Use of cidofovir in a patient with severe mpox and uncontrolled HIV infection.

A 48-year-old man with poorly controlled HIV presented with severe human monkeypox virus (hMPXV) infection, having completed 2 weeks of tecovirimat at another hospital. He had painful, ulcerating skin lesions on most of his body and oropharyngeal cavity, with subsequent Ludwig's angina requiring repeated surgical interventions. Despite commencing a second, prolonged course of tecovirimat, he did not objectively improve, and new lesions were still noted at day 24. Discussion at the UK National Health Service England High Consequence Infectious Diseases Network recommended the use of 3% topical and then intravenous cidofovir, which was given at 5 mg/kg; the patient made a noticeable improvement after the first intravenous dose. He received further intravenous doses at 7 days and 21 days after the dose and was discharged at day 52. Cidofovir is not licensed for use in treatment of hMPXV infection. Data for cidofovir use in hMPXV are restricted to studies in animals. Four other documented cases of cidofovir use against hMPXV have been reported in the USA in 2022, but we present its first use in the UK. The scarcity of studies into the use of cidofovir in this condition clearly shows the need for robust studies to assess efficacy, optimum dosage, timing, and route of administration.

The clinical presentation of monkeypox: a retrospective case-control study of patients with possible or probable monkeypox in a West London cohort.

OBJECTIVES: Since May 2022, cases of human monkeypox virus (hMPXV) with human-to-human cross-transmission have significantly increased in nonendemic countries. Our aim was to characterize diagnostic features of patients with confirmed and possible monkeypox to guide future risk stratification and to describe a virtual care model. METHODS: We performed a retrospective case-control study of 140 patients assessed and screened for suspected monkeypox; on hMPXV polymerase chain reaction testing, 70 were confirmed positive, and 70 were negative. Data were compared to generate odds ratios of demographic and clinical features. RESULTS: Patients who tested positive were predominantly cis-male (99%) and self-identified as gay, bisexual, and other men who have sex with men (94%). Lymphadenopathy at presentation was associated with a higher likelihood of a positive result (odds ratio [OR] 7.69 [95% confidence interval (CI) 3.58, 16.51]). Patients who tested positive were more likely to have a rash affecting the genital (OR 5.38 [95% CI 2.57, 11.23]) or buttocks/perianal region (OR 3.79 [1.70, 8.45]) than negative controls. A total of 79% of patients were engaged with a virtual ward follow-up. CONCLUSION: These data can inform a risk-based approach to the management of suspected monkeypox in gay, bisexual, and other men who have sex with men populations. Lymphadenopathy at presentation and the location of the rash were more associated with a positive hMPXV result. Health authorities can consider a virtual ward approach in the hMPHXV outbreak.

Clinical features and management of individuals admitted to hospital with monkeypox and associated complications across the UK: a retrospective cohort study.

BACKGROUND: The scale of the 2022 global mpox (formerly known as monkeypox) outbreak has been unprecedented. In less than 6 months, non-endemic countries have reported more than 67 000 cases of a disease that had previously been rare outside of Africa. Mortality has been reported as rare but hospital admission has been relatively common. We aimed to describe the clinical and laboratory characteristics and outcomes of individuals admitted to hospital with mpox and associated complications, including tecovirimat recipients. METHODS: In this cohort study, we undertook retrospective review of electronic clinical records and pathology data for all individuals admitted between May 6, and Aug 3, 2022, to 16 hospitals from the Specialist and High Consequence Infectious Diseases Network for Monkeypox. The hospitals were located in ten cities in England and Northern Ireland. Inclusion criteria were clinical signs consistent with mpox and MPXV DNA detected from at least one clinical sample by PCR testing. Patients admitted solely for isolation purposes were excluded from the study. Key outcomes included admission indication, complications (including pain, secondary infection, and mortality) and use of antibiotic and anti-viral treatments. Routine biochemistry, haematology, microbiology, and virology data were also collected. Outcomes were assessed in all patients with available data. FINDINGS: 156 individuals were admitted to hospital with complicated mpox during the study period. 153 (98%) were male and three (2%) were female, with a median age of 35 years (IQR 30-44). Gender data were collected from electronic patient records, which encompassed full formal review of clincian notes. The prespecified options for data collection for gender were male, female, trans, non-binary, or unknown. 105 (71%) of 148 participants with available ethnicity data were of White ethnicity and 47 (30%) of 155 were living with HIV with a median CD4 count of 510 cells per mm3 (IQR 349-828). Rectal or perianal pain (including proctitis) was the most common indication for hospital admission (44 [28%] of 156). Severe pain was reported in 89 (57%) of 156, and secondary bacterial infection in 82 (58%) of 142 individuals with available data. Median admission duration was 5 days (IQR 2-9). Ten individuals required surgery and two cases of encephalitis were reported. 38 (24%) of the 156 individuals received tecovirimat with early cessation in four cases (two owing to hepatic transaminitis, one to rapid treatment response, and one to patient choice). No deaths occurred during the study period. INTERPRETATION: Although life-threatening mpox appears rare in hospitalised populations during the current outbreak, severe mpox and associated complications can occur in immunocompetent individuals. Analgesia and management of superimposed bacterial infection are priorities for patients admitted to hospital. FUNDING: None.

