Cardiovascular mortality in Brazil during the COVID-19 pandemic: a comparison between underlying and multiple causes of death.

OBJECTIVES: The COVID-19 pandemic has differentially impacted cardiovascular disease (CVD) mortality worldwide. Causes of death misclassification may be one of the reasons. We evaluated the impact of the pandemic on CVD mortality in Brazil, comparing underlying causes (UCs) and multiple causes (MCs) of death. STUDY DESIGN: Ecological time-series study. METHODS: An ecological, time-series study was conducted analysing age-standardised death rates for CVD, from epidemiological week (EW) 10/2020 to 39/2021, using data from the Mortality Information System, Brazil. CVD was defined using the International Classification of Diseases (ICD-10) coding, if reported as UC or MC of death. Observed and expected data (mean for the same EW, 2017-2019) were compared. Risk ratios (RiRs) were analysed, and 95% confidence intervals (CIs) were calculated. RESULTS: Age-standardised mortality rate for CVD as UC of death was 165.8 (95%CI: 165.4-166.3) per 100,000 inhabitants, similar to what was expected (165.6/100,000, 95%CI: 165.2-166.1, RiR = 1.00). There was increased out-of-hospital mortality (RiR = 1.18; 95%CI: 1.17-1.19) and deaths of ill-defined causes (RiR = 1.43; 95%CI: 1.42-1.44). The increase in out-of-hospital deaths was more pronounced in the North (RiR = 1.33; 95%CI 1.30-1.36) region, with a less resilient health system. Conversely, as MCs of death, there was a 10% increase in CVD mortality (observed: 243.2 [95%CI: 242.7-243.7], expected: 221.6 [95%CI: 221.1-222.1] per 100,000). An increase also occurred in the North and Central West regions (RiR = 1.16; 95%CI: 1.15-1.18), among men (RiR = 1.11; 95%CI: 1.11-1.12) and individuals aged ≥60 years (RiR = 1.11; 95%CI: 1.10-1.11). CONCLUSIONS: During the pandemic, mortality rates for CVD as MCs of death increased in Brazil, whereas as UC mortality rates did not change. Higher out-of-hospital mortality, misclassification, and competing causes of death may explain this pattern.

Technique and Tips for Multiplanar Correction of Plantar Plate Repairs in Lesser Metatarsophalangeal Joints.

Plantar plate repairs are challenging procedures because of the small anatomy of the plantar plate. This can make them daunting, time-consuming procedures to perform. Advances in technology, such as interference screws and small suture passers, have created improved technique possibilities to decrease difficulty, correct multiple planes of deformity, create stronger constructs, and improve patient results. The plantar plate repair technique presented in this article includes a dorsal approach with a metatarsal osteotomy, a knotless repair that provides a strong construct to allow patients to protectively bear weight immediately, and can reduce operative time by presenting tips to quickly navigate the procedure. The presented technique allows for detailed correction of all three planes of deformity, maximizing patient results.

Ropivacaine and Bupivacaine prevent increased pain sensitivity without altering neuroimmune activation following repeated social defeat stress.

