Lack of judicious testing can result in the incorrect diagnosis of Clostridioides difficile infection (CDI), unnecessary CDI treatment, increased costs and falsely augmented hospital-acquired ...infection (HAI) rates. We evaluated facility-wide interventions used at the VA San Diego Healthcare System (VASDHS) to reduce healthcare-onset, healthcare-facility-associated CDI (HO-HCFA CDI), including the use of diagnostic stewardship with test ordering criteria.
We conducted a retrospective study to assess the effectiveness of measures implemented to reduce the rate of HO-HCFA CDI at the VASDHS from fiscal year (FY)2015 to FY2018.
Measures executed in a stepwise fashion included a hand hygiene initiative, prompt isolation of CDI patients, enhanced terminal room cleaning, reduction of fluoroquinolone and proton-pump inhibitor use, laboratory rejection of solid stool samples, and lastly diagnostic stewardship with C. difficile toxin B gene nucleic acid amplification testing (NAAT) criteria instituted in FY2018.
From FY2015 to FY2018, 127 cases of HO-HCFA CDI were identified. All rate-reducing initiatives resulted in decreased HO-HCFA cases (from 44 to 13; P ≤ .05). However, the number of HO-HCFA cases (34 to 13; P ≤ .05), potential false-positive testing associated with colonization and laxative use (from 11 to 4), hospital days (from 596 to 332), CDI-related hospitalization costs (from $2,780,681 to $1,534,190) and treatment cost (from $7,158 vs $1,476) decreased substantially following the introduction of diagnostic stewardship with test criteria from FY2017 to FY2018.
Initiatives to decrease risk for CDI and diagnostic stewardship of C. difficile stool NAAT significantly reduced HO-HCFA CDI rates, detection of potential false-positives associated with laxative use, and lowered healthcare costs. Diagnostic stewardship itself had the most dramatic impact on outcomes observed and served as an effective tool in reducing HO-HCFA CDI rates.
Chikungunya virus (CHIKV) is an enveloped, positive-sense RNA virus that has re-emerged to cause millions of human infections worldwide. In humans, acute CHIKV infection causes fever and severe ...muscle and joint pain. Chronic and debilitating arthritis and joint pain can persist for months to years. To date, there are no approved antivirals against CHIKV. Recently, the ribonucleoside analog 4'-fluorouridine (4'-FlU) was reported as a highly potent orally available inhibitor of SARS-CoV-2, respiratory syncytial virus, and influenza virus replication. In this study, we assessed 4'-FlU's potency and breadth of inhibition against a panel of alphaviruses including CHIKV, and found that it broadly suppressed alphavirus production in cell culture. 4'-FlU acted on the viral RNA replication step, and the first 4 hours post-infection were the critical time for its antiviral effect.
replication assays identified nsP4 as the target of inhibition.
, treatment with 4'-FlU reduced disease signs, inflammatory responses, and viral tissue burden in mouse models of CHIKV and Mayaro virus infection. Treatment initiated at 2 hours post-infection was most effective; however, treatment initiated as late as 24-48 hours post-infection produced measurable antiviral effects in the CHIKV mouse model. 4'-FlU showed effective oral delivery in our mouse model and resulted in the accumulation of both 4'-FlU and its bioactive triphosphate form in tissues relevant to arthritogenic alphavirus pathogenesis. Together, our data indicate that 4'-FlU inhibits CHIKV infection
and
and is a promising oral therapeutic candidate against CHIKV infection.IMPORTANCEAlphaviruses including chikungunya virus (CHIKV) are mosquito-borne positive-strand RNA viruses that can cause various diseases in humans. Although compounds that inhibit CHIKV and other alphaviruses have been identified
, there are no licensed antivirals against CHIKV. Here, we investigated a ribonucleoside analog, 4'-fluorouridine (4'-FlU), and demonstrated that it inhibited infectious virus production by several alphaviruses
and reduced virus burden in mouse models of CHIKV and Mayaro virus infection. Our studies also indicated that 4'-FlU treatment reduced CHIKV-induced footpad swelling and reduced the production of pro-inflammatory cytokines. Inhibition in the mouse model correlated with effective oral delivery of 4'-FlU and accumulation of both 4'-FlU and its bioactive form in relevant tissues. In summary, 4'-FlU exhibits potential as a novel anti-alphavirus agent targeting the replication of viral RNA.