Anesthesia Exposure during Therapy Predicts Neurocognitive Outcomes in Survivors of Childhood Medulloblastoma.

OBJECTIVE: To examine the contribution of anesthesia exposure during treatment for childhood medulloblastoma to neurocognitive outcomes 3 years after tumor diagnosis. STUDY DESIGN: In this retrospective study, anesthesia data were abstracted from medical records for 111 patients treated with risk-adapted protocol therapy at St Jude Children's Research Hospital. Neurocognitive testing data were obtained for 90.9% of patients. RESULTS: For the 101 patients (62.4% male) who completed testing, mean age at diagnosis was 10.1 years, and 74.3% were staged to have average-risk disease. Anesthesia exposure during treatment ranged from 1 to 52 events (mean = 19.9); mean cumulative duration per patient was 21.1 hours (range 0.7-59.7). Compared with normative expectations (16%), the group had a significantly greater frequency of at-risk scores (<1 SD) on measures of intelligence (28.7%), attention (35.2%), working memory (26.6%), processing speed (46.7%), and reading (25.8%). Including anesthesia exposure duration to linear regression models accounting for age at diagnosis, treatment intensity, and baseline IQ significantly increased the predicted variance for intelligence (r2 = 0.59), attention (r2 = 0.29), working memory (r2 = 0.31), processing speed (r2 = 0.44), and reading (r2 = 0.25; all P values <.001). CONCLUSIONS: In survivors of childhood medulloblastoma, a neurodevelopmentally vulnerable population, greater exposure to anesthesia significantly and independently predicts deficits in neurocognitive and academic functioning. When feasible, anesthesia exposure during treatment should be reduced.

Whole genome sequencing of Neisseria gonorrhoeae reveals transmission clusters involving patients of mixed HIV serostatus.

OBJECTIVES: Prevention and control of gonorrhoea depends on understanding the nature of sexual networks and risk factors for infection. We aimed to use high-resolution typing (whole genome sequencing (WGS)) of Neisseria gonorrhoeae isolates plus patient questionnaire data to gain insights into transmission patterns in a high prevalence setting. METHODS: During a 9-month period (July 2014-March 2015), patients diagnosed with gonorrhoea attending sexual health service in Brighton, UK, were invited to provide anonymised detailed information by questionnaire about risk factors for infection. Questionnaire data plus WGS data from cultured isolates were analysed to yield information about sexual networks and risk factors for infection. RESULTS: 104/149 individuals who consented to participate in the study were culture positive. 97/104 (93%) were male. 80 self-reported to be men who have sex with men (MSM). 35/104 (34%) of patients were HIV positive. 51/104 (49%) individuals reported using geosocial networking applications to facilitate contact. Sex under the influence of drugs was reported by 16/34 (46%) of HIV-positive MSM, 17/41 (41%) of HIV-negative MSM and 5/15 (31%) of heterosexuals. WGS data were available for 100 isolates from 83 patients. 55 isolates (66%) belonged to genetically related subtypes involving one or more patients, who could be plausibly linked through recent direct or indirect transmission. Four transmission clusters containing 3-12 individuals were composed of MSM of mixed HIV serostatus. CONCLUSIONS: We show that data obtained from WGS of N. gonorrhoeae and enhanced epidemiological data obtained from patient questionnaires are mutually supportive and reveal insights into sexual networks. Our findings suggest that serosorting may have declined as a practice and indicate the importance of designing public health interventions that target infection risks associated with recreational drug use and contact made using geosocial networking applications.

WGS to predict antibiotic MICs for Neisseria gonorrhoeae.

