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Proteomic Analysis of 442 Clinical Plasma Samples From Individuals With Symptom Records Revealed Subtypes of Convalescent Patients Who Had COVID-19.

After the coronavirus disease 2019 (COVID-19) pandemic, the postacute effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have gradually attracted attention. To precisely evaluate the health status of convalescent patients with COVID-19, we analyzed symptom and proteome data of 442 plasma samples from healthy controls, hospitalized patients, and convalescent patients 6 or 12 months after SARS-CoV-2 infection. Symptoms analysis revealed distinct relationships in convalescent patients. Results of plasma protein expression levels showed that C1QA, C1QB, C2, CFH, CFHR1, and F10, which regulate the complement system and coagulation, remained highly expressed even at the 12-month follow-up compared with their levels in healthy individuals. By combining symptom and proteome data, 442 plasma samples were categorized into three subtypes: S1 (metabolism-healthy), S2 (COVID-19 retention), and S3 (long COVID). We speculated that convalescent patients reporting hair loss could have a better health status than those experiencing headaches and dyspnea. Compared to other convalescent patients, those reporting sleep disorders, appetite decrease, and muscle weakness may need more attention because they were classified into the S2 subtype, which had the most samples from hospitalized patients with COVID-19. Subtyping convalescent patients with COVID-19 may enable personalized treatments tailored to individual needs. This study provides valuable plasma proteomic datasets for further studies associated with long COVID.

Humans

Doppler assessment of left ventricular diastolic filling pattern during the convalescent stage of acute myocardial infarction. Effects of infarct size and coronary thrombolysis.

Pulsed Doppler echocardiography was used to study left ventricular diastolic filling pattern (LVDFP) over the convalescent stage of acute myocardial infarction (AMI) in 25 patients. Twelve normal subjects served as a control group. The patients were divided on the basis of enzymatically estimated infarct size into 2 groups: 7 as the large AMI group, and the other 18 as the small AMI group. Peak early diastolic filling velocity (E) and the ratio of E to peak filling velocity at atrial contraction (E/A ratio) were determined from the Doppler transmitral flow velocity recordings at 1 and 4 weeks after the onset of AMI. At 1 week E and E/A ratio were significantly lower in the small AMI group compared to the control and the large AMI groups, however, there was no significant difference in E and E/A ratio between the control and the large AMI groups. E/A increased with cumulative CK release among the patients (r = 0.54, p < 0.01). In the following 3 weeks E and E/A ratio decreased only in the large AMI group, and E and E/A ratio at 4 weeks weakly correlated with pulmonary capillary wedge pressure (r = 0.63, p < 0.01 and r = 0.65, p < 0.01) and ejection fraction (r = 0.50, p < 0.05 and r = 0.62, p < 0.01) among the patients. There was no significant difference in E or E/A ratio between patients with and without coronary thrombolysis. Thus, LVDFP in the early convalescent stage of AMI was characterized by low E and E/A ratio in patients with small AMI, however, a "pseudonormalized" pattern was observed in patients with large AMI. The effect of the infarct size on LVDFP diminished in the late convalescent stage of AMI. LVDFP in patients with AMI appears to be influenced by the infarct size and by the time of study. The effect of coronary thrombolysis on LVDFP was not evident throughout the convalescent stage of AMI in this study.

Convalescence

Potential for hepatic and renal dysfunction during influenza B infection, convalescence, and after induction of secondary viremia.

