Ethnicity and deprivation negatively impact the access to disease-modifying therapy for relapsing-remitting multiple sclerosis: a retrospective, single-centre study.

BACKGROUND: A growing body of evidence suggests inequitable access to disease-modifying therapies (DMTs) for multiple sclerosis (MS) in publicly funded healthcare systems. This retrospective study examined the impact of ethnicity and deprivation on the access to DMTs. METHODS: All adults diagnosed with relapsing-remitting MS between 2010 and 2020 were included. The impact of ethnicity and deprivation on being offered and starting any DMTs and high-efficacy DMTs were measured using binary, multinomial logistic and Cox regression models. These analyses were adjusted for sex, age at diagnosis and year of diagnosis. RESULTS: 164/1648 people with MS (PwMS) were from non-white ethnicities. 461/1648 who were living in the most deprived areas, were less likely to be offered DMTs, with an OR of 0.66 (95% CI 0.47 to 0.93), less likely to start high-efficacy DMTs with an OR of 0.67 (95% CI 0.48 to 0.93) and more likely to experience a delay in starting high-efficacy DMTs with an HR of 0.76 (95% CI 0.63 to 0.92), when also adjusted for ethnicity. Although the offer of DMTs did not depend on ethnicity, PwMS from non-white ethnicities were more likely to decline DMTs, less likely to start any DMTs and high-efficacy DMTs with ORs of 0.60 (95% CI 0.39 to 0.93) and 0.61 (95% CI 0.38 to 0.98), respectively, and more likely to experience a delay in starting DMTs with an HR of 0.79 (95% CI 0.66 to 0.95), when also adjusted for deprivation. CONCLUSIONS: In a publicly funded healthcare system, the access to DMTs varied depending on ethnicities and levels of deprivation.

Acute respiratory distress syndrome following alemtuzumab therapy for relapsing multiple sclerosis.

We present the case of a 54 year old woman with known relapsing-remitting multiple sclerosis who presented with acute respiratory deterioration five weeks after a first course of alemtuzumab. Imaging showed bilateral ground glass changes and extensive investigations confirmed chest infection with dual pathogens - Pneumocystis jirovecii and Cytomegalovirus. She responded to standard anti-PJP and CMV therapy and was discharged on oral prophylaxis. Opportunistic infections in the weeks immediately following alemtuzumab therapy remain an uncommon complication but one that requires clinical vigilance, careful monitoring and appropriate prophylactic therapy.

Kinetics and Structure of a Cold-Adapted Hetero-Octameric ATP Phosphoribosyltransferase.

Adenosine 5'-triphosphate phosphoribosyltransferase (ATPPRT) catalyzes the first step in histidine biosynthesis, the condensation of ATP and 5-phospho-α-d-ribosyl-1-pyrophosphate to generate N1-(5-phospho-ß-d-ribosyl)-ATP and inorganic pyrophosphate. The enzyme is allosterically inhibited by histidine. Two forms of ATPPRT, encoded by the hisG gene, exist in nature, depending on the species. The long form, HisGL, is a single polypeptide chain with catalytic and regulatory domains. The short form, HisGS, lacks a regulatory domain and cannot bind histidine. HisGS instead is found in complex with a regulatory protein, HisZ, constituting the ATPPRT holoenzyme. HisZ triggers HisGS catalytic activity while rendering it sensitive to allosteric inhibition by histidine. Until recently, HisGS was thought to be catalytically inactive without HisZ. Here, recombinant HisGS and HisZ from the psychrophilic bacterium Psychrobacter arcticus were independently overexpressed and purified. The crystal structure of P. arcticus ATPPRT was determined at 2.34 Å resolution, revealing an equimolar HisGS-HisZ hetero-octamer. Steady-state kinetics indicate that both the ATPPRT holoenzyme and HisGS are catalytically active. Surprisingly, HisZ confers only a modest 2-4-fold increase in kcat. Reaction profiles for both enzymes cannot be distinguished by 31P nuclear magnetic resonance, indicating that the same reaction is catalyzed. The temperature dependence of kcat shows deviation from Arrhenius behavior at 308 K with the holoenzyme. Interestingly, such deviation is detected only at 313 K with HisGS. Thermal denaturation by CD spectroscopy resulted in Tm's of 312 and 316 K for HisZ and HisGS, respectively, suggesting that HisZ renders the ATPPRT complex more thermolabile. This is the first characterization of a psychrophilic ATPPRT.

Timing of efficacy of thiamine in Wernicke's disease in alcoholics at risk.

This study investigated an optimum window of effectiveness of oral thiamine in alcohol withdrawal in a jail setting using a Librium-based protocol. A total of 19 patients were identified with alcohol withdrawal at intake. Clinical Institute Withdrawal Assessment (CIWA-AR), Cut back, Annoyed, Guilty, Eye-opener (CAGE) questionnaire, and therapy were started immediately. Of these patients, 9 were identified as high risk and 2 developed an excited delirium consistent with Wernicke's disease. This study demonstrated an optimum window of 2 hours or less at intake with oral thiamine. The earlier an oral withdrawal protocol is started, the faster is recovery, regardless of initial presentation. Disease progression was significantly dependent on time to treat. Noncompliance with oral management is likely if treatment is delayed. The routine use of thiamine 100 mg daily during withdrawal and continuation for 30 days is recommended as the best clinical practice.

Extensive lysine methylation in hyperthermophilic crenarchaea: potential implications for protein stability and recombinant enzymes.

In eukarya and bacteria, lysine methylation is relatively rare and is catalysed by sequence-specific lysine methyltransferases that typically have only a single-protein target. Using RNA polymerase purified from the thermophilic crenarchaeum Sulfolobus solfataricus, we identified 21 methyllysines distributed across 9 subunits of the enzyme. The modified lysines were predominantly in alpha-helices and showed no conserved sequence context. A limited survey of the Thermoproteus tenax proteome revealed widespread modification with 52 methyllysines in 30 different proteins. These observations suggest the presence of an unusual lysine methyltransferase with relaxed specificity in the crenarchaea. Since lysine methylation is known to enhance protein thermostability, this may be an adaptation to a thermophilic lifestyle. The implications of this modification for studies and applications of recombinant crenarchaeal enzymes are discussed.

Lesson of the week: a new cause of treatable dementia.

CASE REPORT: A 69-year-old married British man presented with 4 months of falls and confusion. HIV antibody test, performed after exclusion of other diagnoses, was positive. Institution of triple antiretroviral therapy resulted in an almost complete recovery. DISCUSSION: HIV infection is now far more common than syphilis. It may be highly amenable to treatment and needs to be considered in the differential diagnosis of the older person with dementia.

Chorea as a presenting feature of variant Creutzfeldt-Jakob disease.

We report on a patient with pathologically proven variant Creutzfeld-Jakob disease in whom chorea was a presenting feature of the disease, and was unaccompanied by the typical prodrome of psychiatric disturbance or sensory symptoms.