Consensus statement: Supporting Safer Conception and Pregnancy For Men And Women Living with and Affected by HIV.

Safer conception interventions reduce HIV incidence while supporting the reproductive goals of people living with or affected by HIV. We developed a consensus statement to address demand, summarize science, identify information gaps, outline research and policy priorities, and advocate for safer conception services. This statement emerged from a process incorporating consultation from meetings, literature, and key stakeholders. Three co-authors developed an outline which was discussed and modified with co-authors, working group members, and additional clinical, policy, and community experts in safer conception, HIV, and fertility. Co-authors and working group members developed and approved the final manuscript. Consensus across themes of demand, safer conception strategies, and implementation were identified. There is demand for safer conception services. Access is limited by stigma towards PLWH having children and limits to provider knowledge. Efficacy, effectiveness, safety, and acceptability data support a range of safer conception strategies including ART, PrEP, limiting condomless sex to peak fertility, home insemination, male circumcision, STI treatment, couples-based HIV testing, semen processing, and fertility care. Lack of guidelines and training limit implementation. Key outstanding questions within each theme are identified. Consumer demand, scientific data, and global goals to reduce HIV incidence support safer conception service implementation. We recommend that providers offer services to HIV-affected men and women, and program administrators integrate safer conception care into HIV and reproductive health programs. Answers to outstanding questions will refine services but should not hinder steps to empower people to adopt safer conception strategies to meet reproductive goals.

The International Glossary on Infertility and Fertility Care, 2017.

STUDY QUESTION: Can a consensus and evidence-driven set of terms and definitions be generated to be used globally in order to ensure consistency when reporting on infertility issues and fertility care interventions, as well as to harmonize communication among the medical and scientific communities, policy-makers, and lay public including individuals and couples experiencing fertility problems? SUMMARY ANSWER: A set of 283 consensus-based and evidence-driven terminologies used in infertility and fertility care has been generated through an inclusive consensus-based process with multiple stakeholders. WHAT IS KNOWN ALREADY: In 2006 the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) published a first glossary of 53 terms and definitions. In 2009 ICMART together with WHO published a revised version expanded to 87 terms, which defined infertility as a disease of the reproductive system, and increased standardization of fertility treatment terminology. Since 2009, limitations were identified in several areas and enhancements were suggested for the glossary, especially concerning male factor, demography, epidemiology and public health issues. STUDY DESIGN, SIZE, DURATION: Twenty-five professionals, from all parts of the world and representing their expertise in a variety of sub-specialties, were organized into five working groups: clinical definitions; outcome measurements; embryology laboratory; clinical and laboratory andrology; and epidemiology and public health. Assessment for revisions, as well as expansion on topics not covered by the previous glossary, were undertaken. A larger group of independent experts and representatives from collaborating organizations further discussed and assisted in refining all terms and definitions. PARTICIPANTS/MATERIALS, SETTING, METHODS: Members of the working groups and glossary co-ordinators interacted through electronic mail and face-to-face in international/regional conferences. Two formal meetings were held in Geneva, Switzerland, with a final consensus meeting including independent experts as well as observers and representatives of international/regional scientific and patient organizations. MAIN RESULTS AND THE ROLE OF CHANCE: A consensus-based and evidence-driven set of 283 terminologies used in infertility and fertility care was generated to harmonize communication among health professionals and scientists as well as the lay public, patients and policy makers. Definitions such as 'fertility care' and 'fertility awareness' together with terminologies used in embryology and andrology have been introduced in the glossary for the first time. Furthermore, the definition of 'infertility' has been expanded in order to cover a wider spectrum of conditions affecting the capacity of individuals and couples to reproduce. The definition of infertility remains as a disease characterized by the failure to establish a clinical pregnancy; however, it also acknowledges that the failure to become pregnant does not always result from a disease, and therefore introduces the concept of an impairment of function which can lead to a disability. Additionally, subfertility is now redundant, being replaced by the term infertility so as to standardize the definition and avoid confusion. LIMITATIONS, REASONS FOR CAUTION: All stakeholders agreed to the vast majority of terminologies included in this glossary. In cases where disagreements were not resolved, the final decision was reached after a vote, defined before the meeting as consensus if passed with 75%. Over the following months, an external expert group, which included representatives from non-governmental organizations, reviewed and provided final feedback on the glossary. WIDER IMPLICATIONS OF THE FINDINGS: Some terminologies have different definitions, depending on the area of medicine, for example demographic or clinical as well as geographic differences. These differences were taken into account and this glossary represents a multinational effort to harmonize terminologies that should be used worldwide. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: N/A.

