Sleep must serve an essential, universal function, one that offsets the risk of being disconnected from the environment. The synaptic homeostasis hypothesis (SHY) is an attempt to identify this essential function. Its core claim is that sleep is needed to reestablish synaptic homeostasis, which is challenged by the remarkable plasticity of the brain. In other words, sleep is “the price we pay for plasticity.” In this issue, M. G. Frank reviewed several aspects of the hypothesis and raised several issues. The comments below provide a brief summary of the motivations underlying SHY and clarify that SHY is a hypothesis not about specific mechanisms, but about a universal, essential function of sleep. This function is the preservation of synaptic homeostasis in the face of a systematic bias toward a net increase in synaptic strength—a challenge that is posed by learning during adult wake, and by massive synaptogenesis during development. In “Erasing synapses in sleep: is it time to be SHY?” (this issue), Marcos Frank provides an up-to-date evaluation of several aspects of the synaptic homeostasis hypothesis (SHY) of sleep function  and usually, but not always, by immobility. Sleep is present in all species studied so far (from fruit flies to humans), occurs from early development to old age, occupies a large fraction of the day, is tightly regulated (sleep homeostasis) and irresistible (it cannot be postponed indefinitely), and its loss leads to negative consequences, especially on cognitive functions . These fBriefly, the logic behind SHY is as follows. (i) The brain is extraordinarily plastic—changes in the number and efficacy of synapses, in intrinsic excitability, and in several other neuronal and glial parameters are the rule rather than the exception. Plasticity, of course, is essential for the development of neural circuitry and the adaptation to a changing environment. These noncontroversial premises are supported by overwhelming evidence. (ii) During wake, plastic changes are biased toward potentiation—for example, a net strengthening of synaptic efficacy and/or a net increase in the number of synapses. This is a novel claim, based on the premise that neurons usually signal important inputs by spiking more, rather than less. It follows that, to ensure that such signals percolate to other neurons deep inside the brain, connections conveying the signals should be strengthened, rather than weakened. A net increase in synaptic strength after wake is a key prediction of SHY and much effort has gone into testing it in different species using various experimental paradigms. (iii) A net increase in synaptic strength cannot be sustained indefinitely. This is because stronger synapses consume more energy, occupy more space, require more cellular supplies, saturate the capacity to learn and decrease signal-to-noise ratios . (iv) Therefore, synaptic strength must be regulated and returned to a sustainable level, restoring synaptic homeostasis. In this way, the costs in terms of energy, space, supplies, signal-to-noise ratios, and learning capacity are restored to baseline. (v) Synaptic homeostasis is best achieved during sleep, a time when there is no demand for learning and neurons can sample most of their inputs in an unbiased manner through off-line spontaneous activity. By contrast, during wake neurons preferentially sample the particular subsets of inputs determined by interactions with the environment, and they are required to learn on-line. (vi) A similar need for synaptic homeostasis, hence for sleep, may exist during development. In many species, there is an initial overproduction of synapses, followed by net pruning down to adult levels . Sleep wIn addition to its core claim, SHY proposes some corollaries that are specific to animals showing slow wave activity (SWA) during sleep, such as mammals and birds. One corollary is based on the idea that synaptic number and strength influence the amplitude and slope of sleep slow waves. This is because stronger synapses increase neuronal synchrony, which in turn is reflected in larger and steeper slow waves in the EEG. Indeed, converging evidence indicates that the amplitude and slope of EEG slow waves is related to the number of neurons that enter an up state or a down state near-synchronously, and that synchrony is directly related to the number and strength of synaptic connections among them –17. To tA second corollary of SHY is that sleep slow waves may not simply reflect the number/strength of synapses, but they may be causally involved in synaptic homeostasis. Intriguingly, slow waves occur on average once a second or so, a frequency that is often associated with synaptic depression , 24–30. This brief summary of the logic, core claim, and corollaries of SHY provides some context that should help, first, to clarify some misunderstandings that run through Frank's commentary and, second, to address some of the specific issues raised.Drosophila [Drosophila neurons might achieve synaptic homeostasis is an interesting mechanistic question—as pointed out by Frank, Drosophila neurons may not undergo slow oscillations—but it has no bearing on whether the core claim of SHY is true or false. Given that Drosophila does sleep [The most important misunderstanding in Frank's commentary is the conflation between mechanisms and function. As briefly outlined above, SHY is first and foremost a hypothesis about the universal, essential function of sleep, not about which specific mechanisms mediate that function. From the start, SHY assumed that the proposed function of sleep—synaptic homeostasis—might be carried out through different mechanisms in brain structures with different sleep rhythms, such as the hippocampus, and in species with a very different brain, such as osophila , 2. How es sleep , 37, thees sleep , 10, 11.The focus on mechanisms rather than function may explain why, on several occasions, Frank is troubled by the perceived “vagueness” of SHY concerning the particular molecular pathways that may underlie synaptic homeostasis. In fact, SHY is purposely liberal about specific mechanisms not out of vagueness, ignorance , or a desire to eschew falsification, but because it is the proposed function of sleep that is universal, not the particular mechanisms, especially in view of the extraordinary variety of cellular and molecular pathways involved in plasticity. Indeed, if synaptic homeostasis turns out to be implemented differently in different species and brain structures, the hypothesis would be strengthened, not weakened: as with convergent evolution, if the same function is achieved with different means in different species, that function is probably fundamental.synaptic scaling, first observed in vitro after massive manipulations of neuronal