In Vitro Drug Combination Studies of Letermovir (AIC246, MK-8228) with Approved Anti-Human Cytomegalovirus (HCMV) and Anti-HIV Compounds in Inhibition of HCMV and HIV Replication

Despite modern prevention and treatment strategies, human cytomegalovirus (HCMV) remains a common opportunistic pathogen associated with serious morbidity and mortality in immunocompromised individuals, such as transplant recipients and AIDS patients. All drugs currently licensed for the treatment of HCMV infection target the viral DNA polymerase and are associated with severe toxicity issues and the emergence of drug resistance. Letermovir (AIC246, MK-8228) is a new anti-HCMV agent in clinical development that acts via a novel mode of action and has demonstrated anti-HCMV activity in vitro and in vivo. For the future, drug combination therapies, including letermovir, might be indicated under special medical conditions, such as the emergence of multidrug-resistant virus strains in transplant recipients or in HCMV-HIV-coinfected patients. Accordingly, knowledge of the compatibility of letermovir with other HCMV or HIV antivirals is of medical importance. Here, we evaluated the inhibition of HCMV replication by letermovir in combination with all currently approved HCMV antivirals using cell culture checkerboard assays. In addition, the effects of letermovir on the antiviral activities of selected HIV drugs, and vice versa, were analyzed. Using two different mathematical techniques to analyze the experimental data, (i) additive effects were observed for the combination of letermovir with anti-HCMV drugs and (ii) no interaction was found between letermovir and anti-HIV drugs. Since none of the tested drug combinations significantly antagonized letermovir efficacy (or vice versa), our findings suggest that letermovir may offer the potential for combination therapy with the tested HCMV and HIV drugs.     

Epidemiology,pathophysiology and contemporary management of cardiogenic shock – a position statement from the Heart Failure Association of the European Society of Cardiology

Cardiogenic shock (CS) is a complex multifactorial clinical syndrome with extremely high mortality, developing as a continuum, and progressing from the initial insult (underlying cause) to the subsequent occurrence of organ failure and death. There is a large spectrum of CS presentations resulting from the interaction between an acute cardiac insult and a patient's underlying cardiac and overall medical condition. Phenotyping patients with CS may have clinical impact on management because classification would support initiation of appropriate therapies. CS management should consider appropriate organization of the health care services, and therapies must be given to the appropriately selected patients, in a timely manner, whilst avoiding iatrogenic harm. Although several consensus‐driven algorithms have been proposed, CS management remains challenging and substantial investments in research and development have not yielded proof of efficacy and safety for most of the therapies tested, and outcome in this condition remains poor. Future studies should consider the identification of the new pathophysiological targets, and high‐quality translational research should facilitate incorporation of more targeted interventions in clinical research protocols, aimed to improve individual patient outcomes. Designing outcome clinical trials in CS remains particularly challenging in this critical and very costly scenario in cardiology, but information from these trials is imperiously needed to better inform the guidelines and clinical practice. The goal of this review is to summarize the current knowledge concerning the definition, epidemiology, underlying causes, pathophysiology and management of CS based on important lessons from clinical trials and registries, with a focus on improving in‐hospital management.     

Prognostic Factors in Compensated and Decompensated Cirrhosis

There are an increasing number of studies that evaluate predictive factors, mostly of death, in cirrhosis. These are different depending on the presence of compensated or decompensated cirrhosis. In compensated cirrhosis the main event to predict is decompensation. The degree of portal hypertension as determined by the hepatic venous pressure gradient (HVPG) and serum albumin levels are the most relevant predictors of decompensation. Since HVPG determination is obtained through an invasive procedure, recent studies have examined alternative non-invasive methods to establish the presence of clinically significant portal hypertension. In decompensated cirrhosis the main event to predict is death and “further decompensation”, the event that most commonly occurs prior to death. The Child and MELD scores are the most important predictors of death in decompensated disease. Child score continues to be a useful stratifying tool in all patients with cirrhosis. Specific predictive factors in each type of clinical decompensation are discussed.     

Physician empathy and subjective evaluation of medical treatment outcome in trauma surgery patients

Objective

To analyze whether patients’ perception of their medical treatment outcome is higher among patients who experienced a higher empathy by trauma surgeons during their stay in hospital.