OBJECTIVE: Mounting evidence indicates that stress influences the experience of pain. Exposure to psychosocial stress disrupts bi-directional communication pathways between the central nervous system and peripheral immune system, and can exacerbate the frequency and severity of pain experienced by stressed subjects. Repeated social defeat (RSD) is a murine model of psychosocial stress that recapitulates the immune and behavioral responses to stress observed in humans, including activation of stress-reactive neurocircuitry and increased pro-inflammatory cytokine production. It is unclear, however, how these stress-induced neuroimmune responses contribute to increased pain sensitivity in mice exposed to RSD. Here we used a technique of regional analgesia with local anesthetics in mice to block the development of mechanical allodynia during RSD. We next investigated the degree to which pain blockade altered stress-induced neuroimmune activation and depressive-like behavior. METHODS: Following development of a mouse model of regional analgesia with discrete sensory blockade over the dorsal-caudal aspect of the spine, C57BL/6 mice were divided into experimental groups and treated with Ropivacaine (0.08%), Liposomal Bupivacaine (0.08%), or Vehicle (0.9% NaCl) prior to exposure to stress. This specific region was selected for analgesia because it is the most frequent location for aggression-associated pain due to biting during RSD. Mechanical allodynia was assessed 12 h after the first, third, and sixth day of RSD after resolution of the sensory blockade. In a separate experiment, social avoidance behavior was determined after the sixth day of RSD. Blood, bone marrow, brain, and spinal cord were collected for immunological analyses after the last day of RSD in both experiments following behavioral assessments. RESULTS: RSD increased mechanical allodynia in an exposure-dependent manner that persisted for at least one week following cessation of the stressor. Mice treated with either Ropivacaine or Liposomal Bupivacaine did not develop mechanical allodynia following exposure to stress, but did develop social avoidance behavior. Neither drug affected stress-induced activation of monocytes in the bone marrow, blood, or brain. Neuroinflammatory responses developed in all treatment groups, as evidenced by elevated IL-1ß mRNA levels in the brain and spinal cord after RSD. CONCLUSIONS: In this study, psychosocial stress was associated with increased pain sensitivity in mice. Development of mechanical allodynia with RSD was blocked by regional analgesia with local anesthetics, Ropivacaine or Liposomal Bupivacaine. Despite blocking mechanical allodynia, these anesthetic interventions did not prevent neuroimmune activation or social avoidance associated with RSD. These data suggest that stress-induced neuroinflammatory changes are not associated with increased sensitivity to pain following RSD. Thus, blocking peripheral nociception was effective in inhibiting enhanced pain signaling without altering stress-induced immune or behavioral responses.

Sympathetic Release of Splenic Monocytes Promotes Recurring Anxiety Following Repeated Social Defeat.

BACKGROUND: Neuroinflammatory signaling may contribute to the pathophysiology of chronic anxiety disorders. Previous work showed that repeated social defeat (RSD) in mice promoted stress-sensitization that was characterized by the recurrence of anxiety following subthreshold stress 24 days after RSD. Furthermore, splenectomy following RSD prevented the recurrence of anxiety in stress-sensitized mice. We hypothesize that the spleen of RSD-exposed mice became a reservoir of primed monocytes that were released following neuroendocrine activation by subthreshold stress. METHODS: Mice were subjected to subthreshold stress (i.e., single cycle of social defeat) 24 days after RSD, and immune and behavioral measures were taken. RESULTS: Subthreshold stress 24 days after RSD re-established anxiety-like behavior that was associated with egress of Ly6C(hi) monocytes from the spleen. Moreover, splenectomy before RSD blocked monocyte trafficking to the brain and prevented anxiety-like behavior following subthreshold stress. Splenectomy, however, had no effect on monocyte accumulation or anxiety when determined 14 hours after RSD. In addition, splenocytes cultured 24 days after RSD exhibited a primed inflammatory phenotype. Peripheral sympathetic inhibition before subthreshold stress blocked monocyte trafficking from the spleen to the brain and prevented the re-establishment of anxiety in RSD-sensitized mice. Last, ß-adrenergic antagonism also prevented splenic monocyte egress after acute stress. CONCLUSIONS: The spleen served as a unique reservoir of primed monocytes that were readily released following sympathetic activation by subthreshold stress that promoted the re-establishment of anxiety. Collectively, the long-term storage of primed monocytes in the spleen may have a profound influence on recurring anxiety disorders.

A Rare Presentation of Transformed, CD30(+) High-Grade Cutaneous T-Cell Lymphoma of the Hallux A Case Report.