Whether infection with influenza B virus alters hepatic function was examined in the ferret. Also, the possibility that viral-specific antibodies (Ab) could be produced well before their detection in serum was explored. During the febrile period of influenza, reductions in the serum potassium, anion gap, ammonia, albumin and CPK and elevations of the BUN, creatinine and the GGTP levels occurred. With convalescence, the electrolytes, BUN and creatinine normalized, FFA, SGPT and CPK levels rose and the serum GGTP rose even further. Hepatic fatty acid (FA) oxidation, ornithine transcarbamylase (OTC) and carnitine palmitoyltransferase (CPT) activities were minimally altered and liver ATP and total lipid content remained normal. Following experimental secondary viremia, serum FFA continued to rise, TG decreased and CPK remained elevated while SGPT and GGTP levels normalized. In the liver, FA oxidation and OTC rates remained unchanged but CPT activity was inhibited and the liver content of ATP was significantly reduced. Immune complex (IC) protein recovered from postmicrosomal supernatant fractions by polyethylene glycol precipitation was progressively increased in livers from convalescent and viremic animals. While the amount of IC protein recovered in the spleen also increases during convalescence, this is not the case after viremia when the IC formed seem to be processed largely by the liver. By SDS/PAGE, the major proteins identified in the IC were IgM and other viral proteins. However, the viral proteins could not be validated by immunoblot with Ab produced against purified influenza B hemagglutinin (HA) and neuraminidase (NA) most probably due to phagocytic alterations of glycoprotein immunodeterminants. These findings indicate that during influenza, convalescence and post viremia changes in the concentrations of several serum and liver components occur that reflect hepatic involvement. Also, antiviral Ab, largely IgM, appears to be produced early, complexes with Ag and can be found sequestered in both the liver and spleen at a time when Ab is not detectable in the serum.

Adenosine Triphosphate

Widespread Molecular Imprints in the Serum Proteome of COVID-19 Convalescents Uncovering Immune System Sequelae.

Post-COVID-19 sequelae have become an emerging global health issue, but the mechanisms for the sustained susceptibility of convalescents to the sequelae remain poorly understood. Here we report the use of a restricted open-search approach to explore the molecular imprints of SARS-CoV-2 infection left on the proteome of 412 COVID-19 patients and convalescences. A total of 827 non-standard amino acid variations, chemically modified residues as well as post-translational modifications, termed non-coded amino acids (ncAAs), are found spreading over 29,814 sites in patient's serum proteins. Markedly, widespread ncAAs are induced and sustainedly imprinted on the serum proteome predominately perturbing the immunoglobulin-mediated immune response, complement activation and coagulation regulation even 12 months after recovery. Sustained amino acid variations and chemical modifications are found in the complementary&#x2011;determining regions (CDRs) of the variable region of immunoglobulin contributing to the interactions between the emerging antibody and antigens; durable chemical amino acid modifications found in the hyper ncAA-modified regions of the constant region of immunoglobulin important for the interaction with the complement and regulatory receptors. In the complement system, inducible ncAAs are memorized in the components essential for the complement activation, amplification cascades and membrane attack processes. Thus, the workflow described in this study can be used to identify the molecular imprints of viral infection at the proteomic scale, particularly the specific antibodies and the immune targets left in COVID-19 patients and convalescents.

Humans

The response to an oral glucose load during convalescence from hypoxia in newborn infants.

The ability to tolerate an oral glucose load during convalescence from hypoxia was studied in four term and 11 premature appropriate-for-gestational-age infants by sequential measurements of the changes occurring in blood pH, bicarbonate, plasma lactic acid, and plasma glucose following an oral glucose load. All infants developed metabolic acidosis and lactic acidemia after the oral glucose load. The maximum fall in blood bicarbonate occurred at 30 minutes, and the maximum rise in plasma lactic acid concentration was attained at 60 minutes. The metabolic changes were found to be more severe in infants given the oral glucose load early in their convalescence and in those infants less than 10 days of age. The absorption of glucose was also decreased in these infants, as shown by a reduced rise in blood sugar. These observations indicate that newborn infants, term or premature, tolerate glucose loads poorly during convalescence from hypoxia.

Acidosis

Antigenic glycopolypeptides HA1 and HA2 of influenza virus haemagglutinin. III. Reactivity with human convalescent sera.

