IMPORTANCE Short-term and long-term persistent postacute sequelae of COVID-19 (PASC) have not been systematically evaluated. The incidence and evolution of PASC are dependent on time from infection, organ systems and tissue affected, vaccination status, variant of the virus, and geographic region. OBJECTIVE To estimate organ system-specific frequency and evolution of PASC. EVIDENCE REVIEW PubMed (MEDLINE), Scopus, the World Health Organization Global Literature on Coronavirus Disease, and CoronaCentral databases were searched from December 2019 through March 2021. A total of 2100 studies were identified from databases and through cited references.Studies providing data on PASC in children and adults were included. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for abstracting data were followed and performed independently by 2 reviewers. Quality was assessed using the Newcastle-Ottawa Scale for cohort studies. The main outcome was frequency of PASC diagnosed by (1) laboratory investigation, (2) radiologic pathology, and (3) clinical signs and symptoms. PASC were classified by organ system, ie, neurologic; cardiovascular; respiratory; digestive; dermatologic; and ear, nose, and throat as well as mental health, constitutional symptoms, and functional mobility.FINDINGS From a total of 2100 studies identified, 57 studies with 250 351 survivors of COVID-19 met inclusion criteria. The mean (SD) age of survivors was 54.4 (8.9) years, 140 196 (56%) were male, and 197 777 (79%) were hospitalized during acute COVID-19. High-income countries contributed 45 studies (79%). The median (IQR) proportion of COVID-19 survivors experiencing at least 1 PASC was 54.0% (45.0%-69.0%; 13 studies) at 1 month (short-term), 55. 0% (34.8%-65.5%; 38 studies) at 2 to 5 months (intermediate-term), and 54.0% (31.0%-67.0%; 9 studies) at 6 or more months (long-term). Most prevalent pulmonary sequelae, neurologic disorders, mental health disorders, functional mobility impairments, and general and constitutional symptoms were chest imaging abnormality (median [IQR], 62.2% [45.8%-76.5%]), difficulty concentrating (median [IQR], 23.8% [20.4%-25.9%]), generalized anxiety disorder (median [IQR], 29.6% [14.0%-44.0%]), general functional impairments (median [IQR], 44.0% [23.4%-62.6%]), and fatigue or muscle weakness (median [IQR], 37.5% [25.4%-54.5%]), respectively. Other frequently reported symptoms included cardiac, dermatologic, digestive, and ear, nose, and throat disorders. CONCLUSIONS AND RELEVANCEIn this systematic review, more than half of COVID-19 survivors experienced PASC 6 months after recovery. The most common PASC involved functional mobility impairments, pulmonary abnormalities, and mental health disorders. These long-term PASC effects occur on a scale that could overwhelm existing health care capacity, particularly in low-and middleincome countries.

Previous studies have shown that human serum, guinea pig and human red cells, and human white cells contain low and high M, substances that induce gonococcal strains to become serum resistant (1-4) and change lipooligosaccharide (LOS)' pattern (5, 6) . In more recent studies, the same investigators have shown that the low Mr substance in-blood is cytidine monophospho-N-acetylneuraminic acid (CMP-NANA) or a related compound (7,8) . These studies suggest that in vivo, sufficient concentrations of CMP-NANA might induce serum resistance by sialylation of LOS. Because gonococci are not able to synthesize CMP-NANA and it is not present in the usual media, previous in vitro studies of gonococcal LOS may have dealt with different LOS structures than those that occur in vivo .Each gonococcal strain makes multiple types of LOS (9)(10)(11), and the physical (Mr) and antigenic heterogeneity of a strain's LOS reflects physicochemical differences in their glycan moieties (10, 12). mAbs 3F11 and 06B4 identify epitopes on meningococcal and gonococcal LOS that are immunochemically similar to Galo1-4G1cNAc-containing molecules present in human erythrocytes and on other human cells (13) . These epitopes are conserved on gonococcal LOS (11,14) and are variably expressed This work was supported by U. S .

