Effectiveness of a triple-drug regimen for global elimination of lymphatic filariasis: a modelling study.


Lymphatic filariasis is targeted for elimination as a public health problem by 2020. The principal approach used by current programmes is annual mass drug administration with two pairs of drugs with a good safety profile. However, one dose of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) has been shown to clear the transmissible stage of the helminth completely in treated individuals. The aim of this study was to use modelling to assess the potential value of mass drug administration with the triple-drug regimen for accelerating elimination of lymphatic filariasis in different epidemiological settings.


We used three different transmission models to compare the number of rounds of mass drug administration needed to achieve a prevalence of microfilaraemia less than 1% with the triple-drug regimen and with current two-drug regimens.


In settings with a low baseline prevalence of lymphatic filariasis (5%), the triple-drug regimen reduced the number of rounds of mass drug administration needed to reach the target prevalence by one or two rounds, compared with the two-drug regimen. For areas with higher baseline prevalence (10–40%), the triple-drug regimen strikingly reduced the number of rounds of mass drug administration needed, by about four or five, but only at moderate-to-high levels of population coverage (>65%) and if systematic non-adherence to mass drug administration was low.


Simulation modelling suggests that the triple-drug regimen has potential to accelerate the elimination of lymphatic filariasis if high population coverage of mass drug administration can be achieved and if systematic non-adherence with mass drug administration is low. Future work will reassess these estimates in light of more clinical trial data and to understand the effect on an individual country’s programme.

Tracheal Intubation During Adult In-Hospital Cardiac Arrest and Survival.

Key Points

Question  Is tracheal intubation during adult in-hospital cardiac arrest associated with survival?

Findings  In a study of 86 628 adults with in-hospital cardiac arrest using a propensity-matched cohort, tracheal intubation within the first 15 minutes was associated with a significantly lower likelihood of survival to hospital discharge compared with not being intubated (16.3% vs 19.4%, respectively).

Meaning  These findings do not support early tracheal intubation for adult in-hospital cardiac arrest.


Importance  Tracheal intubation is common during adult in-hospital cardiac arrest, but little is known about the association between tracheal intubation and survival in this setting.

Objective  To determine whether tracheal intubation during adult in-hospital cardiac arrest is associated with survival to hospital discharge.

Design, Setting, and Participants  Observational cohort study of adult patients who had an in-hospital cardiac arrest from January 2000 through December 2014 included in the Get With The Guidelines–Resuscitation registry, a US-based multicenter registry of in-hospital cardiac arrest. Patients who had an invasive airway in place at the time of cardiac arrest were excluded. Patients intubated at any given minute (from 0-15 minutes) were matched with patients at risk of being intubated within the same minute (ie, still receiving resuscitation) based on a time-dependent propensity score calculated from multiple patient, event, and hospital characteristics.

Exposure  Tracheal intubation during cardiac arrest.

Main Outcomes and Measures  The primary outcome was survival to hospital discharge. Secondary outcomes included return of spontaneous circulation (ROSC) and a good functional outcome. A cerebral performance category score of 1 (mild or no neurological deficit) or 2 (moderate cerebral disability) was considered a good functional outcome.

Results  The propensity-matched cohort was selected from 108 079 adult patients at 668 hospitals. The median age was 69 years (interquartile range, 58-79 years), 45 073 patients (42%) were female, and 24 256 patients (22.4%) survived to hospital discharge. Of 71 615 patients (66.3%) who were intubated within the first 15 minutes, 43 314 (60.5%) were matched to a patient not intubated in the same minute. Survival was lower among patients who were intubated compared with those not intubated: 7052 of 43 314 (16.3%) vs 8407 of 43 314 (19.4%), respectively (risk ratio [RR] = 0.84; 95% CI, 0.81-0.87; P < .001). The proportion of patients with ROSC was lower among intubated patients than those not intubated: 25 022 of 43 311 (57.8%) vs 25 685 of 43 310 (59.3%), respectively (RR = 0.97; 95% CI, 0.96-0.99; P < .001). Good functional outcome was also lower among intubated patients than those not intubated: 4439 of 41 868 (10.6%) vs 5672 of 41 733 (13.6%), respectively (RR = 0.78; 95% CI, 0.75-0.81; P < .001). Although differences existed in prespecified subgroup analyses, intubation was not associated with improved outcomes in any subgroup.

