The eye in epidermolysis bullosa.

AIMS: To describe the ophthalmic findings in a large cohort of epidermolysis bullosa (EB) patients managed in one large specialist centre. METHODS: A case note review of consecutive patients seen at Great Ormond Street Children's Hospital. Data on the dermatological disease, ophthalmic history, and examination were collected and coded onto a data sheet. RESULTS: 181 patients: 50 (28%) simplex EB; 15 (8%) junctional EB; 28 (15%) autosomal dominant dystrophic EB; 72 (40%) autosomal recessive dystrophic EB; nine patients (5%) with dystrophic EB whose inheritance could not be ascertained; and seven cases (4%) of EB that could not be classified. Ocular problems were found in 12% (n = 6) of simplex patients and 40% (n = 6) of those with junctional disease. One patient (of 28) in the autosomal dominant dystrophic group had ocular involvement and 51% (37/72) of patients in the autosomal recessive dystrophic group had ophthalmic complications: corneal (25/72), lid ectropions (3/72), lid blisters (5/72), and symblepharon (3/72). CONCLUSION: Ophthalmic complications are common in EB overall but the incidence varies widely with subtype. Ophthalmic complications are the most severe in the dystrophic recessive and junctional subtypes where there is a need for extra vigilance. The major treatment modality was use of ocular lubricants.     

Pulmonary Embolism Response Team activation during the COVID-19 pandemic in a New York City Academic Hospital: a retrospective cohort analysis

Journal of Thrombosis and Thrombolysis - Coronavirus disease 2019 (COVID-19) is associated with increased rates of deep vein thrombosis (DVT) and pulmonary embolism (PE). Pulmonary Embolism...     

Feasibility and indicative results from a 12-month low-energy liquid diet treatment and maintenance programme for severe obesity

Background

There is no established primary care solution for the rapidly increasing numbers of severely obese people with body mass index (BMI) > 40 kg/m².

Aim

This programme aimed to generate weight losses of ≥15 kg at 12 months, within routine primary care.

Design and setting

Feasibility study in primary care.

Method

Patients with a BMI ≥40 kg/m² commenced a micronutrient-replete 810–833 kcal/day low-energy liquid diet (LELD), delivered in primary care, for a planned 12 weeks or 20 kg weight loss (whichever was the sooner), with structured food reintroduction and then weight-loss maintenance, with optional orlistat to 12 months.

Result

Of 91 patients (74 females) entering the programme (baseline: weight 131 kg, BMI 48 kg/m², age 46 years), 58/91(64%) completed the LELD stage, with a mean duration of 14.4 weeks (standard deviation [SD] = 6.0 weeks), and a mean weight loss of 16.9 kg (SD = 6.0 kg). Four patients commenced weight-loss maintenance omitting the food-reintroduction stage. Of the remaining 54, 37(68%) started and completed food reintroduction over a mean duration of 9.3 weeks (SD = 5.7 weeks), with a further mean weight loss of 2.1 kg (SD = 3.7 kg), before starting a long-term low-fat-diet weight-loss maintenance plan. A total of 44/91 (48%) received orlistat at some stage. At 12 months, weight was recorded for 68/91 (75%) patients, with a mean loss of 12.4 kg (SD = 11.4 kg). Of these, 30 (33% of all 91 patients starting the programme) had a documented maintained weight loss of ≥15 kg at 12 months, six (7%) had a 10–15 kg loss, and 11 (12%) had a 5–10 kg loss. The indicative cost of providing this entire programme for wider implementation would be £861 per patient entered, or £2611 per documented 15 kg loss achieved.

Conclusion

A care package within routine primary care for severe obesity, including LELD, food reintroduction, and weight-loss maintenance, was well accepted and achieved a 12-month-maintained weight loss of ≥15 kg for one-third of all patients entering the programme.     

Immunity to Staphylococcus aureus secreted proteins protects rabbits from serious illnesses

Staphylococcus aureus causes significant illnesses throughout the world, including toxic shock syndrome (TSS), pneumonia, and infective endocarditis. Major contributors to S. aureus illnesses are secreted virulence factors it produces, including superantigens and cytolysins. This study investigates the use of superantigens and cytolysins as staphylococcal vaccine candidates. Importantly, 20% of humans and 50% of rabbits in our TSS model cannot generate antibody responses to native superantigens. We generated three TSST-1 mutants; G31S/S32P, H135A, and Q136A. All rabbits administered these TSST-1 toxoids generated strong antibody responses (titers>10,000) that neutralized native TSST-1 in TSS models, both in vitro and in vivo. These TSST-1 mutants lacked detectable residual toxicity. Additionally, the TSST-1 mutants exhibited intrinsic adjuvant activity, increasing antibody responses to a second staphylococcal antigen (β-toxin). This effect may be due to TSST-1 mutants binding to the immune co-stimulatory molecule CD40. The superantigens TSST-1 and SEC and the cytolysin α-toxin are known to contribute to staphylococcal pneumonia. Immunization of rabbits against these secreted toxins provided complete protection from highly lethal challenge with a USA200 S. aureus strain producing all three exotoxins; USA200 strains are common causes of staphylococcal infections. The same three exotoxins plus the cytolysins β-toxin and γ-toxin contribute to infective endocarditis and sepsis caused by USA200 strains. Immunization against these five exotoxins protected rabbits from infective endocarditis and lethal sepsis. These data suggest that immunization against toxoid proteins of S. aureus exotoxins protects from serious illnesses, and concurrently superantigen toxoid mutants provide endogenous adjuvant activity.     

