Family-centered interventions and patient outcomes in the adult intensive care unit: A systematic review of randomized controlled trials.

OBJECTIVE: There is a need to understand how family engagement in the intensive care unit (ICU) impacts patient outcomes. We reviewed the literature for randomized family-centered interventions with patient-related outcomes in the adult ICU. DATA SOURCES: The MEDLINE, EMBASE, PsycINFO, CINAHL, and the Cochrane Library databases were searched from inception until July 3, 2023. STUDY SELECTION: Articles involving randomized controlled trials (RCTs) in the adult critical care setting evaluating family-centered interventions and reporting patient-related outcomes. DATA EXTRACTION: Author, publication year, setting, number of participants, intervention category, intervention, and patient-related outcomes (patient-reported, physiological, clinical) were extracted. DATA SYNTHESIS: There were 28 RCTs (12,174 participants) included. The most common intervention types were receiving care and meeting needs (N = 10) and family presence (N = 7). 16 RCTs (57%) reported ≥1 positive outcome from the intervention; no studies reported worse outcomes. Studies reported improvements in patient-reported outcomes such as anxiety, satisfaction, post-traumatic stress symptoms, depression, and health-related quality of life. RCTs reported improvements in physiological indices, adverse events, mechanical ventilation duration, analgesia use, ICU length of stay, delirium, and time to withdrawal of life-sustaining treatments. CONCLUSIONS: Nearly two-thirds of RCTs evaluating family-centered interventions in the adult ICU reported positive patient-related outcomes. KEYPOINTS: Question: Do family-centered interventions improve patient outcomes in the adult intensive care unit (ICU)? FINDINGS: The systematic review found that nearly two-thirds of randomized clinical trials of family-centered interventions in the adult ICU improved patient outcomes. Studies found improvements in patient mental health, care satisfaction, physiological indices, and clinical outcomes. There were no studies reporting worse patient outcomes. Meaning: Many family-centered interventions can improve patient outcomes.

PAM-free diagnostics with diverse type V CRISPR-Cas systems.

Type V CRISPR-Cas effectors have revolutionized molecular diagnostics by facilitating the detection of nucleic acid biomarkers. However, their dependence on the presence of protospacer adjacent motif (PAM) sites on the target double-stranded DNA (dsDNA) greatly limits their flexibility as diagnostic tools. Here we present a novel method named PICNIC that solves the PAM problem for CRISPR-based diagnostics with just a simple ∼10-min modification to contemporary CRISPR-detection protocols. Our method involves the separation of dsDNA into individual single-stranded DNA (ssDNA) strands through a high- temperature and high-pH treatment. We then detect the released ssDNA strands with diverse Cas12 enzymes in a PAM-free manner. We show the utility of PICNIC by successfully applying it for PAM-free detection with three different subtypes of the Cas12 family- Cas12a, Cas12b, and Cas12i. Notably, by combining PICNIC with a truncated 15-nucleotide spacer containing crRNA, we demonstrate PAM-independent detection of clinically important single- nucleotide polymorphisms with CRISPR. We apply this approach to detect the presence of a drug-resistant variant of HIV-1, specifically the K103N mutant, that lacks a PAM site in the vicinity of the mutation. Additionally, we successfully translate our approach to clinical samples by detecting and genotyping HCV-1a and HCV-1b variants with 100% specificity at a PAM-less site within the HCV genome. In summary, PICNIC is a simple yet groundbreaking method that enhances the flexibility and precision of CRISPR-Cas12-based diagnostics by eliminating the restriction of the PAM sequence.

Missed Screening Mammography Appointments: Patient Sociodemographic Characteristics and Mammography Completion After 1 Year.