The immune reactivity to both haemagglutinin glycopolypeptides HA1 and HA2 [prepared from bromelain-released haemagglutinin of influenza virus A/Dunedin/4/73 (H3N2)], was demonstrated by both gel double immundiffusion and radioimmunoassay in human convalescent sera obtained after natural infection during influenza epidemics in 1974/75 and 1976/77. In gel double immunodiffusion, the precipitin line(s) corresponding to glycopolypeptide HA1 were always more distinct than precipin line(s) corresponding to glycopolypeptide HA2. In radioimmunoassay, human convalescent sera revealed higher titres for binding of 125-I-labelled HA2 than for 125-I-labelled HA1. Characterization of human convalescent sera was completed by haemagglutination-inhibition test.

Antibodies, Viral

Left ventricular hemodynamics and function in acute myocardial infarction: studies during the acute phase, convalescence and late recovery.

The left ventricular hemodynamics of 70 patients with acute myocardial infarction were determined from measurements of pulmonary arterial end-diastolic pressure, cardiac index, mean arterial pressure and heart rate during the acute phase(first study, 5 hours after admission), 4 to 6 weeks later (second study, during convalescence) and in 35 percent of all subjects 6 to 12 months after the acute infarction (third study). Serial analysis of serum creatine kinase was carried out during the acute phase. The peak CK value normalized for body surface area was used as a rough index of the extent of the acute myocardial necrosis. The condition of all survivors of the acute stage improved. Patients with only slightly reduced left ventricular performance during the acute stage recovered to nearly normal during convalescence. The condition of patients with greatly reduced left ventricular function also improved but remained impaired during convalescence. In all patients the main changes in left ventricular hemodynamics occurred within the first 4 to 6 weeks; there was almost no further alteration during the following 9 months.

Acute Disease

Developmental and convalescent changes of the anemia caused by excess methionine in the rat.

An experiment was performed to investigate the progressive changes of the anemia caused by excess methionine in rats, during the developmental and convalescent periods. Hemoglobin concentration, hematocrit value and red blood cell count were elevated in the initial stage of excess methionine feeding, they then gradually decreased. During the convalescent period, after ceasing administration of the excess methionine diet, symptoms of anemia gradually disappeared. The nitrogen efficiency ratio was markedly decreased by excess methionine feeding, however, it rapidly recovered after ceasing administration of the excess methionine diet. Iron deposited in the spleen also disappeared quickly during the convalescent period. Of the symptoms of anemia caused by excess methionine, the activity of delta-aminolevulinic acid synthetase (ALAS) in the bone marrow showed the most acute changes. As mentioned previously (1), although lowered globin biosynthesis due to amino acid imbalance could be considered as one of the important causes of the anemia and also would be one of the causes of the compensative elevation of ALAS activity, the possibility still remain that there are other unknown effects of excess methionine on ALAS activity in the bone marrow in this case.

5-Aminolevulinate Synthetase

Impact of High-Titer Convalescent Plasma on Clinical and Virologic Outcomes Among Veterans Hospitalized With SARS-CoV-2 Infection: VA CoronavirUs Research and Efficacy Studies-1 (VA CURES-1).

In the initial absence of proven therapies, empirical COVID-19 convalescent plasma (CCP) was rapidly introduced for individuals hospitalized for COVID-19. Seventy-five participants were randomized from November 2020 to June 2021 in a double-blind, multi-site, placebo-controlled, randomized trial (VA CURES-1) evaluating the impact of CCP vs. saline in Veterans hospitalized with COVID-19 with hypoxemia. The composite primary outcome was acute hypoxemic respiratory failure or all-cause death by Day 29. We analyzed clinical outcomes, nasal viral RNA, plasma cytokines and viral evolution over time. Among 40 participants receiving saline and 35 receiving CCP with high neutralizing titers (median 1:1420), the percent reaching the primary outcome was similar (10%), as were time to clinical recovery and to nasal viral clearance. By whole genome sequencing, viral molecular complexity evolved pre- to posttreatment more frequently in recipients of saline vs. CCP (4 of 7 (57.1%) vs. 1 of 4 (25%), respectively), based on numbers of mixed allele positions. Numbers of amino acid-changing, non-synonymous mutations in the spike protein were greater in saline vs. CCP recipients. Both outcomes suggested purifying selection (reduced overall viral infection complexity) following CCP. In conclusion, convalescent plasma showed no significant clinical impact but may influence SARS-CoV-2 complexity. Trial Registration: ClinicalTrials.gov Identifier: NCT04539275.

