Changes in primary care visits for respiratory illness during the COVID-19 pandemic: a multinational study by the International Consortium of Primary Care Big Data Researchers (INTRePID).

Objectives: The majority of patients with respiratory illness are seen in primary care settings. Given COVID-19 is predominantly a respiratory illness, the INTernational ConsoRtium of Primary Care BIg Data Researchers (INTRePID), assessed the pandemic impact on primary care visits for respiratory illnesses. Design: Definitions for respiratory illness types were agreed on collectively. Monthly visit counts with diagnosis were shared centrally for analysis. Setting: Primary care settings in Argentina, Australia, Canada, China, Norway, Peru, Singapore, Sweden and the United States. Participants: Over 38 million patients seen in primary care settings in INTRePID countries before and during the pandemic, from January 1st, 2018, to December 31st, 2021. Main outcome measures: Relative change in the monthly mean number of visits before and after the onset of the pandemic for acute infectious respiratory disease visits including influenza, upper and lower respiratory tract infections and chronic respiratory disease visits including asthma, chronic obstructive pulmonary disease, respiratory allergies, and other respiratory diseases. Results: INTRePID countries reported a marked decrease in the average monthly visits for respiratory illness. Changes in visits varied from -10.9% [95% confidence interval (CI): -33.1 to +11.3%] in Norway to -79.9% (95% CI: -86.4% to -73.4%) in China for acute infectious respiratory disease visits and - 2.1% (95% CI: -12.1 to +7.8%) in Peru to -59.9% (95% CI: -68.6% to -51.3%) in China for chronic respiratory illness visits. While seasonal variation in allergic respiratory illness continued during the pandemic, there was essentially no spike in influenza illness during the first 2 years of the pandemic. Conclusion: The COVID-19 pandemic had a major impact on primary care visits for respiratory presentations. Primary care continued to provide services for respiratory illness, although there was a decrease in infectious illness during the COVID pandemic. Understanding the role of primary care may provide valuable information for COVID-19 recovery efforts and planning for future global emergencies.

Proteinase-activated receptor-2 (PAR2) and mouse osteoblasts: regulation of cell function and lack of specificity of PAR2-activating peptides.

1. Using synthetic proteinase-activated receptor-2 (PAR(2))-activating peptides (PAR(2)APs) corresponding to the tethered ligand domain of the extracellular N-terminus of PAR(2) to mimic the actions of activating proteinases and using primary cultures of calvarial osteoblasts derived from both wild-type (WT) and PAR(2)-null (KO) mice, we investigated the potential role of PAR(2) in regulating osteoblast function. 2. Primary calvarial osteoblasts from WT and KO mice were evaluated for their growth kinetics and mineralization in the absence of PAR(2) agonists and for their responses in a variety of functional assays to the PAR(2)APs Ser-Leu-Ile-Gly-Arg-Leu-amide (SLIGRL-NH(2)) and 2-furoyl-Leu-Ile-Gly-Arg-Leu-Orn-amide (2-fLIGRLO-NH(2)), as well as to trypsin. 3. In contrast with WT cells, PAR(2)-KO osteoblasts did not exhibit increased collagen Type I mRNA expression in response to SLIGRL-NH(2). When grown in serum-containing medium, KO cells increased in number more rapidly than WT cells, an effect that could be attributed to decreased apoptosis rather than increased proliferation. Surprisingly, in both WT and KO osteoblasts, the two PAR(2)APs induced mobilization of intracellular calcium stores. Similarly, the PAR(2)APs inhibited serum deprivation-induced apoptosis and parathyroid hormone-, 1,25-dihydroxyvitamin D(3)- or interleukin-11-induced mineralization in WT and KO cells. 4. We conclude that PAR(2) plays a role in osteoblast survival and collagen Type I mRNA induction and that osteoblasts can respond to the PAR(2)APs via both PAR(2)-dependent and -independent mechanisms.

Increased variability in Apc(Min)/+ intestinal tissue can be measured with microultrasound.

Altered tissue structure is a feature of many disease states and is usually measured by microscopic methods, limiting analysis to small areas. Means to rapidly and quantitatively measure the structure and organisation of large tissue areas would represent a major advance not just for research but also in the clinic. Here, changes in tissue organisation that result from heterozygosity in Apc, a precancerous situation, are comprehensively measured using microultrasound and three-dimensional high-resolution microscopy. Despite its normal appearance in conventionally examined cross-sections, both approaches revealed a significant increase in the variability of tissue organisation in Apc heterozygous tissue. These changes preceded the formation of aberrant crypt foci or adenoma. Measuring these premalignant changes using microultrasound provides a potential means to detect microscopically abnormal regions in large tissue samples, independent of visual examination or biopsies. Not only does this provide a powerful tool for studying tissue structure in experimental settings, the ability to detect and monitor tissue changes by microultrasound could be developed into a powerful adjunct to screening endoscopy in the clinic.