Methamphetamine acutely inhibits voltage-gated calcium channels but chronically up-regulates L-type channels.

In neurons, calcium (Ca(2+) ) channels regulate a wide variety of functions ranging from synaptic transmission to gene expression. They also induce neuroplastic changes that alter gene expression following psychostimulant administration. Ca(2+) channel blockers have been considered as potential therapeutic agents for the treatment of methamphetamine (METH) dependence because of their ability to reduce drug craving among METH users. Here, we studied the effects of METH exposure on voltage-gated Ca(2+) channels using SH-SY5Y cells as a model of dopaminergic neurons. We found that METH has different short- and long-term effects. A short-term effect involves immediate (< 5 min) direct inhibition of Ca(2+) ion movements through Ca(2+) channels. Longer exposure to METH (20 min or 48 h) selectively up-regulates the expression of only the CACNA1C gene, thus increasing the number of L-type Ca(2+) channels. This up-regulation of CACNA1C is associated with the expression of the cAMP-responsive element-binding protein (CREB), a known regulator of CACNA1C gene expression, and the MYC gene, which encodes a transcription factor that putatively binds to a site proximal to the CACNA1C gene transcription initiation site. The short-term inhibition of Ca(2+) ion movement and later, the up-regulation of Ca(2+) channel gene expression together suggest the operation of cAMP-responsive element-binding protein- and C-MYC-mediated mechanisms to compensate for Ca(2+) channel inhibition by METH. Increased Ca(2+) current density and subsequent increased intracellular Ca(2+) may contribute to the neurodegeneration accompanying chronic METH abuse. Methamphetamine (METH) exposure has both short- and long-term effects. Acutely, methamphetamine directly inhibits voltage-gated calcium channels. Chronically, neurons compensate by up-regulating the L-type Ca(2+) channel gene, CACNA1C. This compensatory mechanism is mediated by transcription factors C-MYC and CREB, in which CREB is linked to the dopamine D1 receptor signaling pathway. These findings suggest Ca(2+) -mediated neurotoxicity owing to over-expression of calcium channels.

The role of neoadjuvant chemotherapy for patients with variant histology muscle invasive bladder cancer undergoing robotic cystectomy: Data from the International Robotic Cystectomy Consortium.

OBJECTIVE: To assess the role of neoadjuvant chemotherapy (NAC) before robot-assisted radical cystectomy (RARC) for patients with variant histology (VH) muscle-invasive bladder cancer (MIBC). METHODS: Retrospective review of 988 patients who underwent RARC (2004-2023) for MIBC. Primary outcomes included the utilization of NAC among this cohort of patients, frequency of downstaging, and discordance between preoperative and final pathology in terms of the presence of VH. Secondary outcomes included disease-specific (DSS), recurrence-free (RFS), and overall survival (OS). RESULTS: A total of 349 (35%) had VH on transurethral resection or at RARC. The 4 most common VH subgroups were squamous (n = 94), adenocarcinoma (n = 64), micropapillary (n = 34), and sarcomatoid (n = 21). There was no difference in OS (log-rank: P = 0.43 for adenocarcinoma, P = 0.12 for micropapillary, P = 0.55 for sarcomatoid, P = 0.29 for squamous), RFS (log-rank: P = 0.25 for adenocarcinoma, P = 0.35 for micropapillary, P = 0.83 for sarcomatoid, P = 0.79 for squamous), or DSS (log-rank P = 0.91 for adenocarcinoma, P = 0.15 for micropapillary, 0.28 for sarcomatoid, P = 0.92 for squamous) among any of the VH based on receipt of NAC. Patients with squamous histology who received NAC were more likely to be downstaged on final pathology compared to those who did not (P < 0.01). CONCLUSION: Our data showed no significant difference in OS, RFS, or DSS for patients with VH MIBC cancer who received NAC before RARC. Patients with the squamous variant who received NAC had more pathologic downstaging compared to those who did not. The role of NAC among patients with VH is yet to be defined. Results were limited by small number in each individual group and lack of exact proportion of VH.