Conclusions and Relevance  Among adult patients with in-hospital cardiac arrest, initiation of tracheal intubation within any given minute during the first 15 minutes of resuscitation, compared with no intubation during that minute, was associated with decreased survival to hospital discharge. Although the study design does not eliminate the potential for confounding by indication, these findings do not support early tracheal intubation for adult in-hospital cardiac arrest.


Generation of mature T cells from human hematopoietic stem and progenitor cells in artificial thymic organoids

Studies of human T cell development require robust model systems that recapitulate the full span of thymopoiesis, from hematopoietic stem and progenitor cells (HSPCs) through to mature T cells. Existing in vitro models induce T cell commitment from human HSPCs; however, differentiation into mature CD3+TCR-αβ+ single-positive CD8+ or CD4+ cells is limited. We describe here a serum-free, artificial thymic organoid (ATO) system that supports efficient and reproducible in vitrodifferentiation and positive selection of conventional human T cells from all sources of HSPCs. ATO-derived T cells exhibited mature naive phenotypes, a diverse T cell receptor (TCR) repertoire and TCR-dependent function. ATOs initiated with TCR-engineered HSPCs produced T cells with antigen-specific cytotoxicity and near-complete lack of endogenous TCR Vβ expression, consistent with allelic exclusion of Vβ-encoding loci. ATOs provide a robust tool for studying human T cell differentiation and for the future development of stem-cell-based engineered T cell therapies.


Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease.


Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain.


We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years.


At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%).


In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets.


Detection of Atherosclerotic Inflammation by 68Ga-DOTATATE PET Compared to [18F]FDG PET imaging.


Background Inflammation drives atherosclerotic plaque rupture. Although inflammation can be measured using fluorine-18-labeled fluorodeoxyglucose positron emission tomography ([18F]FDG PET), [18F]FDG lacks cell specificity, and coronary imaging is unreliable because of myocardial spillover.

Objectives This study tested the efficacy of gallium-68-labeled DOTATATE (68Ga-DOTATATE), a somatostatin receptor subtype-2 (SST2)-binding PET tracer, for imaging atherosclerotic inflammation.

Methods We confirmed 68Ga-DOTATATE binding in macrophages and excised carotid plaques. 68Ga-DOTATATE PET imaging was compared to [18F]FDG PET imaging in 42 patients with atherosclerosis.


Results Target SSTR2 gene expression occurred exclusively in “proinflammatory” M1 macrophages, specific 68Ga-DOTATATE ligand binding to SST2 receptors occurred in CD68-positive macrophage-rich carotid plaque regions, and carotid SSTR2 mRNA was highly correlated with in vivo 68Ga-DOTATATE PET signals (r = 0.89; 95% confidence interval [CI]: 0.28 to 0.99; p = 0.02). 68Ga-DOTATATE mean of maximum tissue-to-blood ratios (mTBRmax) correctly identified culprit versus nonculprit arteries in patients with acute coronary syndrome (median difference: 0.69; interquartile range [IQR]: 0.22 to 1.15; p = 0.008) and transient ischemic attack/stroke (median difference: 0.13; IQR: 0.07 to 0.32; p = 0.003). 68Ga-DOTATATE mTBRmax predicted high-risk coronary computed tomography features (receiver operating characteristics area under the curve [ROC AUC]: 0.86; 95% CI: 0.80 to 0.92; p < 0.0001), and correlated with Framingham risk score (r = 0.53; 95% CI: 0.32 to 0.69; p <0.0001) and [18F]FDG uptake (r = 0.73; 95% CI: 0.64 to 0.81; p < 0.0001). [18F]FDG mTBRmax differentiated culprit from nonculprit carotid lesions (median difference: 0.12; IQR: 0.0 to 0.23; p = 0.008) and high-risk from lower-risk coronary arteries (ROC AUC: 0.76; 95% CI: 0.62 to 0.91; p = 0.002); however, myocardial [18F]FDG spillover rendered coronary [18F]FDG scans uninterpretable in 27 patients (64%). Coronary 68Ga-DOTATATE PET scans were readable in all patients.