The stepwise degradation of a glycosylated aldose. A potential method for sequencing branched oligosaccharides.

2,3,6,2',3',4',6'-Hepta-O-methylmaltose diethyl dithioacetal (2), obtained under mild conditions from N-methyl-hepta-O-methyl-N-p-nitrophenyl-beta-maltosylamine (1), was converted into the disulfone 4. Storage of a solution of 4 in aqueous tetrahydrofuran gave 1,2-dideoxy-1,1-bis(ethylsulfonyl)hepta-O-methylmalt-1-en itol (5). Fragmentation of 5 with aqueous ammonia released 2,3,4,6-tetra-O-methyl-D-glucose. The degradation procedure has potential for the sequencing of branched oligosaccharides.

3-Azi-1-methoxybutyl beta-D-galactopyranoside, a photoaffinity label for monoclonal antigalactan antibodies of the VH GAL 39.1/55.1 gene-family.

3-Azi-1-methoxybutyl beta-D-galactopyranoside, prepared from 2,3,4,6-tetra-O-acetyl-alpha-D-galactopyranosyl bromide in four steps, had an affinity constant for antigalactans IgA (Fab') J539 and X24 of 1550 and 1730 M-1, respectively. 3-Azi-1-methoxybutyl beta-D-(4-3H)galactopyranoside, when photolysed in the presence of IgA X24, specifically labelled the galactan-binding area of the immunoglobulin.

The immunoglobulin-like cell adhesion molecule hepaCAM is cleaved in the human breast carcinoma MCF7 cells.

We previously reported the identification and characteristics of hepaCAM, a new immunoglobulin-like adhesion molecule. Frequently lost in diverse tumors, hepaCAM exhibits antiproliferative effects on cancer cells and promotes cell-extracellular matrix (ECM) interactions when re-expressed. Herein, we demonstrate for the first time that hepaCAM is cleaved in the human breast carcinoma MCF7 cells, generating a fragment containing mainly the cytoplasmic domain. The phorbol ester phorbol 12-myristate 13-acetate (PMA) did not affect the cleavage of hepaCAM. However, calcium-influx promoted hepaCAM cleavage independent of PKC. In addition, inhibitors of proteasome and cysteine proteases strongly suppressed the cleavage of hepaCAM, indicating the involvement of proteasome, calpain-1 and cathepsin B. Furthermore, we showed that functions of hepaCAM were impaired when the cytoplasmic domain was cleaved. The truncation mutant of hepaCAM failed to promote cell-ECM adhesion and migration, and lost the inhibitory effects on cell growth, suggesting a regulatory role of the cleavage in hepaCAM functions.

Combination chemotherapy for children with acute lymphocytic leukemia who fail to respond to standard remission-induction therapy.

Short courses of cytosine arabinoside (Ara-C), cyclophosphamide, and L-asparaginase were given to seven children with newly diagnosed acute lymphocytic leukemia, who had failed to remit on standard remission induction therapy. These 4-day courses of Ara-C and cyclophophamide followed by 4 days of L-asparaginase were repeated at 3- to 4-week intervals for two or four courses. Complete remission occurred in six patients. The median duration of remission was 94+ days, on various maintenance regimens. The most serious side effect was neutropenia. This combination of these three drugs appears to be effective remission-induction therapy for children with ALL with unfavorable prognostic features.

Congenital dyserythropoietic anaemia type I in two brothers presenting with neonatal jaundice.

Two brothers with congenital dyserythropoietic anaemia type I are described. Both presented with neonatal jaundice, required transfusion for anaemia at 8 weeks of age, and have subsequently remained well with only mild anaemia. Peripheral blood findings and bone marrow morphology on light and electron microscopy are discussed.

3-Azi-1-methoxybutyl D-maltooligosaccharides specifically bind to the maltose/maltooligosaccharide-binding protein of Escherichia coli and can be used as photoaffinity labels.

