Critically Ill Patient with Multidrug-Resistant Acinetobacter baumannii Respiratory Infection Successfully Treated with Intravenous and Nebulized Bacteriophage Therapy.

Hospitalized patients are at risk of developing serious multidrug resistant bacterial infections. This risk is heightened in patients who are on mechanical ventilation, are immunocompromised, and/or have chronic comorbidities. We report the case of a 52-year-old critically ill patient with a multidrug resistant Acinetobacter baumannii (MDR-A) respiratory infection who was successfully treated with antibiotics and intravenous and nebulized bacteriophage therapy.

Phage Therapy for Limb-threatening Prosthetic Knee Klebsiella pneumoniae Infection: Case Report and In Vitro Characterization of Anti-biofilm Activity.

BACKGROUND: Prosthetic joint infection (PJI) is a potentially limb-threatening complication of total knee arthroplasty. Phage therapy is a promising strategy to manage such infections including those involving antibiotic-resistant microbes, and to target microbial biofilms. Experience with phage therapy for infections associated with retained hardware is limited. A 62-year-old diabetic man with a history of right total knee arthroplasty 11 years prior who had suffered multiple episodes of prosthetic knee infection despite numerous surgeries and prolonged courses of antibiotics, with progressive clinical worsening and development of severe allergies to antibiotics, had been offered limb amputation for persistent right prosthetic knee infection due to Klebsiella pneumoniae complex. Intravenous phage therapy was initiated as a limb-salvaging intervention. METHODS: The patient received 40 intravenous doses of a single phage (KpJH46Φ2) targeting his bacterial isolate, alongside continued minocycline (which he had been receiving when he developed increasing pain, swelling, and erythema prior to initiation of phage therapy). Serial cytokine and biomarker measurements were performed before, during, and after treatment. The in vitro anti-biofilm activity of KpJH46Φ2, minocycline and the combination thereof was evaluated against a preformed biofilm of the patient's isolate and determined by safranin staining. RESULTS: Phage therapy resulted in resolution of local symptoms and signs of infection and recovery of function. The patient did not experience treatment-related adverse effects and remained asymptomatic 34 weeks after completing treatment while still receiving minocycline. A trend in biofilm biomass reduction was noted 22 hours after exposure to KpJH46Φ2 (P = .063). The addition of phage was associated with a satisfactory outcome in this case of intractable biofilm-associated prosthetic knee infection. Pending further studies to assess its efficacy and safety, phage therapy holds promise for treatment of device-associated infections.

Cefiderocol for the Treatment of Adult and Pediatric Patients With Cystic Fibrosis and Achromobacter xylosoxidans Infections.

Treatment options for Achromobacter xylosoxidans are limited. Eight cystic fibrosis patients with A. xylosoxidans were treated with 12 cefiderocol courses. Pretreatment in vitro resistance was seen in 3 of 8 cases. Clinical response occurred after 11 of 12 treatment courses. However, microbiologic relapse was observed after 11 of 12 treatment courses, notably without emergence of resistance.

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia.

Hereditary sensory and autonomic neuropathy type III, or familial dysautonomia [FD; Online Mendelian Inheritance in Man (OMIM) 223900], affects the development and long-term viability of neurons in the peripheral nervous system (PNS) and retina. FD is caused by a point mutation in the gene IKBKAP/ELP1 that results in a tissue-specific reduction of the IKAP/ELP1 protein, a subunit of the Elongator complex. Hallmarks of the disease include vasomotor and cardiovascular instability and diminished pain and temperature sensation caused by reductions in sensory and autonomic neurons. It has been suggested but not demonstrated that mitochondrial function may be abnormal in FD. We previously generated an Ikbkap/Elp1 conditional-knockout mouse model that recapitulates the selective death of sensory (dorsal root ganglia) and autonomic neurons observed in FD. We now show that in these mice neuronal mitochondria have abnormal membrane potentials, produce elevated levels of reactive oxygen species, are fragmented, and do not aggregate normally at axonal branch points. The small hydroxylamine compound BGP-15 improved mitochondrial function, protecting neurons from dying in vitro and in vivo, and promoted cardiac innervation in vivo. Given that impairment of mitochondrial function is a common pathological component of neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's, Parkinson's, and Huntington's diseases, our findings identify a therapeutic approach that may have efficacy in multiple degenerative conditions.

