Early Diagnostic Measures to Confirm the Diagnosis of Human Prion Diseases.

Human prion diseases are a group of rare and fatal diseases without a cure. Symptoms include rapidly progressive dementia, ataxia, myoclonus, akinetic mutism, and visual disturbances. A broad differential is required to consider prion disease as a diagnosis and rule out other conditions. Historically, to confirm the diagnosis of prion disease, a brain biopsy was needed. Over the past few decades, brain MRI, video electroencephalogram, lumbar puncture results, and a thorough clinical assessment have helped arrive at a probable diagnosis. We present the case of a 60-year-old female with a rapidly worsening altered mental status who received an early diagnosis of prion disease with the help of imaging and lab results. This case shows that a timely diagnosis of prion disease is important to allow the patient and their families to prepare for the inevitable fatality of the disease and discuss the goals of care.

The burden of submicroscopic and asymptomatic malaria in India revealed from epidemiology studies at three varied transmission sites in India.

Malaria in India, while decreasing, remains a serious public health problem, and the contribution of submicroscopic and asymptomatic infections to its persistence is poorly understood. We conducted community surveys and clinic studies at three sites in India differing in their eco-epidemiologies: Chennai (Tamil Nadu), Nadiad (Gujarat), and Rourkela (Odisha), during 2012-2015. A total of 6,645 subject blood samples were collected for Plasmodium diagnosis by microscopy and PCR, and an extensive clinical questionnaire completed. Malaria prevalence ranged from 3-8% by PCR in community surveys (24 infections in Chennai, 56 in Nadiad, 101 in Rourkela), with Plasmodium vivax dominating in Chennai (70.8%) and Nadiad (67.9%), and Plasmodium falciparum in Rourkela (77.3%). A proportional high burden of asymptomatic and submicroscopic infections was detected in community surveys in Chennai (71% and 71%, respectively, 17 infections for both) and Rourkela (64% and 31%, 65 and 31 infections, respectively). In clinic studies, a proportional high burden of infections was identified as submicroscopic in Rourkela (45%, 42 infections) and Chennai (19%, 42 infections). In the community surveys, anemia and fever were significantly more common among microscopic than submicroscopic infections. Exploratory spatial analysis identified a number of potential malaria hotspots at all three sites. There is a considerable burden of submicroscopic and asymptomatic malaria in malarious regions in India, which may act as a reservoir with implications for malaria elimination strategies.

Characterizing Antibody Responses to Plasmodium vivax and Plasmodium falciparum Antigens in India Using Genome-Scale Protein Microarrays.

Understanding naturally acquired immune responses to Plasmodium in India is key to improving malaria surveillance and diagnostic tools. Here we describe serological profiling of immune responses at three sites in India by probing protein microarrays consisting of 515 Plasmodium vivax and 500 Plasmodium falciparum proteins with 353 plasma samples. A total of 236 malaria-positive (symptomatic and asymptomatic) plasma samples and 117 malaria-negative samples were collected at three field sites in Raurkela, Nadiad, and Chennai. Indian samples showed significant seroreactivity to 265 P. vivax and 373 P. falciparum antigens, but overall seroreactivity to P. vivax antigens was lower compared to P. falciparum antigens. We identified the most immunogenic antigens of both Plasmodium species that were recognized at all three sites in India, as well as P. falciparum antigens that were associated with asymptomatic malaria. This is the first genome-scale analysis of serological responses to the two major species of malaria parasite in India. The range of immune responses characterized in different endemic settings argues for targeted surveillance approaches tailored to the diverse epidemiology of malaria across the world.

Impact of medication review, within a shared decision-making framework, on deprescribing in people living in care homes.

