12.4%) had dysglycaemia, among which 46 (9.8%) had prediabetes and 12 (2.6%) had DM, including 4 with known DM. Of the 46 subjects with prediabetes, 25 (54.3%) had normal FG and of the 8 subjects with screened DM in this study, 1 (12.5%) had normal FG. The sensitivity of FG alone in screening for prediabetes, DM and overall dysglycaemia were 45.7, 87.5 and 48.1%, respectively, i.e. missing 54.3% of prediabetes and 12.5% of DM cases as defined by the OGTT. Among the 54 subjects with screened dysglycaemia, 20 (37.0%) had BMI < 25 kg/m(2) and 35 (64.8%) had no family history of DM. LIMITATIONS, REASONS FOR CAUTION: We only reported on the biochemical diagnosis of DM based on a single time point. In clinical practice, confirmatory results at another time point is required for definitive diagnosis in asymptomatic subjects. WIDER IMPLICATIONS OF THE FINDINGS: There is an ongoing debate as to whether FG or an OGTT should be used as a screening method for dysglycaemia in women with PCOS. Some guidelines also recommend glucose screening only in those who are overweight and/or having family history of diabetes (DM). There have been scarce data on this issue in the Chinese population, which the current study aims at addressing. STUDY FUNDING/COMPETING INTERESTS: The study was supported by a research grant from the Hong Kong Obstetrical and Gynaecological Trust Fund, as well as internal research funding of the Department of Obstetrics and Gynaecology, The University of Hong Kong. All authors have no competing interests.

Effect of letrozole on uterine artery Doppler flow indices prior to first-trimester termination of pregnancy: a randomized controlled trial.

OBJECTIVE: We previously demonstrated that a sequential regimen of letrozole and misoprostol resulted in a marked reduction in the serum estradiol concentration and in a higher efficacy of first-trimester termination of pregnancy than misoprostol alone. The aim of this study was to evaluate the effect of letrozole on uterine artery Doppler flow indices during early pregnancy. METHODS: This was a randomized controlled trial. Thirty women requesting termination of pregnancy up to 63 days' gestation were randomized into two groups: a letrozole group receiving 10 mg of letrozole, daily, for 3 days, and a control group receiving a placebo for 3 days. Serum estradiol, progesterone and human chorionic gonadotropin (hCG) concentrations were measured before drug administration and then daily for 6 days. Ultrasound scanning for fetal viability and measurement of the pulsatility (PI) and resistance (RI) indices of the uterine arteries was performed before drug administration, and then on day 3 and day 7 after starting letrozole or placebo. All pregnancies were terminated by surgical evacuation on day 7 or day 8. RESULTS: Uterine artery PI and RI decreased significantly in the letrozole group, but not in the control group. Serum estradiol concentrations were significantly lower in the letrozole group than in the control group from day 2 onwards. Serum progesterone and hCG concentrations were comparable for the two groups throughout the 7 days. There were significantly more women in the letrozole group with vaginal bleeding. CONCLUSION: We have demonstrated that the use of letrozole in the first trimester of pregnancy suppresses serum estradiol levels but results in an increase in blood flow to the uterus. Further studies should be carried out to elucidate the mechanism of letrozole pretreatment in medical abortion.

Relationship between nutritional status, physical activity and quality of life among gastrointestinal cancer survivors.

INTRODUCTION: The objective of this study was to determine the relationship between nutritional status, physical activity and quality of life among gastrointestinal cancer survivors. METHODS: A cross-sectional study was conducted among gastrointestinal cancer survivors attending the oncology outpatient clinic in Hospital Selayang, Malaysia. RESULTS: A total of 70 gastrointestinal cancer survivors with a mean age of 52.54 +/- 14.59 years (95% CI: 47.48 - 57.60) were included in this study. Results showed that 40% of the patients were classified as having low physical activity. The mean Patient Generated Subjective Global Assessment (PGSGA) score was 10.27 +/- 7.36 (95% CI: 8.23-12.31) and nearly half the patients (48.6%) were identified as severely malnourished (Stage C). Mean Gastrointestinal Quality of Life Index (GQLFI) score was 103.57 +/- 23.85 (95% CI: 92.94-114.20), and about 24.3% of the patients were classified as having a low quality of life. Pearson's correlation test showed a highly significant negative relationship between nutritional status and quality of life (r = -0.661, p<0.001) indicating the better the nutritional status (low total mean score of PGSGA), the better the quality of life of the survivors (high total mean score of GQLFI). There was a significant negative relationship between physical activity level and nutritional status score (r = -0.309, p<0.01), indicating the higher the physical activity level of the patients (high MET-min/week), the better their nutritional status (low total mean score of PGSGA). CONCLUSION: This study shows a significant relationship between nutritional status, physical activity and quality of life among gastrointestinal cancer survivors. Those low in nutritional status have a low quality of life while survivors with higher nutritional status have a better quality of life.

