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Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

BACKGROUND: Antimicrobial resistance (AMR) is undermining modern medicine, a problem compounded by bacterial adaptation to antibiotic pressures. Phages are viruses that infect bacteria. Their diversity and evolvability offer the prospect of their use as a therapeutic solution. Reported are outcomes of customized phage therapy for patients with difficult-to-treat antimicrobial resistant infections. METHODS: We retrospectively assessed 12 cases of customized phage therapy from a phage production center. Phages were screened, purified, sequenced, characterized, and Food and Drug Administration-approved via the IND (investigational new drug) compassionate-care route. Outcomes were assessed as favorable or unfavorable by microbiologic and clinical standards. Infections were device-related or systemic. Other experiences such as time to treatment, antibiotic synergy, and immune responses were recorded. RESULTS: Fifty requests for phage therapy were received. Customized phages were generated for 12 patients. After treatment, 42% (5/12) of cases showed bacterial eradication and 58% (7/12) showed clinical improvement, with two-thirds of all cases (66%) showing favorable responses. No major adverse reactions were observed. Antibiotic-phage synergy in vitro was observed in most cases. Immunological neutralization of phages was reported in 5 cases. Several cases were complicated by secondary infections. Complete characterization of the phages (morphology, genomics, and activity) and their production (methods, sterility, and endotoxin tests) are reported. CONCLUSIONS: Customized phage production and therapy was safe and yielded favorable clinical or microbiological outcomes in two-thirds of cases. A center or pipeline dedicated to tailoring the phages against a patients specific AMR bacterial infection may be a viable option where standard treatment has failed.

Managing pelvic osteomyelitis (POM) in the setting of stage IV pressure injuries requires multidisciplinary evaluation as well as patient and caregiver engagement and is complicated by the lack of high-evidence data to guide best practices. In this review, we describe our approach to pressure injury and POM evaluation and management through multidisciplinary collaboration and highlight areas of future research that are necessary to enhance patient outcomes, reduce healthcare costs, and improve the quality of life of those affected by POM. [ABSTRACT FROM AUTHOR]

We examined the effect of preoperative antibiotic exposure and duration on synovial fluid samples from patients with native joint septic arthritis of the hip/knee. While exposure before diagnostic arthrocentesis did not affect fluid parameters, increased duration was associated with a decreased total nucleated cell count, underscoring the complex antibiotic effects on synovial fluid parameters. [ABSTRACT FROM AUTHOR]

Background The first-line management strategy for acute periprosthetic joint infections (PJIs) is debridement, antibiotics, and implant retention (DAIR). Suppressive antibiotic therapy (SAT) after DAIR is proposed to improve outcomes, yet its efficacy remains under scrutiny. Methods We conducted a multicenter retrospective study in patients with acute PJI of the hip or knee who were treated with DAIR in centers from Europe and the United States. We analyzed the effect of SAT using a Cox model landmarked at 12 weeks. The primary covariate of interest was SAT, which was analyzed as a time-varying covariate. Patients who experienced treatment failure or were lost to follow-up within 12 weeks were excluded from the analysis. Results The study included 510 patients with 66 treatment failures with a median follow-up of 801 days. We did not find a statistically significant association between SAT and treatment failure (hazard ratio, 1.37; 95% CI,.79–2.39; P =.27). Subgroup analyses for joint, country cohort, and type of infection (early or late acute) did not show benefit for SAT. Secondary analysis of country cohorts showed a trend toward benefit for the US cohort (hazard ratio, 0.36; 95% CI,.11–1.15; P =.09), which also had the highest risk of treatment failure. Conclusions The utility of routine SAT as a strategy for enhancing DAIR's success in acute PJI remains uncertain. Our results suggest that SAT's benefits might be restricted to specific groups of patients, underscoring the need for randomized controlled trials. Identifying patients most likely to benefit from SAT should be a priority in future studies. [ABSTRACT FROM AUTHOR]

Infections of cardiac implantable electronic devices (CIEDs) and vascular grafts are some of the most dreaded complications of these otherwise life-saving devices. Many of these infections are not responsive to conventional treatment, such as systemic antibiotics and surgical irrigation and debridement. Therefore, innovative strategies to prevent and manage these conditions are warranted. Among these, there is an increasing interest in phages as a therapeutical option. In this review, we aim to collect the available evidence for the clinical application of phage therapy for CIED and vascular graft infections through literature research. We found 17 studies for a total of 34 patients. Most of the indications were left ventricular assist device (LVAD) (n = 20) and vascular graft infections (n = 7). The bacteria most often encountered were Staphylococcus aureus (n = 18) and Pseudomonas aeruginosa (n = 16). Clinical improvements were observed in 21/34 (61.8%) patients, with microbiological eradication in 18/21 (85.7%) of them. In eight cases, an adverse event related to phage therapy was reported. Phage therapy is a promising option for difficult-to-treat CIED and vascular graft infections by means of an individualized approach. Clinical trials and expanded access programs for compassionate use are needed to further unveil the role of phage therapy in clinical application. [ABSTRACT FROM AUTHOR]