Flupirtine enhances the anti-hyperalgesic effects of morphine in a rat model of prostate bone metastasis.

OBJECTIVE: Current treatments for cancer pain are often inadequate, particularly when metastasis to bone is involved. The addition to the treatment regimen of another drug that has a complementary analgesic effect may increase the overall analgesia without the necessity to increase doses, thus avoiding dose-related side effects. This project investigated the synergistic effect of the addition of the potassium channel (KCNQ2-3) modulator flupirtine to morphine treatment in a rat model of prostate cancer-induced bone pain. DESIGN: Syngeneic prostate cancer cells were injected into the right tibia of male Wistar rats under anesthesia. This led to expanding tumor within the bone in 2 weeks, together with the concurrent development of hyperalgesia to noxious heat. Paw withdrawal thresholds from noxious heat were measured before and after the maximum non-sedating doses of morphine and flupirtine given alone and in combinations. Dose-response curves for morphine (0.13-5.0 mg/kg ip) and flupirtine (1.25-10.0 mg/kg ip) given alone and in fixed-dose combinations were plotted and subjected to an isobolographic analysis. RESULTS: Both morphine (ED50 = 0.74 mg/kg) and flupirtine (ED50 = 3.32 mg/kg) caused dose-related anti-hyperalgesia at doses that did not cause sedation. Isobolographic analysis revealed that there was a synergistic interaction between flupirtine and morphine. Addition of flupirtine to morphine treatment improved morphine anti-hyperalgesia, and resulted in the reversal of cancer-induced heat hyperalgesia. CONCLUSIONS: These results suggest that flupirtine in combination with morphine may be useful clinically to provide better analgesia at lower morphine doses in the management of pain caused by tumors growing in bone.

Low free testosterone is associated with increased mortality in frail surgical patients.

BACKGROUND: Preoperative frailty has been associated with adverse postoperative outcomes. Additionally, low testosterone has been associated with physical frailty and cognitive decline. However, the impact of simultaneous frailty and low testosterone on surgical outcomes is understudied. METHODS: Preoperative frailty status and testosterone levels were obtained in patients undergoing a diverse range of surgical procedures. Preoperative frailty was evaluated independently and in combination with testosterone through the creation of composite risk groups. Relationships between preoperative frailty and composite risk groups with overall survival were determined using Kaplan-Meier and logistic regression analyses. Bivariate analysis was used to determine the associations between frailty and testosterone status on postoperative complications, length of hospital stay, and readmission rates. RESULTS: Median age of the cohort was 63 years, and the median follow-up time was 105 weeks. Thirty-one patients (23%) were frail, and 36 (27%) had low free testosterone. Bivariate analysis demonstrated a statistically significant relationship between preoperative frailty and overall survival (P = .044). In multivariate analysis, coexisting frailty and low free testosterone were significantly associated with decreased overall survival (hazard ratio 4.93, 95% confidence interval, 1.68-14.46, P = .004). CONCLUSION: We observed preoperative frailty, both independently and in combination with low free testosterone levels, to be significantly associated with decreased overall survival across various surgical procedures. Personalizing the surgical risk assessment through the incorporation of preoperative frailty and testosterone status may serve to improve the prognostication of patients undergoing major surgery.

Intravenous injection of leconotide, an omega conotoxin: synergistic antihyperalgesic effects with morphine in a rat model of bone cancer pain.