Cutaneous T-cell lymphoma is a type of non-Hodgkin's lymphoma, which is a neoplasm affecting the lymphatic system. Mycosis fungoides is the most common subset of cutaneous T-cell lymphoma and is often treated conservatively. This neoplasm is most common in adults older than 60 years and does not regularly manifest in the toes. A case is reported of a 70-year-old man seen for a nonhealing hallux ulceration leading to amputation. Histopathologic examination revealed a rare transformed CD30(+) high-grade cutaneous T-cell lymphoma. The morbidity of lymphomas is highly dependent on type and grade. Pharmaceutical precision therapies exist that target specific molecular defects or abnormally expressed genes, such as high expression of CD30. This article focuses on treatment protocol and emphasizes the importance of early diagnosis, determination of cell type, and proper referral of atypical dermatologic lesions.

Ynamides in ring forming transformations.

The ynamide functional group activates carbon-carbontriple bonds through an attached nitrogen atom that bears an electron-withdrawing group. As a result, the alkyne has both electrophilic and nucleophilic properties. Through the selection of the electron-withdrawing group attached to nitrogen, chemists can modulate the electronic properties and reactivity of ynamides, making these groups versatile synthetic building blocks. The reactions of ynamides also lead directly to nitrogen-containing products, which provides access to important structural motifs found in natural products and molecules of medicinal interest. Therefore, researchers have invested increasing time and research in the chemistry of ynamides in recent years. This Account surveys and assesses new organic transforma-tions involving ynamides developed in our laboratory and in others around the world. We showcase the synthetic power of ynamides for rapid assembly of complex molecular structures. Among the recent reports of ynamide transformations, ring-forming reactions provide a powerful tool for generating molecular complexity quickly. In addition to their synthetic utility, such reactions are mechanistically interesting. Therefore, we focus primarily on the cyclization chemistry of ynamides. This Account highlights ynamide reactions that are useful in the rapid synthesis of cyclic and polycyclic structural manifolds. We discuss the mechanisms active in the ring formations and describe representative examples that demonstrate the scope of these reactions and provide mechanistic insights. In this discussion, we feature examples of ynamide reactions involving radical cyclizations, ring-closing metathesis, transition metal and non-transition metal mediated cyclizations, cycloaddition reactions, and rearrangements. The transformations presented rapidly introduce structural complexity and include nitrogen within or in close proximity to a newly formed ring (or rings). Thus, ynamides have emerged as powerful synthons for nitrogen-containing heterocycles and nitrogen-substituted rings, and we hope this Account will promote continued interest in the chemistry of ynamides.

Glutathione reductase activity with an oxidized methylated glutathione analog.

The activity of glutathione reductase with an unnatural analog of oxidized glutathione was explored. The analog, L-γ-glutamyl-2-methyl-L-cysteinyl-glycine disulfide, places an additional methyl group on the alpha position of each of the central cysteine residues, which significantly increases steric bulk near the disulfide bond. Glutathione reductase was completely unable to catalyze the sulfur-sulfur bond reduction of the analog. Additionally, enzyme kinetics experiments indicated that the analog acts as a competitive inhibitor of glutathione reductase. Computational studies confirm that the methylated analog fits within the active site of the enzyme but its disulphide bond geometry is altered, preventing reduction by the enzyme. The substitution of (R)-2-methylcysteine in place of natural (R)-cysteine in peptides constitutes a new strategy for stabilizing disulphide bonds from enzyme-catalyzed degradation.

Offloading of the diabetic foot: orthotic and pedorthic strategies.

The diabetic foot is more susceptible than the non-diabetic foot to collapse. This frequently leads to bony prominences followed by ulceration. Offloading of areas of increased pressure is paramount to ulcer prevention and healing. Several devices and accommodations can aid practitioners in saving patients' extremities and allow them to ambulate. A team approach works best, and patient education is a must. Regular assessment and modifications are required for longevity of each device. In this article, different therapeutic options are detailed. A variety of presentations and situations are discussed and the authors' best tips for avoiding complications are offered.

Complex human glucocorticoid receptor dim mutations define glucocorticoid induced apoptotic resistance in bone cells.

