A rhPDGF-BB/bovine type I collagen/ß-TCP mixture for the treatment of critically sized non-union tibial defects: An in vivo study in rabbits.

Non-union during healing of bone fractures affects up to ~5% of patients worldwide. Given the success of recombinant human platelet-derived growth factor-B chain homodimer (rhPDGF-BB) in promoting angiogenesis and bone fusion in the hindfoot and ankle, rhPDGF-BB combined with bovine type I collagen/ß-TCP matrix (AIBG) could serve as a viable alternative to autografts in the treatment of non-unions. Defects (~2 mm gaps) were surgically induced in tibiae of skeletally mature New Zealand white rabbits. Animals were allocated to one of four groups-(1) negative control (empty defect, healing for 8 weeks), (2 and 3) acute treatment with AIBG (healing for 4 or 8 weeks), and (4) chronic treatment with AIBG (injection 4 weeks post defect creation and then healing for 8 weeks). Bone formation was analyzed qualitatively and semi-quantitatively through histology. Samples were imaged using dual-energy X-ray absorptiometry and computed tomography for defect visualization and volumetric reconstruction, respectively. Delayed healing or non-healing was observed in the negative control group, whereas defects treated with AIBG in an acute setting yielded bone formation as early as 4 weeks with bone growth appearing discontinuous. At 8 weeks (acute setting), substantial remodeling was observed with higher degrees of bone organization characterized by appositional bone growth. The chronic healing, experimental, group yielded bone formation and remodeling, with no indication of non-union after treatment with AIBG. Furthermore, bone growth in the chronic healing group was accompanied by an increased presence of osteons, osteonal canals, and interstitial lamellae. Qualitatively and semiquantitatively, chronic application of AI facilitated complete bridging of the induced non-union defects, while untreated defects or defects treated acutely with AIBG demonstrated a lack of complete bridging at 8 weeks.

Immune responses to SARS-CoV-2 mRNA vaccination in people with idiopathic CD4 lymphopenia.

BACKGROUND: The immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines is variable in individuals with different inborn errors of immunity or acquired immune deficiencies and is yet unknown in people with idiopathic CD4 lymphopenia (ICL). OBJECTIVE: We sought to determine the immunogenicity of mRNA vaccines in patients with ICL with a broad range of CD4 T-cell counts. METHODS: Samples were collected from 25 patients with ICL and 23 age- and sex-matched healthy volunteers (HVs) after their second or third SARS-CoV-2 mRNA vaccine dose. Anti-spike and anti-receptor binding domain antibodies were measured. T-cell receptor sequencing and stimulation assays were performed to quantify SARS-CoV-2-specific T-cell responses. RESULTS: The median age of ICL participants was 51 years, and their median CD4 count was 150 cells/µL; 11 participants had CD4 counts ≤100 cells/µL. Anti-spike IgG antibody levels were greater in HVs than in patients with ICL after 2 and 3 doses of mRNA vaccine. There was no detectable significant difference, however, in anti-S IgG between HVs and participants with ICL and CD4 counts >100 cells/µL. The depth of spike-specific T-cell responses by T-cell receptor sequencing was lower in individuals with ICL. Activation-induced markers and cytokine production of spike-specific CD4 T cells in participants with ICL did not differ significantly compared with HVs after 2 or 3 vaccine doses. CONCLUSIONS: Patients with ICL and CD4 counts >100 cells/µL can mount vigorous humoral and cellular immune responses to SARS-CoV-2 vaccination; however, patients with more severe CD4 lymphopenia have blunted vaccine-induced immunity and may require additional vaccine doses and other risk mitigation strategies.

The K9-Teen Pandemic: When Good Boy Goes Bad. The Epidemiology, Management and Public Health Ramifications of Facial Dog Bite Injuries: Newcastle, Australia, Experience.