OBJECTIVE: Leconotide (CVID, AM336, CNSB004) is an omega conopeptide similar to ziconotide, which blocks voltage sensitive calcium channels. However, unlike ziconotide, which must be administered intrathecally, leconotide can be given intravenously because it is less toxic. This study investigated the antihyperalgesic potency of leconotide given intravenously alone and in combinations with morphine-administered intraperitoneally, in a rat model of bone cancer pain. DESIGN: Syngeneic rat prostate cancer cells AT3B-1 were injected into one tibia of male Wistar rats. The tumor expanded within the bone causing hyperalgesia to heat applied to the ipsilateral hind paw. Measurements were made of the maximum dose (MD) of morphine and leconotide given alone and in combinations that caused no effect in an open-field activity monitor, rotarod, and blood pressure and heart rate measurements. Paw withdrawal thresholds from noxious heat were measured. Dose response curves for morphine (0.312-5.0 mg/kg intraperitoneal) and leconotide (0.002-200 µg/kg intravenous) given alone were plotted and responses compared with those caused by morphine and leconotide in combinations. RESULTS: Leconotide caused minimal antihyperalgesic effects when administered alone. Morphine given alone intraperitoneally caused dose-related antihyperalgesic effects (ED(50) = 2.40 ± 1.24 mg/kg), which were increased by coadministration of leconotide 20 µg/kg (morphine ED(50) = 0.16 ± 1.30 mg/kg); 0.2 µg/kg (morphine ED(50) = 0.39 ± 1.27 mg/kg); and 0.02 µg/kg (morphine ED(50) = 1.24 ± 1.30 mg/kg). CONCLUSIONS: Leconotide caused a significant increase in reversal by morphine of the bone cancer-induced hyperalgesia without increasing the side effect profile of either drug. CLINICAL IMPLICATION: Translation into clinical practice of the method of analgesia described here will improve the quantity and quality of analgesia in patients with bone metastases. The use of an ordinary parenteral route for administration of the calcium channel blocker (leconotide) at low dose opens up the technique to large numbers of patients who could not have an intrathecal catheter for drug administration. Furthermore, the potentiating synergistic effect with morphine on hyperalgesia without increased side effects will lead to greater analgesia with improved quality of life.

Capacitance increases of dissociated tilapia prolactin cells in response to hyposmotic and depolarizing stimuli.

Prolactin (PRL) is the major hormonal mediator of adaptation to hyposmotic conditions. In tilapia (Oreochromis mossambicus), PRL cells are segregated to the rostral pars distalis of the anterior pituitary facilitating the nearly pure culture of dissociated PRL cells. Membrane capacitance (C(m)) was recorded at 1Hz or higher for tens of minutes as a surrogate monitor of PRL secretion by exocytosis from cells under perforated patch clamp. The study compares secretory responses to trains of depolarizing clamps (100 at 2.5 Hz, from -70 to +10 mV for 100 ms) to the physiological stimulus, exposure to hyposmotic medium, here a switch from 350 to 300 mOsm saline ([Ca²âº] 15 mM). Two-thirds of cells tested with each stimulus responded. In response to depolarizing clamps, C(m) increased linearly at an average rate of 7.2 fF/s. The increase was also linear in response to hyposmotic perfusion, but the average rate was 0.68 fF/s. Response to depolarization was reversibly blocked in Ca²âº-omitted saline, or in saline with 30 µM Cd²âº. It was unaffected by 0.1 µM tetrodotoxin. By contrast, responses were reduced but not absent during perfusion of hyposmotic saline with Ca²âº-omitted; 30 µM Cd²âº appeared to enhance the hyposmotic response. BAPTA-AM eliminated responses to both stimuli, confirming that secretion was dependent on increases of intracellular [Ca²âº]. Together with previous observations from this laboratory of [Ca²âº](i) with simultaneous collection and immunoassay of perfusate for PRL, we conclude that depolarization and hyposmotic stimuli initiate secretion by independent mechanisms.

Longitudinal impact of bladder cancer diagnosis on common psychiatric disorders.