activity [A second misunderstanding is closely related to the first: Frank often portrays SHY as if it were a hypothesis about sleep implementing a particular mechanism, activity , rather activity . In otheactivity . Synaptiactivity . Homeostactivity . SHY notactivity . Moreoveactivity . In thisactivity , therebyactivity , 2.Retrospectively, the conflation of “synaptic homeostasis” and “homeostatic plasticity” may be attributed to the confusion generated by the shared concept of “homeostasis.” SHY pointedly refers to homeostasis to emphasize that sleep serves a fundamental regulatory function—maintain an appropriate level of a key biological parameter, namely, synaptic strength—in the face of variations imposed by learning and development. Homeostatic plasticity is called so because global synaptic scaling is used to regulate another biologically relevant parameter—the level of neuronal activity . ConsideIn a similar vein, SHY does not assert that plasticity during wake should be exclusively equated with homosynaptic, associative, “Hebbian” long-term potentiation. Again, the core claim is that wake is associated with a net increase in synaptic strength, irrespective of the particular mechanisms involved, and notwithstanding the possibility that synaptic depression may also occur , 2. As bFinally, in his commentary, Frank restricts his discussion of the potential benefits of synaptic homeostasis to the increase in signal-to-noise ratios, which would help memory consolidation. SHY certainly proposes that sleep-dependent synaptic renormalization should increase signal-to-noise ratios and thereby enhance performance, as suggested both by computational and experimental work , 35, 41.Having clarified the core claim and corollaries of SHY, it is helpful to consider specific issues raised by Frank's commentary one-by-one. Some of these issues offer excellent points of discussion, highlight areas of current ignorance, and suggest relevant experiments for the future.“(SHY) argues that learning is largely mediated by LTP. …Learning is a deceptively simple term for a complex set of neural events … while some forms of learning may be associated with LTP, others are not or involve a mixture of LTP and LTD-like synaptic changes … The potentiation hypothesized to occur in wakefulness is considered Hebbian …”SHY claims that learning—an enduring modification of brain circuits as a result of perception, cognition, and action that occurs throughout wakefulness, is inherently biased towards a net increase in synaptic strength. The postulated net increase in synaptic strength after wake was termed “LTP-like” with reference to the most studied experimental paradigms for producing long increases in synaptic efficacy, to indicate that it was an increase (potentiation) and that it was enduring (long term). In reviewing the available evidence for or against SHY when the hypothesis was first proposed, it was pointed out that there were many correlative, indirect data, such as gene expression changes, which were consistent with a predominance of LTP-like changes during wake, and moreover that LTP-like changes underlie the majority of learning paradigms that have been studied from a cellular perspective. This was before direct experimental tests inspired by the hypothesis could be performed, including the demonstration of wake-associated increases in evoked responses, in miniature synaptic potentials, in AMPA receptor density at the synapse, and in the number of synapses themselves –14.As always, however, SHY did not endorse a particular mechanism of plasticity (hence LTP-like), only the end result. It never stated that wake-related potentiation is accounted for by a single mechanism such as classic “Hebbian” homosynaptic plasticity (occurring only at the stimulated synapse), and in fact terms such as “Hebbian” or “homosynaptic” were never mentioned , 2. IndeSimilarly, SHY never claimed that learning during wake only occurs via synaptic potentiation—just that the overall net result is biased towards potentiation. Indeed, there are several well-characterized forms of learning “by depression” that certainly occur during wake. These include reversal learning in the hippocampus, fear extinction in the amygdala, familiarity recognition in perirhynal cortex, and other forms of “behavioral flexibility” that involve either decreasing the response to a familiar stimulus or forgetting old strategies, objects, or spaces . FittingOf note, Frank quotes the work of Manahan-Vaughan and colleagues to make the point that learning includes both synaptic potentiation and depression. He fails to mention, however, that these authors, in discussing the overall implications of their results, noticed that exposure to a novel environment induces synaptic strengthening in all the four types of hippocampal synapses studied, while synaptic depression was not as universal. In their most recent paper, Manahan-Vaughan and colleagues concluded that synaptic potentiation “may represent a fundamental coding response to changes to the environment,” whereas synaptic depression may add “a more qualitative component”  at the end of the day, energy and information constraints on the brain—the fact that strong firing must be reserved for important signals that need to percolate among long chains of neurons—necessarily bias learning toward increasing overall synaptic strength.As anybody studying brain mechanisms of plasticity knows all too well, many forms of LTP-like paradigms have been described in different species, brain structures, and developmental times. Controversies have raged as to whether classic LTP/LTD paradigms induce changes resembling those occurring physiologically, whether changes are primarily postsynaptic, presynaptic, or both; whether changes are strictly “Hebbian” or not; whether “… surprisingly, many … findings cited in support of SHY are inconsistent with net synaptic downscaling … ”in vitro, is expressed at higher levels in the waking rather than in the sleeping brain” [Again, one needs to distinguish between the end result and the specific mechanism. As already stated, the evidence for a net decrease in synaptic strength or number after sleep is strong. If this were not the case, SHY would have to be abandoned. On the other hand, just as SHY did not commit to a specific mechanism resulting in net potentiation after wake, it also did not endorse a particular mechanism for bringing about net synaptic depression during sleep. While SHY referred to the recently discovered mechanisms of global synaptic scaling as a possible means for proportionally depressing synapses without compromising their relative strength, it did not endorse the specific mechanism. Indeed, an earlier paper already pointed out in 2001, as Frank does now in