Paralytic rabies following cat scratch and intra-dermal anti-rabies vaccination


Abstract

Only few reports of failure of intradermal postexposure prophylaxis for rabies following cat scratch exist in the published literature. We are reporting such a case in a 15-year-old girl. The child had category III cat scratch on her face. She presented with progressive paralysis, finally developing quadriplegia and respiratory paralysis. Typical hydrophobia and aerophobia were absent. She received intra-dermal anti-rabies cell culture vaccine. She did not receive anti-rabies immunoglobulin. The girl succumbed on the 10thday of weakness. Diagnosis of rabies was confirmed by isolation of rabies virus RNA in cerebrospinal fluid and skin biopsy sample by reverse transcription polymerase chain reaction.

Introduction

Rabies is a fatal neuropathogenic disease caused by the rabies virus. Rabies can manifest as furious or paralytic forms in humans and dogs. Limbic signs dominate the clinical picture in the former whereas a paralysis of lower motor neuron type dominates the latter. Most (96%) of the human rabies cases are following dog bite.[1] The diagnosis of rabies is not difficult if it presents with classical symptoms of excitations or phobias. However, it poses a diagnostic challenge when presented as acute flaccid paralysis (AFP). We report a case of paralytic rabies following intradermal anti-rabies vaccine, following cat scratch.

Case Report

A 15-year-old girl was brought with the complaints of fever of 5 days, headache and vomiting of 4 days, weakness of bilateral lower limbs, followed by upper limbs, change in voice and nasal regurgitation of feeds since 2 days. Child had tachycardia, shallow respiration with paradoxical movement of the chest wall. Glasgow coma scale was 15/15. Gag reflex was absent with pooling of secretions and absence of movements of soft palate and uvula. Power in bilateral upper and lower limbs was 1/5 (Medical Research Council Grade). Other systemic examination was normal. Child was mechanically ventilated at admission in view of respiratory failure. Initially, a diagnosis of brainstem encephalitis was made. A diagnosis of brain stem mass lesion was also considered. Mother gave history of unprovoked cat scratch over the face 2 months back. She was immunized with a complete course of intradermal cell culture anti-rabies vaccine first dose started on day 2 of cat scratch. Updated Thai Red Cross schedule (2-2-2-2-2) was used for intra dermal vaccination. Cat scratch was not cleaned. Cat was bitten by a rabid dog according to the mother. Rabies immunoglobulin (RIG) was not given. Provisional diagnosis of paralytic rabies was made on the basis of paralysis with history of cat scratch. Although rare with the modern cell culture vaccines, the possibility of vaccine-induced GBS was also considered.

Laboratory investigations revealed normal complete blood counts, serum electrolytes, liver and kidney function tests. Cerebrospinal fluid (CSF) analysis showed 412 cells with 10% neutrophils and 90% lymphocytes with sugar of 62 mg/dl. Computed tomography brain was normal. Rabies virus RNA was detected in CSF and skin biopsy samples by reverse transcription polymerase chain reaction. Neutralizing antibodies to rabies virus were detected in both serum and CSF by the rapid fluorescent focus inhibition test.

Conservative management was started, but rapid progression with respiratory paralysis occurred over the next 2 days. There was no improvement and the patient succumbed on the 10th day of onset of the disease.

Discussion

Rabies is an important public health problem in India. About 55,000 human deaths occur due to rabies annually worldwide; about 36% of these deaths occur in India. Most animal bites in India (96%) are by dogs.[1] The disease infects domestic and wild animals, and is spread to people through close contact with infected saliva via bites or scratches. Our case had history of cat scratch over the face.

