Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

Ovarian hyperstimulation syndrome: review and new classification criteria for reporting in clinical trials.

STUDY QUESTION: What is an objective approach that employs measurable and reproducible physiologic changes as the basis for the classification of ovarian hyperstimulation syndrome (OHSS) in order to facilitate more accurate reporting of incidence rates within and across clinical trials? SUMMARY ANSWER: The OHSS flow diagram is an objective approach that will facilitate consistent capture, classification and reporting of OHSS within and across clinical trials. WHAT IS KNOWN ALREADY: OHSS is a potentially life-threatening iatrogenic complication of the early luteal phase and/or early pregnancy after ovulation induction (OI) or ovarian stimulation (OS). The clinical picture of OHSS (the constellation of symptoms associated with each stage of the disease) is highly variable, hampering its appropriate classification in clinical trials. Although some degree of ovarian hyperstimulation is normal after stimulation, the point at which symptoms transition from those anticipated to those of a disease state is nebulous. STUDY DESIGN, SIZE, DURATION: An OHSS working group, comprised of subject matter experts and clinical researchers who have significantly contributed to the field of fertility, was convened in April and November 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: The OHSS working group was tasked with reaching a consensus on the definition and the classification of OHSS for reporting in clinical trials. The group engaged in targeted discussion regarding the scientific background of OHSS, the criteria proposed for the definition and the rationale for universal adoption. An agreement was reached after discussion with all members. MAIN RESULTS AND THE ROLE OF CHANCE: One of the following conditions must be met prior to making the diagnosis of OHSS in the context of a clinical trial: (i) the subject has undergone OS (either controlled OS or OI) AND has received a trigger shot for final oocyte maturation (e.g. hCG, GnRH agonist [GnRHa] or kisspeptin) followed by either fresh transfer or segmentation (cryopreservation of embryos) or (ii) the subject has undergone OS or OI AND has a positive pregnancy test. All study patients who develop symptoms of OHSS should undergo a thorough examination. An OHSS flow diagram was designed to be implemented for all subjects with pelvic or abdominal complaints, such as lower abdominal discomfort or distention, nausea, vomiting and diarrhea, and/or for subjects suspected of having OHSS. The diagnosis of OHSS should be based on the flow diagram. LIMITATIONS, REASONS FOR CAUTION: This classification system is primarily intended to address the needs of the clinical investigator undertaking clinical trials in the field of OS and may not be applicable for the use in clinical practice or with OHSS occurring under natural circumstances. WIDER IMPLICATIONS OF THE FINDINGS: The proposed OHSS classification system will enable an accurate estimate of the incidence and severity of OHSS within and across clinical trials performed in women with infertility. STUDY FUNDING/COMPETING INTERESTS: Financial support for the advisory group meetings was provided by Merck & Co., Inc., Kenilworth, NJ, USA. P.H. reports unrestricted research grants from MSD, Merck and Ferring, and honoraria for lectures from MSD, Merck and IBSA. S.M.N. reports that he has received fees and grant support from the following companies (in alphabetic order): Beckman Coulter, Besins, EMD Serono, Ferring Pharmaceuticals, Finox, MSD and Roche Diagnostics over the previous 5 years. P.D., C.C.C., J.L.F., H.M.F., and P.L. report no relationships that present a potential conflict of interest. B.C.T. REPORTS: grants and honorarium from Merck Serono; unrestricted research grants, travel grants and honorarium, and participation in a company-sponsored speaker's bureau from Merck Sharp & Dohme; grants, travel grants, honoraria and advisory board membership from IBSA; travel grants from Ferring; and advisory board membership from Ovascience. L.B.S. reports current employment with Merck & Co, Inc., Kenilworth, NJ, USA, and owns stock in the company. K.G. and B.J.S. report prior employment with Merck & Co., Inc., Kenilworth, NJ, USA, and own stock in the company. All reported that competing interests are outside the submitted work. No other relationships or activities exist that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: Not applicable.

Cervical surgery for cervical intraepithelial neoplasia and prolonged time to conception of a live birth: a case-control study.