OBJECTIVE: Patients who miss screening mammogram appointments without notifying the health care system (no-show) risk care delays. We investigate sociodemographic characteristics of patients who experience screening mammogram no-shows at a community health center and whether and when the missed examinations are completed. METHODS: We included patients with screening mammogram appointments at a community health center between January 1, 2021, and December 31, 2021. Language, race, ethnicity, insurance type, residential ZIP code tabulation area (ZCTA) poverty, appointment outcome (no-show, same-day cancelation, completed), and dates of completed screening mammograms after no-show appointments with ≥1-year follow-up were collected. Multivariable analyses were used to assess associations between patient characteristics and appointment outcomes. RESULTS: Of 6,159 patients, 12.1% (743 of 6,159) experienced no-shows. The no-show group differed from the completed group by language, race and ethnicity, insurance type, and poverty level (all P < .05). Patients with no-shows more often had: primary language other than English (32.0% [238 of 743] versus 26.7% [1,265 of 4,741]), race and ethnicity other than White non-Hispanic (42.3% [314 of 743] versus 33.6% [1,595 of 4,742]), Medicaid or means-tested insurance (62.0% [461 of 743] versus 34.4% [1,629 of 4,742]), and residential ZCTAs with ≥20% poverty (19.5% [145 of 743] versus 14.1% [670 of 4,742]). Independent predictors of no-shows were Black non-Hispanic race and ethnicity (adjusted odds ratio [aOR], 1.52; 95% confidence interval [CI], 1.12-2.07; P = .007), Medicaid or other means-tested insurance (aOR, 2.75; 95% CI, 2.29-3.30; P < .001), and ZCTAs with ≥20% poverty (aOR, 1.76; 95% CI, 1.14-2.72; P = .011). At 1-year follow-up, 40.6% (302 of 743) of patients with no-shows had not completed screening mammogram. DISCUSSION: Screening mammogram no-shows is a health equity issue in which socio-economically disadvantaged and racially and ethnically minoritized patients are more likely to experience missed appointments and continued delays in screening mammogram completion.

Retraction: Dealcoholized muscadine wine was partially effective in preventing and treating dextran sulfate sodium-induced colitis and restoring gut dysbiosis in mice.

Retraction of 'Dealcoholized muscadine wine was partially effective in preventing and treating dextran sulfate sodium-induced colitis and restoring gut dysbiosis in mice' by Hao Li et al., Food Funct., 2023, 14, 5994-6011, https://doi.org/10.1039/D3FO00047H.

Availability of Testing for Sexually Transmitted Infections and HIV in U.S. Outpatient Mental Healthcare Settings.

People with mental illnesses experience higher incidence of sexually transmitted illnesses (STIs) and HIV, and estimates show fewer than 50% have received testing. The purpose of this study was to examine the prevalence of STI/HIV testing among United States outpatient mental healthcare service providers. Data from the National Mental Health Services Survey (NMHSS) was used to determine the rates of STI and HIV testing amongst 9,267 outpatient mental healthcare service providers in the U.S. Regression analyses were used to assess whether the likelihood a service provider offered STI or HIV testing was associated with service provider characteristics (facility type, services offered, accepted payments) and state-level incidence of STIs and HIV. We found 7.79% and 6.64% of outpatient mental healthcare service providers provided STI and HIV testing, respectively, with lowest rates in community mental health centers and partial hospitalization facilities. Providing dual-diagnosis for severe mental illness and substance use disorders was an independent predictor of STI testing (aOR = 2.17, [1.72-2.75] and HIV testing (aOR = 2.61, [2.07-3.30]. Higher state-level incidence of STIs and HIV were associated with higher rates of STI testing (ß = 0.28, p = .047) and HIV testing (ß = 0.48, p < .001). Preventing STIs and HIV among patients living with mental illness is a key priority of multiple national initiatives. Despite this, fewer than 10% of outpatient mental healthcare service providers responding to the NMHSS offered STI and HIV testing. Existing service co-delivery models may be one promising method for implementing STI/HIV testing within outpatient mental health settings.

Effects of Carboxymethylcellulose Artificial Tears on Ocular Surface Microbiome Diversity and Composition, A Randomized Controlled Trial.

