Randomized Phase II Study of the Safety and Efficacy of Semorinemab in Participants With Mild-to-Moderate Alzheimer Disease: Lauriet.

BACKGROUND AND OBJECTIVES: Accumulation of tau pathology in Alzheimer disease (AD) correlates with cognitive decline. Anti-tau immunotherapies were proposed as potential interventions in AD. While antibodies targeting N-terminal tau failed to demonstrate clinical efficacy in prodromal-to-mild AD, their utility at other disease stages was not evaluated in prior studies. Lauriet is a phase 2 study of an anti-tau monoclonal antibody, semorinemab, in patients with mild-to-moderate AD. METHODS: The phase 2 Lauriet study included a randomized, placebo-controlled, double-blind period, during which participants with mild-to-moderate AD received 4,500 mg of IV semorinemab or placebo every 4 weeks for 48 or 60 weeks. Participants who chose to continue in the subsequent optional open-label extension received 4,500 mg of semorinemab every 4 weeks for up to 96 weeks. Coprimary efficacy endpoints were change from baseline to week 49 or 61 on the 11-item version of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. Secondary efficacy endpoints included change from baseline on the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Safety, pharmacokinetics, and pharmacodynamic effects were also evaluated. RESULTS: Between December 3, 2018, and February 27, 2020, 624 individuals were screened, 272 participants were randomized, and 238 were included in the modified intent-to-treat population (received ≥1 dose(s) of study medication and underwent baseline and ≥1 postbaseline assessment(s)). Baseline characteristics were well balanced. At week 49, the semorinemab arm demonstrated a 42.2% reduction (-2.89 points, 95% CI -4.56 to -1.21, p = 0.0008) in decline on the ADAS-Cog11 (coprimary endpoint) relative to the placebo arm. However, no treatment effects were observed on the ADCS-ADL scale (coprimary endpoint; absolute difference between the 2 treatment arms in the ADCS-ADL score change from baseline of -0.83 points, 95% CI -3.39 to 1.72, p = 0.52) or on the MMSE or CDR-SB (secondary endpoints). Semorinemab was safe and well tolerated. DISCUSSION: Based on the results of the prespecified coprimary endpoints, this study was negative. While semorinemab had a significant effect on cognition measured by the ADAS-Cog11, this effect did not extend to improved functional or global outcomes. These results may warrant further exploration of semorinemab or other anti-tau therapies in mild-to-moderate AD. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that semorinemab does not slow functional decline in patients with mild-to-moderate AD. TRIAL REGISTRATION INFORMATION: The Lauriet study is registered on ClinicalTrials.gov, NCT03828747, and EudraCT 2018-003398-87.

Tafamidis polyneuropathy amelioration requires modest increases in transthyretin stability even though increases in plasma native TTR and decreases in non-native TTR do not predict response.

BACKGROUND: TTR aggregation causes hereditary transthyretin (TTR) polyneuropathy (ATTRv-PN) in individuals with destabilised TTR variants. ATTRv-PN can be treated with ligands that bind TTR and prevent aggregation. One such ligand, tafamidis, is widely approved to treat ATTRv-PN. We explore how TTR stabilisation markers relate to clinical efficacy in 210 ATTRv-PN patients taking tafamidis. METHODS: TTR concentration in patient plasma was measured before and after tafamidis treatment using assays for native or combined native + non-native TTR. TTR tetramer dissociation kinetics, which are slowed by tafamidis binding, were also measured. RESULTS: Native TTR levels increased by 56.8% while combined native + non-native TTR levels increased by 3.1% after 24 months of tafamidis treatment, implying that non-native TTR decreased. Accordingly, the fraction of native TTR increased from 0.54 to 0.71 with tafamidis administration. Changes in native and non-native TTR levels were uncorrelated with clinical response to tafamidis. TTR tetramer dissociation generally slowed to an extent consistent with ∼40% of TTR being tafamidis-bound. Male non-responders had a lower extent of binding. CONCLUSIONS: Native and non-native TTR concentration changes cannot be used as surrogate measures for therapeutic efficacy. Also, successful tafamidis therapy requires only moderate TTR stabilisation. Male patients may benefit from higher tafamidis doses.