Restructuring patient financial services for maximum effectiveness.

Following its formation as a regional IDS, John Muir/Mt. Diablo Health System in Walnut Creek, California, adopted an innovative approach to reorganizing its patient financial services (PFS) functions. Instead of consolidating all PFS functions into a single centralized business office, the IDS divided PFS leadership responsibilities into two areas: daily operations and technical functions. The director of daily operations oversees PFS clerical staff who are responsible for admitting functions, billing, follow-up, and related activities. The director of technical functions is responsible for implementing, uploading, and maintaining the various information systems; contract tracking and compliance; and regulatory compliance.

UVA-induced oxidative damage in retinal pigment epithelial cells after H2O2 or sparfloxacin exposure.

Retinal impairment is one of the leading causes of visual loss in an aging human population. To explore a possible cause for retinal damage in the human population, we have monitored DNA oxidation in human retinal pigment epithelial (RPE) cells after exposure to hydrogen peroxide (H2O2) or the quinolone antibacterial sparfloxacin. When H2O2- or sparfloxacin-exposed cells were further exposed to ultraviolet A (UVA) irradiation, oxidative damage to the DNA of these cells was greatly increased over baseline values. This RPE+pharmaceutical-UVA cell system was developed to mimic in vivo retinal degeneration, seen in mouse studies using quinolone and UVA exposure. DNA damage produced by sparfloxacin and UVA in RPE cells could be remedied by the use of antioxidants, indicating a possible in vivo method for prevention or minimization of retinal damage in humans

Propofol sedation produces dose-dependent suppression of lidocaine-induced seizures in rats.

UNLABELLED: The association of propofol with excitatory motor activity, such as myoclonic jerking and opisthotonus, in humans and in animals suggests that it may aggravate clinical seizure activity in some circumstances, although evidence suggests that under other circumstances, propofol inhibits seizure activity. In the current study, we assessed the effect of sedating doses of propofol on lidocaine-induced seizure activity in spontaneously breathing rats receiving no other anesthetics. Adult Sprague-Dawley male rats, 300-400 g, were divided into a control group and three experimental groups representing three graded levels of propofol sedation. The control rats then received a lidocaine infusion at the rate of 150 mg x kg(-1) x h(-1), resulting in a slow, progressive increase in systemic lidocaine concentrations. At the onset of electroencephalographic (EEG) seizure activity, arterial lidocaine concentrations were obtained. The treated rats received propofol according to three different dose schedules: Dose 1 = 10 mg x kg(-1) x h(-1) after a 2.5-mg/kg bolus; Dose 2 = 20 mg x kg(-1) x h(-1) after a 5-mg/kg bolus; Dose 3 = 40 mg x kg(-1) x h(-1) after a 10-mg/kg bolus. After 30 min, a steady level of sedation, dependent on the dose of propofol, was achieved. The lidocaine infusion was then started, and systemic lidocaine levels were obtained at the onset of EEG seizure activity. The lidocaine was continued until the onset of death by cardiac arrest. Plasma lidocaine was measured by gas chromatography. Analysis of variance and Dunnett's t-test were used for comparisons with the control values. Continuous propofol sedation increased the seizure dose of lidocaine from 37.7 +/- 3.5 mg/kg (mean +/- SEM) to 52.5 +/- 2.6 mg/kg (Dose 1, P < 0.05) and 67.9 +/- 8.6 mg/kg (Dose 2, P < 0.05), and completely abolished lidocaine seizures at Dose 3. The lethal dose of lidocaine, 89.4 +/- 10.5 mg/kg control versus 108.7 +/- 10.3 mg/kg (Dose 1), 98.3 +/- 10.1 mg/kg (Dose 2), and 93.5 +/- 10.4 mg/kg (Dose 3) did not differ among groups. The lidocaine levels at seizure threshold were increased in the propofol-treated rats: 16.9 +/- 0.5 microg/mL control versus 19.2 +/- 0.7 microg/mL (Dose 1, P = not significant) and 23.7 +/- 1.8 microg/mL (Dose 2, P < 0.05). Continuous propofol sedation in spontaneously breathing rats receiving no other anesthetics exerts a protective effect against lidocaine-induced seizures in a monotonic, dose-dependent fashion. The cardiac arrest dose of lidocaine is unaffected by propofol under these conditions. IMPLICATIONS: The i.v. anesthetic drug propofol, given to rats to produce sedation, was found to suppress seizure activity caused by overdosage of the local anesthetic lidocaine.