Neuro-ophthalmic features of carotid cavernous fistulas and their treatment by endoarterial balloon embolisation.

The neuro-ophthalmic features of 11 traumatic carotid cavernous fistulas and their successful occlusion by endoarterial balloon embolisation is reported. Significant improvement in all neuro-ophthalmic signs and symptoms occurred following treatment, however, ocular motility deficits persisted in 7 patients. All 11 fistulas were occluded and the patency of the internal carotid artery was preserved in 9 patients. Though the internal carotid artery was sacrificed in 2 patients there were no permanent sequelae. Transient complications of the procedure occurred in 2 patients.     

Clinical and metabolic features of the randomised controlled Diabetes Remission Clinical Trial (DiRECT) cohort

Aims/hypothesis

Substantial weight loss in type 2 diabetes can achieve a return to non-diabetic biochemical status, without the need for medication. The Diabetes Remission Clinical Trial (DiRECT), a cluster-randomised controlled trial, is testing a structured intervention designed to achieve and sustain this over 2 years in a primary care setting to determine practicability for routine clinical practice. This paper reports the characteristics of the baseline cohort.

Methods

People with type 2 diabetes for <6 years with a BMI of 27–45 kg/m² were recruited in 49 UK primary care practices, randomised to either best-practice diabetes care alone or with an additional evidence-based weight management programme (Counterweight-Plus). The co-primary outcomes, at 12 months, are weight loss ≥15 kg and diabetes remission (HbA_1c <48 mmol/mol [6.5%]) without glucose-lowering therapy for at least 2 months. Outcome assessors are blinded to group assignment.

Results

Of 1510 people invited, 423 (28%) accepted; of whom, 306 (72%) were eligible at screening and gave informed consent. Seven participants were later found to have been randomised in error and one withdrew consent, leaving 298 (176 men, 122 women) who will form the intention to treat (ITT) population for analysis. Mean (SD) age was 54.4 (7.6) years, duration of diabetes 3.0 (1.7) years, BMI 34.6 (4.4) kg/m² for all participants (34.2 (4.2) kg/m² in men and 35.3 (4.6) kg/m² in women) and baseline HbA_1c (on treatment) 59.3 (12.7) mmol/mol (7.6% [1.2%]). The recruitment rate in the intervention and control groups, and comparisons between the subgroups recruited in Scotland and England, showed few differences.

Conclusions/interpretation

DiRECT has recruited a cohort of people with type 2 diabetes with characteristics similar to those seen in routine practice, indicating potential widespread applicability. Over 25% of the eligible population wished to participate in the study, including a high proportion of men, in line with the prevalence distribution of type 2 diabetes.

Trial registration

www.controlled-trials.com/ISRCTN03267836; date of registration 20 December 2013

     

Evidence for massive and recurrent toxic blooms of Alexandrium catenella in the Alaskan Arctic

Among the organisms that spread into and flourish in Arctic waters with rising temperatures and sea ice loss are toxic algae, a group of harmful algal bloom species that produce potent biotoxins. Alexandrium catenella, a cyst-forming dinoflagellate that causes paralytic shellfish poisoning worldwide, has been a significant threat to human health in southeastern Alaska for centuries. It is known to be transported into Arctic regions in waters transiting northward through the Bering Strait, yet there is little recognition of this organism as a human health concern north of the Strait. Here, we describe an exceptionally large A. catenella benthic cyst bed and hydrographic conditions across the Chukchi Sea that support germination and development of recurrent, locally originating and self-seeding blooms. Two prominent cyst accumulation zones result from deposition promoted by weak circulation. Cyst concentrations are among the highest reported globally for this species, and the cyst bed is at least 6× larger in area than any other. These extraordinary accumulations are attributed to repeated inputs from advected southern blooms and to localized cyst formation and deposition. Over the past two decades, warming has likely increased the magnitude of the germination flux twofold and advanced the timing of cell inoculation into the euphotic zone by 20 d. Conditions are also now favorable for bloom development in surface waters. The region is poised to support annually recurrent A. catenella blooms that are massive in scale, posing a significant and worrisome threat to public and ecosystem health in Alaskan Arctic communities where economies are subsistence based.