OBJECTIVES: The key objectives of this study were to quantify extent of prescribing, reasons for deprescribing, common therapeutic groups of medicines deprescribed and adverse events. METHODS: A retrospective analysis was carried out on a quality improvement project where 422 care home residents in 20 care homes received a medicines optimisation review with a pharmacist and other members of the healthcare team (general medical practitioner, care home nurse). Data on number, type and cost of medicines were collected. Statistical analysis was performed to test for differences between pharmacist-only review and the pharmacist plus general practitioner (GP), and to identify any correlation between the original number of medicines and the number of medicines stopped. RESULTS: Of the 422 patients reviewed, 298 (70.6%) had at least one medicine stopped with 704 medicines being stopped. This represented 19.5% of the medicines originally prescribed (3602 medicines). There was no statistically significant difference between pharmacist only and pharmacist plus GP in terms of stopping medicines. The main groups of medicines stopped were laxatives, skin products and bone protection. There was weak correlation between the original number of medicines prescribed and the number stopped. CONCLUSIONS: This study has shown that medicines optimisation reviews can lead to a reduction in polypharmacy for care home residents through a deprescribing process. Patients' medicine regimens were simplified and optimised while making financial significant savings for the National Health Service.

The use of mosquito repellents at three sites in India with declining malaria transmission: surveys in the community and clinic.

BACKGROUND: Repellents such as coils, vaporizers, mats and creams can be used to reduce the risk of malaria and other infectious diseases. Although evidence for their effectiveness is limited, they are advertised as providing an additional approach to mosquito control in combination with other strategies, e.g. insecticide-treated nets. We examined the use of repellents in India in an urban setting in Chennai (mainly Plasmodium vivax malaria), a peri-urban setting in Nadiad (both P. vivax and P. falciparum malaria), and a more rural setting in Raurkela (mainly P. falciparum malaria). METHODS: The use of repellents was examined at the household level during a census, and at the individual level in cross-sectional surveys and among patients visiting a clinic with fever or other symptoms. Factors associated with their use were examined in a multivariate analysis, and the association between malaria and the use of repellents was assessed among survey- and clinic participants. RESULTS: Characteristics of participants differed by region, with more people of higher education present in Chennai. Use of repellents varied between 56-77 % at the household level and between 32-78 % at the individual level. Vaporizers were the main repellents used in Chennai, whereas coils were more common in Nadiad and Raurkela. In Chennai and Nadiad, vaporizers were more likely to be used in households with young male children. Vaporizer use was associated with higher socio-economic status (SES) in households in Chennai and Nadiad, whereas use of coils was greater in the lower SES strata. In Raurkela, there was a higher use of coils among the higher SES strata. Education was associated with the use of a repellent among survey participants in Chennai and clinic study participants in Chennai and Nadiad. Repellent use was associated with less malaria in the clinic study in Chennai and Raurkela, but not in the surveys, with the exception of the use of coils in Nadiad. CONCLUSIONS: Repellents are widely used in India. Their use is influenced by the level of education and SES. Information on effectiveness and guidance on choices may improve rational use.

What is the value of reactive case detection in malaria control? A case-study in India and a systematic review.

BACKGROUND: Reactive case detection (RCD) for malaria is a strategy to identify additional malaria infections in areas of low malaria transmission and can complement passive surveillance. This study describes experiences with RCD in two Indian sites, and aimed to synthesize experiences with RCD across endemic countries. METHODS: RCD programmes were piloted in two urban areas of India with a low prevalence of mainly Plasmodium vivax malaria in 2014. Cases were identified in a clinic by microscopy and contacts were screened within 2 weeks; PCR, in addition to microscopy, was used to detect Plasmodium parasites. A systematic review was conducted to identify RCD experiences in the literature. RESULTS: In Chennai, 868 contacts were enrolled for 18 index cases of clinical malaria; in Nadiad, 131 contacts were enrolled for 20 index cases. No new malaria infections were detected in Nadiad among contacts, and four new infections were detected in Chennai (three P. vivax and one Plasmodium falciparum), of which two were among household members of index cases. An additional five studies describing results from an RCD strategy were identified in the literature: four in Africa and one in Thailand. Including the results from India, the average number of contacts screened per index case in a total of seven studies ranged from four to 50, and 126 in a case study in Thailand with one index case. Malaria was detected in 0-45 % of the contacted persons. The average number of index cases needed to be traced to find one new case of malaria ranged from one to five, and could not be assessed in one study in India (no contacts positive for 20 cases). Sharing the household with an index case was associated with a five-fold increased risk of malaria compared to contacts from households without an index case (pooled risk ratio 5.29, 95 % CI 3.31-8.47, I(2) 0 %, four studies). CONCLUSIONS: RCD in areas of low malaria transmission is a labour-intensive strategy, and its benefit is not clear. Studies are needed to assess how RCD can be optimized or into alternatives where interventions are targeted to family members or hotspots.