Methods

127 patients were surveyed six weeks after discharge from the trauma surgical general ward. Subjective evaluation of medical treatment outcome was measured with the corresponding scale from the Cologne Patient Questionnaire. Clinical empathy was assessed by using the CARE measure. The influence of physician empathy and control variables on a dichotomized index of subjective evaluation of medical treatment outcome was identified with a logistic regression.

Results

120 patients were included in the logistic regression analysis. Compared to patients with physician empathy ratings of less than 30 points, patients with ratings of 41 points or higher have a 20-fold higher probability to be in the group with a better medical treatment outcome on the CPQ-scale (α-level < .001, R² 46.9).

Conclusion

Findings emphasize the importance of a well-functioning relationship between physician and patient even in a surgical setting where the focus is mostly on the bare medical treatment.

Practice implications

Communication trainings i.e. in surgical education can be an effective way to improve the ability to show empathy with patients’ concerns.     

Towards identifying novel anti-Eimeria agents: trace elements,vitamins, and plant-based natural products

Eimeriosis, a widespread infectious disease of livestock, is caused by coccidian protozoans of the genus Eimeria. These obligate intracellular parasites strike the digestive tract of their hosts and give rise to enormous economic losses, particularly in poultry, ruminants including cattle, and rabbit farming. Vaccination, though a rational prophylactic measure, has not yet been as successful as initially thought. Numerous broad-spectrum anti-coccidial drugs are currently in use for treatment and prophylactic control of eimeriosis. However, increasing concerns about parasite resistance, consumer health, and environmental safety of the commercial drugs warrant efforts to search for novel agents with anti-Eimeria activity. This review summarizes current approaches to prevent and treat eimeriosis such as vaccination and commercial drugs, as well as recent attempts to use dietary antioxidants as novel anti-Eimeria agents. In particular, the trace elements selenium and zinc, the vitamins A and E, and natural products extracted from garlic, barberry, pomegranate, sweet wormwood, and other plants are discussed. Several of these novel anti-Eimeria agents exhibit a protective role against oxidative stress that occurs not only in the intestine of Eimeria-infected animals, but also in their non-parasitized tissues, in particular, in the first-pass organ liver. Currently, it appears to be promising to identify safe combinations of low-cost natural products with high anti-Eimeria efficacy for a potential use as feed supplementation in animal farming.     

CTLA‐4 (CD152) enhances the Tc17 differentiation program

Although CD8⁺ T cells that produce IL‐17 (Tc17 cells) have been linked to host defense, Tc17 cells show reduced cytotoxic activity, which is the characteristic function of CD8⁺ T cells. Here, we show that CTLA‐4 enhances the frequency of IL‐17 in CD8⁺ T cells, indicating that CTLA‐4 (CD152) specifically promotes Tc17 differentiation. Simultaneous stimulation of CTLA‐4^+/+ and CTLA‐4^?/? T cells in cocultures and agonistic CTLA‐4 stimulation unambiguously revealed a cell‐intrinsic mechanism for IL‐17 control by CTLA‐4. The quality of CTLA‐4‐induced Tc17 cells was tested in vivo, utilizing infection with the facultative intracellular bacterium Listeria monocytogenes (LM). Unlike CTLA‐4^+/+ Tc17 cells, CTLA‐4^?/? were nearly as efficient as Tc1 CTLA‐4^+/+ cells in LM clearance. Additionally, adoptively transferred CTLA‐4^?/? Tc17 cells expressed granzyme B after rechallenge, and produced Tc1 cytokines such as IFN‐γ and TNF‐α, which strongly correlate with bacterial clearance. CTLA‐4^+/+ Tc17 cells demonstrated a high‐quality Tc17 differentiation program ex vivo, which was also evident in isolated IL‐17‐secreting Tc17 cells, with CTLA‐4‐mediated enhanced upregulation of Tc17‐related molecules such as IL‐17A, RORγt, and IRF‐4. Our results show that CTLA‐4 promotes Tc17 differentiation that results in robust Tc17 responses. Its inactivation might therefore represent a central therapeutic target to enhance clearance of infection.     