Conclusions We validated 68Ga-DOTATATE PET as a novel marker of atherosclerotic inflammation and confirmed that 68Ga-DOTATATE offers superior coronary imaging, excellent macrophage specificity, and better power to discriminate high-risk versus low-risk coronary lesions than [18F]FDG. (Vascular Inflammation Imaging Using Somatostatin Receptor Positron Emission Tomography)


We provide gene-, cell-, plaque-, and patient-level data demonstrating that SST2 PET imaging using 68Ga-DOTATATE provides a quantifiable, cell-specific marker of atherosclerotic inflammation that outperforms [18F]FDG in the coronary arteries. Further work is needed to confirm these findings in a larger patient population and to compare imaging with clinical outcomes. 68Ga-DOTATATE PET offers measurement of both generalized atherosclerotic disease activity and detailed information about local plaque functional phenotype to complement multimodal assessments of anatomic, morphologic, and hemodynamic disease severity. This approach, in selected patient populations, has the potential to improve CVD risk prediction, allowing personalized tailoring of therapies aimed to improve clinical outcomes.


Should healthcare professionals breach confidentiality when a patient is unfit to drive? 

While all are deeply sympathetic to the victims of road crashes, it is also important that we practice medicine that is evidence-based and supported by principles of public health. Among the many problems with mandatory reporting of medical conditions relevant to driving is the fact that it simply does not work, whether for epilepsy (1), dementia (2) or obstructive sleep apnoea (3) among other conditions. Indeed, there was less reporting of epilepsy in a state with a mandatory reporting regulation than in a state without one (1). The problem of lack of efficacy is compounded by the potential breach in clinician-patient relationship and trust, which may lead to avoidance of seeking treatment which reduce the risk to drivers and the general public.

The one condition for which further study might be helpful in considering mandatory reporting in terms of scale, relevance and major impact on road safety is that of alcohol and substance misuse and dependence. Worryingly, there is much less research in the biomedical literature on this topic (4), and due consideration would need to be given as to whether current guidelines of relatively long periods of driving cessation in many jurisdictions are appropriate in terms of ensuring congruence between mandatory reporting, effective treatment strategies and a due balance between safety and mobility.

Solutions to reducing the relatively modest impact (in public health terms) of other medical conditions on road safety include public campaigns to remind drivers of their responsibility for monitoring and maintaining their own health as well as following professional advice. This needs to be allied to stringent penalties for driving against appropriate professional advice, as occurred in this tragic case. In addition, it is of concern that traffic medicine occupies such a low or absent profile in medical school curricula (4), and it is important all doctors and related healthcare professionals attain a core competence in assessing medical fitness to drive within their scope of practice.

1. Drazkowski JF, Neiman ES, Sirven JI, McAbee GN, Noe KH. Frequency of physician counseling and attitudes toward driving motor vehicles in people with epilepsy: comparing a mandatory-reporting with a voluntary-reporting state. Epilepsy Behav. 2010 Sep;19(1):52-4.
2. Herrmann N, Rapoport MJ, Sambrook R, Hébert R, McCracken P, Robillard A; Canadian Outcomes Study in Dementia (COSID) Investigators.. Predictors of driving cessation in mild-to-moderate dementia. CMAJ. 2006 Sep 12;175(6):591-5.
3. Elgar NJ, Esterman AJ, Antic NA, Smith BJ. Self-Reporting by Unsafe Drivers Is, with Education, More Effective than Mandatory Reporting by Doctors. J Clin Sleep Med. 2016 Mar;12(3):293-9.
4. Mello MJ, Nirenberg TD, Lindquist D, Cullen HA, Woolard R. Physicians’ attitudes regarding reporting alcohol-impaired drivers. Subst Abus. 2003 Dec;24(4):233-42.
5. Hawley CA, Galbraith ND, deSouza VA. Medical education on fitness to drive: a survey of all UK medical schools. Postgrad Med J. 2008 Dec;84(998):635-8.



Sexually Dimorphic Changes of Hypocretin (Orexin) in Depression.


Hypocretin (orexin) changes were studied in human postmortem brain in depression.

A clear sex-related change was found in the hypothalamic hypocretin-1-immunoreactivity in depression.

A rat depression model did not reflect the changes in the hypocretin system in the human brain in depression.

The stress systems of depressed patients are put into a higher gear by genetic and developmental factors. Over-reaction of these systems to stressful environmental situations makes people vulnerable to depression and suicide. This is the first postmortem study on changes in a relatively novel stress system in depression, consisting of the hypothalamic hypocretin neurons and hypocretin receptors in the prefrontal cortex. A clear sex-related change was found in the hypothalamic hypocretin-1-immunoreactivity in depression. Evaluation of the hypocretin system in a frequently used depression animal model, i.e. chronic unpredictable mild stress rats, did not replicate changes found in the hypocretin systems in the human brain in depression.