BACKGROUND: The presence of psychiatric disorders in patients with cancer is associated with increased morbidity and poorer outcomes. We sought to determine the impact of a new bladder cancer diagnosis on the incidence of depression and anxiety. METHODS: We used a database of billing claims (MarketScan®) to identify patients newly diagnosed with bladder cancer between 2009 and 2018. Patients with preexisting psychiatric disorders or use of anxiolytics/antidepressants were excluded. We matched cases to patients without a bladder cancer or psychiatric diagnosis. Our primary outcome was a new diagnosis of depression, anxiety, or use of anxiolytics/antidepressants. Other exposures of interest included gender and treatment received. We used multivariable regression to estimate odds ratios for these exposures. RESULTS: We identified 65,846 cases with a new diagnosis of bladder cancer (31,367 privately insured; 34,479 Medicare-eligible). Compared to controls, bladder cancer patients were more likely to develop new-onset depression/anxiety at 6 months (privately insured: 6.9% vs. 3.4%, p < 0.001; Medicare-eligible: 5.7% vs. 3.4%, p < 0.001) and 36 months (privately insured: 19.2% vs. 13.5%, p < 0.001; Medicare-eligible: 19.3% vs. 16.0%, p < 0.001). Women (vs. men, privately insured: OR 1.65, 95%CI 1.53-1.78; Medicare-eligible: OR 1.63, 95%CI 1.50-1.76) and those receiving cystectomy and chemotherapy (vs. no treatment, privately insured: OR 4.94, 95%CI 4.13-5.90; Medicare-eligible: OR 2.35, 95%CI 1.88-2.94) were more likely to develop significant depression/anxiety. CONCLUSION: A new diagnosis of bladder cancer was associated with increased burden of significant depression/anxiety compared with matched controls. Women and patients receiving more radical treatments had higher rates of depression and anxiety.

A Helpful Tool in the Renal Surgery Armamentarium: Dorsal Lumbotomy nephrectomy for Tumor in Patients with End-Stage Renal Disease.

OBJECTIVE: To compare operative outcomes between the dorsal lumbotomy (DL) and laparoscopic nephrectomy (LN) approaches for patients with end stage renal disease (ESRD) undergoing nephrectomy. DL operative technique is also described. MATERIALS AND METHODS: We performed a retrospective review of all patients undergoing DL nephrectomy at Emory University from 2008-2020. Cases were matched with control patients with ESRD who had undergone LN. Parameters evaluated included operative time, estimated blood loss, length of stay, postoperative narcotic requirements, and complication rates. Statistical analysis performed with SPSS. RESULTS: 43 DL patients and 86 LN patients were assessed. DL had shorter total OR time (173min vs 198min; P = 0.001) and surgery time (101min vs 135min; P<0.001) compared to LN. There was a trend towards decreased mean length of stay among the DL group (2.65d vs 3.14d; P = 0.069) as well as daily narcotic requirement measured in oral morphine equivalents (54.8mg/day vs 73.6mg/day, P = 0.051). There were no differences in estimated blood loss, perioperative complication rates, ICU admissions, or 30-day readmissions. Limitations include retrospective design and small sample size. CONCLUSION: Among patients with ESRD, DL was found to be safe and effective compared to LN, with shorter operative times, a trend towards decreased length of stay and post-operative narcotic requirements, and similar perioperative complication rates. DL should be considered as an approach for nephrectomy in this patient population.

Studies of synergy between morphine and a novel sodium channel blocker, CNSB002, in rat models of inflammatory and neuropathic pain.

OBJECTIVE: This study determined the antihyperalgesic effect of CNSB002, a sodium channel blocker with antioxidant properties given alone and in combinations with morphine in rat models of inflammatory and neuropathic pain. DESIGN: Dose response curves for nonsedating doses of morphine and CNSB002 given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat pain models: carrageenan-induced paw inflammation and streptozotocin (STZ)-induced diabetic neuropathy. RESULTS: The maximum nonsedating doses were: morphine, 3.2 mg/kg; CNSB002 10.0 mg/kg; 5.0 mg/kg CNSB002 with morphine 3.2 mg/kg in combination. The doses calculated to cause 50% reversal of hyperalgesia (ED50) were 7.54 (1.81) and 4.83 (1.54) in the carrageenan model and 44.18 (1.37) and 9.14 (1.24) in the STZ-induced neuropathy model for CNSB002 and morphine, respectively (mg/kg; mean, SEM). These values were greater than the maximum nonsedating doses. The ED50 values for morphine when given in combination with CNSB002 (5 mg/kg) were less than the maximum nonsedating dose: 0.56 (1.55) in the carrageenan model and 1.37 (1.23) in the neuropathy model (mg/kg; mean, SEM). The antinociception after morphine (3.2 mg/kg) was increased by co-administration with CNSB002 from 28.0 and 31.7% to 114.6 and 56.9% reversal of hyperalgesia in the inflammatory and neuropathic models, respectively (P < 0.01; one-way analysis of variance-significantly greater than either drug given alone). CONCLUSIONS: The maximum antihyperalgesic effect achievable with nonsedating doses of morphine may be increased significantly when the drug is used in combination with CNSB002.