Successful Treatment of Antibiotic-resistant, Poly-microbial Bone Infection With Bacteriophages and Antibiotics Combination.

A patient with a trauma-related left tibial infection associated with extensively drug-resistant Acinetobacter baumannii and multidrug-resistant Klebsiella pneumoniae was treated with bacteriophages and antibiotics. There was rapid tissue healing and positive culture eradication. As a result, the patient's leg did not have to be amputated and he is undergoing rehabilitation.

Early clinical experience of bacteriophage therapy in 3 lung transplant recipients.

Bacteriophage therapy (BT) uses bacteriophages to treat pathogenic bacteria and is an emerging strategy against multidrug-resistant (MDR) infections. Experience in solid organ transplant is limited. We describe BT in 3 lung transplant recipients (LTR) with life-threatening MDR infections caused by Pseudomonas aeruginosa (n = 2) and Burkholderia dolosa (n = 1). For each patient, lytic bacteriophages were selected against their bacterial isolates. BT was administered for variable durations under emergency Investigational New Drug applications and with patient informed consent. Safety was assessed using clinical/laboratory parameters and observed clinical improvements described, as appropriate. All patients received concurrent antibiotics. Two ventilator-dependent LTR with large airway complications and refractory MDR P. aeruginosa pneumonia received BT. Both responded clinically and were discharged from the hospital off ventilator support. A third patient had recurrent B. dolosa infection following transplant. Following BT initiation, consolidative opacities improved and ventilator weaning was begun. However, infection relapsed on BT and the patient died. No BT-related adverse events were identified in the 3 cases. BT was well tolerated and associated with clinical improvement in LTRs with MDR bacterial infection not responsive to antibiotics alone. BT may be a viable adjunct to antibiotics for patients with MDR infections.

Renal ischemia-reperfusion injury causes hypertension and renal perfusion impairment in the CD1 mice which promotes progressive renal fibrosis.

Renal ischemia-reperfusion injury (IRI) is a severe complication of major surgery and a risk factor for increased morbidity and mortality. Here, we investigated mechanisms that might contribute to IRI-induced progression to chronic kidney disease (CKD). Acute kidney injury (AKI) was induced by unilateral IRI for 35 min in CD1 and C57BL/6 (B6) mice. Unilateral IRI was used to overcome early mortality. Renal morphology, NGAL upregulation, and neutrophil infiltration as well as peritubular capillary density were studied by immunohistochemistry. The composition of leukocyte infiltrates in the kidney after IRI was investigated by flow cytometry. Systemic blood pressure was measured with a tail cuff, and renal perfusion was quantified by functional magnetic resonance imaging (fMRI). Mesangial matrix expansion was assessed by silver staining. Following IRI, CD1 and B6 mice developed similar morphological signs of AKI and increases in NGAL expression, but neutrophil infiltration was greater in CD1 than B6 mice. IRI induced an increase in systemic blood pressure of 20 mmHg in CD1, but not in B6 mice; and CD1 mice also had a greater loss of renal perfusion and kidney volume than B6 mice ( P < 0.05). CD1 mice developed substantial interstitial fibrosis and decreased peritubular capillary (PTC) density by day 14 while B6 mice showed only mild renal scarring and almost normal PTC. Our results show that after IRI, CD1 mice develop more inflammation, hypertension, and later mesangial matrix expansion than B6 mice do. Subsequently, CD1 animals suffer from CKD due to impaired renal perfusion and pronounced permanent loss of peritubular capillaries.

Do circulating cells transdifferentiate and replenish stem cell pools in the brain and periphery?