Aged

Preparing for the next round: convalescent care after acute infection.

Infections pose a nutritional stress on the growing child. No therapeutic goal is as important as the rapid recovery of preillness weight after acute infections. Successful convalescence, with supernormal growth rates, can be achieved with relatively brief periods of intensive refeeding, offsetting any tendency toward reduced immune defenses or other nutritionally determined susceptibilities to further infection. Since the mother is the only person who can effectively manage convalescent care, she must be given specific tasks with measurable targets in order to reliably oversee the child's rehabilitation. Not generally considered in the realm of preventive medicine, effective home-based convalencent care is the first crucial step in preventing the next round of illness. An approach to the widespread mobilization of mothers to monitor and sustain their children's growth is proposed in this paper. Rather than a passive recipient of health services, the mother becomes the basic health worker, providing diagnostic and therapeutic primary care for her child. Only the mother can break the malnutrition-infection cycle.

Body Weight

Postpsychotic state, convalescent environment, and therapeutic relationship in schizophrenic outcome.

The authors evaluated the following variables in the 2-3-year outcomes of 30 schizophrenic patients: the acute/chronic dichotomy, the presence of a postpsychotic regressive state, the quality of the convalescent environment, and the formation of a therapeutic relationship. They found that the presence of a postpsychotic regressive state was not associated with either good or poor short-term outcome; that the diagnosis of acute schizophrenia was almost invariably followed by good outcome, but a diagnosis of chronic schizophrenia had little predictive value; and that a favorable convalescent environment and the presence of a therapeutic relationship were signigicantly associated with good outcome.

Acute Disease

[The prevention of chickenpox in high risk children. Comparison of the effectiveness of specific immunoglobulins and of defibrinated convalescent plasma. 414 cases (author's transl)].

Comparison between 157 children treated with defibrinated convalescent plasma and 257 children treated with specific immunoglobulins revealed the improved effectiveness of the latter treatment in the prevention of chickenpox. Specific Herpes Zoster-Chickenpox immunoglobulins are prepared by caprylic acid fractionation of convalescent plasma. The prevention obtained in more than 90% of cases would appear to be clinically and biologically total as shown by serological surveillance of certain children with particularly severe immune depression.

Chickenpox

[Incidence and duration of blood HBs antigen in convalescents after type B viral hepatitis].

The presence of HBs Ag was determined by contraelectrophoresis in 500 convalescents after hepatitis B, at the moment of discharge and after 1--3 and 6 months. Antigen carriage is prolonged in hepatitis B, 51% of the convalescents being positive on discharge and 10% remaining persistent carriers. This was more frequent in males, young adults and those who had suffered from mild, prolonged forms of the disease. As only 42% of the patients became negative within the first 20 days of hospitalization it became necessary to prolong their stay in hospital and to follow up the patients subsequently in an out-patient unit.

Adolescent

Prevalence and patterns of hyperimmunoglobulinemia in acute viral hepatitis convalescents.