Purpose: Carboxymethylcellulose is an artificial tear ingredient known to decrease gut microbiome diversity when ingested. This study examines the effect of carboxymethylcellulose on ocular surface microbiome diversity and composition. Methods: Healthy adult participants without significant ophthalmic disease or concurrent carboxymethylcellulose artificial tear use were allocated randomly to take carboxymethylcellulose or control polyethylene glycol artificial tears for seven days. Conjunctival swabs were collected before and after artificial tear treatment. This trial is registered at clinicaltrials.gov (NCT05292755). Primary outcomes included abundance of bacterial taxa and microbiome diversity as measured by the Chao-1 richness estimate, Shannon's phylogenetic diversity index, and UniFrac analysis. Secondary outcomes included Ocular Surface Disease Index scores and artificial tear compliance. Results: Of the 80 enrolled participants, 66 completed the trial. Neither intervention affected Chao-1 richness (analysis of variance [ANOVA], P = 0.231) or Shannon's diversity index (ANOVA, P = 0.224). Microbiome samples did not separate by time point (permutation multivariate analysis of variance [PERMANOVA], P = 0.223) or intervention group (PERMANOVA, P = 0.668). LEfSe taxonomic analysis revealed that carboxymethylcellulose depleted several taxa including Bacteroides and Lachnoclostridium, but enriched Enterobacteriaceae, Citrobacter, and Gordonia. Both interventions decreased OSDI scores (Wilcoxon signed rank test, P < 0.05), but there was no significant difference between interventions (Mann-Whitney U, P = 0.54). Conclusions: Carboxymethylcellulose artificial tears increased Actinobacteriota but decreased Bacteroides and Firmicutes bacteria. Carboxymethylcellulose artificial tears do not affect ocular surface microbiome diversity and are not significantly more effective than polyethylene glycol artificial tears for dry eye treatment. Translational Relevance: The 16S microbiome analysis has revealed small changes in the ocular surface microbiome associated with artificial tear use.

Pneumocystis jirovecii pneumonia presenting as a large pulmonary mass in a patient with AIDS.

Pneumocystis jirovecii pneumonia typically presents with diffuse bilateral infiltrates or ground-glass opacities. However, the radiographic pattern may be atypical. We report a case of a woman in her 40s who presented with multiple pulmonary masses and prolonged symptoms of non-productive cough, generalised weakness and fatigue. Serial chest CT performed prior to her presentation showed a large right lower lobe lung mass with multiple additional bilateral pulmonary nodules. Her workup revealed a new diagnosis of AIDS. Pathology of several CT-guided needle biopsies was consistent with Pneumocystis which was confirmed by microbial DNA sequencing. No additional pathogens were identified. Her clinical symptoms and radiographs improved significantly with trimethoprim-sulfamethoxazole and treatment of her HIV infection. Clinicians should evaluate for underlying immunodeficiency and seek infectious disease and pulmonary consultation early for consideration of alternative diagnoses when patients present with cough, dyspnoea and atypical chest radiographs, and initial pathological examination is unrevealing.

Dealcoholized muscadine wine was partially effective in preventing and treating dextran sulfate sodium-induced colitis and restoring gut dysbiosis in mice.

Muscadine wine has a unique polyphenol profile consisting of anthocyanins, ellagic acids, and flavonols. This study aims to compare the prevention, treatment, and combined activity (P + T) of dealcoholized muscadine wine (DMW) on DSS-induced colitis in mice and its impact on the gut microbiome. Male C57BL/6 mice in the healthy and colitis group received an AIN-93M diet for 28 days. In the prevention, treatment, and P + T (prevention + treatment) groups, mice received an AIN-93M diet containing 2.79% (v/w) DMW on days 1-14, 15-28, and 1-28, respectively. Except for mice in the healthy group, all mice were given water with 2.5% (w/v) DSS on days 8-14 to induce colitis. DMW in all three receiving groups reduced myeloperoxidase activity, histology scores, and phosphorylation of Iκb-α in the colon. Colon shortening, serum IL-6, and colonic mRNA of TNF-α were blunted only in the P + T group. Gut permeability was reduced in the treatment and P + T groups. DMW in P + T group showed higher activity to increase microbiome evenness, modulate ß-diversity, elevate the cecal content of SCFAs, and enrich SCFA-producing bacteria, including Lactobacillaceae, Lachnospiraceae, Ruminococcaceae, and Peptococcaceae. This was accompanied by a decrease in pathogenic Burkholderiaceae in mice. This study suggests that muscadine wine has partial preventive and therapeutic effects against inflammatory bowel disease. The combination of prevention and treatment using DMW showed better activities than either prevention or treatment.