A mutation in the D-loop of the second zinc finger of the DNA-binding domain of the human glucocorticoid receptor (hGR), A458T (GR(dim)), has been suggested to be essential for dimerization and DNA binding of the GR, and genetically altered GR(dim) mice survive, whereas murine GR knockout mice die. Interestingly, thymocytes isolated from the GR(dim) mice were reported to be resistant to glucocorticoid-induced apoptosis. To further evaluate the dim mutations in glucocorticoid-induced apoptosis, we stably expressed either the hGR(dim) (A458T) or the hGR(dim4) (A458T, R460D, D462C, and N454D) mutant receptors in human osteosarcoma (U-2 OS) cells that are devoid of hGR and unresponsive to glucocorticoids. We analyzed these cell lines by comparison with a stable expression hGRα U-2 OS cell line, which undergoes apoptosis after glucocorticoid treatment. Transient reporter gene assays with glucocorticoid response element-driven vectors revealed that the hGR(dim) mutation had diminished steroid responsiveness and cells carrying the hGR(dim4) mutation were unresponsive to steroid, whereas glucocorticoid-induced nuclear factor κB repression was unaffected by either mutation. Interestingly, both the hGR(dim) and hGR(dim4) receptors readily formed dimers as measured by immunoprecipitation. Examination of GR-mediated apoptosis showed that hGR(dim) cells were only partially resistant to apoptosis, whereas hGR(dim4) cells were completely resistant to glucocorticoid-induced cell death despite remaining sensitive to other apoptotic stimuli. Global gene expression analysis revealed that hGR(dim4) cells widely regulated gene expression but differentially regulated apoptotic mRNA when compared with cells expressing wild-type hGRα. These studies challenge conclusions drawn from previous studies of GR dim mutants.

Using automated extraction of hepatitis B tests for surveillance: evidence of decreasing incidence of acute hepatitis B in England.

Surveillance of acute hepatitis B in England is necessary to estimate incidence, determine routes of transmission and inform public health actions. Here we describe an automated process to extract information on testing for markers of hepatitis B infection in English sentinel laboratories between 2002 and 2008. The resulting data were used to identify individuals with acute infections, describe their characteristics and estimate the incidence of infection. Two-thirds of acute infections were in males. Heterosexual exposure and injecting drug use were the main risks reported. Annual incidence was estimated at 1.3/100 000 person-years overall (1.7 and 0.6 for males and females, respectively) and declined each year. Automated extraction of hepatitis B markers, including quantitative results where available, can help to classify HBV status more accurately for surveillance. HBV incidence in England is at its lowest level in recent years.

Hematologic and immunological indicators are altered by chronic intake of flaxseed in Wistar rats.

This work sought to evaluate the effects of chronic intake of flaxseed upon hematologic parameters and immunological findings on body development of Wistar rats. Female Wistar rats were used after gestation. They were randomly assigned into two groups during lactation period: Control group (CG), fed with casein based diet, made up of 17% protein and flaxseed group (FG), fed with casein based diet with the addition of 25% flaxseed. At weaning, 12 male pups of each group continued to receive the experimental diets of their mothers (with only 10% of protein) until adult age, when they were killed at 250 days of life aiming at blood collection. At 250 days old FG presented significant reduction in body mass (p<0.000) and higher levels of hemoglobin (p=0.019) and albumin (p=0.030) than CG. It was observed smaller percentage of segmented lymphocytes (p=0.016) in rats from FG and bigger percentage of segmented leucocytes (p=0.023) when compared to CG. The chronic consumption of flaxseed altered hematologic and immunological indicators in adult Wistar rats. Supplementation with flaxseed seems to be beneficial to maintenance or reduction of body mass.

Recruiting individuals into the HTLV cohort study in the United Kingdom: clinical findings and challenges in the first six years, 2003 to 2009.