The purpose of this study was to investigate the epidemiology, pattern of injury and management of facial dog bite injuries. Methods: The authors conducted a retrospective cohort study over a 5-year period of patients who sustained a facial dog bite injury. The study setting was an Oral and Maxillofacial Surgery Department at a level 1 trauma centre, servicing an estimated catchment population in excess of 950,000 people. Results: In total, 171 patients were managed in the designated period from January 2017 to January 2022. The median age was 9 years (range 11 months to 77 years), with the highest incidence of a single age 4 years. The frequency was slightly greater amongst males (n = 93) than females (n = 78). The most common responsible breed were Pitbull types (n = 26). Overall, bites most often resulted from the family dog (n = 87), in the victim's own home (n = 84) and whilst playing with the dog (n = 64). The primary sites involved were the lips (n = 70), cheek (n = 53) and nose, representing the so called 'target area'. In 53 cases, the injuries were classified as severe. 138 patients required hospital admission, and of these, 130 required surgical management under general anaesthesia. Conclusions: Facial dog bite injuries present a significant burden on the healthcare system and result in physical, functional and/or emotional distress for the patient. As the rates of dog ownership continue to rise, a consequential increase in these injuries is also likely. Further, public health intervention is essential, particularly as the most susceptible demographic remains young male children.

Dynamics of SARS-CoV-2 Seroprevalence in a Large US population Over a Period of 12 Months.

Due to a combination of asymptomatic or undiagnosed infections, the proportion of the United States population infected with SARS-CoV-2 was unclear from the beginning of the pandemic. We previously established a platform to screen for SARS-CoV-2 positivity across a representative proportion of the US population, from which we reported that almost 17 million Americans were estimated to have had undocumented infections in the Spring of 2020. Since then, vaccine rollout and prevalence of different SARS-CoV-2 variants have further altered seropositivity trends within the United States population. To explore the longitudinal impacts of the pandemic and vaccine responses on seropositivity, we re-enrolled participants from our baseline study in a 6- and 12- month follow-up study to develop a longitudinal antibody profile capable of representing seropositivity within the United States during a critical period just prior to and during the initiation of vaccine rollout. Initial measurements showed that, since July 2020, seropositivity elevated within this population from 4.8% at baseline to 36.2% and 89.3% at 6 and 12 months, respectively. We also evaluated nucleocapsid seropositivity and compared to spike seropositivity to identify trends in infection versus vaccination relative to baseline. These data serve as a window into a critical timeframe within the COVID-19 pandemic response and serve as a resource that could be used in subsequent respiratory illness outbreaks.

Incidence of Infections, Explantations, and Displacements/Mechanical Complications of Spinal Cord Stimulation During the Past Eight Years.

OBJECTIVES: The overall awareness and potential of real-world data have drastically increased in the medical field, with potential implications for postmarket medical device surveillance. The goal of this study was to evaluate real-world data on incidence of infections, explantations, and displacements/mechanical complications of spinal cord stimulation (SCS) during the past eight years and to forecast point estimates for the upcoming three years on the basis of the identified patterns. MATERIALS AND METHODS: Based on electronic health records from 80 healthcare organizations within the TriNetX data base in the USA, data of 11,934 patients who received SCS as treatment for persistent spinal pain syndrome type 2 (PSPS T2) were extracted. Events of interest were explantations and displacements/mechanical complications of both the lead and implanted pulse generator (IPG), in addition to infection rates from 2015 to 2022. Mann-Kendall tests were performed to detect monotonic trends in the time series. Forecasts were conducted for the upcoming three years for every event of interest. RESULTS: Statistically significant increasing time trends were revealed for the annual incidence of IPG and lead displacements/mechanical complications in patients with PSPS T2 over the past eight years. These time trends were visible in both male and female patients and in smokers and nonsmokers. For annual incidence of explantations and infections, no significant time effect was observed. In 2025, the incidence of displacements/mechanical complications of the lead (3.07%) is predicted to be the highest, followed by explantations of the IPG (2.67%) and lead (2.02%). CONCLUSIONS: Based on real world data, device explantation was the most frequent event of interest, with negative peaks in the time series in 2016 and 2020, presumably due to the introduction of rechargeable pulse generators and to the COVID-19 pandemic, respectively.

Choroid plexus tumors: A spectrum from benign to malignant.

Choroid plexus tumors (CPT) are believed to originate from outgrowths of the choroid plexus. Despite their broad spectrum of symptoms, invasive nature, and prognosis, most CPTs typically exhibit similar presentations due to their relationship with the cerebral ventricles, as well as the mechanical obstruction and mass effect associated with their growth. In addition, these tumors mainly affect the pediatric population, further complicating the differentiation between benign and malignant subtypes. The World Health Organization classifies CPTs into three grades, namely, grades I, II, or III, based on their mitotic activity, which determine the benign or malignant nature of the tumors. CPTs classified by the World Health Organization (WHO) include choroid plexus papillomas (CPP), atypical CPPs (aCPP), and malignant choroid plexus carcinomas (CPC). Choroid plexus adenomas represent an additional category of benign CPTs not officially classified by the WHO. Despite the variations in histology, immunohistochemistry, imaging, treatment, and prognosis, CPTs cannot be reliably distinguished based solely on clinical presentation. Therefore, in this review, we aim to provide a comprehensive overview of each tumor subtype, along with the current management approach and emerging treatments.