Neurophysiological and behavioral processes regulated by hypocretin (orexin) are severely affected in depression. However, alterations in hypocretin have so far not been studied in the human brain. We explored the hypocretin system changes in the hypothalamus and cortex in depression from male and female subjects.


We quantified the differences between depression patients and well-matched controls, in terms of hypothalamic hypocretin-1 immunoreactivity (ir) and hypocretin receptors (Hcrtr-receptors)-mRNA in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex. In addition, we determined the alterations in the hypocretin system in a frequently used model for depression, the chronic unpredictable mild stress (CUMS) rat.


i) Compared to control subjects, the amount of hypocretin-immunoreactivity (ir) was significantly increased in female but not in male depression patients; ii) hypothalamic hypocretin-ir showed a clear diurnal fluctuation, which was absent in depression; iii) male depressive patients who had committed suicide showed significantly increased ACC Hcrt-receptor-2-mRNA expression compared to male controls; and iv) female but not male CUMS rats showed a highly significant positive correlation between the mRNA levels of corticotropin-releasing hormone and prepro-hypocretin in the hypothalamus, and a significantly increased Hcrt-receptor-1-mRNA expression in the frontal cortex compared to female control rats.


The clear sex-related change found in the hypothalamic hypocretin-1-ir in depression should be taken into account in the development of hypocretin-targeted therapeutic strategies.


Our study shows, for the first time in postmortem human brain, that hypothalamic hypocretin/orexin is increased in female – but not in male – depressive patients. In addition, there was a diurnal fluctuation in hypothalamic hypocretin-1-ir in the control subjects, which was absent in depression. Moreover, we observed that Hcrt-receptor-mRNA expression showed differences in the ACC and DLPFC depending on age. Male depressive patients who had committed suicide had significantly increased ACC Hcrt-receptor-2-mRNA expression. Our data thus indicate sex-, brain area-, age-, and potentially suicide-related changes in the hypocretin/orexin system in depression. Finally, a significant positive correlation between hypothalamic CRH-mRNA and prepro-hypocretin-mRNA and a significant increase in Hcrt-receptor-1-mRNA expression in the frontal cortex in female – but not male – CUMS rats strengthen the presence of sexually dimorphic hypocretin/orexin system changes in mood disorder.

4.1. Hypocretin-ir in the Hypothalamus in Depression

It should be noted that the increased IOD of hypocretin-ir may indicate an increase in either hypocretin-expressing neuron number (related to the area stained) and/or staining intensity (measured as OD). An increase of either of these parameters indicates an increased expression of hypocretin protein levels. The significantly increased hypocretin-ir in female depressive patients indicates that hypocretin may play a key role in the etiology of depression, which is more prevalent in females than in males (Piccinelli and Wilkinson, 2000). As we have indicated in the Introduction section, studies have found that Hcrt-receptor-1 gene, or a linked locus, may modulate the risk for mood disorders (Rainero et al., 2011) and Hcrt-receptor-1 gene knockout mice showed increased anxiety-like behavior and altered depression-like behaviors (Abbas et al., 2015). One may thus speculate that the higher levels of hypocretin-1-ir in female patients may enhance depressive symptoms. It should be noted that since all the female subjects studied in our study were in their postmenopausal stage, one would not expect to see the hot flash-related hypocretin changes reported earlier (Federici et al., 2016).

The sex difference in the alterations of hypocretin, which happens in the framework of the stress-hypothesis, was further supported by our animal study, showing a significant positive correlation between hypothalamic prepro-hypocretin-mRNA and CRH-mRNA only in female CUMS rats. In view of this, it is of interest to note that the dual Hcrt-receptor antagonist almorexant was found to prevent HPA axis dysregulation caused by CUMS and offers evidence for the possibility that pharmacological blockade of the hypocretin system induces a robust antidepressant-like effect as well as the restoration of the stress-related HPA axis defect (Nollet et al., 2012). It should be noted, however, that other animal models of depression showed different results in terms of changes in the hypocretin system, such as the genetically depressed Wistar-Kyoto male rats, which showed a lower number and size of hypocretin-1 neurons than its control Wistar male rats (Allard et al., 2004). In another genetically depressed rat model, i.e. the Flinders Sensitive Line (FSL), the number of hypothalamic hypocretin-positive neurons was higher in female FSL rats than in the female control rats, i.e. Flinders Resistant Line (FRL) although this publication by Mikrouli et al. offers no data on male rats (Mikrouli et al., 2011). It is a frequent phenomenon that animal models tend to mimic “just a few symptoms rather than a complete psychiatric disorder”. This is a reason to validate the data obtained in animal models on human postmortem material.