As the earth’s climate has warmed, the Pacific sector of the Arctic Ocean has experienced dramatic changes, particularly the wide and shallow Chukchi Sea north of Bering Strait. The persistence of sea ice has decreased markedly due to earlier melt back and later freeze up (1), the input of warmer and fresher Pacific water through Bering Strait has increased (2), and air–sea buoyancy fluxes have led to enhanced heat gain in spring (3). These changes are significantly altering hydrographic patterns and structure over the Chukchi Shelf, as well as the timing and extent of biological production and the biogeographic boundaries of species at all trophic levels, driving an unprecedented regime shift in this ecosystem (4).Many organisms will spread and flourish in Arctic waters as a result of climate warming, but few present as significant a threat to human and ecosystem health as Alexandrium catenella^*, a harmful algal bloom (HAB) species that produces paralytic shellfish toxins (PSTs)—one of the most potent and globally widespread of all HAB toxin families (5).There is a long history of PST-related illness and fatality events in southeastern Alaska and along the Aleutian Islands, some dating back more than 200 y (6–9). North of the Bering Strait, however, observations of this species are scattered and few. Near Point Barrow, high concentrations (∼3,000 to 16,000 cells ⋅ L⁻¹) of A. catenella (then called Goniaulax tamarensis) vegetative cells were recorded in 1954 (10), yet surveys in subsequent decades did not detect this species (11, 12). In 2003, Walsh et al. (13) reported low concentrations in the Bering Strait and on the Chukchi Shelf. More recently, Gu et al. (14) conducted morphological and phylogenetic analysis on cultures established from Chukchi Sea sediments, definitively confirming the presence and toxicity of A. catenella in the region. Soon after, Natsuike et al. (15) reported high concentrations of A. catenella resting cysts in sediments of the eastern Chukchi Sea, as well as vegetative cells of this species in surface waters (16). At that time, these cyst concentrations represented the highest levels yet recorded, indicating that a dense cyst population of unknown spatial extent existed in the Chukchi Sea.Shore-based records of HABs in the Alaskan Arctic are scarce, with the exception of folklore cited by Fair and Ningeulook (17), describing Ipnauraq (north shore of the Seward Peninsula) as “the location of a red tide at one time which caused many deaths.” No details are provided on symptomology or timing. More recent reports [e.g., Lefebvre et al. (18)] document PSTs in seals, walruses, sea lions, whales, and other marine mammals throughout the coast of Alaska, including in the Bering, Chukchi, and Beaufort Seas. PSTs have also been implicated but not confirmed as the cause of seabird and walrus mortalities (19, 20). The baseline picture is of blooms of A. catenella occurring on a sporadic basis in Alaskan Arctic waters over the last 65+ years but not to the extent where they have been recognized as a significant threat to human and ecosystem health in the region.In this study, the distributions of both cysts and planktonic vegetative cells of A. catenella are presented from the Chukchi Sea and adjacent waters in 2018 and 2019. These are related to hydrographic and circulation patterns that enhance the mechanisms for bloom formation north of the Bering Strait. This extensive, multiyear field program documented a massive regional cyst bed that is unprecedented globally, as well as equally large and dense vegetative cell blooms. While we lack the long-term observations needed to definitively link these blooms to climate change, it seems likely that shifting regimes are leading to an Arctic environment increasingly hospitable to A. catenella bloom formation and persistence. This recently characterized A. catenella population represents a serious and growing threat to Alaskan Arctic communities who are justifiably concerned about their health and the health of the ecosystems on which they depend for food in a region where biotoxin-monitoring programs are often not feasible.     

CF gene and cystic fibrosis transmembrane conductance regulator expression in autosomal dominant polycystic kidney disease

Disease-modifying genes might participate in the significant intrafamilial variability of the renal phenotype in autosomal dominant polycystic kidney disease (ADPKD). Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is a chloride channel that promotes intracystic fluid secretion, and thus cyst progression, in ADPKD. The hypothesis that mutations of the CF gene, which encodes CFTR, might be associated with a milder renal phenotype in ADPKD was tested. A series of 117 unrelated ADPKD probands and 136 unaffected control subjects were screened for the 12 most common mutations and the frequency of the alleles of the intron 8 polymorphic TN: locus of CF. The prevalence of CF mutations was not significantly different in the ADPKD (1.7%, n = 2) and control (3.7%, n = 5) groups. The CF mutation was DeltaF508 in all cases, except for one control subject (1717-1G A). The frequencies of the 5T, 7T, and 9T intron 8 alleles were also similar in the ADPKD and control groups. Two additional patients with ADPKD and the DeltaF508 mutation were detected in the families of the two probands with CF mutations. Kidney volumes and renal function levels were similar for these four patients with ADPKD and DeltaF508 CFTR (heterozygous for three and homozygous for one) and for control patients with ADPKD collected in the University of Colorado Health Sciences Center database. The absence of a renal protective effect of the homozygous DeltaF508 mutation might be related to the lack of a renal phenotype in CF and the variable, tissue-specific expression of DeltaF508 CFTR. Immunohistochemical analysis of a kidney from the patient with ADPKD who was homozygous for the DeltaF508 mutation substantiated that hypothesis, because CFTR expression was detected in 75% of cysts (compared with <50% in control ADPKD kidneys) and at least partly in the apical membrane area of cyst-lining cells. These data do not exclude a potential protective role of some CFTR mutations in ADPKD but suggest that it might be related to the nature of the mutation and renal expression of the mutated CFTR.