his commentary, that the available evidence was not supportive: “BDNF, which plays a critical role in synaptic scaling g brain” . Moreoveg brain” . Since tg brain” , page 87“What seems more likely is that sleep is characterized by multiple forms of synaptic plasticity, including classic Hebbian LTP and LTD, as well as downscaling and upscaling. This may explain why the evidence for “net” downscaling after sleep critically depends on what is measured   …” in vivo (AMPA receptors density in synaptoneurosomes and slope of evoked responses), then electrophysiological markers ex vivo (minis), and finally structural markers (synapse size and number).Once more, it is virtually certain that multiple forms of plasticity can occur both in wake and in sleep—what matter for SHY is only whether wake inevitably tends toward net potentiation, and sleep is needed to restore homeostasis. Before more direct tests of net synaptic strength could be performed, the overall picture provided by gene expression studies in the waking and sleeping brain –61, thouIncidentally, while as Frank suggests the results of early studies of gene expression in wake and sleep may have inspired the idea of a bias toward potentiation in wake, the central motivation for SHY was the search for a function for sleep that should be carried out off-line rather than on-line, and one that could have universal significance. Many ideas about the function of sleep start from the notion that wake may result in the accumulation of some “toxin” and that sleep may be necessary to restore the brain to a healthier state. If one adds the insight that one needs to explain the apparent need for such restoration to occur off-line, despite the considerable risk imposed by the disconnection from the environment, one could say that the “toxin” that necessarily accumulates in wake may be synaptic strength itself.“… the term “net” is somewhat nebulous …” … “This broad description of the mechanisms of downscaling has the advantage that any evidence of synaptic weakening after sleep … can be cited in support of the theory. It is disadvantageous in that no single, clear mechanism is presented for careful and in depth investigation… One important future direction is to delve more deeply into the underlying mechanisms of SHY. To date, this has received less attention than studies aimed at collecting supportive findings.”After evaluating the evidence for SHY as if the hypothesis were not about function but about the occurrence during sleep of a specific mechanism—activity-dependent scaling—and finding the evidence wanting, Frank then remarkably goes on to chastise SHY because it does not single out a single, clear mechanism. Once more, Frank seems to value whatever SHY may or may not say about mechanism much more than what it says about function. SHY aims at identifying a universal, essential function for sleep—a function that must necessarily transcend specific mechanisms if it is to apply to many species, brain circuits, and developmental periods in the face of an extraordinary biological diversity. This does not mean, however, that SHY ignores mechanisms. A case in point is the suggestion that, in mammals and birds, sleep slow waves may constitute an advantageous mechanism both for sampling in an unbiased manner the overall synaptic strength impinging on a neuron, and for renormalizing it in a controlled, self-limiting way , 2. But A priori, the results of many different experiments conducted in different species and with different approaches could easily have been negative—most of the plasticity literature implicitly assumes that a balance between potentiation and depression is a given—or it might have turned out that sleep leads to a net potentiation. Collecting evidence that turned out to be supportive (so far) is not the same as “collecting supportive evidence.”Incidentally, characterizing the experimental work conducted so far as aimed at “collecting supportive findings” is puzzling because it suggests that evidence was collected selectively. The core claim of SHY, according to which wake led to a net increase in synaptic strength and sleep to a net decrease, had never been considered or tested before. Sleep SWA features in two prominent corollaries of SHY, in the first as a possible sensor of synaptic weight, and in the second as a possible effector of sleep-dependent synaptic renormalization. Frank discusses these two corollaries at some length, and it is important to maintain a clear distinction between these two postulated roles for sleep SWA.in vivo is sufficient to induce synaptic potentiation, results in an increase in SWA only in the injected cortex [The evidence for SWA as an index of synaptic strength rests on the fact that the sleep slow waves recorded from the scalp by the EEG are a reflection of near-synchronous transitions between up and down states in large populations of cortical neurons , 63. Botd cortex . Moreoved cortex .There are also developmental studies that link SWA to synaptic strength. In both mice and cats, visual deprivation during the critical period, which is associated with synaptic depression , results“if decreases in SWA directly reflect decreases in synaptic strength … … physiological markers of synaptic weakening should be detectable when SWA first declines….The few studies….have produced very mixed results….”Frank rightly notices that more studies are needed to show that the time course of synaptic renormalization is linked to that of sleep. However, some evidence that markers of synaptic strength decline in proportion to sleep already exists. In flies, spine pruning after an enriched experience occurs only if they are allowed to sleep, but not if they remain awake . Crucial“… SHY is supported by an impressive number of findings … mostly reported by the same group …”in vivo as well as ex vivo. These include molecular studies in rats , several of the findings have already received independent support from three different laboratories [Over the past several years, the core claim of SHY has been put to direct test using several experimental approaches aimed at estimating synaptic efficacy, in different species, ceptors; ) and fliceptors; ; electro[in vivo , changes[in vivo , and chain vitro ; as wellin vitro , 8 and min vitro . None ofratories –13. Obvi“… the most dramatic evidence of SHY is found in ectothermic insects …”Frank sees the structural changes in flies as the most dramatic examples of sleep/wake effects on synaptic strength. While this may indeed be the case, trying to compare effect size across studies done in different species and using very different methods is tricky. At this point, it is not obvious that when comparing wake to sleep, the 100% increase in the frequency of miniature postsynaptic