For nearly two centuries, developmental biologists have known that body organs are derived from distinct germ layers. They have argued that adult stem cells formed in one of these, mesoderm for example, cannot give rise to cells that originate in another. We disagree. An exception to this "rule" has been described in crayfish recently. In this species, hemocytes appear to replenish neurogenic cells. This may happen in humans as well. In women who were given male bone marrow-derived cells, Y chromosome positive cheek cells and brain neurons were detected. While repopulation of these tissues by bone marrow derived cells may not occur normally, and while it does not appear to be terribly efficient, the phenomenon should be studied in more detail. Perhaps cells in the marrow could be used to regenerate tissues elsewhere.

The utility of the irritability scale in Huntington's disease patients with evidence of irritability or aggression.

INTRODUCTION: Irritability, a common neuropsychiatric symptom in Huntington's disease (HD), lacks a standardized measurement. The Irritability Scale (IS), tailored for HD, has patient and informant versions, but variable interrater agreement has been reported frequently in previous studies. To enhance the clinical utility of the IS, this study aimed to identify the most reliable components estimating the underlying construct and develop a shortened version for time-limited contexts. METHODS: Participant and informant/observer concordance and the relationship of individual items to the complete IS scale were assessed. The short-form (SF) items were selected based on interrater agreement, exploratory factor analysis (EFA), and Item Response Theory (IRT) analysis results. Pair-wise correlation and covariance models were used to examine how SF predicted total IS score in 106 participants from the STAIR (Safety, Tolerability, and Activity of SRX246 in Irritable Subjects with Huntington's Disease) trial. Item Response Theory (IRT) analysis was used to evaluate the range and function of the selected items. RESULTS: IS interrater agreement was statistically significant (r = 0.33, p = .001). In combination with EFA factors and IRT analyses, five items were identified that showed good reliability and performance in differentiating levels of irritability. CONCLUSION: The proposed 5-item SF IS provided a reliable measure of the full scale and may be less burdensome for use in a clinical setting.

Recurrent ESBL Escherichia coli Urosepsis in a Pediatric Renal Transplant Patient Treated With Antibiotics and Bacteriophage Therapy.

INTRODUCTION: Treating recurrent multidrug resistant (MDR) urosepsis in pediatric transplant recipients can be challenging. Particularly when antibiotics fail to prevent future occurrence and the nidus is seemingly undiscoverable. While there is an increasing amount of data on phage therapy, to our knowledge, there are no published cases involving pediatric renal transplant recipients. Therefore, we present a challenging clinical case in which phage therapy was used in a pediatric renal transplant recipient who developed recurrent MDR urosepsis with an unclear source. CASE PRESENTATION: Our patient was a 17-year-old female who initially developed urosepsis caused by extended-spectrum ß-lactamase (ESBL) Escherichia coli , while being treated with an immunosuppressant regimen because of kidney rejection secondary to poor immunosuppression therapy compliance. She was admitted to our hospital intermittently for 4 months with 4 episodes of urosepsis caused by ESBL E. coli . She received multiple courses of antibiotics (mainly ertapenem) and underwent a fecal material transplant to eradicate her ESBL E. coli colonized gastrointestinal tract. Because of recurrent development of urosepsis after antibiotic treatment, she later underwent treatment with a phage cocktail consisting of 2 isolate-specific phages. After a prolonged antibiotic course and subsequent 3-week intravenous phage treatment, she had no ESBL E. coli in her urinary cultures for 4 years post-treatment. DISCUSSION: This case highlights the challenges of treating recurrent ESBL E. coli infections in a pediatric renal transplant patient and provides evidence that phage therapy may prove useful in such cases.

Glucagon-like peptide-1: a multi-faceted anti-inflammatory agent.

Inflammation contributes to many chronic conditions. It is often associated with circulating pro-inflammatory cytokines and immune cells. GLP-1 levels correlate with disease severity. They are often elevated and can serve as markers of inflammation. Previous studies have shown that oxytocin, hCG, ghrelin, alpha-MSH and ACTH have receptor-mediated anti-inflammatory properties that can rescue cells from damage and death. These peptides have been studied well in the past century. In contrast, GLP-1 and its anti-inflammatory properties have been recognized only recently. GLP-1 has been proven to be a useful adjuvant therapy in type-2 diabetes mellitus, metabolic syndrome, and hyperglycemia. It also lowers HbA1C and protects cells of the cardiovascular and nervous systems by reducing inflammation and apoptosis. In this review we have explored the link between GLP-1, inflammation, and sepsis.