Background: Tracking the spread of antimicrobial-resistant Neisseria gonorrhoeae is a major priority for national surveillance programmes. Objectives: We investigate whether WGS and simultaneous analysis of multiple resistance determinants can be used to predict antimicrobial susceptibilities to the level of MICs in N. gonorrhoeae. Methods: WGS was used to identify previously reported potential resistance determinants in 681 N. gonorrhoeae isolates, from England, the USA and Canada, with phenotypes for cefixime, penicillin, azithromycin, ciprofloxacin and tetracycline determined as part of national surveillance programmes. Multivariate linear regression models were used to identify genetic predictors of MIC. Model performance was assessed using leave-one-out cross-validation. Results: Overall 1785/3380 (53%) MIC values were predicted to the nearest doubling dilution and 3147 (93%) within ±1 doubling dilution and 3314 (98%) within ±2 doubling dilutions. MIC prediction performance was similar across the five antimicrobials tested. Prediction models included the majority of previously reported resistance determinants. Applying EUCAST breakpoints to MIC predictions, the overall very major error (VME; phenotypically resistant, WGS-prediction susceptible) rate was 21/1577 (1.3%, 95% CI 0.8%-2.0%) and the major error (ME; phenotypically susceptible, WGS-prediction resistant) rate was 20/1186 (1.7%, 1.0%-2.6%). VME rates met regulatory thresholds for all antimicrobials except cefixime and ME rates for all antimicrobials except tetracycline. Country of testing was a strongly significant predictor of MIC for all five antimicrobials. Conclusions: We demonstrate a WGS-based MIC prediction approach that allows reliable MIC prediction for five gonorrhoea antimicrobials. Our approach should allow reasonably precise prediction of MICs for a range of bacterial species.

Genomic analysis of urogenital and rectal Neisseria meningitidis isolates reveals encapsulated hyperinvasive meningococci and coincident multidrug-resistant gonococci.

OBJECTIVE: Invasive meningococcal disease (IMD) outbreaks in men who have sex with men (MSM) have been associated with meningococcal colonisation of the urethra and rectum, but little is known about this colonisation or co-colonisation with the closely related gonococcus. Whole genome sequencing (WGS) was employed to explore these phenomena. METHODS: Meningococci isolated from the urogenital tract and rectum (n=23) and coincident gonococci (n=14) were analysed by WGS along with contemporary meningococci from IMD (n=11). All isolates were obtained from hospital admissions in Brighton, UK, 2011-2013. Assembled WGS were deposited in the PubMLST/neisseria database (http://pubmlst.org/neisseria) and compared at genomic loci common to gonococci or meningococci. RESULTS: As expected, most meningococci from IMD were encapsulated and belonged to hyperinvasive lineages. So too were meningococci found in the urogenital tract and rectum, contrasting to those asymptomatically carried in the nasopharynx where such meningococci are rare. Five hyperinvasive meningococcal lineages and four distinct gonococcal genotypes were recovered, including multiresistant ST-1901 (NG MAST-1407) gonococci. CONCLUSIONS: These data were consistent with a predisposition for potentially virulent encapsulated hyperinvasive meningococci to colonise the urethra and rectum, which suggests their involvement in MSM IMD outbreaks. The coincidence of multiresistant gonococci raises wider public health concerns.

Whole-genome sequencing to determine transmission of Neisseria gonorrhoeae: an observational study.

BACKGROUND: New approaches are urgently required to address increasing rates of gonorrhoea and the emergence and global spread of antibiotic-resistant Neisseria gonorrhoeae. We used whole-genome sequencing to study transmission and track resistance in N gonorrhoeae isolates. METHODS: We did whole-genome sequencing of isolates obtained from samples collected from patients attending sexual health services in Brighton, UK, between Jan 1, 2011, and March 9, 2015. We also included isolates from other UK locations, historical isolates from Brighton, and previous data from a US study. Samples from symptomatic patients and asymptomatic sexual health screening underwent nucleic acid amplification testing; positive samples and all samples from symptomatic patients were cultured for N gonorrhoeae, and resulting isolates were whole-genome sequenced. Cefixime susceptibility testing was done in selected isolates by agar incorporation, and we used sequence data to determine multi-antigen sequence types and penA genotypes. We derived a transmission nomogram to determine the plausibility of direct or indirect transmission between any two cases depending on the time between samples: estimated mutation rates, plus diversity noted within patients across anatomical sites and probable transmission pairs, were used to fit a coalescent model to determine the number of single nucleotide polymorphisms expected. FINDINGS: 1407 (98%) of 1437 Brighton isolates between Jan 1, 2011, and March 9, 2015 were successfully sequenced. We identified 1061 infections from 907 patients. 281 (26%) of these infections were indistinguishable (ie, differed by zero single nucleotide polymorphisms) from one or more previous cases, and 786 (74%) had evidence of a sampled direct or indirect Brighton source. We observed multiple related samples across geographical locations. Of 1273 infections in Brighton (including historical data), 225 (18%) were linked to another case elsewhere in the UK, and 115 (9%) to a case in the USA. Four lineages initially identified in Brighton could be linked to 70 USA sequences, including 61 from a lineage carrying the mosaic penA XXXIV allele, which is associated with reduced cefixime susceptibility. INTERPRETATION: We present a whole-genome-sequencing-based tool for genomic contact tracing of N gonorrhoeae and demonstrate local, national, and international transmission. Whole-genome sequencing can be applied across geographical boundaries to investigate gonorrhoea transmission and to track antimicrobial resistance. FUNDING: Oxford National Institute for Health Research Health Protection Research Unit and Biomedical Research Centre.