Spinal and cortical evoked potential studies in the ketamine-anesthetized rabbit: fentanyl exerts component-specific, naloxone-reversible changes dependent on stimulus intensity.

This study examined the changes in spinal and cortical evoked potentials (EPs) produced by fentanyl in the rabbit. The reversibility of these effects by naloxone and the effects of varying stimulus intensity also were examined. Eleven ketamine-anesthetized rabbits underwent analysis of spinal and cortical EPs produced by posterior tibial nerve electrical stimulation. Progressive fentanyl doses up to 100 micrograms/kg total were given intravenously. Stimulus intensities of two to eight times the motor threshold (MT) were used. The lowest stimulus (2 x MT) was insufficient to activate A delta fibers whereas the highest (8 x MT) produced consistent A delta activation. Two spinal potential waveform components (N1, P2), at 4 and 10 ms, and four cortical components (P1, N2, P3, N4), at 15, 30, 60, and 95 ms, were analyzed. Significant amplitude reductions in spinal P2 (46%), cortical N2 (54%), cortical P3 (47%), and cortical N4 (45%), P < 0.01, as well as latency prolongation in cortical P1 (11%), P < 0.01, resulted from administration of a total dose of 100 micrograms/kg of fentanyl. The effect of fentanyl was critically dependent on stimulus intensity for the cortical P3 component (P < 0.01). All changes were reversed by naloxone. Fentanyl produced dose-related changes in specific spinal and cortical EP waveform components in the ketamine-anesthetized rabbit. This effect was significantly dependent on stimulus intensity in at least one cortical component (P3). Such an interaction between drug dose and stimulus intensity may be relevant to interpreting other human and animal evoked potential studies.

Non-narcotic modalities for the management of acute pain.

The possible options for the management of acute pain are quite numerous and continue to expand as our understanding of the mechanisms of pain becomes increasing sophisticated. Many of the options discussed have been available for years, and their present underutilization may be a reflection of the lack of emphasis on the importance of management of acute pain. An illustration of this would be our present ritual of prescribing narcotics postoperatively, a longstanding, but unfortunately inadequate practice. Because of poor selection and scheduling of doses, postoperative analgesia is typically a less than satisfactory experience for many patients convalescing in a hospital following surgery. The clinician should of course be guided by the clinical situation itself in order to determine what modality or combination of modalities may be appropriate for pain management. Certain techniques, such as continuous local anesthetic infusions, may warrant an escalated level of monitoring and ancillary care. Other techniques, such as the infiltration of a wound with local anesthetic or the addition of a nonsteroidal anti-inflammatory agent to a regimen of mild oral narcotics are so simple that excluding them from patient care is almost callous and inconsiderate. Attention to the mechanisms of pain that may be present in a given situation, whether it be muscle spasm, ischemia, inflammation, edema, or nerve injury, may guide the clinician toward a more rational approach in managing that pain.

Clearance from cerebrospinal fluid of intrathecally administered beta-endorphin in monkeys.

Five adult male monkeys (Macaca mulatta) weighing 7.1-9.9 kg were given synthetic human beta-endorphin (800 micrograms) and [14C]methoxy-inulin (50 microCi) in 400 microliters of normal saline intrathecally. Serial samples of cerebrospinal fluid were drawn through a previously positioned indwelling spinal catheter and were assayed for concentrations of beta-endorphin (determined by radioimmunoassay) and inulin (determined by liquid scintillation counter). Spinal fluid concentrations of beta-endorphin and inulin peaked and declined in a parallel manner. The clearance ratio (calculated from the reciprocal of the ratio of the areas under the respective curves of elimination of the two species) remained remarkably similar from animal to animal, giving a mean value of 1.060 +/- 0.090 (SEM). This ratio, being near unity, suggests that beta-endorphin is eliminated from spinal fluid in a fashion similar to that of inulin, which is removed exclusively by bulk absorption.