Characterization of the antispike IgG immune response to COVID-19 vaccines in people with a wide variety of immunodeficiencies.

Research on coronavirus disease 2019 vaccination in immune-deficient/disordered people (IDP) has focused on cancer and organ transplantation populations. In a prospective cohort of 195 IDP and 35 healthy volunteers (HV), antispike immunoglobulin G (IgG) was detected in 88% of IDP after dose 2, increasing to 93% by 6 months after dose 3. Despite high seroconversion, median IgG levels for IDP never surpassed one-third that of HV. IgG binding to Omicron BA.1 was lowest among variants. Angiotensin-converting enzyme 2 pseudo-neutralization only modestly correlated with antispike IgG concentration. IgG levels were not significantly altered by receipt of different messenger RNA-based vaccines, immunomodulating treatments, and prior severe acute respiratory syndrome coronavirus 2 infections. While our data show that three doses of coronavirus disease 2019 vaccinations induce antispike IgG in most IDP, additional doses are needed to increase protection. Because of the notably reduced IgG response to Omicron BA.1, the efficacy of additional vaccinations, including bivalent vaccines, should be studied in this population.

Clinical, Virologic, and Immunologic Evaluation of Symptomatic Coronavirus Disease 2019 Rebound Following Nirmatrelvir/Ritonavir Treatment.

BACKGROUND: Nirmatrelvir/ritonavir, the first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease inhibitor, reduces the risk of hospitalization and death by coronavirus disease 2019 (COVID-19) but has been associated with symptomatic rebound after therapy completion. METHODS: Six individuals with relapse of COVID-19 symptoms after treatment with nirmatrelvir/ritonavir, 2 individuals with rebound symptoms without prior antiviral therapy and 7 patients with acute Omicron infection (controls) were studied. Soluble biomarkers and serum SARS-CoV-2 nucleocapsid protein were measured. Nasal swabs positive for SARS-CoV-2 underwent viral isolation and targeted viral sequencing. SARS-CoV-2 anti-spike, anti-receptor-binding domain, and anti-nucleocapsid antibodies were measured. Surrogate viral neutralization tests against wild-type and Omicron spike protein, as well as T-cell stimulation assays, were performed. RESULTS: High levels of SARS-CoV-2 anti-spike immunoglobulin G (IgG) antibodies were found in all participants. Anti-nucleocapsid IgG and Omicron-specific neutralizing antibodies increased in patients with rebound. Robust SARS-CoV-2-specific T-cell responses were observed, higher in rebound compared with early acute COVID-19 patients. Inflammatory markers mostly decreased during rebound. Two patients sampled longitudinally demonstrated an increase in activated cytokine-producing CD4+ T cells against viral proteins. No characteristic resistance mutations were identified. SARS-CoV-2 was isolated by culture from 1 of 8 rebound patients; Polybrene addition increased this to 5 of 8. CONCLUSIONS: Nirmatrelvir/ritonavir treatment does not impede adaptive immune responses to SARS-CoV-2. Clinical rebound corresponds to development of a robust antibody and T-cell immune response, arguing against a high risk of disease progression. The presence of infectious virus supports the need for isolation and assessment of longer treatment courses. CLINICAL TRIALS REGISTRATION: NCT04401436.

Perceptions of pain in aging females undergoing spinal cord stimulation.

Aim: Effects of age and sex on chronic pain outcomes following spinal cord stimulation (SCS) have not yet been assessed. Methods: We retrospectively reviewed 1 year outcomes from a database of patients receiving thoracic SCS. Subjects were divided into four cohorts: pre-menopausal and post-menopausal females, and aged-matched males. Improvement using the numerical rating scale, Oswestry Disability Index (ODI), Beck's Depression Inventory (BDI), McGill Pain Questionnaire and Pain Catastrophizing Scale (PCS) was assessed. Results: Older females were notably different from males and females under 60 as they had greater improvements in ODI, BDI and PCS. Further, females ≥60 had greater improvement in PCS compared with males ≥60. Conclusion: Our findings suggest greater improvement with 1 year SCS treatment in post-menopausal females, compared with age-matched males.