currents observed in rodent cortex , or the “It also appears that SWA cannot be a common mechanism for downscaling in mammals and insects.”Drosophila, there is a major reduction in the number of synapses and in the expression of both pre- and postsynaptic proteins after sleep. How this renormalization happens—especially if it happens using very different mechanisms from those employed in mammalian cortex—is an intriguing question for the future.It is currently unknown whether neurons in the fly brain (or in the brain of other insects) undergo slow oscillations in membrane potential or alternate between firing and silence during sleep. Do they instead stop firing altogether, as is reportedly the case in some part of the mammalian brainstem? It is also unknown whether sleep and wake are accompanied by systematic changes in the levels of neuromodulators. On the other hand, since the demonstration that fruit flies sleep more than 10 years ago , 37, it An important issue brought up by Frank concerns alternative mechanisms that could account for the observed changes in synaptic strength across sleep and wake: specifically, changes in brain temperature and changes in glucocorticoids levels. In principle, these mechanisms could complement the others discussed in SHY, such as the switch between tonic and burst firing that accompanies the transition from wake to sleep, and the changes in the levels of neuromodulators. As discussed below, however, the evidence supporting a role for temperature and glucocorticoids is far from compelling.Drosophila studies, on the other hand, flies were kept inside environmental chambers whose temperature was carefully maintained at 20°C at all times. Moreover, presynaptic structural changes occurred in flies kept in small glass tubes that allow for little movement, so it is unlikely that locomotor activity could cause major changes in core temperature—of the order of 15–30°C—that are necessary to trigger massive dendritic and spine remodeling. In relation to the results obtained in rodent cerebral cortex, Frank also refers to in vivo studies showing that locomotor activity can enhance synaptic currents in the hippocampus by increasing hippocampal temperature by 2-3°C [In relation to changes in brain temperature, Frank notices that the sleep/wake changes in dendritic branching and spine number that were observed in flies  are similar to those seen in hibernators. However, during hibernation, core temperature drops by 20–30°C, and the work quoted by Frank  shows thby 2-3°C . Howeverin vivo repeated two-photon imaging), and focusing on the same cortical area (barrel cortex) as the study of synaptogenesis and pruning as a function of sleep and wake [Glucocorticoids can both enhance and suppress synaptic plasticity. Frank quotes evidence for their role in enhancing glutamatergic transmission and AMPA receptor trafficking, but there is strong evidence also for the opposite: stress-induced glucocorticoids also reduce synaptic efficacy in cortex , affect and wake . Maret, BDNF (for which a role in synaptic potentiation is overwhelming) and the associated buildup of sleep pressure are related to the activation of the noradrenergic system [in vitro, while no such evidence is available for low levels of glucocorticoids.More generally, not unlike catecholamines, glucocorticoids are important for optimal performance and behavioral adaptation. Thus, it is reasonable to assume that mildly elevated levels of glucocorticoids and catecholamines during wake may both contribute to the net increase in synaptic strength observed in this behavioral state . Direct c system , 82, 83,c system . Moreovec system , 33, 85 “… sleep amounts are maximal during periods of heightened synaptogenesis including in utero when waking experience is negligible. It seems highly unlikely that a fundamental purpose of sleep is to principally weaken synapses during these developmental periods.”When SHY was initially proposed, it emphasized predictions that could be tested in adult mammals, where sleep would be essential in rebalancing net synaptic strength that is biased towards an increase during wake. Many of these predictions have since been corroborated. However, it was clear from the start that if sleep serves an essential function, and if that function is synaptic homeostasis, then it should apply even more to development, a time when sleep is an even more prominent part of life. Indeed, the main reason why sleep need, and thereby the need for synaptic homeostasis, would be paramount during development is fairly obvious, and it has little to do with the amount of wake: it is well known that neurodevelopment is characterized by an early phase of net synaptogenesis, followed by net pruning . The incFrank correctly points out that it is not clear why stronger synapses, if that is indeed the price we pay for plasticity, should produce sleepiness. It is worth remembering, however, why according to SHY renormalization is necessary: a net increase in synaptic strength comes at a substantial price to nerve cells, most relevantly in this context a price in terms of energy metabolism, since stronger synapses consume more energy , 43; andRecently, it was reported that, the longer a rat stays awake, the more cortical neurons show brief periods of silence in their firing that are essentially indistinguishable from the OFF periods observed during slow oscillations in a sleeping animal . These OFrank's detailed commentary provides a helpful, critical review of the evidence concerning the mechanisms that may bring about an imbalance of synaptic homeostasis during wake and its restoration by sleep. As this response hopefully shows, it is important to distinguish between the particular mechanisms of plasticity that are engaged in the waking and sleeping brain and the universal, essential function that SHY attributes to sleep—the reestablishment of synaptic homeostasis. So far, structural, molecular, and electrophysiological studies support the notion that sleep leads to the renormalization of synaptic strength in several species. Instead, the specific mechanisms involved in the constant battle between upregulation and rebalancing of synaptic strength are bound to be many, not mutually exclusive, and different in different species, brain structures, and developmental periods. While SHY offers several corollary claims, such as the significance of sleep slow waves in mammals and birds, its core claim remains that sleep is universally needed to combat, through off-line renormalization, the neural costs of increasing synaptic strength: energy, space, cellular supplies, signal-to-noise ratios, and saturation of the ability to learn.