Susceptibility to distraction in autism spectrum disorder: probing the integrity of oscillatory alpha-band suppression mechanisms.

When attention is directed to one information stream over another, the brain can be configured in advance to selectively process the relevant stream and suppress potentially distracting inputs. One key mechanism of suppression is through the deployment of anticipatory alpha-band (~10 Hz) oscillatory activity, with greater alpha-band power observed in cortical regions that will ultimately process the distracting stream. Atypical attention has been implicated in autism spectrum disorder (ASD), including greater interference by distracting task-irrelevant inputs. Here we tested the integrity of these alpha-band mechanisms in ASD using an intersensory attention task. Electroencephalography (EEG) was recorded while participants were cued on a trial-by-trial basis to selectively deploy attention to the visual or auditory modality in anticipation of a target within the cued modality. Whereas typically developing (TD) children showed the predicted alpha-band modulation, with increased alpha-band power over parieto-occipital scalp when attention was deployed to the auditory compared with the visual modality, this differential pattern was entirely absent at the group level in the ASD cohort. Further, only the ASD group showed impaired performance due to the presence of task-irrelevant sensory information. These data suggest that impaired modulation of alpha-band activity plays a role in increased distraction from extraneous sensory inputs in ASD.

Multiorgan dysfunction caused by travel-associated African trypanosomiasis.

We describe a case of multiorgan dysfunction secondary to Trypanosoma brucei rhodesiense infection acquired on safari in Zambia. This case was one of several recently reported to ProMED-mail in persons who had traveled to this region. Trypanosomiasis remains rare in travelers but should be considered in febrile patients who have returned from trypanosomiasis-endemic areas of Africa.

The human transcriptome during nontyphoid Salmonella and HIV coinfection reveals attenuated NFkappaB-mediated inflammation and persistent cell cycle disruption.

BACKGROUND: Invasive nontyphoid Salmonella (iNTS) disease is common and severe in adults with human immunodeficiency virus (HIV) infection in Africa. We previously observed that ex vivo macrophages from HIV-infected subjects challenged with Salmonella Typhimurium exhibit dysregulated proinflammatory cytokine responses. METHODS: We studied the transcriptional response in whole blood from HIV-positive patients during acute and convalescent iNTS disease compared to other invasive bacterial diseases, and to HIV-positive and -negative controls. RESULTS: During iNTS disease, there was a remarkable lack of a coordinated inflammatory or innate immune signaling response. Few interferon γ (IFNγ)-induced genes or Toll-like receptor/transcription factor nuclear factor κB (TLR/NFκB) gene pathways were upregulated in expression. Ex vivo lipopolysacharide (LPS) or flagellin stimulation of whole blood, however, showed that convalescent iNTS subjects and controls were competent to mount prominent TLR/NFκB-associated patterns of mRNA expression. In contrast, HIV-positive patients with other invasive bacterial infections (Escherichia coli and Streptococcus pneumoniae) displayed a pronounced proinflammatory innate immune transcriptional response. There was also upregulated mRNA expression in cell cycle, DNA replication, translation and repair, and viral replication pathways during iNTS. These patterns persisted for up to 2 months into convalescence. CONCLUSIONS: Attenuation of NFκB-mediated inflammation and dysregulation of cell cycle and DNA-function gene pathway expression are key features of the interplay between iNTS and HIV.