A proof-of-concept randomized crossover clinical trial of a first-in-class vasopressin 1a receptor antagonist for PTSD: Design, methods, and recruitment.

Background: Almost eight million Americans suffer from Posttraumatic Stress Disorder (PTSD). Current PTSD drug therapies rely on repurposed antidepressants and anxiolytics, which produce undesirable side effects and have recognized compliance issues. Vasopressin represents a promising and novel target for pharmacological intervention. Logistical issues implementing a clinical trial for a novel PTSD pharmaceutical are relatively uncharted territory as trials concerning a new agent have not been published in the past several decades. All published trials have repurposed FDA-approved psychoactive medications with known risk profiles. Our recruitment challenges are discussed in this context. Methods: An 18-week proof-of-concept randomized crossover clinical trial of a first-in-class vasopressin 1a receptor antagonist (SRX246) for PTSD was conducted. All participants received SRX246 for 8 weeks, the placebo for 8 weeks, and the drug vs. placebo arms were compared. Participants were assessed every 2 weeks for PTSD symptoms as well as other medication effects. Results were expected to provide an initial demonstration of safety and tolerability in this clinical population and potentially clinical efficacy in SRX246-treated patients measured by Clinician Administered PTSD Scale (CAPS) score changes, clinical impression, and other indices compared to placebo. The primary hypothesis was that SRX246 would result in a clinically meaningful 10-point reduction in mean CAPS score compared to placebo. Discussion: This study is the first to investigate an oral vasopressin 1a receptor antagonist for PTSD. As a wave of PTSD clinical trials with new pharmaceutical compounds are beginning now, lessons learned from our recruitment challenges may be invaluable to these endeavors.

Refractory Pseudomonas aeruginosa infections treated with phage PASA16: A compassionate use case series.

BACKGROUND: A growing number of compassionate phage therapy cases were reported in the last decade, with a limited number of clinical trials conducted and few unsuccessful clinical trials reported. There is only a little evidence on the role of phages in refractory infections. Our objective here was to present the largest compassionate-use single-organism/phage case series in 16 patients with non-resolving Pseudomonas aeruginosa infections. METHODS: We summarized clinical phage microbiology susceptibility data, administration protocol, clinical data, and outcomes of all cases treated with PASA16 phage. In all intravenous phage administrations, PASA16 phage was manufactured and provided pro bono by Adaptive Phage Therapeutics. PASA16 was administered intravenously, locally to infection site, or by topical use to 16 patients, with data available for 15 patients, mainly with osteoarticular and foreign-device-associated infections. FINDINGS: A few minor side effects were noted, including elevated liver function enzymes and a transient reduction in white blood cell count. Good clinical outcome was documented in 13 out of 15 patients (86.6%). Two clinical failures were reported. The minimum therapy duration was 8 days with a once- to twice-daily regimen. CONCLUSIONS: PASA16 with antibiotics was found to be relatively successful in patients for whom traditional treatment approaches have failed previously. Such pre-phase-1 cohorts can outline potential clinical protocols and facilitate the design of future trials. FUNDING: The study was funded in part by The Israeli Science Foundation IPMP (ISF_1349/20), Rosetrees Trust (A2232), United States-Israel Binational Science Foundation (2017123), and the Milgrom Family Support Program.

Synthesis and evaluation of potent and selective human V1a receptor antagonists as potential ligands for PET or SPECT imaging.

SRX246 is a potent, highly selective human vasopressin V1a antagonist that crosses the blood-brain barrier in rats. CNS penetration makes SRX246 an ideal candidate for potential radiolabeling and use in visualization and characterization of the role of the V1a receptor in multiple stress-related disorders. Before radiolabeling studies, cold reference analogs of SRX246 were prepared. This study describes the synthesis and in vitro screening for human V1a receptor binding and permeability of fluoro, iodo, and methyl reference compounds for SRX246 and the preparation of a tin precursor. For each compound, the potential utility of corresponding radiolabeled analogs for PET and SPECT imaging is discussed.