OBJECTIVE: To determine whether women with a history of surgery for cervical intraepithelial neoplasia (CIN) are at an increased risk of subfertility, measured as a time to pregnancy of more than 12 months. DESIGN: Case-control study. SETTING: Iowa Health in Pregnancy Study (IHIPS), a population-based case-control study of preterm and small-for-gestational-age (SGA) live birth outcomes (from May 2002 through June 2005) in the USA. SAMPLE: Women with an intended pregnancy and a history of either one prior cervical surgery (n = 152), colposcopy only (n = 151), or no prior cervical surgery or colposcopy (n = 1021). METHODS: Cervical treatment history, pregnancy intention, time to pregnancy, and other variables were self-reported by computer-assisted telephone interviews. Odds ratios were calculated using logistic regression to estimate the risk of prolonged time to pregnancy among women with a history of cervical surgery or colposcopy alone, compared with untreated women (control group). MAIN OUTCOME MEASURE: Prolonged time to pregnancy (i.e. >1 year). RESULTS: Prolonged time to pregnancy was most prevalent among treated women (16.4%), compared with untreated women (8.4%) and women with colposcopy only (8.6%) (P = 0.039). After adjusting for covariates, women with prior cervical surgery had a more than two-fold higher risk of prolonged time to pregnancy compared with untreated women (aOR 2.09, 95% CI 1.26-3.46). In contrast, women with a history of colposcopy only had a risk equivalent to that found among untreated women (aOR 1.02, 95% CI 0.56-1.89). CONCLUSIONS: Women with a history of cervical treatment for CIN are at increased risk of subfertility, measured as a time to pregnancy of more than 12 months.

Achievement test performance in children conceived by IVF.

BACKGROUND: Long-term follow-up studies of children conceived by IVF are limited. We examine academic performance on standardized tests [Iowa Tests of Basic Skills/Educational Development (ITBS/ITED)] of children conceived by IVF. METHODS: Parents of children 8-17 years of age at the onset of the study (March 2008) who were conceived by IVF at the University of Iowa Hospitals and Clinics and living in the state of Iowa were contacted by mail. Parents completed questionnaires on their child's health and education and parental education. ITBS/ITED scores from school grades 3-12 were obtained on IVF children and a group of anonymous children matched by grade, year, gender and school district. Scores were analyzed using linear mixed models. RESULTS: Four hundred and ninety-seven couples were contacted. Two hundred and ninety-five couples (463 children) agreed to participate (59.4% of parents), with ITBS/ITED scores available on 423 children (91.4% of participants). IVF children scored higher than the national mean (P < 0.0001) across all grades and subtests and higher than their matched peers for grades 3-11. A trend toward lower test scores in multiple gestations was present (but not significant). Factors found to affect test scores included parental level of education, maternal age, divorce and child's BMI. Cryopreservation, length of embryo culture and method of insemination did not affect scores. CONCLUSIONS: IVF children scored higher on standardized tests than their matched peers, suggesting that IVF does not have a negative effect on cognitive development. However, long-term follow-up of IVF children is still limited. Further research should be performed on the effect of multiple gestation on academic performance.

Hyperbaric oxygen in the treatment of delayed radiation injuries of the extremities.

Hyperbaric oxygen (HBO2) is used as an adjunct in the treatment of radiation injury at many sites, including the mandible, larynx, chest wall, bladder, and rectum. In these disorders, HBO2 is effective in stimulating neovascularization and reducing fibrosis. No previous publications report the application of HBO2 to radiation injuries of the extremities. From 1979 until 1997, 17 patients were treated at the Southwest Texas Methodist and Nix Hospitals for nonhealing necrotic wounds of the extremities within previously irradiated fields. All but one wound involved a lower extremity. Most of the patients had been irradiated for soft tissue sarcomas or skin cancers. The rest were irradiated for a variety of malignancies. HBO2 was delivered in a multiplace chamber at 2.4 atm abs daily for 90 min of 100% oxygen at pressure. This report is a retrospective, uncontrolled review of these patients. Eleven patients (65%) healed completely whereas five (29%) failed to heal and one (6%) was lost to follow-up. Three (60%) of those who failed were found to have local or distant recurrence of their tumor early in their course of hyperbaric treatment and were discontinued from therapy at that time. When last seen in the clinic, the wound of the patient who was lost to follow-up was improved but not completely healed. Four of those who failed (including the two with local tumor recurrence) required amputation. If we exclude those with active cancer and the patient lost to follow-up, the success rate was 11 of 13 or 85%. HBO2 was applied successfully with complete wound healing and the avoidance of amputation in a majority of these patients. The consequences of failure in patients suffering from radiation necrosis of the extremities (some complicated by the presence of tumor) are significant, with 80% of the five failures requiring amputation. In radiation injuries of the extremities as in delayed radiation injury at other sites, HBO2 is a useful adjunct and should be part of the overall management.