Bacillus influenzae – was determined as playing a necessary but not sufficient role in its aetiology, transmission and pathogenesis. In defining ‘modern influenza’, bacteriological concepts and techniques were adapted to and selectively incorporated into existing clinical, pathological and epidemiological approaches. Mutual alignment thus was crucial to its construction and, more generally, to shaping developing relationships between laboratory, clinical and public health medicine in turn-of-the-century Britain. While these relationships were marked by tension and conflict, they were also characterised by important patterns of convergence, in which the problems, interests and practices of public health professionals, clinicians and laboratory pathologists were made increasingly commensurable. Rather than retrospectively judge the late nineteenth-century definition of influenza as being based on the wrong microbe, this article argues for the need to examine how it was established through a particular alignment of medical knowledge, which then underpinned medical approaches to the disease up to and beyond the devastating 1918–19 pandemic.This article reconstructs the process of defining influenza as an infectious disease in the contexts of British medicine between 1890 and 1914. It shows how professional agreement on its nature and identity involved aligning different forms of knowledge produced in the field , in the clinic  and in the laboratory (bacteriology). Two factors were crucial to this process: increasing trust in bacteriology and the organisation of large-scale collective investigations into influenza by Britain’s central public authority, the Medical Department of the Local Government Board. These investigations integrated epidemiological, clinical and bacteriological evidence into a new definition of influenza as a specific infection, in which a germ –  In this article I show how, after 1889, medical practitioners were not simply mapping new behaviours of an old disease, but those of a new influenza. This new influenza was constructed principally with the ideas and tools of bacteriology and their integration into epidemiological and clinical knowledge and practices.This article reconstructs the process of defining ‘modern’ influenza in the contexts of British medicine between 1890 and 1914. It shows how professional agreement on its nature and identity involved aligning different forms of knowledge produced in the field , in the clinic  and in the laboratory (bacteriology). While there existed different influenzas in the wake of the 1889–90 pandemic, the problems, interests and practices of public health professionals, clinicians and laboratory pathologists were made increasingly commensurable, such that by the early 1900s influenza was generally characterised as a specific infectious disease.status quo ante in studies of the relations between the laboratory, the clinic and the field, with each domain characterised as having distinctive, if not incommensurable, institutional commitments, interests, values, skills, norms of practice and evidence.Examining this process provides particular insight into the developing relationships between laboratory, clinical and public health medicine in Britain. Revisionist histories of the adoption and use of laboratory knowledge and practices have demonstrated the evolutionary rather than revolutionary nature of this process.While the conflict model has been dominant, recent historical work has pointed to an important pattern of convergence, in which clinical and epidemiological knowledge shaped and was shaped by laboratory knowledge.Bacillus influenzae – was determined as playing a necessary but not sufficient role in its aetiology, transmission and pathogenesis. In defining ‘modern influenza’, bacteriological concepts and techniques were simultaneously adapted to and incorporated into existing clinical, pathological and epidemiological frameworks. The LGB was uniquely positioned to draw together such evidence and its relative success in doing so demonstrates the importance of paying attention to mutual alignment in the construction of a disease identity and, more generally, in the shaping of relationships between laboratory, clinical and public health medicine in turn-of-the-century Britain. While these relationships were certainly marked by tension and conflict, my analysis shows that they were also characterised by an important pattern of convergence in efforts to make sense of a highly protean disease.Studying patterns of convergence and alignment between the different professions, specialisms, disciplines, institutions and practices around which modern medicine has been built can yield a more rounded and empirically rich picture of the dynamics of producing medical knowledge, striking a balance between conflict and consensus. With this aim in view, this article approaches the process of defining influenza in late nineteenth-century British medicine as an example of how aligning different forms of knowledge was integral to creating the identity of a modern infectious disease. The first sections trace the respective ways in which public health, clinical and bacteriological studies defined influenza in the wake of the 1889–90 pandemic, stressing how each provided the other with conceptual and practical resources, and with specific problems to solve. The article then examines how evidence from these different lines of investigation was drawn together, and incorporated and used in public health, clinical medicine and pathology. Increasing trust in bacteriological ideas and methods in British medicine, especially after 1900, was a crucial factor in this realignment. Another significant factor was the organisation of large-scale collective investigations by Britain’s central public authority, the Medical Department of the Local Government Board (LGB). These investigations integrated epidemiological, clinical and bacteriological evidence into a new definition of influenza as a specific infection, in which a germ – Historians of influenza know that its late nineteenth-century definition as a specific infection was based on what was later shown to be the wrong microbe.Through much of the nineteenth century the disease termed influenza played only a minor role in the affairs of government, medicine, public health and everyday experience. It existed on the fringes of Victorian life. London mortality statistics told part of this story. From when ‘influenza’ was first used as a term in English medicine in the 1740s to the 1850s, epidemics had visited London seven times.This period of decline came to an abrupt end in autumn 1889, when a massive epidemic swept across Europe and the rest of the world. Two ‘recrudescences’, one less widespread but more deadly in 1890–1 and another in 1892, followed this epidemic. Influenza killed no fewer than 