There are two forms of human rabies: (1) The well-known encephalitic (furious) and (2) the paralytic (dumb) rabies. The encephalitic form starts with fever, malaise, pharyngitis, and paraesthesia at the site of the bite, followed by the classical neurological symptoms of hydrophobia, aerophobia, agitation, hypersalivation, and seizures. This is followed by paralysis and coma; death is usually due to respiratory failure. The second clinical form of rabies, paralytic (dumb) or Guillain-Barre-like, is characterized by progressive paralysis without an initial furious phase. Even though, the paralytic rabies is unfamiliar to health care providers, 20-30% of rabies victims present in this manner.[2]

Paralytic rabies is more common after rabid vampire bat bites and in persons who have received post-exposure vaccination.[3] Studies conducted in the United States by the Center for Disease Control and Prevention have documented that a regimen of one dose of RIG and five doses of the human diploid cell culture vaccine (HDCV) over a period of 28 days was safe and induced an excellent antibody response in all recipients.[4] Clinical trials with rabies vaccine adsorbed and purified chick embryo cell vaccine have also demonstrated immunogenicity equivalent to that of HDCV.[5] Occasional failure has been reported with cell culture vaccines due to incorrect administration. Many individuals did not receive immunoglobulin where indicated, and some of them received the vaccine in the gluteal region instead of in the deltoid.[6] Although our patient had grade III cat scratch for which RIG is strongly recommended, she only received the vaccine in the deltoid region without RIG. This was most probably the cause of vaccine failure.

Neurological reactions following newer vaccine administration have been extremely rare. After millions of vaccinations worldwide, three Guillain-Barre type paralytic reactions have been described, and all cases recovered completely.[7,8] Rare findings in our case are paralytic rabies following cat scratch and development rabies after administration of intradermal rabies vaccine. The limitation of our report was that we were not able to do magnetic resonance imaging of brain and nerve conduction studies. Paralytic rabies should be considered if any child presenting with AFP with brain stem symptoms and signs, even if they had already received anti-rabies vaccination and also following cat scratch. Most rapidly immunogenic vaccine regimen should be used in patients at high risk, especially if RIG has not been given.

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Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias


Abstract

We previously showed that Th1/type 1 inflammation marked by increased IFN-γ levels in the airways can be appreciated in 50% of patients with severe asthma, despite high dose corticosteroid (CS) treatment. We hypothesized that a downstream target of IFN-γ, CXCL10, which recruits Th1 cells via the cognate receptor CXCR3, is an important contributor to Th1highasthma and CS unresponsiveness. We show high levels of CXCL10 mRNA closely associated with IFNG levels in the BAL cells of 50% of severe asthmatics and also in the airways of mice subjected to a severe asthma model, both in the context of high-dose CS treatment. The inability of CS to dampen IFNG or CXCL10 expression was not because of impaired nuclear translocation of the glucocorticoid receptor (GR) or its transactivational functions. Rather, in the presence of CS and IFN-γ, STAT1 and GR were recruited on critical regulatory elements in the endogenous CXCL10 promoter in monocytes, albeit without any abatement of CXCL10 gene expression. High CXCL10 gene expression was also associated with a mast cell signature in both humans and mice, CXCR3 being also expressed by mast cells. These findings suggest that the IFN-γ–CXCL10 axis plays a central role in persistent type 1 inflammation that may be facilitated by CS therapy through GR-STAT1 cooperation converging on the CXCL10 promoter.

Introduction

Asthma is a disease with significant prevalence and morbidity throughout the developed world, affecting nearly 5%–10% of populations (1). It is increasingly recognized that asthma is a disease with multiple phenotypes, each with its own unique molecular mechanisms, natural history, and response to therapy (23). Corticosteroids (CS) have remained the mainstay of therapy, but for many patients, these therapies are ineffective (4), and research of underlying mechanisms may give insight into the etiologies of CS resistance and identify future therapeutic targets.

Our previous studies have shown that the number of Th1 cells, which produce IFN-γ, is elevated in approximately 50% of severe asthma (SA) patients and in our mouse model of SA (5), and increased IFNG mRNA levels are also evident in the airways of these subjects (6). Furthermore, IFN-γ was associated with increased airway hyperreactivity (AHR) and poor CS response (5). A high Th1/IFN-γ response in any tissue is typically induced during infections by bacteria and viruses (7). Infections by viruses (rhinovirus being the most common) and bacteria have been observed in patients with SA and can trigger asthma exacerbations (7). Several bacterial species have also been associated with severe disease (8). Once generated in lung-draining lymph nodes, Th1 cells need to be recruited to the site of infection, and the best known chemoattractant for Th1 cells is CXCL10 (9), initially cloned as an IFN-γ–induced molecule from monocytes (10). Additional chemokines that belong to the same family induced by IFN-γ include CXCL9 and CXCL11, although CXCL10 is the most studied (11). While there is significant redundancy in their effects, the expression of the 3 family members is not uniform in disease settings, including allergic disease (1112).