Key points
Chronic limb ischaemia, characterized by inflammatory mediator release and a low extracellular pH, leads to acid‐sensing ion channel (ASIC) activation and reflexively increases mean ...arterial pressure; endomorphin release is also increased under inflammatory conditions.
We examined the modulation of ASIC currents by endomorphins in sensory neurons from rats with freely perfused and ligated femoral arteries: peripheral artery disease (PAD) model.
Endomorphins potentiated sustained ASIC currents in both groups of dorsal root ganglion neurons, independent of mu opioid receptor stimulation or G protein activation.
Intra‐arterial administration of lactic acid (to simulate exercising muscle and evoke a pressor reflex), endomorphin‐2 and naloxone resulted in a significantly greater pressor response than lactic acid alone, while administration of APETx2 inhibited endomorphin's enhancing effect in both groups.
These results suggest a novel role for endomorphins in modulating ASIC function to effect lactic acid‐mediated reflex increase in arterial pressure in patients with PAD.
Chronic muscle ischaemia leads to accumulation of lactic acid and other inflammatory mediators with a subsequent drop in interstitial pH. Acid‐sensing ion channels (ASICs), expressed in thin muscle afferents, sense the decrease in pH and evoke a pressor reflex known to increase mean arterial pressure. The naturally occurring endomorphins are also released by primary afferents under ischaemic conditions. We examined whether high affinity mu opioid receptor (MOR) agonists, endomorphin‐1 (E‐1) and ‐2 (E‐2), modulate ASIC currents and the lactic acid‐mediated pressor reflex. In rat dorsal root ganglion (DRG) neurons, exposure to E‐2 in acidic solutions significantly potentiated ASIC currents when compared to acidic solutions alone. The potentiation was significantly greater in DRG neurons isolated from rats whose femoral arteries were ligated for 72 h. Sustained ASIC current potentiation was also observed in neurons pretreated with pertussis toxin, an uncoupler of G proteins and MOR. The endomorphin‐mediated potentiation was a result of a leftward shift of the activation curve to higher pH values and a slight shift of the inactivation curve to lower pH values. Intra‐arterial co‐administration of lactic acid and E‐2 led to a significantly greater pressor reflex than lactic acid alone in the presence of naloxone. Finally, E‐2 effects were inhibited by pretreatment with the ASIC3 blocker APETx2 and enhanced by pretreatment with the ASIC1a blocker psalmotoxin‐1. These findings have uncovered a novel role of endomorphins by which the opioids can enhance the lactic acid‐mediated reflex increase in arterial pressure that is MOR stimulation‐independent and APETx2‐sensitive.
Key points
Chronic limb ischaemia, characterized by inflammatory mediator release and a low extracellular pH, leads to acid‐sensing ion channel (ASIC) activation and reflexively increases mean arterial pressure; endomorphin release is also increased under inflammatory conditions.
We examined the modulation of ASIC currents by endomorphins in sensory neurons from rats with freely perfused and ligated femoral arteries: peripheral artery disease (PAD) model.
Endomorphins potentiated sustained ASIC currents in both groups of dorsal root ganglion neurons, independent of mu opioid receptor stimulation or G protein activation.
Intra‐arterial administration of lactic acid (to simulate exercising muscle and evoke a pressor reflex), endomorphin‐2 and naloxone resulted in a significantly greater pressor response than lactic acid alone, while administration of APETx2 inhibited endomorphin's enhancing effect in both groups.
These results suggest a novel role for endomorphins in modulating ASIC function to effect lactic acid‐mediated reflex increase in arterial pressure in patients with PAD.
Data on antimicrobial resistance (AMR) and association with outcomes in resource-variable intensive care units (ICU) are lacking. Data currently available are limited to large, urban centers. We ...attempted to understand this locally through a dual-purpose, retrospective study. Cohort A consisted of adult and pediatric patients who had blood, urine, or cerebrospinal fluid cultures obtained from 2016 to 2020. A total of 3,013 isolates were used to create the Kijabe Hospital's first antibiogram. Gram-negative organisms were found to be less than 50% susceptible to third- and fourth-generation cephalosporins, 67% susceptible to piperacillin-tazobactam, 87% susceptible to amikacin, and 93% susceptible to meropenem. We then evaluated the association between AMR and clinical characteristics, management, and outcomes among ICU patients (Cohort B). Demographics, vital signs, laboratory results, management data, and outcomes were obtained. Antimicrobial resistance was defined as resistance to one or more antimicrobials. Seventy-six patients were admitted to the ICU with bacteremia during this time. Forty complete paper charts were found for review. Median age was 34 years (interquartile range, 9-51), 26 patients were male (65%), and 28 patients were older than 18 years (70%). Septic shock was the most common diagnosis (n = 22, 55%). Six patients had AMR bacteremia; Escherichia coli was most common (n = 3, 50%). There was not a difference in mortality between patients with AMR versus non-AMR infections (P = 0.54). This study found a prevalence of AMR. There was no association between AMR and outcomes among ICU patients. More studies are needed to understand the impact of AMR in resource-variable settings.