Epithelia of the ovine and bovine forestomach express basolateral maxi-anion channels permeable to the anions of short-chain fatty acids

It has long been established that the absorption of short-chain fatty acids (SCFA) across epithelia stimulates sodium proton exchange. The apically released protons are not available as countercations for the basolateral efflux of SCFA anions and a suitable transport model is lacking. Patch clamp and microelectrode techniques were used to characterize an anion conductance expressed by cultured cells of the sheep and bovine rumen and the sheep omasum and to localize the conductance in the intact tissue. Cells were filled with a Na-gluconate solution and superfused with sodium salts of acetate, propionate, butyrate, or lactate. Reversal potential rose and whole cell current at +100 mV decreased with the size of the anion. Anion-induced currents could be blocked by diisothiocyanato-stilbene-2,2′-disulfonic acid (DIDS), NPPB (200?μmol l^?1), or pCMB (1 mmol l^?1). In patches of bovine ruminal cells, single channels were observed with a conductance for chloride (327?±?11 pS), acetate (115?±?8 pS), propionate (102?±?10 pS), butyrate (81?±?2 pS), and gluconate (44?±?3 pS). Channels expressed by sheep rumen and omasum were similar. Microelectrode experiments suggest basolateral localization. In conclusion, forestomach epithelia express basolateral maxi-anion channels with a permeability sequence of chloride?>?acetate?>?propionate?>?butyrate. SCFA absorption may resemble functionally coupled transport of NaCl, with the Na⁺/K⁺-ATPase driving the basolateral efflux of the anion through a channel. Since protons are apically extruded, the model accurately predicts that influx of buffers with saliva is essential for the pH homeostasis of the ruminant forestomach.     

Graft Copolymers with Complex Polyether Structures: Poly(ethylene oxide)‐graft‐Poly(isobutyl vinyl ether) by Combination of Living Anionic and Photoinduced Cationic Graft Polymerization

A novel polymerization mechanism transformation strategy, involving anionic ring‐opening polymerization and photoinduced cationic polymerization, is successfully applied for the synthesis of poly(ethylene oxide)‐graft‐poly(isobutyl vinyl ether) (PEO‐g‐PIBVE). First, poly(ethylene oxide‐co‐ethoxyl vinyl glycidyl ether) [P(EO‐co‐EVGE)] is synthesized by living anionic polymerization. The vinyl moieties of the functional PEO‐based polymer are converted to the hydrogen iodide adduct by photolysis of diphenyliodonium iodide, monitored using NMR spectroscopy. A modified mode of Lewis acid‐catalyzed living cationic polymerization is performed as a “grafting from” method to generate PIBVE segments grafted onto the PEO main chain. Both the intermediates and the final graft copolymers are characterized by gel‐permeation chromato­graphy (GPC) and ¹H NMR analysis.

     

Mutation of POC1B in a Severe Syndromic Retinal Ciliopathy

We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA), Joubert syndrome (JBTS), and polycystic kidney disease (PKD). Targeted next‐generation sequencing for excluding mutations in known LCA and JBTS genes, homozygosity mapping, and whole‐exome sequencing identified a homozygous missense variant, c.317G>C (p.Arg106Pro), in POC1B, a gene essential for ciliogenesis, basal body, and centrosome integrity. In silico modeling suggested a requirement of p.Arg106 for the formation of the third WD40 repeat and a protein interaction interface. In human and mouse retina, POC1B localized to the basal body and centriole adjacent to the connecting cilium of photoreceptors and in synapses of the outer plexiform layer. Knockdown of Poc1b in zebrafish caused cystic kidneys and retinal degeneration with shortened and reduced photoreceptor connecting cilia, compatible with the human syndromic ciliopathy. A recent study describes homozygosity for p.Arg106Pro_POC1B in a family with nonsyndromic cone‐rod dystrophy. The phenotype associated with homozygous p.Arg106Pro_POC1B may thus be highly variable, analogous to homozygous p.Leu710Ser in WDR19 causing either isolated retinitis pigmentosa or Jeune syndrome. Our study indicates that POC1B is required for retinal integrity, and we propose POC1B mutations as a probable cause for JBTS with severe PKD.     