Solutions for bone and joint infection (BJI) are needed where conventional treatments are inadequate. Bacteriophages (phages) are naturally occurring viruses that infect bacteria and have been harnessed for refractory bone and joint infections (BJI) in many case reports. Here we examine the safety and efficacy of English-language published cases of BJI since 2010 with phage therapy. From 33 reported cases of BJI treated with phage therapy, 29 (87%) achieved microbiological or clinical success, 2 (5.9%) relapsed with the same organisms, and 2 (5.9%) with a different organism. Of these 4 relapses, all but 1 had eventual clinical resolution with additional surgery or phage treatments. Eight out of 33 cases (24%) reported mild, transient adverse events with no serious events reported. Further work is needed to understand the true efficacy of phages and the role of phages in BJI. Opportunities lay ahead for thoughtfully designed clinical trials adapted to individualized therapies. [ABSTRACT FROM AUTHOR]

Background Cutibacterium acnes can cause spinal implant infections. However, little is known about the optimal medical management and outcomes of C. acnes spinal implant infections (CSII). Our study aims to describe the management of patients with CSII and evaluate the clinical outcomes. Methods We performed a retrospective cohort study of patients aged 18 years or older who underwent spinal fusion surgery with instrumentation between January 1, 2011, and December 31, 2020, and whose intraoperative cultures were positive for C. acnes. The primary outcome was treatment failure based on subsequent recurrence, infection with another organism, or unplanned surgery secondary to infection. Results There were 55 patients with a median follow-up (interquartile range) of 2 (1.2–2.0) years. Overall, there were 6 treatment failures over 85.8 total person-years, for an annual rate of 7.0% (95% CI, 2.6%–15.2%). Systemic antibiotic treatment was given to 74.5% (n = 41) of patients for a median duration of 352 days. In the subgroup treated with systemic antibiotics, there were 4 treatment failures (annual rate, 6.3%; 95% CI, 1.7%–16.2%), all of which occurred while on antibiotic therapy. Two failures occurred in the subgroup without antibiotic treatment (annual rate, 8.8%; 95% CI, 1.1%–31.8%). Conclusions Our study found that the estimated annual treatment failure rate was slightly higher among patients who did not receive antibiotics. Of the 6 failures observed, 4 had recurrence of C. acnes either on initial or subsequent treatment failures. More studies are warranted to determine the optimal duration of therapy for CSII. [ABSTRACT FROM AUTHOR]

Managing pelvic osteomyelitis (POM) in the setting of stage IV pressure injuries requires multidisciplinary evaluation as well as patient and caregiver engagement and is complicated by the lack of high-evidence data to guide best practices. In this review, we describe our approach to pressure injury and POM evaluation and management through multidisciplinary collaboration and highlight areas of future research that are necessary to enhance patient outcomes, reduce healthcare costs, and improve the quality of life of those affected by POM. [ABSTRACT FROM AUTHOR]

Background: Increasing antimicrobial resistance combined with a lagging pipeline of novel antimicrobial compounds have resulted in a resurgence of interest in phage therapy. To select optimal phage or phage combinations for patients for whom phage therapy is considered, assessment of activity of a panel of phages against the patients' bacterial isolate(s) should ideally be performed. Classical phage susceptibility testing methods (i.e., agar overlay) may be laborious, with expertise outside of normal training and competency of medical laboratory science staff needed. Content: Adaptive Phage Therapeutics™ leveraged a commercially available phenotyping system (Biolog OmniLog®) to generate the PhageBank Susceptibility Test™, which uses a custom data analysis pipeline (PhageSelect™) to measure the delay in reaching log-phase metabolic activity ("hold time") when a given isolate is challenged with a specific phage. The goal of this study was to preliminarily assess reproducibility of this approach by testing 2 bacterial species at 2 sites, APT and an academic site. Nineteen Escherichia coli phages were tested against 18 bacterial isolates, and 21 Staphylococcus aureus phages, against 11 bacterial isolates. Result comparisons were statistically excellent for E. coli (κ = 0.7990) and good/fair for S. aureus (κ = 0.6360). Summary: The described method provides good/fair to excellent statistical reproducibility for assessment of phage susceptibility of 2 commonly encountered bacterial species. [ABSTRACT FROM AUTHOR]

Although the enteric reflex pathway triggered by volume distension is known to depend on an adrenergic nerve, it is not known whether the slowing of intestinal transit by fat or peptide YY (PYY) also depends on an adrenergic pathway. The aim of this study was to test the hypotheses that the slowing of transit by fat or PYY may depend on a [beta]-adrenergic pathway, and this adrenergic pathway may act via the serotonergic and opioid pathways previously observed for the slowing of transit by fat. Eighteen dogs were equipped with duodenal and midgut fistulas. The small intestine was compartmentalized into the proximal and distal half of gut. The role of adrenergic, serotonergic, and opioid pathways was then tested in the slowing of intestinal transit by fat, PYY, and norepinephrine. Intestinal transit results were compared as the cumulative percent marker of recovery over 30 min. We found that the slowing of transit by fat, PYY, or norepinephrine was reversed by propranolol. In addition, the slowing effect of fat was reversed by metoprolol ([[beta].sub.1]-adrenoreceptor antagonist) but not phentolamine [alpha]-adrenoreceptor antagonist). Furthermore, norepinephrine-induced slowing of transit was reversed by ondansetron (5-H[T.sub.3] receptor antagonist) or naloxone (opioid receptor antagonist). Extending these physiological results, we also found by immunohistochemistry that [[beta].sub.1]-adrenoreceptors are expressed by neurons of the intrinsic plexuses of the small intestine. We conclude that the slowing of intestinal transit by fat or PYY depends on a [beta]-adrenergic pathway and that this adrenergic pathway acts on serotonergic and opioid pathways. enteric neurons; ileal brake; serotonin; opioid; myenteric plexus