We found a clear day-night fluctuation in hypothalamic hypocretin-1-ir in the control subjects, with higher levels at night, which is similar to the pattern reported for lumbar puncture CSF hypocretin-1 levels obtained by continuous in vivo sampling (Salomon et al., 2003). These findings are in agreement with the concept that hypocretin neurons may play a key role in sleep-wake regulation (Saper, 2013), and the absence of the day-night hypocretin-1-ir fluctuation in depression may thus relate to the frequently occurring symptoms of sleep disorders in this condition. It should be noted that in our earlier research we demonstrated a clear diurnal rhythm in the biological clock, the suprachiasmatic nucleus (SCN), for its main neuropeptide, vasopressin, both on the protein level (Hofman et al., 1993) and on the mRNA level (Zhou et al., 2001) in postmortem material, when the patients were grouped according to time of death. Interestingly, a direct projection from the SCN onto the hypocretin neurons was observed in the brains of rat and human (Abrahamson et al., 2001), which indicates that the SCN may directly regulate the function of hypocretin-immunoreactive neurons. Our finding of the absence of a diurnal hypocretin rhythm in depression agrees with our earlier observation of a diminished SCN function in depression (Zhou et al., 2001). Our data (Zhou et al., 2001) and those of others (Li et al., 2013) thus also show that postmortem studies can indeed reflect the day-night fluctuations during life.

It is of interest to note that in rats the maximal activity of the hypocretin system takes place in their active period, i.e. at night (Mileykovskiy et al., 2005 ;Yoshida et al., 2001) Surprisingly, we found the highest hypocretin-1-ir levels in the human hypothalamus at night. However, this observation agrees with two human studies that reported the lowest CSF hypocretin levels during the daytime (Salomon et al., 2003 ;Grady et al., 2006). This means that the nocturnal elevation of hypocretin-1-ir in the hypothalamus is not simply due to a lack of transport or secretion. A similar phenomenon was observed for melatonin, which is also involved in sleep-wake control: in rats, melatonin levels increase during the dark period (their active phase) and decrease during the light period (rest phase) (Gutjahr et al., 2004), while in humans its levels increase during the dark period (rest phase) and decrease during the light period (active phase) (Zeitzer et al., 2007). The possibility that the diurnal regulation systems act in a different way in a diurnal and a nocturnal species (such as rodents) warrants further investigation.

A recent study showed an age-related decline in the number of hypothalamic hypocretin neurons in the range from 0 to 60 years of age in control subjects (Hunt et al., 2015). We did not find such a correlation, but it should be noted that, unlike in the study by others, the control subjects we studied did not contain very young ages.

4.2. PFC Hcrt-receptors in Depression and in Relation to Suicide

Earlier, our group found, with NBB cortex samples (depression patients without suicide), that the ACC seems to be more vulnerable than the DLPFC to alterations in depression-related molecules, such as nitric oxide synthase, gamma-aminobutyric acid and glutamate (Gao et al., 2013 ;Zhao et al., 2012). In our study, with NBB cortex samples, again we observed a trend for lower Hcrt-receptor-1-mRNA expression in the ACC in depression but no changes in Hcrt-receptors in the DLPFC. The novel finding with SMRI cortex samples (containing depressive patients who committed suicide or died of causes other than suicide) that there was a significantly increased Hcrt-receptor-2-mRNA expression in the ACC, but not in the DLPFC, in male MDD patients who had committed suicide is in agreement with previous findings that the ACC is more vulnerable to suicide than the DLPFC (Zhao et al., 2012 ;  Drevets et al., 2008) and that there is a sex difference in the prevalence of suicide (Maguen et al., 2015). Our data concerning increased ACC Hcrt-receptor-2-mRNA expression in male suicide patients are thus interesting, although too limited for a final conclusion. They do represent, however, a strong rationale for further studies on this topic. Finally, the decreased Hcrt-receptor-1-mRNA expression with aging we observed in the DLPFC may at least partly explain the findings that in SMRI cortex samples (younger) both Hcrt-receptors were detectable in ACC and DLPFC, while in the NBB series (older) Hcrt-receptor-1-mRNA expression was only detectable in ACC and Hcrt-receptor-2-mRNA expression was only detectable in the DLPFC.