Impact of perioperative chemotherapy on postoperative morbidity after gastrectomy for gastric cancer / Impacto de la quimioterapia perioperatoria sobre la morbilidad postoperatoria después de gastrectomía por cáncer gástrico

Introduction: The use of perioperative chemotherapy (CT) in patients with advanced gastric carcinoma increases their overall survival. This therapy may also increase the number of patients with R0 resection. Potential drawbacks of this therapy, besides its toxicity, include increased surgical morbidity.Methods: We retrospectively evaluated the records of patients undergoing gastrectomy with curative intent, for carcinoma, at our institution between January 2009 and August 2018. They were divided into two groups: direct surgery (SURG) and perioperative CT (CHEMO). Patients with other neoadjuvant therapies and cardia Siewert I and II carcinomas were excluded. The primary objective was to evaluate the impact of perioperative CT on surgical morbidity. As secondary objectives, resection radicality and total lymph node count were compared between the two groups. Results: A total of 307 patients (97 direct surgery and 210 perioperative CT) were evaluated. Median age was 67 years old. The overall major surgical morbidity (Clavien-Dindo 3–5) was 10.6% in the CHEMO group and 12.4 in the SURG group (p=0.643). There was no statistically significant difference between the surgical radicality (R0 98% in the SURG group vs 97.5% CHEMO group (p=0.865). There was an increase in the total number of lymph nodes retrieved in the specimen in the CHEMO group (25 vs 22, p=0.001), a difference that was not maintained in the subgroup analysis as a function of the surgery performed. Conclusions: Perioperative CT in gastric carcinoma does not increase surgical morbidity, surgical radicality and total lymph node count. (AU)

Introducción: El uso de quimioterapia perioperatoria (QT) en pacientes con carcinoma gástrico avanzado aumenta su supervivencia. Esta terapia también puede aumentar el número de pacientes con resección R0. Entre los posibles inconvenientes de esta terapia, además de su toxicidad, está una mayor morbilidad quirúrgica. El objetivo principal fue evaluar el impacto de la QT perioperatoria en la morbilidad quirúrgica. Como objetivos secundarios, la radicalidad de la resección y el recuento total de ganglios linfáticos, que se compararon entre los dos grupos. Métodos: Evaluamos retrospectivamente los registros de pacientes sometidos a gastrectomía con intención curativa para carcinoma, en nuestra institución, entre enero de 2009 y agosto de 2018. Se dividieron en dos grupos: cirugía directa (SURG) y QT perioperatoria (CHEMO). Se evaluó un total de 307 pacientes (97 SURG y 210 CHEMO). La mediana de edad fue de 67 años. Resultados: La morbilidad quirúrgica mayor (Clavien-Dindo 3-5) fue de 10,6% en el grupo CHEMO y de 12,4 en el grupo SURG (p = 0,643). No hubo diferencias estadísticamente significativas entre el radical quirúrgico (R0 98% en el grupo de SURG vs. 97,5% del grupo CHEMO (p = 0,865). Hubo un aumento en el número total de ganglios linfáticos recuperados en la muestra en el grupo CHEMO (25 vs. 22, p = 0,001), una diferencia que no se mantuvo en el análisis de subgrupos en función de la cirugía realizada. Conclusiones: La QT perioperatoria en el carcinoma gástrico no aumenta la morbilidad quirúrgica, la radicalidad quirúrgica y el recuento total de ganglios linfáticos. (AU)

Impact of perioperative chemotherapy on postoperative morbidity after gastrectomy for gastric cancer.

INTRODUCTION: The use of perioperative chemotherapy (CT) in patients with advanced gastric carcinoma increases their overall survival. This therapy may also increase the number of patients with R0 resection. Potential drawbacks of this therapy, besides its toxicity, include increased surgical morbidity. METHODS: We retrospectively evaluated the records of patients undergoing gastrectomy with curative intent, for carcinoma, at our institution between January 2009 and August 2018. They were divided into two groups: direct surgery (SURG) and perioperative CT (CHEMO). Patients with other neoadjuvant therapies and cardia Siewert I and II carcinomas were excluded. The primary objective was to evaluate the impact of perioperative CT on surgical morbidity. As secondary objectives, resection radicality and total lymph node count were compared between the two groups. RESULTS: A total of 307 patients (97 direct surgery and 210 perioperative CT) were evaluated. Median age was 67 years old. The overall major surgical morbidity (Clavien-Dindo 3-5) was 10.6% in the CHEMO group and 12.4 in the SURG group (p=0.643). There was no statistically significant difference between the surgical radicality (R0 98% in the SURG group vs 97.5% CHEMO group (p=0.865). There was an increase in the total number of lymph nodes retrieved in the specimen in the CHEMO group (25 vs 22, p=0.001), a difference that was not maintained in the subgroup analysis as a function of the surgery performed. CONCLUSIONS: Perioperative CT in gastric carcinoma does not increase surgical morbidity, surgical radicality and total lymph node count.

Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-LRx (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy.

INTRODUCTION: AKCEA-TTR-LRx is a ligand-conjugated antisense (LICA) drug in development for the treatment of hereditary transthyretin amyloidosis (hATTR), a fatal disease caused by mutations in the transthyretin (TTR) gene. AKCEA-TTR-LRx shares the same nucleotide sequence as inotersen, an antisense medicine approved for use in hATTR polyneuropathy (hATTR-PN). Unlike inotersen, AKCEA-TTR-LRx is conjugated to a triantennary N-acetylgalactosamine moiety that supports receptor-mediated uptake by hepatocytes, the primary source of circulating TTR. This advanced design increases drug potency to allow for lower and less frequent dosing. The NEURO-TTRansform study will investigate whether AKCEA-TTR-LRx is safe and efficacious, with the aim of improving neurologic function and quality of life in hATTR-PN patients. METHODS/DESIGN: Approximately 140 adults with stage 1 (independent ambulation) or 2 (requires ambulatory support) hATTR-PN are anticipated to enroll in this multicenter, open-label, randomized, phase 3 study. Patients will be assigned 6:1 to AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks or inotersen 300 mg once weekly until the prespecified week 35 interim efficacy analysis, after which patients receiving inotersen will receive AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks. All patients will then receive AKCEA-TTR-LRx through the remainder of the study treatment period. The final efficacy analysis at week 66 will compare the AKCEA-TTR-LRx arm with the historical placebo arm from the phase 3 trial of inotersen (NEURO-TTR). The primary outcome measures are between-group differences in the change from baseline in serum TTR, modified Neuropathy Impairment Score + 7, and Norfolk Quality of Life-Diabetic Neuropathy questionnaire. CONCLUSION: NEURO-TTRansform is designed to determine whether targeted delivery of AKCEA-TTR-LRx to hepatocytes with lower and less frequent doses will translate into clinical and quality-of-life benefits for patients with hATTR-PN. TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov (NCT04136184) and EudraCT (2019-001698-10).

Hereditary transthyretin amyloidosis with peripheral neuropathy (hATTR-PN for short) is a rare inherited condition. In hATTR-PN, a protein called transthyretin (TTR for short) builds up and damages nerves throughout the body. This neuropathy causes symptoms such as weakness, loss of sensation, and pain. Currently available medicines can slow disease progression, but researchers are looking for more effective treatments with fewer side effects. AKCEA-TTR-L_Rx is an investigational treatment for hATTR-PN. AKCEA-TTR-L_Rx prevents the liver from making TTR, reducing the amount that causes disease progression. It is similar to an existing treatment called inotersen, but designed for better delivery to the liver and is more potent. This article describes the NEURO-TTRansform study that will evaluate how effective AKCEA-TTR-L_Rx is for treating hATTR-PN. Around 140 adults with hATTR-PN from the USA, Canada, and Europe will be able to take part in this study. The study treatment period will be 85 weeks long. People will receive injections underneath the skin of either: AKCEA-TTR-L_Rx every 4 weeks, or Inotersen once a week for 35 weeks, followed by a switch to AKCEA-TTR-L_Rx every 4 weeks. People may continue to receive AKCEA-TTR-L_Rx after the study treatment period ends. In this study, researchers will compare results from people who received AKCEA-TTR-L_Rx to results from people who received no active ingredients (called placebo) in a similar study (called NEURO-TTR). Researchers will measure the differences in peoples': Neuropathy symptoms. Quality of life. TTR protein levels in the blood.

A circulating, disease-specific, mechanism-linked biomarker for ATTR polyneuropathy diagnosis and response to therapy prediction.