A low-Mr factor which induces gonococcal resistance to complement-mediated serum killing has been partially purified from lysates of mixed red and buffy coat cells from human blood. The lysates were dialysed against Tris buffer for 24 h at 25 degrees C with the diffusate being continuously recycled through a column of QAE-Sephadex A25. After elution in an NaCl gradient, the active fractions were both desalted and further purified on Sephadex G10. A second fractionation on QAE-Sephadex A25 and desalting with Sephadex G10 preceded further purification by repeated high-pressure liquid chromatography (HPLC) using a DEAE anion exchange column and desalting with Sephadex G10. Less than 500 micrograms of material showing one peak in HPLC was obtained from 1 litre of blood. After NMR had indicated the possible presence of pyrimidine nucleotide, carbohydrate and N-acetyl groups, nanogram quantities of a commercial preparation of cytidine 5'-monophospho-N-acetylneuraminic acid (CMP-NANA) were shown to induce gonococci to serum resistance. The synthetic CMP-NANA also co-eluted with the preparation from blood cells in HPLC, and the two materials were indistinguishable in their patterns of acid and heat lability. Furthermore, the resistance-inducing activity of both materials was inhibited by cytidine monophosphate, which is known to inhibit sialylation reactions by CMP-NANA. It appears therefore that the resistance-inducing factor is CMP-NANA or a closely related compound. If the factor is CMP-NANA, biological activities indicated that the cell lysate from 1 litre of blood contained about 40 micrograms, and the most purified preparation contained only about 1%. With this minute amount in a mixture, the presence of CMP-NANA or a closely related analogue could not be established unequivocally by NMR.

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Over the past decade, studies of Neisseria gonorrhoeae have shown that in media containing glucose, lactate stimulates metabolism, and this could affect pathogenicity (7,19). Recently, the probable mechanism of this stimulation has been identified as one that could apply to other pathogens (68). Earlier studies implicated lactate metabolism in the serum resistance of Haemophilus influenzae (30), and during the past year, the use of signature-tagged mutagenesis and an infant rat model identified a putative (i.e., homologous with the gene in Escherichia coli) lactate permease-deficient mutant of Neisseria meningitidis with diminished virulence (62; C. M. Tang, personal communication). There may be a common role for lactate in the pathogenicity of these and other pathogens. Lactate and glucose are present together in most sites where infection occurs in vivo. This review summarizes the present position on gonococci and its implications regarding other pathogens. Throughout, the phrase "stimulation of metabolism by lactate" refers to this event occurring in a medium containing glucose. ENERGY SOURCES OF GONOCOCCIThe nutritional requirements for growth of gonococci include amino acids, purines, pyrimidines, vitamins, and an energy source (8). The last is restricted; only glucose, pyruvate, and lactate are used efficiently (39). The mechanism for lactate stimulation of gonococcal metabolism depends on interaction between it and glucose. The literature records information on the metabolism of one or the other alone but not in combination; it is summarized below.Glucose is metabolized at pH 7.2 and 8.0 primarily (ca. 80%) via the Entner-Doudoroff pathway, with some contribution (ca. 20%) from the pentose phosphate pathway (40). At a pH above 7, most of the pyruvate and acetyl coenzyme A (CoA) generated from glucose accumulates as acetate, with only small amounts being oxidized by the tricarboxylic acid (TCA) cycle (40). However, at pH 6, the contribution of the pentose pathway increases to about 50% and more acetyl-CoA is metabolized via the TCA cycle (40).Lactate provides energy for growth by being a substrate for electron transport when it is oxidized to pyruvate (3, 4). Gonococci contain at least three lactic dehydrogenase (LDH) enzymes. The most important are two electron transport-linked LDHs that are associated with the cytoplasmic membrane and independent of NAD ϩ (13, 67). Isoenzyme LDH-I utilizes lactate exclusively as its substrate and with a preference for the D-isomer, while isoenzyme LDH-II has broad substrate specificity (lactate, phenyl-lactate, and 4-hydroxy-phenyl-lactate), but it is steriospecific for L-isomers. The third LDH is a cytoplasmic, soluble NAD ϩ -dependent LDH (25). Pyruvate produced from lactate is catabolized by the TCA cycle (24). STIMULATION OF METABOLISM BY LACTATEEvidence for the stimulation of metabolism by lactate comes from several sources.Interaction of gonococci with neutrophils. Cohen and his colleagues showed that when gonococci were phagocytosed by neutrophils, their metabolic...

S U M M A R YGonococci (strain ss3) passaged three times and harvested directly from plastic chambers implanted subcutaneously in guinea pigs were compared with the parent strain (BS) grown in vitro. The strain grown in vivo produced smaller colonies than that grown in vitro and when examined directly in chamber fluid was sometimes not pilated. It was more resistant to the bactericidal action of human serum and more infective for guinea-pig chambers. In gel diffusion, extracts of the organisms adapted in vivo and cultured once on agar appeared to contain one or two antigens that were different from those in extracts of the in vitvo grown organisms; and on polyacrylamide gels, electrophoresis of similar extracts showed one or more protein components for strain ss3 which were not seen for strain BS. Gonococci grown in guinea-pig subcutaneous chambers appear to be suitable for studies on the determinants of gonococcal pathogenicity.