A novel class of small RNAs bind to MILI protein in mouse testes.

Small RNAs bound to Argonaute proteins recognize partially or fully complementary nucleic acid targets in diverse gene-silencing processes. A subgroup of the Argonaute proteins--known as the 'Piwi family'--is required for germ- and stem-cell development in invertebrates, and two Piwi members--MILI and MIWI--are essential for spermatogenesis in mouse. Here we describe a new class of small RNAs that bind to MILI in mouse male germ cells, where they accumulate at the onset of meiosis. The sequences of the over 1,000 identified unique molecules share a strong preference for a 5' uridine, but otherwise cannot be readily classified into sequence families. Genomic mapping of these small RNAs reveals a limited number of clusters, suggesting that these RNAs are processed from long primary transcripts. The small RNAs are 26-31 nucleotides (nt) in length--clearly distinct from the 21-23 nt of microRNAs (miRNAs) or short interfering RNAs (siRNAs)--and we refer to them as 'Piwi-interacting RNAs' or piRNAs. Orthologous human chromosomal regions also give rise to small RNAs with the characteristics of piRNAs, but the cloned sequences are distinct. The identification of this new class of small RNAs provides an important starting point to determine the molecular function of Piwi proteins in mammalian spermatogenesis.

Case Report: successful use of phage therapy in refractory MRSA chronic rhinosinusitis.

We present a case of refractory methicillin-resistant Staphylococcus aureus that was successfully treated with a combination of antibiotics, systemic phage and intranasal phage therapy.

The Vasopressin 1a Receptor Antagonist SRX246 Reduces Aggressive Behavior in Huntington's Disease.

SRX246, an orally available CNS penetrant vasopressin (VP) V1a receptor antagonist, was studied in Huntington's disease (HD) patients with irritability and aggressive behavior in the exploratory phase 2 trial, Safety, Tolerability, and Activity of SRX246 in Irritable HD patients (STAIR). This was a dose-escalation study; subjects received final doses of 120 mg BID, 160 mg BID, or placebo. The compound was safe and well tolerated. In this paper, we summarize the results of exploratory analyses of measures of problematic behaviors, including the Cohen-Mansfield Agitation Inventory (CMAI), Aberrant Behavior Checklist (ABC), Problem Behaviors Assessment-short form (PBA-s), Irritability Scale (IS), Clinical Global Impression (CGI), HD Quality of Life (QoL), and Caregiver Burden questionnaires. In addition to these, we asked subjects and caregivers to record answers to short questions about mood, irritability, and aggressive conduct in an eDiary. STAIR was the first rigorously designed study of behavioral endpoints like these in HD. The exploratory analyses showed that SRX246 reduced aggressive acts. Readily observed behaviors should be used as trial endpoints.

Oxytocin and Related Peptide Hormones: Candidate Anti-Inflammatory Therapy in Early Stages of Sepsis.

Sepsis is a potentially life-threatening systemic inflammatory syndrome characterized by dysregulated host immunological responses to infection. Uncontrolled immune cell activation and exponential elevation in circulating cytokines can lead to sepsis, septic shock, multiple organ dysfunction syndrome, and death. Sepsis is associated with high re-hospitalization and recovery may be incomplete, with long term sequelae including post-sepsis syndrome. Consequently, sepsis continues to be a leading cause of morbidity and mortality across the world. In our recent review of human chorionic gonadotropin (hCG), we noted that its major properties including promotion of fertility, parturition, and lactation were described over a century ago. By contrast, the anti-inflammatory properties of this hormone have been recognized only more recently. Vasopressin, a hormone best known for its anti-diuretic effect, also has anti-inflammatory actions. Surprisingly, vasopressin's close cousin, oxytocin, has broader and more potent anti-inflammatory effects than vasopressin and a larger number of pre-clinical studies supporting its potential role in limiting sepsis-associated organ damage. This review explores possible links between oxytocin and related octapeptide hormones and sepsis-related modulation of pro-inflammatory and anti-inflammatory activities.