The 99th-percentile values of a large control group were used to determine the frequency and patterns of hyperimmunoglobulinemia (HIg) in 119 convalescents from viral hepatitis in whom Ig quantitation was performed on two occasions within 6 1/2 months after their acute episode. The mean levels of IgG, IgA and IgM, but not of IgD, were significantly higher in convalescents than in controls. There was no significant difference (p greater than 0.1) in the overall frequency of HIg (at least one Ig-class value greater than or equal to 99th percentile of controls) between the initial (30.2%; n = 119) and repeat (20.6%; n = 97) samples, though differences in the distribution of HIg patterns occurred between the two samples. At the time of repeat testing, 7 out of 77 subjects with normo-Ig, but 13 out of 20 with HIg had clinical and/or laboratory abnormalities (p less than or equal to 0.001).

Acute Disease

Suppression of spontaneous in vitro transformation of autologous leukocytes by plasma from convalescent and postconvalescent infectious mononucleosis patients.

All 14 plasma samples from 13 convalescent and postconvalescent infectious mononucleosis (IM) patients suppressed the spontaneous in vitro transformation of autologous leukocytes. In contrast, only 2 of 8 plasma samples from patients with acute IM suppressed this transformation. All 7 patients whose blood was tested both in the acute and convalescent or postconvalescent phases of IM showed either a conversion in transformation suppression status from negative to positive or an increase in the strength of transformation suppression. Thus recovery from IM appeared to be associated with the ability of plasma to suppress the in vitro spontaneous transformation of autologous leukocytes.

Antibodies, Viral

Evaluation of isoosmotic tube feeding formula in the diets of convalescent malnourished infants and children.

The quality of the protein in a complete tube feeding formula intended for use in adults was evaluated in convalescent malnourished children. The casein-soy protein isolate blend was found to be similar to casein by comparative nitrogen balance studies carried out in five children, with protein providing 6.4% of calories. Three- and four-hour postprandial plasma free amino acid determinations at the same level of protein intake did not show the drop of plasma free methionine or of the methionine/total essential amino acid molar fraction characteristically seen when this amino acid is first limiting for protein synthesis. Three additional children were fed the formula, altered only by the addition of water, for periods of up to 3.6 months to test the tolerance to and completeness of the diet. No untoward effects nor signs of specific nutrient deficiency were encountered. Linear growth was appropriate for the stage of recuperation. The failure to achieve a normal (greater than 3.8 g/dl) serum albumin concentration in two of the three children may have been due to their rapid weight gain. Although it is intended for the adult, our results indicate that the formula could meet the nutritional requirements of infants and children.

Amino Acids

Heterogeneity of linear B cell epitopes of the measles virus fusion protein reacting with late convalescent sera.

B cell epitopes of the measles virus fusion protein were mapped, by reacting sera from late convalescent donors with synthetic overlapping pentadecapeptides, segments covering the whole F protein sequence. Unselected individual sera recognized 7 to 20% of the total sequence. Cumulation of the binding patterns of 30 sera identified eight to 10 clusters of antibody-binding peptides spread over most of the sequence. The B cell epitopes included regions of transition between the more hydropathic (including the N-terminal end of the F1 and F2 protein) and hydrophilic sequences. When the regions of antibody binding were compared with the predicted secondary structure of the F protein, no detectable pattern became apparent. Exposed sequences as well as sequences hidden in the viral membrane or in the protein core of both the F1 and F2 polypeptides were recognized by the antibodies. The heterogeneity of the binding patterns was not merely dependent on the anti-measles virus titre. The importance of antibodies recognizing linear epitopes of the measles virus fusion protein for the immune protection is presently not known.

Adult

Convalescence following coronary surgery: a group experience.

The patient who has heart surgery and returns home will experience many problems in adjusting to a modified lifestyle. Successful rehabilitation depends on many factors-the knowledge the patient has about his condition, his own motivation and the support he receives from family and friends. If he has received good teaching in the hospital, his task will be much easier. But is in-hospital teaching enough? Current nursing research suggests that patients are more receptive to health teaching after they have returned home and benefit from sharing experiences with a group. The author describes the results of an investigation into the concerns of convalescent coronary patients and their wives and tells how group sessions helped ease their transition from hospital to a productive lifestyle.

Adult