Spinal cord stimulation (SCS) has been shown to be an effective treatment for chronic pain that does not respond to other therapies. It is well recognized that men and women differ in how they perceive pain and how they respond to pain treatments. However, whether women who are over 60 years old and thus presumed to be menopausal respond differently to SCS has not been evaluated. We looked at our database which collected outcomes related to pain, measured before patients had SCS and 1 year after SCS. We found that women over 60 responded better to SCS treatment. They experienced significantly greater improvements in the disability, depression and catastrophizing associated with their pain than did women under 60. Further SCS resulted in more improvements in catastrophizing in women over 60 than in men over 60. Taken together, our hope is that these data help physicians to determine the best patients for SCS and to counsel their patients appropriately. To the best of our knowledge, this study is the first to show the impact of sex-specific aging on response to spinal cord stimulation. While we used age as a surrogate for menopause, menopausal status should be documented in the future to confirm that it effects response.

Comprehensive profiling of the human viral exposome in households containing an at-risk child with mitochondrial disease during the 2020-2021 COVID-19 pandemic.

BACKGROUND: Viral infection is a major cause of morbidity in children with mitochondrial disease (MtD). As a result, families with children with MtD are highly adherent to risk mitigation behaviours (RMBs) advised by the Centers for Disease Control and Prevention during the COVID-19 pandemic that can modulate infection risk. METHODS: Deep serologic phenotyping of viral infections was performed via home-based sampling by combining SARS-CoV-2 serologic testing and phage display immunoprecipitation and sequencing. Samples were collected approximately 1 year apart (October 2020 to April 2021 and October 2021 to March 2022) on households containing a child with MtD. RESULTS: In contrast to our first collection in 2020-2021, SARS-CoV-2 antibody profiles for all participants in 2021-2022 were marked by greater isotype diversity and the appearance of neutralizing antibodies. Besides SARS-CoV-2, households (N = 15) were exposed to >38 different respiratory and gastrointestinal viruses during the study, averaging five viral infections per child with MtD. Regarding clinical outcomes, children with MtD (N = 17) experienced 34 episodes of illness resulting in 6 hospitalizations, with some children experiencing multiple episodes. Neurologic events following illness were recorded in five patients. Infections were identified via clinical testing in only seven cases. Viral exposome profiles were consistent with clinical testing and even identified infections not captured by clinical testing. CONCLUSIONS: Despite reported adherence to RMBs during the COVID-19 pandemic by families with a child with MtD, viral infection was pervasive. Not all infections resulted in illness in the child with MtD, suggesting that some were subclinical or asymptomatic. However, selected children with MtD did experience neurologic events. Our studies emphasize that viral infections are inexorable, emphasizing the need for further understanding of host-pathogen interactions through broad serologic surveillance.

Interval between prior SARS-CoV-2 infection and booster vaccination impacts magnitude and quality of antibody and B cell responses.

SARS-CoV-2 mRNA booster vaccines provide protection from severe disease, eliciting strong immunity that is further boosted by previous infection. However, it is unclear whether these immune responses are affected by the interval between infection and vaccination. Over a 2-month period, we evaluated antibody and B cell responses to a third-dose mRNA vaccine in 66 individuals with different infection histories. Uninfected and post-boost but not previously infected individuals mounted robust ancestral and variant spike-binding and neutralizing antibodies and memory B cells. Spike-specific B cell responses from recent infection (<180 days) were elevated at pre-boost but comparatively less so at 60 days post-boost compared with uninfected individuals, and these differences were linked to baseline frequencies of CD27lo B cells. Day 60 to baseline ratio of BCR signaling measured by phosphorylation of Syk was inversely correlated to days between infection and vaccination. Thus, B cell responses to booster vaccines are impeded by recent infection.

Recent SARS-CoV-2 infection abrogates antibody and B-cell responses to booster vaccination.

SARS-CoV-2 mRNA booster vaccines provide protection from severe disease, eliciting strong immunity that is further boosted by previous infection. However, it is unclear whether these immune responses are affected by the interval between infection and vaccination. Over a two-month period, we evaluated antibody and B-cell responses to a third dose mRNA vaccine in 66 individuals with different infection histories. Uninfected and post-boost but not previously infected individuals mounted robust ancestral and variant spike-binding and neutralizing antibodies, and memory B cells. Spike-specific B-cell responses from recent infection were elevated at pre-boost but comparatively less so at 60 days post-boost compared to uninfected individuals, and these differences were linked to baseline frequencies of CD27 lo B cells. Day 60 to baseline ratio of BCR signaling measured by phosphorylation of Syk was inversely correlated to days between infection and vaccination. Thus, B-cell responses to booster vaccines are impeded by recent infection.