The Impact of Randomized Family-Centered Interventions on Family-Centered Outcomes in the Adult Intensive Care Unit: A Systematic Review.

Objective: To review the literature for randomized family-centered interventions with family-centered outcomes in the adult intensive care unit (ICU). Data Sources: We searched MEDLINE, EMBASE, PsycINFO, CINAHL, and the Cochrane Library database from inception until February 2023. Study Selection: We included articles involving randomized controlled trials (RCTs) in the adult critical care setting evaluating family-centered interventions and reporting family-centered outcomes. Data Extraction: We extracted data on author, year of publication, setting, number of participants, intervention category, intervention, and family-centered outcomes. Data Synthesis: There were 52 RCTs included in the analysis, mostly involving communication and receiving information (38%) and receiving care and meeting family member needs (38%). Nearly two-thirds of studies (N = 35; 67.3%) found improvements in at least 1 family-centered outcome. Most studies (N = 24/40; 60%) exploring the impact of family-centered interventions on mental health outcomes showed improvement. Improvements in patient-centered outcomes (N = 7/17; 41%) and healthcare worker outcomes (N = 1/5; 20%) were less commonly found. Conclusions: Family-centered interventions improve family-centered outcomes in the adult ICU and may be beneficial to patients and healthcare workers.

Improving Diabetes Care Through Population Health Innovations and Payments: Lessons from Western Maryland.

BACKGROUND: Global budgets might incentivize healthcare systems to develop population health programs to prevent costly hospitalizations. In response to Maryland's all-payer global budget financing system, University of Pittsburgh Medical Center (UPMC) Western Maryland developed an outpatient care management center called the Center for Clinical Resources (CCR) to support high-risk patients with chronic disease. OBJECTIVE: Evaluate the impact of the CCR on patient-reported, clinical, and resource utilization outcomes for high-risk rural patients with diabetes. DESIGN: Observational cohort study. PARTICIPANTS: One hundred forty-one adult patients with uncontrolled diabetes (HbA1c > 7%) and one or more social needs who were enrolled between 2018 and 2021. INTERVENTIONS: Team-based interventions that provided interdisciplinary care coordination (e.g., diabetes care coordinators), social needs support (e.g., food delivery, benefits assistance), and patient education (e.g., nutritional counseling, peer support). MAIN MEASURES: Patient-reported (e.g., quality of life, self-efficacy), clinical (e.g., HbA1c), and utilization outcomes (e.g., emergency department visits, hospitalizations). KEY RESULTS: Patient-reported outcomes improved significantly at 12 months, including confidence in self-management, quality of life, and patient experience (56% response rate). No significant demographic differences were detected between patients with or without the 12-month survey response. Baseline mean HbA1c was 10.0% and decreased on average by 1.2 percentage points at 6 months, 1.4 points at 12 months, 1.5 points at 18 months, and 0.9 points at 24 and 30 months (P<0.001 at all timepoints). No significant changes were observed in blood pressure, low-density lipoprotein cholesterol, or weight. The annual all-cause hospitalization rate decreased by 11 percentage points (34 to 23%, P=0.01) and diabetes-related emergency department visits also decreased by 11 percentage points (14 to 3%, P=0.002) at 12 months. CONCLUSIONS: CCR participation was associated with improved patient-reported outcomes, glycemic control, and hospital utilization for high-risk patients with diabetes. Payment arrangements like global budgets can support the development and sustainability of innovative diabetes care models.

Smoking-induced subgingival dysbiosis precedes clinical signs of periodontal disease.