While there are no studies investigating the efficacy of daith piercings for the treatment of migraine headaches, there are some theories to support the idea. The patient and family had worried that ...if the piercing was removed for surgery, they would be unable to replace it, possibly resulting in a return of migraines. ...the authors, as the attending anesthesiologist and surgeon, committed to maintain the piercing tract during surgery and replace the earring at the conclusion of surgery while the patient was still anesthetized. First we unscrewed one of the end beads, then inserted an angiocatheter over the bar and through the pierced area using the Seldinger technique.
•The learning curve for MRI-targeted prostate biopsies is approximately 100 cases•Obtaining only 3 cores in the learning curve misses 17% of prostate cancers•After the learning curve, 3 cores detect ...95% of prostate cancers
We hypothesized that the number of cores needed to detect prostate cancer would decrease with increasing MRI-targeted biopsy (TBx) experience.
All patients undergoing TBx at our institution from May 2017 to August 2019 were enrolled in a prospectively maintained database. Five biopsy cores were obtained from each lesion ≥3 on PI-RADS v2.0 followed by a systematic 12-core biopsy. To assess learning curve, the study population was divided into quartiles by sequential biopsies. Clinically significant prostate cancer (csPC) was defined as Gleason Grade Group 2 or higher.
377 patients underwent prostate biopsy (533 lesions); 233 lesions (44%) were positive for prostate cancer and 173 lesions (32%) were csPC. There was a significant decline in the number of cores required for diagnosing any cancer (P < 0.001) and csPC (P < 0.05) after the first quartile. There was no difference when stratifying by PI-RADS score or lesion volume. Within the first quartile, limiting the biopsy to 3 cores would miss 16.2% of csPC, decreasing to 6.6% after approximately 100 patients.
MRI TBx is associated with a learning curve of approximately 100 cases. Four or 5 cores should be considered during the initial experience, but thereafter, 3 cores per lesion is sufficient to detect csPC.
Do Patients with a PI-RADS 5 Lesion Identified on Magnetic Resonance Imaging Require Systematic Biopsy in Addition to Targeted Biopsy?•MRI-targeted biopsy alone may be sufficient in the setting of a ...PI-RADS 5 lesion.•The addition of systematic biopsy did not change clinical management.•Omission of systematic biopsy could be considered in this setting.
Magnetic Resonance Imaging (MRI)-targeted prostate biopsy (MRI-TB) improves the detection of prostate cancer. These biopsies typically involve both a 12-core systematic biopsy (SB) and MRI-TB of the lesion. Since the majority of PI-RADS 5 lesions represent clinically significant cancers, the utility of SB in addition to MRI-TB is unclear. We evaluate the utility of SB in the setting of PI-RADS 5 lesions in biopsy naïve and active surveillance patients.
Patients undergoing MRI-TB+SB with a PI-RADS 5 lesion were retrospectively reviewed in a prospectively collected database. Pathology obtained from the MRI-TB was then compared to that of the SB, and each was reported based on the highest Gleason Grade from the sample. In patients with a prior biopsy, we identified instances in which the MRI-TB+SB resulted in upgraded pathology and further subdivided these patients based on whether the pathology upgrade was a result of the TB or the SB.
We identified PI-RADS 5 lesions in 97 patients. All lesions biopsied were found to be prostate cancer, and 86.9% were clinically significant. Gleason Grade from the MRI-TB of the PI-RADS 5 lesions was the same or higher to that of the SB in all but 3 cases (3.1%). Among 59 patients with a prior prostate biopsy, 54 had upgraded pathology from MRI-TB+SB (91.5%). Of these 54 patients, MRI-TB pathology of the PI-RADS 5 lesion was the same or higher to that of the SB in 52 patients (96.3%). In all patients with higher Gleason Grade on SB than MRI-TB, the MRI-TB demonstrated GG3 or higher and SB did not change subsequent clinical management.
In the presence of a PI-RADS 5 lesion, SB offers minimal additional clinical value and could potentially be omitted when performing MRI-TB.
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