COVID-19 redux: clinical, virologic, and immunologic evaluation of clinical rebound after nirmatrelvir/ritonavir.

Clinical rebound of COVID-19 after nirmatrelvir/ritonavir treatment has been reported. We performed clinical, virologic, and immune measurements in seven patients with symptomatic rebound, six after nirmatrelvir/ritonavir treatment and one without previous treatment. There was no evidence of severe disease or impaired antibody and T-cell responses in people with rebound symptoms.

Undiagnosed COVID-19 in households with a child with mitochondrial disease.

Background: The impact of the COVID-19 pandemic on medically fragile populations, who are at higher risk of severe illness and sequelae, has not been well characterized. Viral infection is a major cause of morbidity in children with mitochondrial disease (MtD), and the COVID-19 pandemic represents an opportunity to study this vulnerable population. Methods: A convenience sampling cross-sectional serology study was conducted (October 2020 to June 2021) in households (N = 20) containing a child with MtD (N = 22). Samples (N = 83) were collected in the home using a microsampling apparatus and shipped to investigators. Antibodies against SARS-CoV-2 nucleocapsid (IgG), spike protein (IgG, IgM, IgA), and receptor binding domain (IgG, IgM, IgA) were determined by enzyme linked immunosorbent assay. Results: While only 4.8% of participants were clinically diagnosed for SARS-CoV-2 infection, 75.9% of study participants were seropositive for SARS-CoV-2 antibodies. Most samples were IgM positive for spike or RBD (70%), indicating that infection was recent. This translated to all 20 families showing evidence of infection in at least one household member. For the children with MtD, 91% had antibodies against SARS-CoV-2 and had not experienced any adverse outcomes at the time of assessment. For children with recent infections (IgM+ only), serologic data suggest household members as a source. Conclusions: COVID-19 was highly prevalent and undiagnosed in households with a child with MtD through the 2020-2021 winter wave of the pandemic. In this first major wave, children with MtD tolerated SARS-CoV-2 infection well, potentially due to household adherence to CDC recommendations for risk mitigation.

The key role of the latent N-H group in Milstein's catalyst for ester hydrogenation.

We previously demonstrated that Milstein's seminal diethylamino-substituted PNN-pincer-ruthenium catalyst for ester hydrogenation is activated by dehydroalkylation of the pincer ligand, releasing ethane and eventually forming an NHEt-substituted derivative that we proposed is the active catalyst. In this paper, we present a computational and experimental mechanistic study supporting this hypothesis. Our DFT analysis shows that the minimum-energy pathways for hydrogen activation, ester hydrogenolysis, and aldehyde hydrogenation rely on the key involvement of the nascent N-H group. We have isolated and crystallographically characterized two catalytic intermediates, a ruthenium dihydride and a ruthenium hydridoalkoxide, the latter of which is the catalyst resting state. A detailed kinetic study shows that catalytic ester hydrogenation is first-order in ruthenium and hydrogen, shows saturation behavior in ester, and is inhibited by the product alcohol. A global fit of the kinetic data to a simplified model incorporating the hydridoalkoxide and dihydride intermediates and three kinetically relevant transition states showed excellent agreement with the results from DFT.

Outcomes of Coronavirus Disease 2019 (COVID-19) Related Hospitalization Among People With Human Immunodeficiency Virus (HIV) in the ISARIC World Health Organization (WHO) Clinical Characterization Protocol (UK): A Prospective Observational Study.