CNSB004 (Leconotide) causes antihyperalgesia without side effects when given intravenously: a comparison with ziconotide in a rat model of diabetic neuropathic pain.

OBJECTIVE: Leconotide is an omega-conotoxin that blocks neuronal voltage sensitive calcium channels. This study compared the antihyperalgesic potencies of leconotide and ziconotide given intravenously alone and in combinations with a potassium channel modulator flupirtine, given intraperitoneally, in a rat model of diabetic neuropathic pain. DESIGN: Rats were given streptozotocin (150 mg/kg ip) to induce diabetic neuropathy and hyperalgesia. Experiments were performed on diabetic rats with >or=30% hyperalgesia to noxious heat. Rats were given each conopeptide alone and with flupirtine. Open field activity monitoring and non-invasive blood pressure measurements were used to define the maximum doses and combinations that caused no side effects. Doses in a range up to maximum no side effect doses were tested for antihyperalgesic effects in rats with hyperalgesia. RESULTS: The maximum no side effect dose of leconotide (2 mg/kg intravenously) caused 51.7% reversal of hyperalgesia compared with 0.4% for the highest no side effect dose of ziconotide (0.02 mg/kg; P < 0.001, one-way anova). Leconotide caused dose-related antihyperalgesic effects that were potentiated by coadministration with flupirtine at doses that were ineffective when given alone. Leconotide (0.02 mg/kg) and flupirtine (5 mg/kg) caused 25.3 +/- 7.6 and -6 +/- 9.5% reversal of hyperalgesia, respectively when given alone but in combination they caused 84.1 +/- 7.2% reversal of hyperalgesia (P < 0.01; one-way anova). No such interaction occurred with ziconotide. CONCLUSION: Leconotide could have wider clinical applications than ziconotide. Unlike ziconotide, powerful antihyperalgesia without side effects can be achieved by intravenous administration of leconotide thus avoiding the need for an intrathecal injection.

In utero model for pharmacologically investigating spontaneous activity during early ontogeny.

We describe an in utero model in which it is possible to investigate the involvement of supraspinal and spinal neurons in the genesis of spontaneous motor activity, a feature of early fetal life. To date almost all studies of the circuits that give rise to spontaneous motor activity during early ontogeny, and the neurotransmitters involved, have been carried out with in vitro models. Limitations of in vitro models include the relatively short viability of the preparation and the need to stimulate the nervous system either pharmacologically or electrically to produce the activity to be studied, in contrast to the activity that spontaneously occurs normally in utero. Our model uses fetal sheep, chronically instrumented with electromyogram electrodes and a catheter placed either intrathecally at the spinal level or in the peritoneal cavity. Motor activity can be studied over lengthy periods of fetal life and it is possible to examine the effects of infusing agonists and antagonists of central neurotransmitters on spontaneous motor activity. The use of our new model in parallel with the pre-existing in vitro models has the potential to add substantially to our understanding of the mechanisms behind changes in spontaneous activity that occur throughout fetal life.

Combination therapy with flupirtine and opioid: studies in rat pain models.

OBJECTIVES: Flupirtine is an established clinical analgesic for mild to moderate musculoskeletal pain states. It has recently been shown to be a KCNQ2-3 potassium channel opener. These experiments were performed to see if this property could be useful in treating pain states characterized by central sensitization with the drug either given alone or in combination with morphine. DESIGN: Experiments were performed in rats in an observer-blinded fashion with vehicle controls. Nonsedating doses of flupirtine, morphine, and combinations containing both drugs were defined using the rotarod test and open-field activity monitoring. Dose-response relationships were determined for nonsedating doses of both drugs given alone and together in combination in causing antinociception in two nociception paradigms: carrageenan paw inflammation and streptozotocin-induced diabetic neuropathy. RESULTS: Flupirtine and morphine, when given alone at the highest nonsedating doses, caused slight to moderate antinociception in both paradigms. Flupirtine also caused significant increases in morphine antinociception in both models. In carrageenan paw inflammation, complete reversal of carrageenan-induced hyperalgesia was caused by 10 mg/kg flupirtine in combination with 0.4 mg/kg morphine. These doses of the two drugs were ineffective when given alone, but the combination caused complete antinociception in this model of inflammatory pain. In the diabetic neuropathy model, morphine 3.2 mg/kg given alone caused no significant antinociception. However, a lower dose of morphine (1.6 mg/kg shown to be ineffective when it was given alone) given in combination with flupirtine 10 mg/kg caused highly significant antinociceptive effects causing complete reversal of hyperalgesia caused by diabetic neuropathy (P < 0.001, one-way analysis of variance). This combination of drugs was not sedating. CONCLUSIONS: Flupirtine increases morphine antinociception without causing an increase in sedation. Flupirtine should be investigated as an adjunct analgesic with opioids for the management of patients with pain states involving central sensitization.

