SummaryBackgroundClostridium difficile infection is the most common health-care-associated infection in the USA. We assessed the safety and efficacy of ridinilazole versus vancomycin for treatment of C difficile infection.MethodsWe did a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Participants with signs and symptoms of C difficile infection and a positive diagnostic test result were recruited from 33 centres in the USA and Canada and randomly assigned (1:1) to receive oral ridinilazole (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was achievement of a sustained clinical response, defined as clinical cure at the end of treatment and no recurrence within 30 days, which was used to establish non-inferiority (15% margin) of ridinilazole versus vancomycin. The primary efficacy analysis was done on a modified intention-to-treat population comprising all individuals with C difficile infection confirmed by the presence of free toxin in stool who were randomly assigned to receive one or more doses of the study drug. The study is registered with ClinicalTrials.gov, number NCT02092935.FindingsBetween June 26, 2014, and August 31, 2015, 100 patients were recruited; 50 were randomly assigned to receive ridinilazole and 50 to vancomycin. 16 patients did not complete the study, and 11 discontinued treatment early. The primary efficacy analysis included 69 patients (n=36 in the ridinilazole group; n=33 in the vancomycin group). 24 of 36 (66·7%) patients in the ridinilazole group versus 14 of 33 (42·4%) of those in the vancomycin group had a sustained clinical response (treatment difference 21·1%, 90% CI 3·1–39·1, p=0·0004), establishing the non-inferiority of ridinilazole and also showing statistical superiority at the 10% level. Ridinilazole was well tolerated, with an adverse event profile similar to that of vancomycin: 82% (41 of 50) of participants reported adverse events in the ridinilazole group and 80% (40 of 50) in the vancomycin group. There were no adverse events related to ridinilazole that led to discontinuation.InterpretationRidinilazole is a targeted-spectrum antimicrobial that shows potential in treatment of initial C difficile infection and in providing sustained benefit through reduction in disease recurrence. Further clinical development is warranted.FundingWellcome Trust and Summit Therapeutics.

The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701).

Deaths occurring among agitated or violent individuals subjected to physical restraint have been attributed to positional asphyxia. Restraint in the prone position has been shown to alter respiratory and cardiac physiology, although this is thought not to be to the degree that would cause asphyxia in a healthy, adult individual. This comprehensive review identifies and summarizes the current scientific literature on prone position and restraint, including experiments that assess physiology on individuals restrained in a prone position. Some of these experimental approaches have attempted to replicate situations in which prone restraint would be used. Overall, most findings revealed that individuals subjected to physical prone restraint experienced a decrease in ventilation and/or cardiac output (CO) in prone restraint. Metabolic acidosis is noted with increased physical activity, in restraint-associated cardiac arrest and simulated encounters. A decrease in ventilation and CO can significantly worsen acidosis and hemodynamics. Given these findings, deaths associated with prone physical restraint are not the direct result of asphyxia but are due to cardiac arrest secondary to metabolic acidosis compounded by inadequate ventilation and reduced CO. As such, the cause of death in these circumstances would be more aptly referred to as “prone restraint cardiac arrest” as opposed to “restraint asphyxia” or “positional asphyxia.”

We postulate that most atraumatic deaths during police restraint of subjects in the prone position are due to prone restraint cardiac arrest (PRCA), rather than from restraint asphyxia or a stress-induced cardiac condition, such as excited delirium. The prone position restricts ventilation and diminishes pulmonary perfusion. In the setting of a police encounter, metabolic demand will be high from anxiety, stress, excitement, physical struggle, and/or stimulant drugs, leading to metabolic acidosis and requiring significant hyperventilation.Although oxygen levels may be maintained, prolonged restraint in the prone position may result in an inability to adequately blow off CO 2 , causing blood pCO 2 levels to rise rapidly.The uncompensated metabolic acidosis (low pH) will eventually result in loss of myocyte contractility. The initial electrocardiogram rhythm will generally be either pulseless electrical activity (PEA) or asystole, indicating a noncardiac etiology, more consistent with PRCA and inconsistent with a primary role of any underlying cardiac pathology or stress-induced cardiac etiology. We point to two animal models: in one model rats unable to breathe deeply due to an external restraint die when their metabolic demand is increased, and in the other model, pressure on the chest of rats results in decreased venous return and cardiac arrest rather than death from asphyxia. We present two cases of subjects restrained in the prone position who went into cardiac arrest and had low pHs and initial PEA cardiac rhythms. Our cases demonstrate the danger of prone restraint and serve as examples of PRCA. K E Y W O R D Sprone restraint, in-custody deaths, arrest-related deaths (ARDs), police-involved deaths, restraint asphyxia, positional asphyxia, excited delirium, sudden cardiac death, metabolic acidosis, George Floyd, forensic pathology, autopsy Highlights• Prone restraint deaths result from metabolic acidosis, not hypoxic asphyxia.• Metabolic demand is increased by stimulant drugs, physical exertion, and stress.• Metabolic acidosis requires hyperventilation to "blow off" carbon dioxide (CO 2 ).• Prolonged restraint in the prone position may prevent adequate elimination of CO 2 .• An initial ECG rhythm of PEA or asystole after a cardiac arrest is generally inconsistent with a primary cardiac etiology.How to cite this article: Weedn V, Steinberg A, Speth P. Prone restraint cardiac arrest in in-custody and arrest-related deaths.

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