Some concerns of the present postmortem brain material study should be mentioned. We did not find significant differences in the hypothalamic hypocretin-1-ir expression between MDD and BD patients, which is in accordance with our previous findings for CRH, AVP and OXT and for receptors in the hypothalamus (Bao et al., 2005 ;  Wang et al., 2008), although a final conclusion on this phenomenon should be based upon a larger sample size. Secondly, one of the inherent potential confounding factors in a postmortem study is medication use. However, we do not think that our main conclusions are cofounded by antidepressants, since increased hypothalamic hypocretin-1-ir was only observed in female depressive patients and increased expression of Hcrt-receptor-2-mRNA in the ACC was only observed in male depressive suicides, although all the depressive groups had been on antidepressants. In addition, animal studies showed that benzodiazepines (Panhelainen and Korpi, 2012), haloperidol (Dalal et al., 2003) and fluoxetine (Nollet et al., 2011), taken by the depressive patients in the present study, may inhibit hypocretin neurons and/or decrease hypocretin levels. Therefore, had antidepressants interfered with our measurements, this would have led to an underestimation of the increased hypocretin-1 levels observed in female depressive patients. It is noted that Calegare et al. found that sub-chronic treatment of adult malerats with fluoxetine increased the levels of prepro-hypocretin mRNA in the hypothalamus without affecting the hypocretin-1 CSF levels ( Calegare et al., 2016). In our study, there were 2 out of 10 male depression patients who had taken fluoxetine, while their hypothalamic hypocretin-1-ir levels (IOD: 0.128 and 0.134) were fully within the range of the other male depression patients (IOD range from 0.103 to 0.248, median value 0.166). Finally, it should also be noted that the Hcrt-receptor data are based upon mRNA measurements and have yet to be confirmed on the protein level.

5. Conclusions

A clear sex-related change was found in the hypothalamic hypocretin-1-ir in depression. The CUMS rat depression model did not replicate changes found in the hypocretin systems in the human brain in depression. Since sex-related changes in hypothalamic hypocretin-1-ir expression were observed in depression, this factor should be taken into account in the development of hypocretin-targeted therapeutic strategies.


Work organization and mental health problems in PhD students


One in two PhD students experiences psychological distress; one in three is at risk of a common psychiatric disorder.

The prevalence of mental health problems is higher in PhD students than in the highly educated general population, highly educated employees and higher education students.

Work and organizational context are significant predictors of PhD students’ mental health.


Research policy observers are increasingly concerned about the potential impact of current academic working conditions on mental health, particularly in PhD students. The aim of the current study is threefold. First, we assess the prevalence of mental health problems in a representative sample of PhD students in Flanders, Belgium (N = 3659). Second, we compare PhD students to three other samples: (1) highly educated in the general population (N = 769); (2) highly educated employees (N = 592); and (3) higher education students (N = 333). Third, we assess those organizational factors relating to the role of PhD students that predict mental health status. Results based on 12 mental health symptoms (GHQ-12) showed that 32% of PhD students are at risk of having or developing a common psychiatric disorder, especially depression. This estimate was significantly higher than those obtained in the comparison groups. Organizational policies were significantly associated with the prevalence of mental health problems. Especially work-family interface, job demands and job control, the supervisor’s leadership style, team decision-making culture, and perception of a career outside academia are linked to mental health problems.


Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, dose-escalation study.



Roughly 70–80% of patients with advanced stage Hodgkin’s lymphoma are cured with various first-line and second-line treatments, including ABVD, BEACOPP, and stem-cell transplantation. Brentuximab vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin’s lymphoma. We aimed to assess the safety and early clinical efficacy of this drug as first-line treatment in combination with standard or modified-standard treatment in patients with previously untreated Hodgkin’s lymphoma.