The transthyretin (TTR) amyloidoses (ATTR) are progressive, degenerative diseases resulting from dissociation of the TTR tetramer to monomers, which subsequently misfold and aggregate, forming a spectrum of aggregate structures including oligomers and amyloid fibrils. To determine whether circulating nonnative TTR (NNTTR) levels correlate with the clinical status of patients with V30M TTR familial amyloid polyneuropathy (FAP), we quantified plasma NNTTR using a newly developed sandwich enzyme-linked immunosorbent assay. The assay detected significant plasma levels of NNTTR in most presymptomatic V30M TTR carriers and in all FAP patients. NNTTR was not detected in age-matched control plasmas or in subjects with other peripheral neuropathies, suggesting NNTTR can be useful in diagnosing FAP. NNTTR levels were substantially reduced in patients receiving approved FAP disease-modifying therapies (e.g., the TTR stabilizer tafamidis, 20 mg once daily). This NNTTR decrease was seen in both the responders (average reduction 56.4 ± 4.2%; n = 49) and nonresponders (average reduction of 63.3 ± 4.8%; n = 32) at 12 mo posttreatment. Notably, high pretreatment NNTTR levels were associated with a significantly lower likelihood of clinical response to tafamidis. Our data suggest that NNTTR is a disease driver whose reduction is sufficient to ameliorate FAP so long as pretreatment NNTTR levels are below a critical clinical threshold.

Oesophageal GIST.

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract. Oesophageal GISTs are extremely uncommon, accounting for 0.7% of all GISTs, and their management is surrounded by some debate. We report a case of a 70-year-old man who was incidentally diagnosed with an oesophageal lesion on a 18F-fluorodeoxyglucose positron emission tomography. An endoscopic study revealed a non-obstructing 40 mm oesophageal lesion. Endoscopic ultrasound showed a well-circumscribed submucosal tumour on the middle oesophagus. Fine-needle aspiration was positive for CD117 and the overall features were of a GIST. After an initial thoracoscopic approach, the tumour was completely enucleated through a thoracotomy incision. The patient experienced no surgical complications and was discharged on day 4. Histopathology and immunohistochemical staining confirmed a low-risk GIST.

A critical analysis of the impact of endocrine disruptors as a possible etiology of primary ovarian insufficiency.

Primary ovarian insufficiency is a cause of infertility that affects about 1% of women under 40 years old, and is considered as idiopathic in 75% of cases. This review aims to carry out a critical synthesis of the knowledge of the chemical agents likely to affect follicular stock in humans and / or animals, by direct toxicity to follicles, or by increasing their recruitments. For the majority of toxic agents, only experimental data are currently available. We propose a strategy to encourage progress in identifying occupational factors responsible for premature ovarian failure.

Uterine alterations in women undergoing routine hysteroscopy before in vitro fertilization: high prevalence of unsuspected lesions.

OBJECTIVE: The aim of this study was to verify the prevalence of uterine cavity abnormalities diagnosed by routine office hysteroscopy in women preparing to IVF. METHODS: We carried out a retrospective cross-sectional study of 1141 consecutive women who underwent outpatient hysteroscopy before IVF at a tertiary academic center. Of these, 961 participants had a normal transvaginal sonography (TVS) of the uterine cavity. The prevalence of hysteroscopic alterations in successive age strata was submitted to Mantel-Haenzsel Chi-square test for linear trend. The diagnostic accuracy of TVS using hysteroscopy as reference was assessed by calculating the sensitivity, specificity, positive and negative likelihood ratios. RESULTS: Hysteroscopic alterations were present in 265/961 of patients with a negative TVS (prevalence 27.6%, 95% confidence interval [CI] 24.8%-30.5%). The prevalence of unsuspected submucous leiomyoma was higher among older women (p=0.005, chi-square test for linear trend) and reached 7.2% (95% CI 3.5%-14.1%) after 40 years. The sensitivity of TVS ranged from 8% (95% CI 2%-20%) for uterine synechiae to 41% (95% CI 28%-56%) for submucous leiomyoma, resulting in low likelihood ratios for negative TVS results. CONCLUSIONS: These findings suggest a high prevalence of unsuspected alterations found by routine hysteroscopy before IVF, an age-dependent increase in the frequency of submucous leiomyoma and a low diagnostic sensitivity of TVS to detect intracavitary lesions.

Predictive model of response to tafamidis in hereditary ATTR polyneuropathy.