57 980 in Britain in 1890 and 1891. Unlike in the past, however, it did not abate. In no year between 1890 and 1915 did fewer than 496 Londoners die from it; in ten of these years more than a thousand deaths were allotted to influenza. Major epidemics struck London in 1895, 1899–1900 and 1908–9.Raw numbers underscored influenza’s changing epidemiological presence in the social experience of health and illness.The Department’s reputation for epidemiological investigations was well established among European public health bodies.At the height of the epidemic in December 1889, the LGB’s Medical Officer, George Buchanan, asked his assistant, Henry Franklin Parsons, to organise a ‘collective’ epidemiological investigation, with the aim of determining its origins and modes of spread – issues that sharply divided medical observers Figure . Harry MIn early January 1890, Parsons issued a questionnaire to collect information on influenza on a ‘uniform plan’ Figure . Case idLancet noted: In the first place, it spreads with remarkable rapidity once it is established in a centre. Secondly, it tends more or less rapidly to become pandemic …its liability to diffusion over whole continents, and indeed from one hemisphere to the other, is one of the best-known facts concerning it. The disease therefore has no geographical limitation …and its virus travels over seas and land in manner so baffling and contradictory to the ordinary conceptions of the transmission of infection as to render any simple explanation of its nature almost impossible.The avalanche of reports revealed deep fissures on crucial questions about the influenza’s identity, the factors that caused the epidemic, how it spread and the speed it travelled. Part of the problem stemmed from the epidemiological complexity of the disease itself. Influenza’s ‘mode of diffusion stands almost alone among epidemic diseases’, the But disputes over influenza’s epidemiology, and efforts to decide its clinical characteristics, were also rooted in competing medical epistemologies.influence – occult, telluric, astral or meteorological – that conspired to excite an epidemic.A priority for public health professionals was to explain how influenza had spread so rapidly and appeared so suddenly. At first, disagreement reigned. Some observers invoked theories based on the original meaning of ‘influenza’, which presupposed an external British Medical Journal (BMJ) editorial argued that, ‘like other epidemic diseases, influenza is spread by a contagium, and must be due to a living organism, a microbe’, but there remained dispute over whether the stunning diffusion of influenza was the product of ‘microbes carried in the air’, microbes spread from one person to person or a combination of the two.Lancet, ‘was the rapidity, almost suddenness, with which large numbers of persons, or entire communities, were attacked, exceeding anything observed in the case of other infectious diseases, and not easily explicable on the ordinary theory of contagion, but apparently suggesting an aerial conveyance of some kind’.Historians have focused on rivalries in epidemiological thinking between supporters of miasmatic and contagion theories, but, as Pelling has shown, in practice the dominant view in England was that of contingent contagionism and there were different models for different diseases.Report on the Influenza Epidemic of 1889–1890, published in July 1891, reflected on the different aetiological theories aired during the epidemic and concluded that the evidence supported a new contagionist position. He wrote that influenza was ‘an eminently infectious complaint, communicable in the ordinary personal relations of individuals, one with another’, in cities, institutions and homes.Report defined influenza as a disease that spread on the ‘lines of human intercourse’. It posited a ‘germ’ as the contagion, which was communicated directly from person to person, and it inferred that, because its incubation period was short it spread more rapidly and extensively than any epidemic disease.Henry Parsons’ BMJ noted that although ‘the theory that influenza is mainly if not entirely spread by contagion is no new one …[it] had needed to be born again.’Lancet endorsed the new concept: ‘there does appear to be an abundance of evidence to show that [the epidemic] travelled mainly along the lines of human intercourse, attacking large towns and population centres first …and that the disease travelled only just as fast as any humanly conveyed infection …might have expected to travel’.The Report was much anticipated and well received. The Lancet described as the ‘exceptional risk of contracting the disease, the risk depending in part on the closeness of aggregation’.Influenza was drawn into a new discourse that associated risk of infection with specific conditions of the modern city. Catching and spreading influenza was attributed to increasing urban interconnection and propinquity. ‘The assembly of people in churches, chapels, the Houses of Parliament, places of business, or other institutions’ involved what the Times, an ‘essentially democratic’ disease that embraced ‘all the people, not just the lower section of them’.Hygiene and Public Health, ‘notification of cases, isolation of the sick, and disinfection of premises, should be, as for other infectious diseases, the proper means of checking or stamping out an epidemic’.BMJ, ‘is isolation of the sick anything more than a dream?’In this framework, the ecological conditions of the modern city and communications fostered influenza and its dangers. Yet unlike with cholera or tuberculosis, which sharply revealed class divisions, this risk was presented as being shared by all. Influenza was, in the words of the Public health authorities needed answers to two crucial questions: What constituted a case of influenza and what was its disease agent?Parsons’ first report relied on descriptions of influenza supplied by GPs and medical officers, but it revealed significant gaps in existing clinical knowledge. Few practitioners had experience identifying or managing influenza. It did not fall under the 1889 Infectious Diseases Notification Act, so doctors were not obligated to report it.status quo of an earlier generation. One striking discrepancy was the relative absence of ‘catarrh’ in 1890.catarrhus a contagio’ in the 1780s, clinical accounts of the 1830s and 1840s made catarrh – general inflammation of the respiratory tract – a defining symptom, and textbooks categorised influenza as an epidemic ‘catarrhal fever.’Without first-hand experience of influenza, practitioners were forced to turn to existing textbooks for guidance. Yet the descriptions they found had not been revised since the 1850s. Significant gaps emerged between physicians’ own observations