We did a phase 1, open-label, dose-escalation safety study comparing brentuximab vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment. Patients were enrolled into the groups sequentially. Main entry criteria were newly diagnosed, treatment-naive, CD30-positive patients with Hodgkin’s lymphoma who had histologically confirmed stage IIA bulky disease or stage IIB–IV disease and an Eastern Cooperative Oncology Group performance status of two or less. Patients received doses of 0·6, 0·9, or 1·2 mg/kg brentuximab vedotin by intravenous infusion every 2 weeks with either ABVD (25 mg/m2 doxorubicin, 10 units/m2 bleomycin, 6 mg/m2 vinblastine, and 375 mg/m2 dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin) for up to six cycles. Our primary objectives were to assess the safety profile and establish the maximum tolerated dose (MTD) of brentuximab vedotin in combination with ABVD and AVD. The safety profile and MTD was assessed for the safety population. The study has completed and the final analysis is presented. This study was registered with ClinicalTrials.gov, number NCT01060904.


Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab vedotin. The maximum tolerated dose of brentuximab vedotin when combined with ABVD or AVD was not exceeded at 1·2 mg/kg. 21 (95%) of 22 patients given brentuximab vedotin and ABVD achieved complete remission, as did 24 (96%) of 25 patients given brentuximab vedotin and AVD. Adverse events were generally grade 1 or 2; however, an unacceptable number of patients in the brentuximab vedotin and ABVD groups had pulmonary toxic effects (11 [44%] of 25), which exceeded the historical incidence for ABVD alone. No patients experienced pulmonary toxic effects when treated with brentuximab vedotin plus AVD. The most common grade 3 or worse events were neutropenia (20 [80%] of 25 patients in the brentuximab vedotin and ABVD group vs 20 [77%] of 26 patients in the brentuximab vedotin and AVD group), anaemia (five [20%] vs three [12%]), febrile neutropenia (five [20%] vs two [8%]), pulmonary toxic effects (six [24%] vs 0), syncope (three [12%] vstwo [8%]), dyspnoea (three [12%] vs one [4%]), pulmonary embolism (three [12%] vs 0), fatigue (one [4%] each), and leucopenia (one [4%] each). Serious events occured in 41% of all patients (14 [56%] in the brentuximab vedotin and ABVD group and seven [27%] in the brentuximab vedotin and AVD group). Serious events occurring in 10% of patients or more overall were febrile neutropenia (four [16%] in the brentuximab vedotin and ABVD group vs two [8%] in the brentuximab vedotin and AVD group), and, in the brentuximab vedotin and ABVD group only, pulmonary toxic effects (six [24%]).


Brentuximab vedotin should not be given with bleomycin in general or specifically as first-line therapy for patients with treatment naive, advanced stage Hodgkin’s lymphoma. 1·2 mg/kg brentuximab vedotin combined with AVD given every 2 weeks was generally well tolerated by patients. At present, a phase 3 trial comparing brentuximab vedotin plus AVD to ABVD alone is ongoing (ClinicalTrials.gov, number NCT01712490) and will formally assess whether brentuximab vedotin plus AVD might redefine therapy in treatment-naive patients with Hodgkin’s lymphoma.


Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning. 


Drugs that modulate serotonin (5-HT) synaptic concentrations impact neurogenesis and hippocampal (HPC)-dependent learning. The primary objective is to determine the extent to which psilocybin (PSOP) modulates neurogenesis and thereby affects acquisition and extinction of HPC-dependent trace fear conditioning. PSOP, the 5-HT2A agonist 25I-NBMeO and the 5-HT2A/C antagonist ketanserin were administered via an acute intraperitoneal injection to mice. Trace fear conditioning was measured as the amount of time spent immobile in the presence of the conditioned stimulus (CS, auditory tone), trace (silent interval) and post-trace interval over 10 trials. Extinction was determined by the number of trials required to resume mobility during CS, trace and post-trace when the shock was not delivered. Neurogenesis was determined by unbiased counts of cells in the dentate gyrus of the HPC birth-dated with BrdU co-expressing a neuronal marker. Mice treated with a range of doses of PSOP acquired a robust conditioned fear response. Mice injected with low doses of PSOP extinguished cued fear conditioning significantly more rapidly than high-dose PSOP or saline-treated mice. Injection of PSOP, 25I-NBMeO or ketanserin resulted in significant dose-dependent decreases in number of newborn neurons in hippocampus. At the low doses of PSOP that enhanced extinction, neurogenesis was not decreased, but rather tended toward an increase. Extinction of “fear conditioning” may be mediated by actions of the drugs at sites other than hippocampus such as the amygdala, which is known to mediate the perception of fear. Another caveat is that PSOP is not purely selective for 5-HT2A receptors. PSOP facilitates extinction of the classically conditioned fear response, and this, and similar agents, should be explored as potential treatments for post-traumatic stress disorder and related conditions.