BACKGROUNDThe hereditary transthyretin (TTR) amyloidoses are a group of diseases for which several disease-modifying treatments are now available. Long-term effectiveness of these therapies is not yet fully known. Moreover, the existence of alternative therapies has resulted in an urgent need to identify patient characteristics that predict response to each therapy.METHODSWe carried out a retrospective cohort study of 210 patients with hereditary TTR amyloidosis treated with the kinetic stabilizer tafamidis (20 mg qd). These patients were followed for a period of 18-66 months, after which they were classified by an expert as responders, partial responders, or nonresponders. Correlations between baseline demographic and clinical characteristics, as well as plasma biomarkers and response to therapy, were investigated.RESULTS34% of patients exhibited an almost complete arrest of disease progression (classified by an expert as responders); 36% had a partial to complete arrest in progression of some but not all disease components (partial responders); whereas the remaining 30% continued progressing despite therapy (nonresponders). We determined that disease severity, sex, and native TTR concentration at the outset of treatment were the most relevant predictors of response to tafamidis. Plasma tafamidis concentration after 12 months of therapy was also a predictor of response for male patients. Using these variables, we built a model to predict responsiveness to tafamidis.CONCLUSIONOur study indicates long-term effectiveness for tafamidis, a kinetic stabilizer approved for the treatment of hereditary TTR amyloidosis. Moreover, we created a predictive model that can be potentially used in the clinical setting to inform patients and clinicians in their therapeutic decisions.

The impact of dehydroepiandrosterone in poor ovarian responders on assisted reproduction technology treatment.

One in six couples worldwide will experience at least one infertility problem during their reproductive years. Between 5.6% and 35.1% of women will exhibit poor ovarian response. A variety of methods have been applied to improve ovarian response, including dehydroepiandrosterone. In the ovaries, dehydroepiandrosterone promotes follicular development and granulosa cell proliferation by increasing intraovarian androgen concentrations while simultaneously enhancing the level of follicular insulin-like growth factor-1, which promotes folliculogenesis. Dehydroepiandrosterone supplementation may improve in vitro fertilization outcomes and ovarian response in patients with poor ovarian response. However, a few questions still loom over the effectiveness of dehydroepiandrosterone.

A designed protein binding-pocket to control excited-state intramolecular proton transfer fluorescence.

Excited-state intramolecular proton transfer involves a photochemical isomerization and creates the opportunity for the emission of two distinct wavelengths of light from a single fluorophore. The selectivity between these two wavelengths of emission is dependent on the environment around the fluorophore and suggests the possibility for ratiometric monitoring of protein microenvironments. Unfortunately, nonspecific binding of ESIPT fluorophores does not often lead to dramatic changes in the ratio between the two wavelengths of emission. A protein binding pocket was designed to selectively discriminate between the two channels of emission available to an ESIPT fluorophore. This work is significant because it demonstrates that specific interactions between the protein and the fluorophore are essential to realize strong ratiometric differences between the two possible wavelengths of emission. The design strategies proposed here lead to an ESIPT fluorophore that can discern subtle differences in the interface between two proteins.

Tenosynovial and Cardiac Amyloidosis in Patients Undergoing Carpal Tunnel Release.

BACKGROUND: Patients with cardiac amyloidosis often have carpal tunnel syndrome that precedes cardiac manifestations by several years. However, the prevalence of cardiac involvement at the time of carpal tunnel surgery has not been established. OBJECTIVES: The authors sought to identify the prevalence and type of amyloid deposits in patients undergoing carpal tunnel surgery and evaluate for cardiac involvement. The authors also sought to determine if patients with soft tissue transthyretin (TTR) amyloid had abnormal TTR tetramer kinetic stability. METHODS: This was a prospective, cross-sectional, multidisciplinary study of consecutive men age ≥50 years and women ≥60 years undergoing carpal tunnel release surgery. Biopsy specimens of tenosynovial tissue were obtained and stained with Congo red; those with confirmed amyloid deposits were typed with mass spectrometry and further evaluated for cardiac involvement with biomarkers, electrocardiography, echocardiography with longitudinal strain, and technetium pyrophosphate scintigraphy. Additionally, serum TTR concentration and tetramer kinetic stability were examined. RESULTS: Of 98 patients enrolled (median age 68 years, 51% male), 10 (10.2%) had a positive biopsy for amyloid (7 ATTR, 2 light chain [AL], 1 untyped). Two patients were diagnosed with hereditary ATTR (Leu58His and Ala81Thr), 2 were found to have cardiac involvement (1 AL, 1 ATTR wild-type), and 3 were initiated on therapy. In those patients who had biopsy-diagnosed ATTR, there was no difference in plasma TTR concentration or tetramer kinetic stability. CONCLUSIONS: In a cohort of patients undergoing carpal tunnel release surgery, Congo red staining of tenosynovial tissue detected amyloid deposits in 10.2% of patients. Concomitant cardiac evaluation identified patients with involvement of the myocardium, allowing for implementation of disease-modifying therapy. (Carpal Tunnel Syndrome and Amyloid Cardiomyopathy; NCT02792790).