In this study, we sought to better understand the possible etiologies of this resistance to CS therapy, and as such, we focused on CXCL10, given its role in recruiting Th1 cells to reinforce type 1 inflammation to combat and eliminate viral and bacterial pathogens, a function that when uncontrolled can lead to significant pathology (13). The expression of CXCL10 can be induced not only by IFN-γ, but also by additional stimuli, including LPS, which can lead to differential levels of CXCL10 production and response to therapies (111416). In addition to its expression on Th1 cells, the CXCR3 receptor — which mediates chemoattraction by CXCL10 and its family members — is also present on mast cells (17), neutrophils (18), and eosinophils (19). Elevated CXCL10 levels have been detected in multiple compartments, including blood and bronchoalveolar lavage (BAL) in mild and atopic asthma (2022) and may be increased during asthma exacerbations (23). CXCL10 can be secreted by multiple cell types, including airway epithelial cells, smooth muscle cells, monocytes, and macrophages (11). However, several studies have implicated monocytes/macrophages as possible drivers of CXCL10 expression in asthma (2425).

Given its association with IFN-γ, we asked whether CXCL10 may be a contributor to steroid resistance in SA. Here, we show high levels of CXCL10 mRNA closely associated with IFNGlevels in the airways of 50% of SA subjects and in mice subjected to our SA model, both in the context of high-dose CS treatment. Our investigation of possible impairment of glucocorticoid receptor (GR) function in the presence of IFN-γ showed no such impairment with preservation of nuclear translocation and transactivational functions of GR. However, as revealed using ChIP assay, in the presence of CS and IFN-γ, we observed simultaneous enrichment of STAT1 and GR on critical regulatory elements in the endogenous CXCL10 promoter in monocytes; importantly, this did not cause inhibition of CXCL10 expression at either mRNA or protein levels. In contrast, CS inhibited LPS-induced binding of NF-κB to the CXCL10 promoter and inhibited LPS-induced CXCL10 gene expression, showing selective impairment of CS-mediated suppression in the presence of IFN-γ. High CXCL10 gene expression was also associated with markers of mast cells in the airways of severe asthmatics, consistent with known human mast cell expression of CXCR3. Taken together, these findings suggest that the IFN-γ/CXCL10 axis is prominent in CS-refractory disease. Increased expression of both IFN-γ and the chemokine that recruits IFN-γ–producing Th1 cells may establish a persistent type 1 inflammation that may actually worsen with CS therapy through GR-STAT1 cooperation in promoting CXCL10 gene expression.

Source:insight.jci.org

 

Constructing the cyber-troll: Psychopathy, sadism, and empathy


Highlights

Trolling is an online antisocial behaviour with negative psychological outcomes.

Current study predicted trolling perpetration from gender and personality.

Trolls more likely to be male with high levels of trait psychopathy and sadism

Trolls have lower affective empathy, and psychopathy moderates cognitive empathy.

Results have implications for establishing education and prevention programs.


Abstract

Online trolling is of particular concern due to the harmful negative outcomes its victims experience. The current study sought to explore and extend the personality profile of Internet trolls. After gender was controlled for, psychopathy, sadism, and empathy (affective empathy, cognitive empathy, and social skills) were examined for their predictive utility of trolling behaviour. A sample of 415 participants (36% men, 63% women, 1% other) with a mean age of 23.37 years (SD = 7.19) completed an online questionnaire. Results showed that men were more likely than women to engage in trolling, and higher levels of trait psychopathy and sadism predicted trolling behaviour. Lower levels of affective empathy predicted perpetration of trolling, and trait psychopathy moderated the association between cognitive empathy and trolling. Results indicate that when high on trait psychopathy, trolls employ an empathic strategy of predicting and recognising the emotional suffering of their victims, while abstaining from the experience of these negative emotions. Thus, trolls appear to be master manipulators of both cyber-settings and their victims’ emotions.

Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids


Abstract

The calcium channel of sperm (CatSper) is essential for sperm hyperactivated motility and fertility. The steroid hormone progesterone activates CatSper of human sperm via binding to the serine hydrolase ABHD2. However, steroid specificity of ABHD2 has not been evaluated. Here, we explored whether steroid hormones to which human spermatozoa are exposed in the male and female genital tract influence CatSper activation via modulation of ABHD2. The results show that testosterone, estrogen, and hydrocortisone did not alter basal CatSper currents, whereas the neurosteroid pregnenolone sulfate exerted similar effects as progesterone, likely binding to the same site. However, physiological concentrations of testosterone and hydrocortisone inhibited CatSper activation by progesterone. Additionally, testosterone antagonized the effect of pregnenolone sulfate. We have also explored whether steroid-like molecules, such as the plant triterpenoids pristimerin and lupeol, affect sperm fertility. Interestingly, both compounds competed with progesterone and pregnenolone sulfate and significantly reduced CatSper activation by either steroid. Furthermore, pristimerin and lupeol considerably diminished hyperactivation of capacitated spermatozoa. These results indicate that (i) pregnenolone sulfate together with progesterone are the main steroids that activate CatSper and (ii) pristimerin and lupeol can act as contraceptive compounds by averting sperm hyperactivation, thus preventing fertilization.

Discussion

Our results demonstrate that testosterone, estrogen, and hydrocortisone alone did not activate CatSper but that they reduce or prevent CatSper activation by progesterone (P4). In the case of testosterone and hydrocortisone, the effects were the strongest with a significant inhibition of P4-mediated CatSper stimulation under physiological concentrations of either steroid. One possibility for this effect could be that testosterone binds with a much higher affinity to ABHD2 than P4, thereby preventing CatSper activation. The blood serum concentration of P4 in men is about 2 nM (22), whereas the minimum concentration needed for CatSper activation is 10 pM, with an EC50 of 7.7 nM (3). Testosterone blocked CatSper activation even in the presence of 1 µM P4 with an IC50 of 429 nM, which is within the physiological range, as testosterone concentrations reach 2 µM in the blood plasma of men (23). CatSper can also be activated by PregS, which can reach high concentrations in male reproductive tissues. However, testosterone also inhibits CatSper response to PregS by shifting its EC50 10-fold to 172 nM. Therefore, even if sperm are exposed to elevated concentrations of PregS, high concentrations of testosterone in the male genital tract prevent premature CatSper activation by P4, or even PregS. It is therefore possible that testosterone acts as an anticapacitation factor by preventing CatSper activation until it is removed in the female reproductive tract, presumably by chelation with albumin.

Resting serum E2 levels in women are about 110 pM, which peak at ovulation to concentrations of around 403 pM (24). Therefore, sperm encounter an E2-enriched milieu in the uterus and the fallopian tube. Our results show that E2 did not alter resting CatSper currents but that it also did not allow full channel activation by P4. We assume that elevated levels of E2 during ovulation render CatSper in its closed state to prevent premature calcium influx and thus sperm activation. However, the significantly weaker IC50 for E2 of 833 nM indicates that E2 acts as a much less potent P4 antagonist. Right after ovulation, E2 levels decrease, whereas P4 concentrations surge to ∼7 nM (24) in the blood. Because cumulus cells surrounding the oocyte also secrete P4 (2528), sperm travel through a P4 gradient with maximal concentrations in close proximity to the egg. It is therefore possible that P4 outcompetes E2, leading to CatSper activation, as P4 is the natural E2 antagonist (29).

Various conditions, such as stress and elevated levels of glucocorticoids, particularly hydrocortisone, are known to impair male fertility (16) by either inhibiting spermatogenesis (30) or reducing sperm counts and sperm motility (31). Stress and elevated hydrocortisone levels can also affect female fertility. One study shows that in women who underwent in vitro fertilization, baseline urine cortisol levels increased from ∼230 nM to ∼500 nM (32). According to our results, hydrocortisone blocked CatSper activation by P4 with an IC50 of 153 nM. It is therefore possible that elevated levels of stress hormones in the female genital tract impair not only early stages but also late stages of sperm acquisition of their fertilizing potential, thus significantly contributing to infertility.