Maltooligosaccharides with two to six (alpha 1-4)-linked glucose residues, carrying at their reducing end a 3-azi-1-methoxybutyl group in either alpha or in beta glycosidic linkage, were synthesized. These maltooligosaccharide analogues inhibit maltose uptake via the maltose-binding-protein-dependent transport system in Escherichia coli. The concentration of half-maximal inhibition of maltose transport, at 15 nM concentration, decreases with increasing chain length of the analogue, levelling off at 40 microM after a chain length of four glucose residues in the alpha series and at 350 microM after a chain length of three glucose residues in the beta series. The inhibition of maltose transport occurs at the level of the periplasmic maltose-binding protein. 3-Azi-1-methoxybutyl alpha-D-[3H]maltotrioside was bound by the maltose-binding protein with a Kd of 0.18 mM. Irradiation at 350 nm of purified maltose-binding protein in the presence of 4 microM of this substrate labeled the protein covalently; labeling was prevented by 1 mM maltose. Using a crude preparation of periplasmic proteins two proteins were labeled, the maltose-binding protein and alpha-amylase. Thus, 3-azi-1-methoxybutyl alpha-D-maltooligosaccharides are potent photoaffinity labels for proteins with maltooligosaccharides-binding sites.

Tyr-503 of beta-galactosidase (Escherichia coli) plays an important role in degalactosylation.

Substitutions for Tyr-503 of beta-galactosidase caused large decreases of the activity. Both the galactosylation (k2) and degalactosylation (k3) rates were decreased. Substitutions by residues without transferable protons, caused k3 to decrease much more than k2 while substitutions with residues having transferable protons, caused approximately equal decreases of k2 and k3. Several lines of evidence showed this. The Km values of the substituted enzymes were much smaller than those for the wild type if the substituted amino acid residues did not have transferable protons; this was not the case when the substituted residues had transferable protons. Inhibition studies showed that the Km values were not small because of small Ks values but were small because of relatively small k3 values (compared with the k2 values). The conclusion that the k3 values are small relative to k2 upon substitution with residues without transferable protons is also based upon other studies: studies indicating that the reaction rates were similar with different substrates, studies in the presence of alcohol acceptors, studies showing that the rate of inactivation by 2,4-dinitrophenyl-2-deoxy-2-F-beta-D-galactopyranoside decreased much less than the rate of reactivation; studies on burst kinetics, and pH studies. The data suggest that Tyr-503 may be important for the degalactosylation reaction because of its ability to transfer protons and thereby facilitate cleavage of the transient covalent bond between galactose and Glu-537.

Intermittent chemotherapy and immunotherapy with BCG in remission maintenance of children with acute lymphocytic leukemia: effects upon immunological function.

Twelve children with acute lymphocytic leukemia who had been in complete remission on continuous chemotherapy for at least 12 months, were treated with intermittent courses of chemotherapy alternating with BCG inoculation during the drug-free intervals. Measurements were made of leukocyte populations in blood and bone marrow leukemic blastogenic responses of blood lymphoid cells to phytohemmagglutinin and soluble leukemic blast cell membrane antigen. Antibody titers to a soluble leukemic blast-cell membrane-derived antigen were determined. Comparison was made with similar measurements during a second phase of intermittent chemotherapy without BCG inoculation (phase II). Two children showed bone-marrow relapse and two developed central nervous system leukemia during the study. Rises in blood and bone-marrow lymphoid cell numbers were found during both phases of the study. Blastogenic responses to phytohemagglutinin, depressed at the start of the study following at least 12 months of continuous chemotherapy, rose during intermittent chemotherapy and BCG and remained within normal ranges during phase II. Antibody titers and blastogenic responses to leukemia blast-cell membrane antigens increased in eight of twelve and six of seven children respectively during the BCG phase and were maintained during phase II. Only one child showed further increases in phase II. The combination of BCG and intermittent chemotherapy may increase leukemia-associated immunity in some patients with acute lymphocytic leukemia in remission. The separate contributions of either BCG or intermittent chemotherapy in producing this effect cannot be determined by this study.

Evident risk factors for younger stroke patients in Taiwan.

Risk factors for stroke in the young are often different from those in older patients. Since a rather high incidence of stroke exists in Taiwan, we prospectively studied risk factors in 208 stroke patients aged between 15 and 45 years seen in four main hospitals in Taiwan from 1986 to 1993. Of the 116 patients with cerebral infarction, 48 (41.4%) had related premature atherosclerosis mainly caused by hypertension (18.1%), hyperlipidemia (4.3%), and diabetes mellitus (3.4%). Thirty-four patients (29.3%) had an identifiable predisposing factor of cardiac origin including valvular diseases. In 92 patients with cerebral hemorrhage, hypertension was present in 30 patients (32.6%) and a vascular malformation of brain in 21 patients (22.8%). For a specific district in Taiwan, the major risk factors for strokes in younger patients were hypertension, rheumatic heart disease, and vascular malformation of brain. Cardiac and neuroradiologic investigations are particularly indicative, and clinical effort in the management of these treatable causes needs emphasis.