Smoking accelerates periodontal disease and alters the subgingival microbiome. However, the relationship between smoking-associated subgingival dysbiosis and progression of periodontal disease is not well understood. Here, we sampled 233 subgingival sites longitudinally from 8 smokers and 9 non-smokers over 6-12 months, analyzing 804 subgingival plaque samples using 16 rRNA sequencing. At equal probing depths, the microbial richness and diversity of the subgingival microbiome was higher in smokers compared to non-smokers, but these differences decreased as probing depths increased. The overall subgingival microbiome of smokers differed significantly from non-smokers at equal probing depths, which was characterized by colonization of novel minority microbes and a shift in abundant members of the microbiome to resemble periodontally diseased communities enriched with pathogenic bacteria. Temporal analysis showed that microbiome in shallow sites were less stable than deeper sites, but temporal stability of the microbiome was not significantly affected by smoking status or scaling and root planing. We identified 7 taxa-Olsenella sp., Streptococcus cristatus, Streptococcus pneumoniae, Streptococcus parasanguinis, Prevotella sp., Alloprevotella sp., and a Bacteroidales sp. that were significantly associated with progression of periodontal disease. Taken together, these results suggest that subgingival dysbiosis in smokers precedes clinical signs of periodontal disease, and support the hypothesis that smoking accelerates subgingival dysbiosis to facilitate periodontal disease progression.

Muscadine grape (vitis rotundifolia) and wine polyphenols alleviated arthritis and restored the gut microbial composition in mice.

This study aimed to investigate the effect of muscadine grape polyphenols (MGP) and muscadine wine polyphenols (MWP) on the onset and progression of arthritis in mice. Arthritis in male DBA/1J mice was induced by two intradermal injections of type II collagen. MGP or MWP (400 mg/kg) were orally gavaged to mice. MGP and MWP were found to delay the onset and reduce the severity and clinical symptoms of collagen induced arthritis (CIA) (P ≤ .05). In addition, MGP and MWP significantly reduced the plasma concentration of TNF-α, IL-6, anticollagen antibodies, and matrix metalloproteinase-3 in CIA mice. Based on nano computerized tomography (CT) and histological analysis, MGP and MWP reduced pannus formation, cartilage destruction, and bone erosion in CIA mice. Analysis of 16S ribosomal RNA revealed that arthritis in mice is associated with gut dysbiosis. MWP was more effective than MGP at alleviating such dysbiosis by shifting the microbiome composition toward the direction of healthy mice. Relative abundance of several genera of gut microbiome correlated with plasma inflammatory biomarkers and bone histology scores, suggesting they play a role in the development and progression of arthritis. This study suggests that muscadine grape or wine polyphenols can be used as a diet-based strategy to prevent and manage arthritis in humans.

Emulsification by vitamin E TPGS or Quillaja extract enhanced absorption of berberine without affecting its metabolism in humans.

Berberine is widely used for the prevention of cancers and diabetes. However, the absorption rate of berberine is less than 1% in humans. The objective of this research was to determine whether emulsification improves the absorption and affects the metabolism of orally ingested berberine. Twelve healthy subjects, both men and women, received 800 mg berberine in a powder or emulsified form by vitamin E TPGS or Quillaja extract using a randomized crossover design. Blood samples were collected 12 hours after a dose. Berberine and its metabolites in plasma were analyzed with and without hydrolysis by glucuronidase and sulfatase on UHPLC-MS/MS. The area under the curve (AUC0-12 h) and peak plasma concentration (Cmax) of berberine was 6.7 nM h and 0.9 nM in participants who received berberine powder. They were increased to 12.6 nM h and 2.0 nM by TPGS emulsification and 28.0 nM h and 5.1 nM by Quillaja extract emulsification, respectively. Berberrubine and demethyleneberberine were detected as major phase-1 metabolites of berberine. The AUC0-12 of both free and total berberrubine was significantly increased by TPGS and Quillaja extract. Emulsification by Quillaja extract was more effective than TPGS to increase the plasma concentrations of free and total demethyleneberberine. However, the ratios of phase-1 metabolites and ratios of phase-2 conjugates were not affected by emulsification. Absorption increases of berberine by TPGS or Quillaja extract emulsification may lead to enhanced bioactivity in humans.

A randomized controlled trial to evaluate the effectiveness of a novel mouth rinse in patients with gingivitis.