Double-blind multicenter study comparing alprostadil alpha-cyclodextrin with moxisylyte chlorhydrate in patients with chronic erectile dysfunction.

PURPOSE: We compared the efficacy and safety of alprostadil alpha-cyclodextrin and moxisylyte chlorhydrate to induce erections adequate for sexual intercourse in a prospective, randomized, parallel double-blind study in patients with erectile dysfunction. MATERIALS AND METHODS: A total of 156 men with erectile dysfunction due to organic, nonorganic and mixed origin was randomized into 2 parallel treatment groups receiving titrations of an individual optimum dose of alprostadil alpha-cyclodextrin or moxisylyte chlorhydrate. Erectile response was measured by the buckling test. A positive test was associated with axial erection rigidity that did not buckle/deform to 1.0 kg. load. The buckling test was repeated every 10 minutes for up to 60 minutes. RESULTS: A total of 56 patients (75%) in the alprostadil alpha-cyclodextrin group and 32 patients (40%) in the moxisylyte chlorhydrate group responded with at least 1 positive buckling test during the office period. Investigators assessed erections after alprostadil alpha-cyclodextrin to be adequate for sexual intercourse in 61 patients (81%) compared to 37 patients (46%) after moxisylyte chlorhydrate. All efficacy parameters in office reached statistical significance of p < 0.001 in favor of alprostadil alpha-cyclodextrin. During self-injection therapy at home 58 patients (85%) reported at least 1 rigid erection after alprostadil alpha-cyclodextrin compared to 37 patients (61%) after moxisylyte chlorhydrate. Patient and partner opinion of treatment achieved statistically significantly better scores in the alprostadil alpha-cyclodextrin group compared to the moxisylyte chlorhydrate group. CONCLUSIONS: Alprostadil alpha-cyclodextrin is significantly more effective than moxisylyte chlorhydrate in producing full penile rigidity in office and at home. Injection related side effects occur with the same frequency but moxisylyte results in more systemic side effects and alprostadil results in more painful and prolonged erections. Patients and partners are significantly more satisfied with alprostadil alpha-cyclodextrin.

Hyperbaric oxygen an adjunctive treatment for delayed radiation injuries of the abdomen and pelvis.

Radiation therapy is often utilized as adjunctive or primary treatment for malignancies of the abdomen and pelvis. Radiation complications are infrequent, but can be life threatening or significantly diminish the quality of life. Radiation necrosis is an approved indication for hyperbaric oxygen (HBO2). Previous publications have reported results in treating delayed radiation injuries involving many sites. This paper reports the experience of a single physician group in treating delayed injuries of the abdomen and/or pelvis. Forty-four such patients have been treated since 1979. Of the 41 patients available for follow up, 26 have healed; 6 failed to heal; and 9 patients had an inadequate course of therapy (fewer than 20 treatments). Especially encouraging was the resolution of fistulae in six of eight patients with only three requiring surgery for closure. Overall, the success rate in patients receiving at least 20 HBO2 treatments was 81%. Hyperbaric oxygen is a useful adjunct in treatment of delayed radiation injuries of the pelvis and abdomen.

Hyperbaric oxygen as an adjunctive treatment for delayed radiation injury of the chest wall: a retrospective review of twenty-three cases.

Since 1979, 23 cases of radiation-induced chest wall necrosis have been treated in the Hyperbaric Medicine Departments of Southwest Texas Methodist Hospital and the Nix Hospital, San Antonio, Texas. Eight cases involved soft tissue only. Six of eight (75%) patients with soft tissue involvement healed without requiring surgical debridement, although four patients (50%) did have flaps or grafts. Fifteen patients had bony and soft tissue necrosis. Eight of these patients (53%) resolved with adjunctive hyperbaric oxygen (HBO), but all required aggressive surgical debridement including skeletal resection. Four (27%) had reconstructive flaps as well. Six patients (40%) with bony necrosis who had either no or incomplete debridement failed to heal. Three patients (13%)(two soft tissue and one bony) were found to have residual tumor during HBO and were discontinued from treatment. HBO is an effective adjunctive therapy for soft tissue chest-wall, radiation-induced necrosis, but must be coupled with appropriate debridement to include surgical removal of all necrotic bone to ensure a successful outcome of bony plus soft tissue necrosis.