Clinical utility and validity of minoxidil response testing in androgenetic alopecia.

Clinical response to 5% topical minoxidil for the treatment of androgenetic alopecia (AGA) is typically observed after 3-6 months. Approximately 40% of patients will regrow hair. Given the prolonged treatment time required to elicit a response, a diagnostic test for ruling out nonresponders would have significant clinical utility. Two studies have previously reported that sulfotransferase enzyme activity in plucked hair follicles predicts a patient's response to topical minoxidil therapy. The aim of this study was to assess the clinical utility and validity of minoxidil response testing. In this communication, the present authors conducted an analysis of completed and ongoing studies of minoxidil response testing. The analysis confirmed the clinical utility of a sulfotransferase enzyme test in successfully ruling out 95.9% of nonresponders to topical minoxidil for the treatment of AGA.

Single-base pair differences in a shared motif determine differential Rhodopsin expression.

The final identity and functional properties of a neuron are specified by terminal differentiation genes, which are controlled by specific motifs in compact regulatory regions. To determine how these sequences integrate inputs from transcription factors that specify cell types, we compared the regulatory mechanism of Drosophila Rhodopsin genes that are expressed in subsets of photoreceptors to that of phototransduction genes that are expressed broadly, in all photoreceptors. Both sets of genes share an 11-base pair (bp) activator motif. Broadly expressed genes contain a palindromic version that mediates expression in all photoreceptors. In contrast, each Rhodopsin exhibits characteristic single-bp substitutions that break the symmetry of the palindrome and generate activator or repressor motifs critical for restricting expression to photoreceptor subsets. Sensory neuron subtypes can therefore evolve through single-bp changes in short regulatory motifs, allowing the discrimination of a wide spectrum of stimuli.

Absence of catagen/telogen phase and loss of cytokeratin 15 expression in hair follicles in lichen planopilaris.

BACKGROUND: Lichen planopilaris (LPP) is a lymphocyte-mediated cicatricial alopecia mostly involving the bulge region of the hair follicle. The origin of LPP is unknown. Therapy for LPP often does not prevent disease progression. We describe histologic and immunohistologic features that aid in diagnosis and provide an explanation for disease progression in LPP. OBJECTIVE: We sought to demonstrate a decrease in the number of catagen-/telogen-phase follicles and to confirm the loss of cytokeratin 15 (CK15) expression in the stem cells of LPP-affected follicles. METHODS: In all, 144 LPP cases were retrieved; 55 cases were stained immunohistochemically, targeting the CK15 antigen with 40 cases ultimately analyzed for CK15 expression. RESULTS: Catagen/telogen phase was significantly decreased or absent in all cases of LPP, a novel clue useful in histologic diagnostics. The loss of CK15+ stem cells in most affected follicles in LPP was also confirmed, with unaffected follicles retaining CK15+ stem cells. LIMITATIONS: Limited tissue for analysis remained in the clinical sample tissue blocks. CONCLUSION: Damaged follicles that have lost their CK15+ stem cells disappear when they enter catagen phase. CK15+ stem cell loss explains the clinical observation that LPP progresses despite immunosuppressive therapies. Finally, the absence of catagen/telogen hair follicles is a helpful diagnostic clue for LPP.

Sulfotransferase activity in plucked hair follicles predicts response to topical minoxidil in the treatment of female androgenetic alopecia.