BACKGROUND: This single-center, randomized controlled trial aimed to determine the effectiveness of a novel, biofilm-disrupting, mouth rinse that combines Cetylpyridinium chloride (CPC) and essential oils in preventing re-accumulation of supragingival plaque and supragingival microbiome in patients with gingivitis after dental prophylaxis. METHODS: One hundred eighteen participants were randomly assigned in a 1:1 ratio to receive twice-daily test mouth rinse (59) or carrier rinse control (59) for 12 weeks after dental prophylaxis. RESULTS: In a per-protocol analysis that included patients who completed the intervention, the treatment group (39) had significantly lower supragingival plaque scores at 6 and 12 weeks compared to the control group (41; p = 0.022). Both groups showed similar improvement in gingivitis score, but neither group had improvement in bleeding score or probing depth. Thirty-eight (29%) patients did not complete the study due to loss of follow-up (17) or early discontinuation of the assigned intervention (21). Microbiome sequencing showed that the treatment rinse significantly depleted abundant and prevalent members of the supragingival plaque microbiome consortium. CONCLUSIONS: Among patients with gingivitis, the novel mouth rinse significantly reduced re-accumulation of supragingival plaque following dental prophylaxis by depleting supragingival plaque microbiome. However, long-term adherence to the rinse may be limited by adverse effects ( ClinicalTrials.gov number, NCT03154021).

The Role of Social Biases, Race, and Condom Use in Willingness to Prescribe HIV Pre-exposure Prophylaxis to MSM: An Experimental, Vignette-Based Study.

INTRODUCTION: Daily antiretroviral pre-exposure prophylaxis (PrEP) is a safe and effective method of preventing HIV. Clinicians' assumptions, biases, and judgments may impede access to PrEP. Specifically, concern that patients will engage in more condomless sex ("risk compensation") has been cited by clinicians as a reason for not prescribing PrEP. METHODS: In this experimental study among medical students, we systematically varied race (White or Black) and condom-use behaviors (continued-use, planned-discontinuation, or continued-nonuse) of a fictional patient (all men with multiple male sex partners). Participants indicated the patients' assumed adherence to PrEP, patients' overall HIV risk, and willingness to prescribe PrEP. Participants completed an implicit association test to detect implicit racism and measures of heterosexism and attitudes toward nonmonogamy, which were examined as moderators of patient race and condom-use effects on participants' assumptions and ultimate willingness to prescribe PrEP. RESULTS: Participants ( N = 600) were most willing to prescribe PrEP to the continued-nonuse patient and least willing to prescribe to the planned-discontinuation patient. No differences were identified based on patient race. The continued-nonuse (vs. continued-use) patient was perceived as less likely to adhere to PrEP, which was associated with lower willingness to prescribe. Negative attitudes toward nonmonogamy exacerbated this effect. No effects of implicit racism or explicit heterosexism were identified. CONCLUSIONS: Participants were least willing to prescribe PrEP to patients who planned to discontinue condom use. Patients seeking PrEP are exhibiting agency over their sexual health, and clinicians should fulfill their role in ensuring access to this primary preventative therapy. Training and curricular reform regarding PrEP are needed.

Efficacy and Safety of RBX2660 in PUNCH CD3, a Phase III, Randomized, Double-Blind, Placebo-Controlled Trial with a Bayesian Primary Analysis for the Prevention of Recurrent Clostridioides difficile Infection.