Another interesting candidate among the hormones tested in this study was the sulfated neurosteroid PregS, as it stimulates CatSper currents via the P4-related pathway. Although significant, the response to PregS was not as pronounced as the response to P4 and the EC50 of PregS was twofold higher than the EC50 of P4 [15 nM vs. 7 nM (3)]. Nevertheless, we show that PregS acted via an ABHD2 mechanism to activate CatSper—the same mechanism of channel activation as demonstrated for P4 (7). These findings identify PregS as the third steroid hormone to exert nongenomic actions on CatSper apart from P4 and its close analog 17-OH-P4 (3533) and demonstrate the importance of sulfated steroids to regulate physiological processes in human sperm. Even though the concentrations of PregS in human testes are higher than those of pregnenolone (51 μg/100 g tissue) (34), it is unclear whether elevated concentrations of PregS exist within the entire testis or only in specific domains. Because testosterone inhibits the response to PregS with an IC50 of 172 nM, it will prevent CatSper activation by PregS even if sperm cells are exposed to high PregS concentrations. Interestingly, the plasma concentration of PregS in women is about 14 nM (35). This concentration matches the EC50 we determined for PregS to activate CatSper. It is therefore possible that once testosterone is removed from sperm cells within the female genital tract, both P4 and PregS can bind to ABHD2, resulting in CatSper activation. These two compounds indeed compete for the ABHD2 binding site(s), but further studies are needed to reveal whether PregS and P4 act synergistically or independently to activate CatSper.

Our earlier findings identified the acylglycerol lipase ABHD2 as the P4 binding partner (7). Therefore, we tested whether the monoacylglycerol lipase inhibitor pristimerin, a plant triterpenoid (18), can inhibit both the P4- and the PregS-mediated activation of CatSper of human sperm. Although basal CatSper currents were not affected, both P4 and PregS-mediated CatSper potentiation was significantly reduced. Lupeol, another plant triterpenoid, had similar effects on ICatSper as pristimerin. It is possible that both triterpenoids occupy the steroid binding site of ABHD2, thus preventing CatSper activation by P4 via a competitive antagonist-type mechanism. Both compounds were also able to inhibit sperm hyperactivation and slightly reduced basal motility of capacitated sperm cells, as evident from computer-assisted sperm analyses (CASAs). Interestingly, pristimerin and lupeol had no effect on sperm motility of noncapacitated cells, which indicates their low toxicity effect toward spermatozoa. These results correlate with our electrophysiological data, which showed a significant reduction of ICatSper with pristimerin + P4 and lupeol + P4, respectively. Because CatSper is indispensable for hyperactivated sperm motility (3640), it is evident that the reduction of sperm hyperactivation by both triterpenoids may significantly impair sperm ability to fertilize an egg.

CASA experiments also revealed that although P4 increased hyperactivated motility, PregS failed to do so. This could be due to the fact that PregS is a charged molecule, which cannot pass the plasma membrane (41). It is therefore possible that the nonpolar P4 can activate additional intracellular pathways, contributing to a more pronounced activation of CatSper. Indeed, for full sperm hyperactivation in vitro, two events must be met at the same time: (i) CatSper must be relieved from inhibition by 2-AG, and (ii) the sperm plasma membrane needs to be depolarized. Because CatSper is a voltage-dependent channel, it requires at least +30 mV for half-activation (3). The latter can be achieved via the P4-mediated inhibition of the potassium channel KSper (6), which creates membrane depolarization required for full CatSper activation. If P4 inhibits KSper from the intracellular side, which PregS fails to do, as it cannot cross plasma membrane, then P4 is able to cause a more pronounced hyperactivation.

In conclusion, our findings show that apart from P4, PregS is another steroid hormone that can activate CatSper via ABHD2 in human spermatozoa, whereas testosterone, E2, and HC may bind to ABHD2 competitively to modulate the response to P4 and PregS. In addition, we describe two plant triterpenoids that can serve as promising candidates for contraception, as they reduce the number of hyperactive spermatozoa, thus preventing sperm from reaching and fertilizing an egg.

Materials and Methods

Reagents.