Combination therapy with flupirtine and opioid: open-label case series in the treatment of neuropathic pain associated with cancer.

OBJECTIVES: This study is a case series that was designed to provide data on the efficacy and the incidence and duration of adverse effects of flupirtine in the treatment of cancer-related neuropathic pain. DESIGN: This was an 8-day, open-label study of palliative care patients with neuropathic pain despite maximal opioid treatment. They received an initial dose of flupirtine 100 mg orally four times daily (QID) that could be titrated. Efficacy measures included: a neuropathic pain discriminant score; scales measuring average pain and quality of life activities; and a score of percentage pain relief. RESULTS: Ten patients were recruited. Only one patient was withdrawn because of side effects. Several pain measurements were used. All patients were able to participate in these measurements apart from two who did not understand the concept of percentage pain relief. There were significant reductions of average pain (P < 0.01) and neuropathic pain discriminant scores (P < 0.01), as well as an increase in percentage pain relief (P < 0.01). There was no statistically significant change in overall opioid use but 8/10 patients had some reduction in opioid use and three of those required substantially reduced doses of opioid when flupirtine was added to their treatment regime. Eight patients elected to continue to take flupirtine after the trial, two taking 200 mg QID and the others 100 mg QID. Of these eight, six said that flupirtine was of considerable help and two said it helped a little. All of these continued to take flupirtine with very good pain control until death, one of which was 18 months after the trial course. CONCLUSIONS: These results in humans follow animal studies that suggest a role for flupirtine in the treatment of neuropathic pain. This short duration open-label study in 10 subjects suggests that flupirtine may be useful in the treatment of neuropathic pain when used in combination with opioids.

The development of descending projections from the brainstem to the spinal cord in the fetal sheep.

BACKGROUND: Although the fetal sheep is a favoured model for studying the ontogeny of physiological control systems, there are no descriptions of the timing of arrival of the projections of supraspinal origin that regulate somatic and visceral function. In the early development of birds and mammals, spontaneous motor activity is generated within spinal circuits, but as development proceeds, a distinct change occurs in spontaneous motor patterns that is dependent on the presence of intact, descending inputs to the spinal cord. In the fetal sheep, this change occurs at approximately 65 days gestation (G65), so we therefore hypothesised that spinally-projecting axons from the neurons responsible for transforming fetal behaviour must arrive at the spinal cord level shortly before G65. Accordingly we aimed to identify the brainstem neurons that send projections to the spinal cord in the mature sheep fetus at G140 (term = G147) with retrograde tracing, and thus to establish whether any projections from the brainstem were absent from the spinal cord at G55, an age prior to the marked change in fetal motor activity has occurred. RESULTS: At G140, CTB labelled cells were found within and around nuclei in the reticular formation of the medulla and pons, within the vestibular nucleus, raphe complex, red nucleus, and the nucleus of the solitary tract. This pattern of labelling is similar to that previously reported in other species. The distribution of CTB labelled neurons in the G55 fetus was similar to that of the G140 fetus. CONCLUSION: The brainstem nuclei that contain neurons which project axons to the spinal cord in the fetal sheep are the same as in other mammalian species. All projections present in the mature fetus at G140 have already arrived at the spinal cord by approximately one third of the way through gestation. The demonstration that the neurons responsible for transforming fetal behaviour in early ontogeny have already reached the spinal cord by G55, an age well before the change in motor behaviour occurs, suggests that the projections do not become fully functional until well after their arrival at the spinal cord.