Cerebrospinal fluid and vitreous body exposure to orally administered tafamidis in hereditary ATTRV30M (p.TTRV50M) amyloidosis patients.

Hereditary transthyretin (TTR) amyloidosis associated with the TTRV30M (p.TTRV50M) mutation presents predominantly as an axonal polyneuropathy, with variable involvement of other organs. Serious central nervous system (CNS) and eye manifestations, including stroke, dementia, vitreous opacities and glaucoma, have been reported in untreated V30M TTR amyloidosis patients, and in these patients after treatment with liver transplantation (LT). Distinct therapies for V30M TTR amyloidosis developed during the last decade exhibit promising results in slowing the peripheral and autonomic nervous system pathology. However, the effect of these therapies on the CNS and eye manifestations of V30M TTR amyloidosis is not known. Herein, we show that in a small cohort of patients taking tafamidis orally (20 mg tafamidis meglumine daily) we could detect this small molecule in the cerebrospinal fluid (CSF) and the vitreous body. In the CSF, the ratio of TTR tetramer to tafamidis was ≈2:1, leading to a moderate kinetic stabilization of TTR in the CSF of these patients. Our data suggest that tafamidis can cross the CSF-blood and eye-blood barriers. Future studies comparing CNS and eye manifestations in patients treated with LT, kinetic stabilizers or TTR lowering drugs are essential to understand the clinical effect of our observations.

Age-dependent cognitive dysfunction in untreated hereditary transthyretin amyloidosis.

Central nervous system (CNS) involvement in hereditary transthyretin (TTR) amyloidosis has been described in patients whose disease course was modified by liver transplant. However, cognitive dysfunction has yet to be investigated in those patients. Moreover, CNS involvement in untreated patients or asymptomatic mutation carriers remains to be studied. A series of 340 carriers of the TTRVal30Met mutation (180 symptomatic and 160 asymptomatic) underwent a neuropsychological assessment, which included the Dementia Rating Scale-2 (DRS-2), auditory verbal learning test, semantic fluency, phonemic fluency, and trail making test. Cognitive deficits were identified at the individual level, after adjusting the neuropsychological test scores for demographic characteristics (sex, age, and education), based on large national normative data. The presence of cognitive dysfunction was determined by deficit in DRS-2 and/or multiple cognitive domains. Participants were also screened for depression based on a self-report questionnaire. The frequency of cognitive dysfunction was higher (p = 0.003) in symptomatic (9%) than in asymptomatic (2%) carriers. Among older carriers (≥ 50 years), the frequency of cognitive dysfunction was higher (p < 0.001) in symptomatic (36%) than asymptomatic (4%) individuals. Among younger participants (< 50 years), the frequency of cognitive dysfunction was not different (p = 0.631) between symptomatic patients (2%) and asymptomatic (1%) carriers. This cross-sectional study shows that cognitive dysfunction is part of the broad spectrum of clinical manifestations in older hereditary TTR amyloidosis patients with peripheral polyneuropathy, even in the early stages of the disease.

Craniossinostose complexa não-sindrômica: um relato de caso / Nonsyndromic complex craniosynostosis: a case report