Human T-lymphotropic virus (HTLV) infection is rare in the United Kingdom (UK) and few studies are available worldwide. Following introduction of blood donation testing in 2002, a cohort of individuals could be identified and prospectively recruited to describe progression and onset of disease. Here we describe baseline characteristics of participants, and evaluate recruitment into the UK HTLV National Register over the first six years, from July 2003 to June 2009. A multicentre cohort study recruited participants from the UK blood services (recipients and donors) and specialist HTLV clinics. Almost half of the 148 participants recruited were blood donors, nine were blood transfusion recipients, 40 contacts and 29 clinic attendees (nine asymptomatic and 20 symptomatic). Most participants were HTLV-1 positive (n=115); 11 had HTLV-2 and 22 were HTLV-negative. Baseline self-completion questionnaires were received for 83%. The most commonly reported condition was a past operation/serious illness (69%). Twenty-six participants reported four or more possible signs/symptoms of HTLV-1-associated myelopathy/tropical spastic paraparesis. Recruitment into a study of a rare, long-term infection is challenging. This cohort will enable descriptions of HTLV-associated disease progression amongst people recruited from varying sources; it is the first prospective study of its kind in Europe.

A re-evaluation of the risk of transfusion-transmitted HIV prevented by the exclusion of men who have sex with men from blood donation in England and Wales, 2005-2007.

BACKGROUND AND OBJECTIVES One component of the rationale for lifetime exclusion of men who have sex with men (MSM) from blood donation in the UK is the probable reduction in the risk of transfusion-transmitted HIV; this exclusion has recently been questioned. MATERIALS AND METHODS Data about HIV in blood donors and MSM were analysed to estimate the risk of infectious donations entering the blood supply under different scenarios of donor selection criteria (and donor compliance) for MSM and a heterosexual group with increased risk of HIV. RESULTS In 2005-2007, a change from lifetime exclusion of MSM to 5-year deferral or no deferral increased the point estimate of HIV risk by between 0·4% and 7·4% depending on compliance with the deferral (range -4% to 15%) and 26·5% (range 18% to 43%) respectively. A change from a 12-month deferral of the high-risk heterosexual group to lifetime exclusion reduced the estimated risk by about 7·2% (range 6% to 9%). Each point estimate was within the probable range of risk under the current criteria. CONCLUSION If prevalence is the only factor affected by a reduced deferral, then the increased risk of HIV is probably negligible. However, the impact of a change depends on compliance; if this stays the same or worsens, the risk is expected to increase because of more incident infections in MSM who donate blood. The risk of transfusion-transmitted HIV could probably be reduced further by improving compliance with any exclusion, particularly after recent risk behaviours.

The problem with using computer programmes to assign ethnicity: immigration decreases sensitivity.

OBJECTIVES: It is recognized that ethnic group is important in describing differences in infection and disease, but is often not routinely available to surveillance systems. Computerized programmes, such as NamPehchan, can assign ethnicity according to name; however, sensitivity and positive predictive value (PPV) can vary. The aim of this study was to assess whether the sensitivity and PPV of NamPehchan had changed, after an observation that surnames previously associated with South Asians were increasingly reported as Black. STUDY DESIGN: Cross-sectional. METHODS: NamPehchan was used to classify women as South Asian using name, and compared with the gold standard (midwife-reported ethnicity). Sensitivity and PPV were calculated overall and by year. Frequency of infection by ethnic group was estimated. RESULTS: A total of 627 women positive for hepatitis B surface antigen were identified. The majority were from minority ethnic groups, particularly Asian. The overall sensitivity of NamPehchan was 74.5% and PPV was 68.5%. Almost 50% of Black African women were classified as South Asian by NamPehchan. CONCLUSIONS: Immigration from African countries has reduced the sensitivity of NamPehchan in this group. Care is needed when using NamPehchan for groups which include Africans from Muslim areas, as misclassification is likely to occur.

Time-dependent association of total serum cholesterol and cancer incidence in a cohort of 172,210 men and women: a prospective 19-year follow-up study.