From the Cover: Synchronization in human musical rhythms and mutually interacting complex systems

Though the music produced by an ensemble is influenced by multiple factors, including musical genre, musician skill, and individual interpretation, rhythmic synchronization is at the foundation of musical interaction. Here, we study the statistical nature of the mutual interaction between two humans synchronizing rhythms. We find that the interbeat intervals of both laypeople and professional musicians exhibit scale-free (power law) cross-correlations. Surprisingly, the next beat to be played by one person is dependent on the entire history of the other person’s interbeat intervals on timescales up to several minutes. To understand this finding, we propose a general stochastic model for mutually interacting complex systems, which suggests a physiologically motivated explanation for the occurrence of scale-free cross-correlations. We show that the observed long-term memory phenomenon in rhythmic synchronization can be imitated by fractal coupling of separately recorded or synthesized audio tracks and thus applied in electronic music. Though this study provides an understanding of fundamental characteristics of timing and synchronization at the interbrain level, the mutually interacting complex systems model may also be applied to study the dynamics of other complex systems where scale-free cross-correlations have been observed, including econophysics, physiological time series, and collective behavior of animal flocks.In his book Musicophilia, neurologist Oliver Sacks writes: “In all societies, a primary function of music is collective and communal, to bring and bind people together. People sing together and dance together in every culture, and one can imagine them having done so around the first fires, a hundred thousand years ago” (1). Sacks adds, “In such a situation, there seems to be an actual binding of nervous systems accomplished by rhythm” (2). These thoughts lead to the question: Is there any underlying and quantifiable structure to the subjective experience of “musical binding”? Here, we examine the statistical nature of musical binding (also referred to as musical coupling) when two humans play rhythms in synchrony.Every beat a single (noninteracting) layperson or musician plays is accompanied by small temporal deviations from the exact beat pattern, i.e., even a trained musician will hit a drum beat slightly ahead or behind the metronome (with a SD of typically 5–15 ms). Interestingly, these deviations are statistically dependent and exhibit long-range correlations (LRC) (3, 4). Listeners significantly prefer music mirroring long-range correlated temporal deviations over uncorrelated (white noise) fluctuations (5, 6). LRC are also inherent in the reproduction of both spatial and temporal intervals of single subjects (4, 7–9) and in musical compositions, such as pitch fluctuations (a simple example of pitch fluctuations is a melody) (10, 11) and note lengths (12). The observation of power law correlations in fluctuations of pitch and note length in compositions reflects a hierarchical, self-similar structure in these compositions.In this article, we examine rhythmic synchronization, which is at the foundation of musical interaction, from orchestral play to audience hand-clapping (13). More specifically, we show that the interbeat intervals (IBIs) of two subjects synchronizing musical rhythms exhibit long-range cross-correlations (LRCCs), which appears to be a general phenomenon given that these LRCC were found both in professional musicians and in laypeople.The observation of LRCCs may point to characteristics of criticality in the dynamics of the considered complex system. LRCCs are characterized by a power law decay of the cross-correlation function and indicate that the two time series of IBIs form a self-similar (fractal) structure. Here, self-similarity implies that trends in the IBIs are likely to repeat on different timescales, i.e., patterns of IBI fluctuations of one musician tend to reproduce in a statistically similar way at a later time—even in the other musician’s play. A variety of complex systems exhibit LRCCs; examples include price fluctuations of the New York Stock Exchange (where the LRCCs become more pronounced during economic crises) (14–16), heartbeat and EEG fluctuations (15, 17), particles in a Lorentz channel (18), the binding affinity of proteins to DNA (15), schools of fish (19), and the collective response of starling flocks (20, 21). The origin of collective dynamics and LRCCs based on local interactions often appears elusive (20), and is the focus of current research (19, 21). Of particular interest are the rules of interactions of the individuals in a crowd (22, 23) and transitions to synchronized behavior (16, 24). We introduce a stochastic model for mutually interacting complex systems (MICS) that generates LRCCs and provides a physiologically motivated explanation for the surprising presence of long-term memory in the cross-correlations of musical performances.Interbrain synchronization has received growing attention recently, including studies of interpersonal synchronization (see ref. 4 for an overview), coordination of speech rhythm (25), social interactions (26), cortical phase synchronization while playing guitar in duets (27, 28), and improvisation in classical music performances (29).Notably, the differences between the beats of two musicians are on the order of only a few milliseconds, not much larger than the typical duration of a single action potential (∼1 ms). The neurophysical mechanisms of timing in the millisecond range are still widely open (30, 31). EEG oscillatory patterns are associated with error prediction during music performance (32). Fine motor skills, such as finger-tapping rhythm and rate, are used to establish an early diagnosis of Huntington disease (33). The neurological capacity to synchronize with a beat may offer therapeutic applications for Parkinson disease, but the mechanisms are unknown to date (34). This study offers a statistical framework that may help to understand these mechanisms.