BACKGROUND: Recurrent Clostridioides difficile infection, associated with dysbiosis of gut microbiota, has substantial disease burden in the USA. RBX2660 is a live biotherapeutic product consisting of a broad consortium of microbes prepared from human stool that is under investigation for the reduction of recurrent C. difficile infection. METHODS: A randomized, double-blind, placebo-controlled, phase III study, with a Bayesian primary analysis integrating data from a previous phase IIb study, was conducted. Adults who had one or more C. difficile infection recurrences with a positive stool assay for C. difficile and who were previously treated with standard-of-care antibiotics were randomly assigned 2:1 to receive a subsequent blinded, single-dose enema of RBX2660 or placebo. The primary endpoint was treatment success, defined as the absence of C. difficile infection diarrhea within 8 weeks of study treatment. RESULTS: Of the 320 patients screened, 289 were randomly assigned and 267 received blinded treatment (n = 180, RBX2660; n = 87, placebo). Original model estimates of treatment success were 70.4% versus 58.1% with RBX2660 and placebo, respectively. However, after aligning the data to improve the exchangeability and interpretability of the Bayesian analysis, the model-estimated treatment success rate was 70.6% with RBX2660 versus 57.5% with placebo, with an estimated treatment effect of 13.1% and a posterior probability of superiority of 0.991. More than 90% of the participants who achieved treatment success at 8 weeks had sustained response through 6 months in both the RBX2660 and the placebo groups. Overall, RBX2660 was well tolerated, with manageable adverse events. The incidence of treatment-emergent adverse events was higher in RBX2660 recipients compared with placebo and was mostly driven by a higher incidence of mild gastrointestinal events. CONCLUSIONS: RBX2660 is a safe and effective treatment to reduce recurrent C. difficile infection following standard-of-care antibiotics with a sustained response through 6 months. CLINICAL TRIAL REGISTRATION: NCT03244644; 9 August, 2017.

Clostridioides difficile is a diarrhea-causing bacterium that is associated with potentially serious and fatal consequences. Antibiotics used to treat or prevent infections have a side effect of damaging the healthy protective gut bacteria (microbiota). Damage to the gut microbiota can allow C. difficile to over-grow and produce toxins that injure the colon. Paradoxically, the standard of care treatment of C. difficile infection (CDI) is antibiotics. Although initially effective for the control of diarrhea, antibiotics can leave a patient at risk for CDI recurrence after antibiotic treatment is stopped. Live biotherapeutic products are microbiota-based treatments used to repair the gut microbiota. These products have been shown to reduce the recurrence of CDI. RBX2660 is an investigational microbiota-based live biotherapeutic. RBX2660 contains a diverse set of microorganisms. RBX2660 has been developed to reduce CDI recurrence in adults following antibiotic treatment for recurrent CDI. This study was conducted to demonstrate that RBX2660 is effective and safe in treating patients with recurrent CDI. Treatment was considered successful in participants who did not experience CDI recurrence within 8 weeks after administration. Overall, statistical modeling demonstrated that 70.6% of participants treated with RBX2660 and 57.5% of participants treated with placebo remained free of CDI recurrence through 8 weeks. A 13.1 percentage point increase in treatment success was observed with RBX2660 treatment compared with placebo. In participants who achieved treatment success at 8 weeks, more than 90% remained free of CDI recurrence through 6 months. The most common side effects with RBX2660 treatment were abdominal pain and diarrhea. No serious treatment-related side effects were reported. The current data from the comprehensive clinical development program support a positive benefit-risk profile for RBX2660 in the reduction of CDI recurrence in adults following antibiotic therapy for recurrent CDI.

A point mutation in HIV-1 integrase redirects proviral integration into centromeric repeats.

Retroviruses utilize the viral integrase (IN) protein to integrate a DNA copy of their genome into host chromosomal DNA. HIV-1 integration sites are highly biased towards actively transcribed genes, likely mediated by binding of the IN protein to specific host factors, particularly LEDGF, located at these gene regions. We here report a substantial redirection of integration site distribution induced by a single point mutation in HIV-1 IN. Viruses carrying the K258R IN mutation exhibit a high frequency of integrations into centromeric alpha satellite repeat sequences, as assessed by deep sequencing, a more than 10-fold increase over wild-type. Quantitative PCR and in situ immunofluorescence assays confirm this bias of the K258R mutant virus for integration into centromeric DNA. Immunoprecipitation studies identify host factors binding to IN that may account for the observed bias for integration into centromeres. Centromeric integration events are known to be enriched in the latent reservoir of infected memory T cells, as well as in elite controllers who limit viral replication without intervention. The K258R point mutation in HIV-1 IN is also present in databases of latent proviruses found in patients, and may reflect an unappreciated aspect of the establishment of viral latency.