BACKGROUND: The relationship between serum cholesterol and cancer incidence remains controversial. PATIENTS AND METHODS: We investigated the association of total serum cholesterol (TSC) with subsequent cancer incidence in a population-based cohort of 172 210 Austrian adults prospectively followed up for a median of 13.0 years. Cox regression, allowing for time-dependent effects, was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) for the association of TSC with cancer. RESULTS: We observed pronounced short-term associations of TSC and overall cancer incidence in both men and women. For malignancies diagnosed shortly (<5 months) after baseline TSC measurement, the highest TSC tertile (>235.0 mg/dl in men and >229.0 in women) compared with the lowest tertile (<194.0 mg/dl in men and <190.0 in women) was associated with a significantly lower overall cancer risk [HR = 0.58 (95% CI 0.43-0.78, P(trend) = 0.0001) in men, HR = 0.69 (95% CI 0.49-0.99, P(trend) = 0.03) in women]. However, after roughly 5 months from baseline measurement, overall cancer risk was not significantly associated with TSC. The short-term inverse association of TSC with cancer was mainly driven by malignancies of the digestive organs and lymphoid and hematopoietic tissue. CONCLUSION: The short-term decrease of cancer risk seen for high levels of TSC may largely capture preclinical effects of cancer on TSC.

Diagnoses of, and deaths from, severe liver disease due to hepatitis C in England between 2000 and 2005 estimated using multiple data sources.

Matching individuals reported to a sentinel surveillance scheme for hepatitis C between 2000 and 2005 to individuals with a hospital episode for hepatitis C-related liver disease in the same hospitals, we estimated that the number of cases of hepatitis C-related end-stage liver disease in these English hospitals was 42% (597/419) higher than Hospital Episode Statistics (HES) would indicate. Further, matching records of hepatitis C-related deaths in HES to death certificates, we estimated that, between 2000 and 2005, the true number of deaths from hepatitis C-related end-stage liver disease was between 185% (353/124) and 257% (378/106) higher than the number recorded in routine mortality statistics. We provide estimates of under-recording that can be used to modify existing models of disease burden due to hepatitis C and provide a simple approach to improve the monitoring of trends in severe hepatitis C-related morbidity over time.

Setting up an enhanced surveillance of newly acquired hepatitis C infection in men who have sex with men: a pilot in London and South East region of England.

Preliminary findings suggest ongoing HCV transmission among MSM infected with human immunodeficiency virus (HIV) and that enhanced surveillance for newly acquired HCV in MSM is feasible.

Diagnosis of acute hepatitis C virus infection and estimated incidence in low- and high-risk English populations.

The diagnosis of acute hepatitis C virus (HCV) infection is not straightforward; few people exhibit clinical symptoms and genome/antigen detection techniques do not indicate when infection had occurred. Here, a strategy to detect HCV RNA in the absence of antibody ('window-period') for diagnosis of acute infection is assessed. The sentinel surveillance of hepatitis testing study was used to retrospectively identify anti-HCV negative samples from high-risk individuals (2002-2003), for testing singly for HCV RNA. Additional samples were identified prospectively (2005) and tested in pools for HCV RNA. Positive samples were genotyped. Incidence and costs of adopting the pooling strategy were estimated. In the retrospective study, 8/390 (2.1%) samples were confirmed HCV RNA positive, anti-HCV negative. Prospectively, 3237 samples were tested in 325 pools. Five positive pools identified four confirmed HCV RNA positive patients (one false positive). Estimated incidence was 12.9 per 100 person-years in injecting drug users (IDUs) (retrospective study) and 3.7 per 100 person-years among drug/alcohol services and prison attendees (prospective study). Estimated costs were pound 850 per positive sample, in areas of higher risk. The yield from a window-period strategy depends upon the population tested. Pooled HCV RNA testing of anti-HCV negative samples from the current IDUs is realistic and relatively inexpensive to identify recently infected individuals.