Preinflation before acceleration on tolerance to simulated Space Shuttle reentry G profiles in dehydrated subjects.

This study was conducted to determine if preinflation of a standard five-bladder anti-g suit 10 minutes before exposure to a centrifuge simulation of a Space Shuttle reentry would provide significantly better protection against orthostasis than the standard symptomatic inflation regimen. This study differed significantly from prior studies: The rate of g onset was slower, peak g was lower, duration of exposure was longer, and the subjects were dehydrated to mimic conditions observed in astronauts immediately postflight. Preinflation demonstrated physiological advantages as determined by arterial blood pressure and heart rate changes in seven healthy male, experienced centrifuge subjects.

Grafting with the internal mammary artery: correlation between preoperative angiography and intraoperative findings.

No data exist on the relation between angiography of the internal mammary artery and intraoperative findings during bypass surgery. We studied 47 consecutive patients and found no atherosclerotic changes. Intraoperatively, however, 4 left internal mammary arteries were judged unsuitable for grafting. No relation could be found to the diameter of the vessel as judged angiographically. Possible causes of unsuitability are discussed.

100th anniversary of Dr. Louis H. Bauer's birth.

Louis H. Bauer, M.D., 1888-1964, founded the Aero Medical Association of the United States, which has become the Aerospace Medical Association. He founded the Association's journal and was its editor for 25 years. The accompanying short article highlights some of his accomplishments.

Low infectivity of HSV-1 DNA caused by defective-interfering genomes.

The infectivity of herpes simplex virus, type 1, strain ANG progeny DNA from standard virus infections and of progeny DNA from infections involving defective-interfering virus particles (DI DNA) was compared in transfection assays. No difference in infectivity of virus DNA isolated either from infected cells or from progeny virus was found for a given type of infection. However, the values for two types of infection differed markedly, with DI progeny DNA being less infectious by more than 2 log10. The low infectivity was mainly due to the presence of interfering DNA molecules in DI progeny DNA, regardless of whether intracellular DNA or DNA extracted from mature virions was analysed. The interfering capacity of DI progeny DNA did not depend on the integrity of the genomes. The physical proximity provided by simultaneous precipitation of infectious and of interfering DNA is an important factor influencing the degree to which DI DNA interferes. Interference by DI DNA in the transfection assay can be partly reversed by the addition of XbaI fragments of standard DNA; in control experiments this fragmented DNA was shown to lead to a reduction rather than to an enhancement of the infectivity of standard virus DNA.

Synthesis and packaging of herpes simplex virus DNA in the course of virus passages at high multiplicity.

Herpes simplex virus type 1 (HSV-1), strain ANG, was passaged serially at high MOI or undiluted on RC-37 cells. The yields of infectious virus decreased and increased periodically with a maximum of about 3 log units variation in titer. The amount of newly synthesized HSV-1 DNA, however, did not vary by more than a factor of 2. On the other hand, the fraction of total HSV-1 DNA associated with virions was reduced at passage numbers coinciding with the minima in the yields of infectious progeny virus. Apparently, low yields of infectious virus mainly reflected a reduced efficiency of packaging of viral DNA into mature virus particles. One step in the process of virus maturation which appeared to be impaired was the assembly of nucleocapsids. HSV-1 ang was shown to be capable of generating different classes of defective particle in independent series of virus passages at high MOI.

An unusual defective genotype derived from herpes simplex virus strain ANG.

A defective genotype of herpes simplex virus strain Angelotti (HSV ANG) accumulates in the course of controlled serial high MOI virus passages representing 50-60% of the total number of mature virions in the seventh of these passages. Defective HSV ANG significantly differs from other defective HSV genotypes described so far: the DNA of the defective particles has the same buoyant density as nondefective DNA. In contrast to non-defective HSV ANG DNA, it is not attacked by the restriction endonucleases Eco R I, Hpa I and Hind III. Defective virions strongly suppress the formation of progeny virus. They do not interfere, however, with the synthesis of HSV-specified thymidine (TdR) kinase.