Objetivos: 1 ­ primário: Relatar um caso de craniossinostose (CS) complexa não-sindrômica de paciente nascido no Hospital do Servidor Público Municipal (HSPM) em 2017. 2 ­ secundário: Compreender a CS, as principais causas, seus fatores de risco e as principais síndromes envolvidas nesta alteração craniana. Método: Relato de caso de paciente nascido no ano de 2017, no HSPM que no ultrassom morfológico, durante o pré-natal, feito a hipótese diagnóstica de CS. Confirmado ao nascimento, no alojamento conjunto. Discussão: O crânio de um recém-nascido é composto de múltiplos ossos e suturas, as quais facilitam sua passagem através do canal de parto e acomodam o encéfalo. As assimetrias cranianas podem ser de origem deformacional, que ocorrem devido às forças externas e esta diferenciação nem sempre é simples. A CS é uma anomalia congênita comum resultante do fechamento precoce de uma ou mais suturas do crânio. A incidência é de 1:1200-2500 nascimentos, podendo apresentar diferentes graus de desproporção volumétrica entre o crânio e o encéfalo. As CS são classificadas como primária ou secundária, sindrômica ou não-sindrômica, sendo as síndromes mais comuns: Crouzon, Apert, Pfeiffer, Muenke e Saethre - Chotzen.F. A suspeita diagnóstica inicia-se na fase intrauterina, no entanto o exame definitivo e de escolha é a tomografia de crânio com reconstrução tridimensional, após o nascimento. Várias teorias tentam explicar a patogênese de uma fusão anormal de sutura craniana, mutação genética é uma delas. O reconhecimento precoce da deformação do crânio e a classificação precisa, são fatores cruciais para o sucesso do tratamento, sendo esta conduzida a partir de equipe multidisciplinar. Palavras chave: Craniossinostose. Anormalidades Craniofaciais. Síndrome.

Peptide probes detect misfolded transthyretin oligomers in plasma of hereditary amyloidosis patients.

Increasing evidence supports the hypothesis that soluble misfolded protein assemblies contribute to the degeneration of postmitotic tissue in amyloid diseases. However, there is a dearth of reliable nonantibody-based probes for selectively detecting oligomeric aggregate structures circulating in plasma or deposited in tissues, making it difficult to scrutinize this hypothesis in patients. Hence, understanding the structure-proteotoxicity relationships driving amyloid diseases remains challenging, hampering the development of early diagnostic and novel treatment strategies. We report peptide-based probes that selectively label misfolded transthyretin (TTR) oligomers circulating in the plasma of TTR hereditary amyloidosis patients exhibiting a predominant neuropathic phenotype. These probes revealed that there are much fewer misfolded TTR oligomers in healthy controls, in asymptomatic carriers of mutations linked to amyloid polyneuropathy, and in patients with TTR-associated cardiomyopathies. The absence of misfolded TTR oligomers in the plasma of cardiomyopathy patients suggests that the tissue tropism observed in the TTR amyloidoses is structure-based. Misfolded oligomers decrease in TTR amyloid polyneuropathy patients treated with disease-modifying therapies (tafamidis or liver transplant-mediated gene therapy). In a subset of TTR amyloid polyneuropathy patients, the probes also detected a circulating TTR fragment that disappeared after tafamidis treatment. Proteomic analysis of the isolated TTR oligomers revealed a specific patient-associated signature composed of proteins that likely associate with the circulating TTR oligomers. Quantification of plasma oligomer concentrations using peptide probes could become an early diagnostic strategy, a response-to-therapy biomarker, and a useful tool for understanding structure-proteotoxicity relationships in the TTR amyloidoses.

Avaliação crítica do papel da citologia cervical em meio líquido no rastreamento do câncer do colo uterino / Critical evaluation of the role of liquid based cervical cytology in screening for cervical cancer

A citologia cervical em meio líquido (CML) foi aprovada pela Administração de Drogas e Alimentos dos EUA (Food and Drug Administration - FDA) com objetivo de reduzir as falhas da citologia cervical convencional (CC). Segundo a literatura atual, a CML aumenta a sensibilidade da citologia cervical, a adequabilidade das amostras e diminui o número de esfregaços insatisfatórios quando comparada com a CC. Embora alguns países tenham legitimado o modelo de CML no rastreio de neoplasia do colo do útero, há controvérsias a respeito da escolha do melhor método de exame citopatológico cervical. Dessa forma, o objetivo da presente revisão é avaliar o impacto da introdução da CML em termos de eficácia, custos, conhecimento técnico necessário e implicações para a sua introdução.(AU)

The liquid based cervical cytology has been approved by the Food and Drug Administration (FDA) in order to reduce failures of conventional cervical cytology (CC). According to current literature, CML increases the sensitivity of cervical cytology, the suitability of the samples and reduce the number of poor smears compared with CC. Although some countries have legitimized the CML model in screening cancer of the cervix, there is a controversy about the choice of the best cervical Pap smear method. Thus, the aim of the current review is to evaluate the impact of the introduction of CML in terms of effectiveness, costs, necessary technical knowledge and implications of its introduction.(AU)