and the Physicians attributed the change in influenza’s predominant symptoms to its clinical variations, a fact demonstrated in historical records and medical observations. But gaps in clinical knowledge also stemmed from significant changes in the social organisation and epistemology of medicine since ‘epidemic influenza’ last appeared in 1848. To learn how to identify influenza, the profession had to re-shape its clinical identity to fit contemporary medical knowledge and practice. The most significant change was from defining influenza as a species of ‘catarrh’ to its identification as an acute disease in which catarrh and fever were symptoms of a respiratory infection.The practical transformation of influenza’s clinical identity was rooted in London’s voluntary and teaching hospitals, where elite clinicians codified clinical knowledge and practice.Lancet led the push: ‘[W]e…suggest, in the interest of scientific medicine, that, as nearly half a century has elapsed since the last outbreak of the disease in England, no means should be left untried to ensure full records of the occurrences of cases $\ldots $’.At the outset of the 1889–90 epidemic, London’s leading medical bodies called upon physicians to put the production of ‘exact clinical records’ at the forefront of the medical agenda. The But rather than clarify influenza’s clinical picture, the call to collect new information initially complicated it. As the first epidemic reached its apex in early January 1890, clinical descriptions filled the pages of the medical and general press.The lack of an agreed diagnosis worried the medical establishment. Elite physicians blamed GPs’ lack of training and discipline for these difficulties. At the height of the 1889–90 epidemic it was not unusual for a GP to see two or three hundred patients a day. The majority had only brief encounters; their aim was to provide rapid diagnoses and treatment. Critics claimed that in their haste GPs pandered to diagnostic ‘fashions’ and used ‘popular symptoms’ derived from the general press or patients. This proliferated clinical definitions, added confusion to a complex problem and threatened professional authority.The elaboration of influenza’s clinical identity at St Bartholomew’s Hospital in the early 1890s exemplifies how a general diagnostic framework was built.In the first stages of the epidemic, early symptoms were so indistinct that house physicians failed to identify them. John Ogle, a junior houseman, confessed that he was initially unable to ‘recognise the nature of the disease’; he and his colleagues thought it was ‘pneumonia, scarlet fever, or rheumatic fever’. Early attacks ‘remained an enigma until the epidemic arrived in full force’.Annals of Influenza, the first historical chronicle of the disease.Thermometry yielded new physical signs that became crucial to the prognosis of influenza. But clinical tools could not identify a single pathognomonic marker on which to anchor diagnosis. Clinicians resorted to grouping symptoms into patho-physiological forms. This practice had started in the early nineteenth century. During the 1848 epidemic, for instance, the London physician, Thomas Peacock, divided influenza into ‘simple catarrhal fever’, ‘catarrhal fever with pulmonary complications’ and ‘catarrhal fever with abdominal complications’.simple uncomplicated febrile’ form, characterised by mild respiratory symptoms and influenzal fever, which rose quickly in the first forty-eight hours and subsided after three or four days; a ‘gastro-intestinal form’, marked by mild gastric symptoms in addition to fever and prostration; a ‘catarrhal form’, which was ‘singularly infrequent’; and a ‘nervous’ form, which involved excruciating neuralgic pains that produced debilitating paroxysms.Influenza was typically distinguished into ‘simple’ or uncomplicated and complicated cases. West characterised simple influenza as an acute disease, with an abrupt onset, in which ‘the temperature …rose at once’ and the patient was suddenly crippled by severe prostration, involving a range of constitutional symptoms, the most prominent of which were intolerable pain in the limbs, loins, eyes, back, spine and forehead. As the fever increased, ‘patients lay in a dull, heavy, drowsy state, though sleep was unrefreshing and disturbed by dreams, or even slight delirium’.Medical Annual, an indispensable tool for general practitioners that synthesised current medical knowledge into a standard reference, recommended that influenza be grouped into four clinically distinct forms: ‘simple catarrhal fever’, pulmonary, gastro-intestinal and nervous.As clinicians around London produced similar classificatory schemes, there was a recognised need to make them commensurable. In 1890, the Hygeia, or City of Health, described influenza as an ‘epidemic neuroparesis’ that directly affected ‘organic nervous function’ and produced ‘intense depression’ in patients.Prevailing medical and social concerns shaped the taxonomy and meanings ascribed to key symptoms.fin de siècle obsessions with moral and physical weakness, uncertainty, vulnerability, irrationality and sudden death.Althaus, Richardson and others linked nervous influenza to the demands of modern life. People exhausted ‘by age, by work, by nervous excitability, by late hours, by anxiety, by strain mental or physical, by confinement in close rooms, by broken rest’ were the most susceptible, while the ‘nervously exhausted’ were the most stricken. Influenza worsened existing neuroses and produced a raft of ‘nerve invalids’.But nervous diseases were more a symbolic than an epidemiologically significant danger. Chronic and acute respiratory diseases such as tuberculosis, bronchitis and pneumonia were far more formidable.Clinicians most feared the signs of influenza moving into the lungs, as this signalled the beginnings of pneumonia. Among the deadliest of nineteenth-century respiratory diseases, pneumonia was influenza’s gravest complication. Different kinds of pneumonia were evident in influenza. Bronchopneumonia was the most prevalent. Clinicians also identified a specific ‘influenzal pneumonia’. West led the way in characterising this complication. Studying hundreds of patients at Barts between 1890 and 1894, he noted that although pneumonic complications could appear at the onset, influenzal pneumonia often followed convalescence. It could proceed from bronchitis or attack the lungs directly. Men were more susceptible than women, in part because they often returned to work after the initial fever had fallen and, without having fully recovered, made themselves vulnerable. While it presented typical pneumonic signs – raking cough, crackling rales, chest pain and asthenia – in other respects it was ‘atypical and eccentric’.Principles