Two percent topical minoxidil is the only US Food and Drug Administration-approved drug for the treatment of female androgenetic alopecia (AGA). Its success has been limited by the low percentage of responders. Meta-analysis of several studies reporting the number of responders to 2% minoxidil monotherapy indicates moderate hair regrowth in only 13-20% of female patients. Five percent minoxidil solution, when used off-label, may increase the percentage of responders to as much as 40%. As such, a biomarker for predicting treatment response would have significant clinical utility. In a previous study, Goren et al. reported an association between sulfotransferase activity in plucked hair follicles and minoxidil response in a mixed cohort of male and female patients. The aim of this study was to replicate these findings in a well-defined cohort of female patients with AGA treated with 5% minoxidil daily for a period of 6 months. Consistent with the prior study, we found that sulfotransferase activity in plucked hair follicles predicts treatment response with 93% sensitivity and 83% specificity. Our study further supports the importance of minoxidil sulfation in eliciting a therapeutic response and provides further insight into novel targets for increasing minoxidil efficacy.

Bullous Sweet's syndrome after granulocyte colony-stimulating factor therapy in a child with congenital neutropenia.

We present the case of a 20-month-old boy with congenital neutropenia for which he was being treated with granulocyte colony-stimulating factor (G-CSF) who developed bullous Sweet's syndrome. Because of the challenging and extensive differential diagnosis of an acute bullous eruption in an immunocompromised child, we highlight the importance of a prompt and precise diagnosis before initiation of any systemic therapy in children with Sweet's syndrome.

A clinico-ethical framework for multidisciplinary review of medication in nursing homes.

Residents in care homes are more likely to be prescribed multiple medicines yet often have little involvement in these prescribing decisions. Reviewing and stopping inappropriate medicines is not currently adopted across the health economy. This Health Foundation funded Shine project developed a pragmatic approach to optimising medicines in care homes while involving all residents in decision making. The pharmacist undertook a detailed medication review using primary care records. The results were discussed at a multidisciplinary team (MDT) meeting involving the care home nurse and the resident's general practitioner (GP), with input from the local psychiatry of old age service (POAS) where appropriate. Suggestions for medicines which should be stopped, changed or started, and other interventions (eg monitoring) were discussed with the resident and/or their family. Over 12 months 422 residents were reviewed, and 1346 interventions were made in 91% of residents reviewed with 15 different types of interventions. The most common intervention (52.3%) was to stop medicines; 704 medicines stopped in 298 residents (70.6%). On average, 1.7 medicines were stopped for every resident reviewed (range zero to nine medicines; SD=1.7), with a 17.4% reduction in medicines prescribed (3602 medicines prescribed before and 2975 after review). The main reasons for stopping medicines were: no current indication (401 medicines; 57%), resident not wanting medicine after risks and benefits were explained (120 medicines; 17%), and safety concerns (42 medicines; 6%). The net annualised savings against the medicines budget were £77,703 or £184 per person reviewed. The cost of delivering the intervention was £32,670 (pharmacist, GP, POAS consultant, and care home nurse time) for 422 residents; for every £1 invested, £2.38 could be released from the medicines budget. This project demonstrated that a multidisciplinary medication review with a pharmacist, doctor, and care home nurse can safely reduce inappropriate medication in elderly care home residents.

Clinical utility of testing for autoimmunity in chronic idiopathic urticaria.

BACKGROUND: Positive autoimmune testing in patients with chronic idiopathic urticaria (CIU) has previously been associated with more severe disease. OBJECTIVE: We sought to determine whether patients with CIU and a positive autoimmune urticaria test finding were more difficult to treat clinically. METHODS: In this retrospective study, 428 patients seen by physicians of the Department of Dermatology, University of Pittsburgh between January 2007 and March 2010 were identified by International Classification of Diseases, Ninth Revision code 708.9 for urticaria. Included individuals met clinical criteria for CIU and had an autoimmune urticaria test (chronic urticaria index or CD203 expression test) result in their medical record. RESULTS: Twenty patients met the study criteria set forth and positive autoimmune urticaria test results occurred in 8 of the 20 patients. In all, 75% of patients in each group (positive and negative autoimmune test findings) were more than 75% clear of disease (P = 1) by the last visit. Mean number of distinct medications prescribed for urticaria management in the positive and negative autoimmune groups was 6.9 and 8.4, respectively (P = .4). No significant difference was detected between the various medications that led to more than 75% disease clearance in either group. The mean number of patient clinic visits over the study period was 3.1 and 4.8, respectively, for positive and negative groups (P = .5). LIMITATIONS: This was a retrospective study with a small sample size. CONCLUSION: A positive autoimmune urticaria test finding in the setting of CIU is not indicative of a more complicated clinical course.