Progesterone and pristimerin were purchased from Calbiochem (EMD Millipore). MAFP was from Cayman Chemical Company, and NNC 55–0396 was from Tocris. All other compounds were from Sigma Aldrich. Testosterone was purchased in accordance with the controlled substance protocol (CS084484), as a collaborative effort with Yuriy Kirichok (University of California, San Francisco).

Donors and Purification of Human Ejaculated Spermatozoa.

The participation of four healthy human sperm donor volunteers was approved by the Committee on Human Research at the University of California, Berkeley (protocol number 2013–06-5395). All donors provided informed consent. Freshly ejaculated semen samples were obtained by masturbation. Sperm were purified with the swim-up technique (3) using artificial human tubal fluid solution (HTF), containing (in mM) 21 Hepes, 21 lactic acid, 98 NaCl, 4.7 KCl, 3 glucose, 2 CaCl2, 0.3 KH2PO4, 0.3 sodium pyruvate, and 0.2 MgSO4, pH 7.4 (adjusted with NaOH).

Electrophysiology.

All recordings were performed as described in ref. 3. Briefly, gigaohm seals between patch pipette and spermatozoa were formed at the cytoplasmic droplet in high saline (HS) solution containing (in mM) 135 NaCl, 20 Hepes, 10 lactic acid, 5 KCl, 5 glucose, 2 CaCl2, 1 MgSO4, 1 sodium pyruvate, pH 7.4 (adjusted with NaOH), and ∼320 mOsm/L. Transition into whole-cell mode was achieved by applying suction and short voltage pulses. For CatSper recordings, the divalent-free bath solution contained (in mM) 140 Cs-methanesulfonate, 40 Hepes, 1 EDTA, pH 7.4 (adjusted with CsOH), and ∼325 mOsm/L. Pipettes (10–15 MΩ) were filled with 130 mM Cs-methanesulfonate, 70 mM Hepes, 3 mM EGTA, 2 mM EDTA, 0.5 mM Tris·HCl, pH 7.4 (adjusted with CsOH), and ∼335 mOsm/L. Access resistance was 42–60 MΩ. Cells were stimulated every 5 s, and data were sampled at 2–5 kHz and filtered at 1 kHz. All experiments were performed at room temperature and currents elicited by a voltage ramp from –80 mV to 80 mV with a holding potential of 0 mV. Data were analyzed with Clampfit 9.2 and OriginPro 9.0. To build dose–response curves, data were fitted with the Hill-based equation: y = Imin + (Imax – Imin)/(1 + (x/IC50)k), where Imax is close to 100% activation, Imin is close to inactivation, and k is the Hill slope factor.

CASA.

Purified human spermatozoa were capacitated for 3.5 h at 37 °C and 5% CO2 in capacitation media (HS supplemented with 15 mM NaHCO3 and 5% BSA) as reported in ref. 7. Aliquots of the cell suspension were preincubated for 15 min with 3 μM pristimerin or 3 μM lupeol before exposure to steroids (3 μM progesterone or 3 μM PregS). Sperm motility was analyzed at 37 °C with an HTM-IVOS sperm analysis system (version 12.3, Hamilton Thorne Biosciences). We pipetted 10 μL of sperm suspension into a two-chamber slide (Leja), and sperm movement of a minimum of 300 cells was recorded. Parameters measured were the four motility classes (A–D), average path velocity (VAP, μm/s), straight line velocity (VSL, μm/s), and VCL (μm/s). Measurements on a given day were performed in duplicates and defined as one experiment.

Data Analysis.

Statistical data were calculated as the mean ± SEM, and n indicates number of individual cells analyzed unless stated otherwise. Statistical significance (unpaired t test) is indicated by *P < 0.05, **P < 0.005, ***P < 0.001, and ****P < 0.0001.

Source:http://www.pnas.org

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


Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Abstract

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.

Source:http://jamanetwork.com

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.

Source:www.nature.com

Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease.


BACKGROUND

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.

METHODS

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.

RESULTS

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%).

CONCLUSIONS

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.

source:nejm.org

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


Abstract

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.

Figure1

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)

Conclusions

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.

source:onlinejacc.org

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.

 

Source:.bmj.com