BACKGROUND: Evidence is conflicting about how human immunodeficiency virus (HIV) modulates coronavirus disease 2019 (COVID-19). We compared the presentation characteristics and outcomes of adults with and without HIV who were hospitalized with COVID-19 at 207 centers across the United Kingdom and whose data were prospectively captured by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) World Health Organization (WHO) Clinical Characterization Protocol (CCP) study. METHODS: We used Kaplan-Meier methods and Cox regression to describe the association between HIV status and day-28 mortality, after separate adjustment for sex, ethnicity, age, hospital acquisition of COVID-19 (definite hospital acquisition excluded), presentation date, 10 individual comorbidities, and disease severity at presentation (as defined by hypoxia or oxygen therapy). RESULTS: Among 47 592 patients, 122 (0.26%) had confirmed HIV infection, and 112/122 (91.8%) had a record of antiretroviral therapy. At presentation, HIV-positive people were younger (median 56 vs 74 years; P < .001) and had fewer comorbidities, more systemic symptoms and higher lymphocyte counts and C-reactive protein levels. The cumulative day-28 mortality was similar in the HIV-positive versus HIV-negative groups (26.7% vs. 32.1%; P = .16), but in those under 60 years of age HIV-positive status was associated with increased mortality (21.3% vs. 9.6%; P < .001 [log-rank test]). Mortality was higher among people with HIV after adjusting for age (adjusted hazard ratio [aHR] 1.47, 95% confidence interval [CI] 1.01-2.14; P = .05), and the association persisted after adjusting for the other variables (aHR 1.69; 95% CI 1.15-2.48; P = .008) and when restricting the analysis to people aged <60 years (aHR 2.87; 95% CI 1.70-4.84; P < .001). CONCLUSIONS: HIV-positive status was associated with an increased risk of day-28 mortality among patients hospitalized for COVID-19.

Pneumocystis pneumonia, a COVID-19 mimic, reminds us of the importance of HIV testing in COVID-19.

While clinical environments are highly focused on COVID-19, reports of missed or delayed treatment for conditions that imitate COVID-19, such as pneumonia caused by the fungus Pneumocystis jirovecii, are emerging. Given the uncertain spectrum of COVID-19 presentations and variable sensitivity of laboratory tests for SARS-CoV-2, there is a risk that, without a high index of suspicion, alternative aetiologies may be overlooked while pursuing a diagnosis of COVID-19. The British HIV Association has been calling for the inclusion of HIV testing in all patients admitted to hospital with suspected COVID-19. In this article we reflect on the importance of including HIV testing to prevent avoidable morbidity and mortality in our patients.

Hepatitis A and Hepatitis E: Clinical and Epidemiological Features, Diagnosis, Treatment, and Prevention.

Hepatitis A and E are both ancient diseases but have only been properly recognized as being caused by distinct pathogens in modern times. Despite significantly different genomic structures, both viruses employ remarkably similar strategies to avoid host detection and increase environmental transmission. There are millions of cases of acute viral hepatitis due to hepatitis A virus (HAV) and hepatitis E virus (HEV) each year, resulting in tens of thousands of deaths. The presentations can be clinically indistinguishable, but each virus also has a range of less common but more specific phenotypes. The epidemiology of HAV is complex, and is shifting in countries that are making improvements to public health and sanitation. HEV presents a significant public health challenge in resource-limited settings but has historically been incorrectly regarded as having little clinical relevance in industrialized countries.

Can we give culturally competent care?

Sophie Kelly, currently studying for MA Nursing (children and young people), University of Salford, reflects on the challenges of providing care for families with differing cultural backgrounds.

Statistical Signal Properties of the Pressure-Reactivity Index (PRx).

OBJECTIVES: The pressure-reactivity index (PRx) is defined in terms of the moving correlation coefficient between intracranial pressure (ICP) and mean arterial pressure (MAP) and is a measure of cerebral autoregulation ability. Plots of PRx against cerebral perfusion pressure (CPP) show a U-shaped behaviour: the minimum reflecting optimal cerebral autoregulation (CPPopt). However U-shaped behaviour may also occur by chance. To date there has been no evaluation of the statistical properties of these signals. MATERIALS AND METHODS: We simulated PRx/CPP distributions using synthetic ICP and MAP signals from Gaussian noise with known cross-correlation and calculated the statistical distribution of extrema in the PRx/CPP relationship. RESULTS: The calculation of PRx on random data is statistically biased to show a U-shaped behaviour when the signals are positively cross-correlated (equivalent to PRx > 0). For PRx < 0, the bias is towards an inverse U-shaped behaviour. We demonstrate that this bias is eliminated by Fisher transforming the PRx data before CPPopt analysis. CONCLUSIONS: Cross-correlated signals are biased to show a U-shaped distribution. A CPPopt-like behaviour will be observed more often than not even from random ICP and MAP signals that do not exhibit autoregulation, unless PRx is Fisher transformed. Care must be taken in interpreting CPPopt in terms of physiology calculated from untransformed data.