A map of the major nuclei of the fetal sheep brainstem.

The fetal sheep has been used to investigate a wide range of developmental and pathological processes such as the effect of severe hypoxia, asphyxia, or intrauterine infection on the brain but, until now, there has been no complete description of the normal anatomical organisation of neuronal groups to facilitate interpretation of these studies. In this paper, we describe the major nuclei of the fetal sheep brainstem based on a study of 5 fetal sheep at 140 days of gestation (G140: term is G147). Nuclei were identified with the aid of brain atlases available for other species, and from the previously published, partial descriptions available for the sheep. Fifty-five distinct nuclei were identified after Nissl (thionin) staining, and their caudal and rostral margins were defined. This paper provides an easy reference to the position of the major nuclei within the fetal sheep brainstem, and can be used as a guide for future studies examining the organisation of neuronal populations under normal and pathological conditions in this animal model.

The International Glossary on Infertility and Fertility Care, 2017.

STUDY QUESTION: Can a consensus and evidence-driven set of terms and definitions be generated to be used globally in order to ensure consistency when reporting on infertility issues and fertility care interventions, as well as to harmonize communication among the medical and scientific communities, policy-makers, and lay public including individuals and couples experiencing fertility problems? SUMMARY ANSWER: A set of 283 consensus-based and evidence-driven terminologies used in infertility and fertility care has been generated through an inclusive consensus-based process with multiple stakeholders. WHAT IS KNOWN ALREADY: In 2006 the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) published a first glossary of 53 terms and definitions. In 2009 ICMART together with WHO published a revised version expanded to 87 terms, which defined infertility as a disease of the reproductive system, and increased standardization of fertility treatment terminology. Since 2009, limitations were identified in several areas and enhancements were suggested for the glossary, especially concerning male factor, demography, epidemiology and public health issues. STUDY DESIGN, SIZE, DURATION: Twenty-five professionals, from all parts of the world and representing their expertise in a variety of sub-specialties, were organized into five working groups: clinical definitions; outcome measurements; embryology laboratory; clinical and laboratory andrology; and epidemiology and public health. Assessment for revisions, as well as expansion on topics not covered by the previous glossary, were undertaken. A larger group of independent experts and representatives from collaborating organizations further discussed and assisted in refining all terms and definitions. PARTICIPANTS/MATERIALS, SETTING, METHODS: Members of the working groups and glossary co-ordinators interacted through electronic mail and face-to-face in international/regional conferences. Two formal meetings were held in Geneva, Switzerland, with a final consensus meeting including independent experts as well as observers and representatives of international/regional scientific and patient organizations. MAIN RESULTS AND THE ROLE OF CHANCE: A consensus-based and evidence-driven set of 283 terminologies used in infertility and fertility care was generated to harmonize communication among health professionals and scientists as well as the lay public, patients and policy makers. Definitions such as 'fertility care' and 'fertility awareness' together with terminologies used in embryology and andrology have been introduced in the glossary for the first time. Furthermore, the definition of 'infertility' has been expanded in order to cover a wider spectrum of conditions affecting the capacity of individuals and couples to reproduce. The definition of infertility remains as a disease characterized by the failure to establish a clinical pregnancy; however, it also acknowledges that the failure to become pregnant does not always result from a disease, and therefore introduces the concept of an impairment of function which can lead to a disability. Additionally, subfertility is now redundant, being replaced by the term infertility so as to standardize the definition and avoid confusion. LIMITATIONS, REASONS FOR CAUTION: All stakeholders agreed to the vast majority of terminologies included in this glossary. In cases where disagreements were not resolved, the final decision was reached after a vote, defined before the meeting as consensus if passed with 75%. Over the following months, an external expert group, which included representatives from non-governmental organizations, reviewed and provided final feedback on the glossary. WIDER IMPLICATIONS OF THE FINDINGS: Some terminologies have different definitions, depending on the area of medicine, for example demographic or clinical as well as geographic differences. These differences were taken into account and this glossary represents a multinational effort to harmonize terminologies that should be used worldwide. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: N/A.