The value of irbesartan in the management of hypertension.

Elevated blood pressure levels are highly prevalent and are a major reason for cardiovascular events and thus place a significant financial burden on healthcare systems worldwide. Guidelines recommend five first-line anti-hypertensive drug classes, but compelling indications may indicate favoring one drug class over another. Angiotensin receptor blockers (ARBs) have demonstrated a blood pressure lowering efficacy which is at least comparable with other drug classes, including ACE inhibitors (ACE-I), beta-blockers, calcium channel blockers and diuretics. They have, in addition, a lower side effect profile than other drug classes and patients on ARBs are more persistent with therapy. Compelling indications for the use of ARBs are heart failure, post-myocardial infarction, diabetic nephropathy, proteinuria/microalbuminuria, left ventricular hypertrophy, atrial fibrillation, metabolic syndrome and ACE-I induced cough. The ARB irbesartan has demonstrated a high efficacy in lowering blood pressure, which has been shown to be at least comparable with ACE-Is and superior to other ARBs such as losartan and valsartan. This translated into a better cost-effectiveness for irbesartan than for valsartan and losartan in the treatment of hypertension. In addition, irbesartan has been shown to be effective in both early and late stage diabetic nephropathy. It has further demonstrated considerable cost savings over standard therapy including beta-blockers, diuretics and non-dihydropyridine calcium channel blockers at all stages of kidney disease. Based on efficacy data from the Irbesartan Diabetic Nephropathy Trial and Reduction of Endpoints in NIDDM (non insulin dependant diabetes melitis) with the Angiotensin II Antagonist Losartan Study, it has also demonstrated cost savings over losartan in late stage renal disease. While both losartan and irbesartan are registered for the treatment of late stage diabetic nephropathy, irbesartan is also registered for early stage diabetic nephropathy in the EU. In summary, the data from randomized clinical trials on the efficacy of antihypertensive drugs provides an indication of their real value to patients. In addition observational data from clinical practice and proven end-organ protection in diabetic nephropathy provides further evidence of the true value of irbesartan compared to other ARBs in the treatment of hypertension.

A pilot quality-of-life instrument for pruritus.

OBJECTIVE: We sought to develop a validated, reliable pruritus-specific quality-of-life (QOL) instrument, ItchyQoL. METHODS: From 21 in-depth interviews with patients with pruritus, we developed 22 pruritus-specific items, and hypothesized 3 major constructs that explain the way pruritus affects patients' QOL: symptoms, functional limitations, and emotions. We developed two versions of the pruritus QOL instrument, which assess for level of bother or frequency using items from the interviews and from generic skin QOL instruments, Skindex-16 (bother) and Skindex-29 (frequency). The instrument was tested for validity, reliability, and responsiveness. The frequency version was subsequently applied clinically to further evaluate its face validity. RESULTS: A total of 89 patients with dermatologic conditions participated in the validation phase and 101 patients participated in the clinical application phase of the study. Construct validity was demonstrated by principal axes factor analyses and by demonstrating that differences in symptoms, functioning, and emotion differed among the varying levels of self-reported pruritus severity more than would be expected by chance (P < .05 by analysis of variance). The instrument demonstrated reliability with internal consistency (Cronbach alpha: frequency 0.72-0.93 and bother 0.78-0.81) and reproducibility (intraclass correlation coefficient: frequency 0.91 and bother 0.84-0.87). The instrument suggested preliminary responsiveness for patients with improved disease for both frequency and bother items with both overall scores and the majority of the subscales scored demonstrating significant changes. Discriminant validity was shown by comparing differences in and the number of insensitive items between the pruritus-specific QOL instrument and the generic Skindex instruments. LIMITATIONS: Lack of generalizability and potential selection bias are limitations. CONCLUSIONS: This study represents, to our knowledge, the first attempt at a pruritus-specific QOL instrument that is reliable, valid, and responsive.