and Practice of Medicine, the great Canadian clinician William Osler noted that, ‘when [influenza] occurs in epidemic form’ it could be easily identified by its ‘sudden onset, short duration, acute fever, great prostration, more or less severe catarrh, neuralgic pains, or gastrointestinal disturbance and the disease’s tendency towards severe respiratory complications’.For all their work, physicians still had trouble determining a case of influenza on symptoms alone. Although new classifications ensured continuity in clinical descriptions and became part of textbook medicine, they did little to relieve practical difficulties. By illuminating influenza’s protean identity, they also multiplied the number of possible symptoms and complications that could fall under the name. With no specific sign, physicians relied on influenza’s epidemiological characteristics to direct their clinical observations. In the second edition of his BMJ summed up the practical constraints: ‘A rational systematic mode of treatment is of course impossible, so long as the aetiology remains obscure, and hence we have at present to rely upon the main symptoms for indications’.Part of the diagnostic challenge related to practitioners’ inability to identify influenza’s cause. The Bacillus influenzae’.Historians treat Pfeiffer’s bacillus as the wrong aetiological agent around which an entire generation organised its knowledge. Retrospective assessments of Pfeiffer’s research point to flaws in his methods and interpretations, and the failure of the bacillus to meet Koch’s postulates. ‘No organism’, wrote the London pathologist, Robert Donaldson, in an authoritative review of the bacteriology of influenza in 1922, ‘has had such wide acceptance on grounds so insufficient as Pfeiffer’s so-called It is worth remembering, however, that the bacillus was represented, investigated, mobilised and disputed as the primary cause of influenza for nearly forty years, from the mid-1890s to the early 1930s. In medical, hygiene and bacteriology textbooks it was viewed as central to influenza’s definition as a specific infectious disease.BMJ and the Lancet. Edward Klein, the Vienna-trained histologist and reputed ‘father’ of British bacteriology, headed the Department’s investigations. Between 1892 and 1893 he confirmed Pfeiffer’s aetiological claims. Legitimising Pfeiffer’s bacillus, the Department also legitimised the role of the laboratory in defining influenza  and diphtheria patients, the spread of Influenza from person to person may be to a corresponding extent controlled.The bacillus did, however, produce noticeable changes in the professional perceptions Influenza prevention became modelled on frameworks established for tuberculosis, diphtheria and other infectious diseases. Contagion-minded epidemiologists outlined ‘human intercourse’ and the ‘assemblage of large numbers of people’ as the main pathways for spreading influenza. Bacteriologists identified the spreading agent and used laboratory knowledge of its properties to identify sneezing, coughing, spitting and talking as the principal vehicles of infection. Focus on the bacillus made it possible to monitor influenza through the minute corporeal exchanges of urban life. Public health authorities and medical officers acquired a rationale for intervening in everyday behaviours and social interactions.Official prevention approaches targeted the routes and places through which influenza bacillus spread.Little laboratory work was actually done on Pfeiffer’s bacillus before 1900. But by the turn of the century, as bacteriology became increasingly institutionalised in medicine and public health, and bacteriological education created professionals trained in bacteriological methods, laboratory work on the bacillus multiplied.Questions about its role first surfaced in 1899, when, during the largest epidemic since 1890, workers in Germany, France and the US, including Pfeiffer himself, failed to identify it in most clinical cases. The epidemic raised two issues that would loom large in the new century. The first concerned the identity of the bacillus itself. A number of researchers had identified haemophilic bacilli that were indistinguishable from Pfeiffer’s bacillus, but did not cause influenza. Found in other diseases these ‘influenza-like’ bacilli complicated bacteriological diagnosis. The second problem involved the specificity of Pfeiffer’s bacillus. While failing to find it in influenza, researchers found it in other diseases, including scarlet fever, measles and pneumonia, as well as in healthy people. Moreover, other pathogens appeared to play a role in influenza. The Cambridge University pathologist P.N. Panton summed up the difficulties: ‘While there is no doubt that this bacillus …is the causative agent of some influenzal epidemics, it must not be expected to recognise it in all cases of so-called influenza’.Micrococcus catarrhalis, captured much attention.Bacteriologists developed two contending approaches to this problem. The first, proposed by Pfeiffer, insisted that influenza be regarded as a specific disease, solely caused by his bacillus, and that clinically identical diseases caused by other organisms be called ‘pseudo-influenza’.The only possible solution that is entirely satisfactory is absolutely hypothetical and unsupported by any evidence. It is that influenza is a specific disease, due to a definite single cause, but that this cause is undiscovered, and perhaps unsuspected; it may be an ‘invisible’ microbe, a protozoan, or some depressing ‘influence’ acting directly on the human constitution, and of a nature as little known as were bacteria when influenza received its name.The combination of mounting laboratory evidence against Pfeiffer’s bacillus, and concerns over the implications of a shift in influenza’s bacteriology for medical and public health understandings, prompted moves to reframe its aetiology. Clifford Albutt, Regius Professor of Physic at Cambridge, described ‘the bacteriological position’ as ‘rather exasperating’, but concluded that, ‘the responsible microbes seem to be several’.While ‘invisible’ microbes had yet to fully emerge as laboratory objects, the idea that influenza might be caused by such agents reflected the difficulty of using Pfeiffer’s bacillus to establish consensus on influenza’s identity. Nevertheless, we should not overlook its importance in establishing new ways of understanding influenza. Work on the bacillus drove the development of the bacteriology of influenza. The spread of Pfeiffer’s investigations shaped and was shaped by clinical and epidemiological knowledge, and provided the medical profession with a cause-based definition, which supplemented and, some hoped, would supplant symptom-based definitions. In clinical medicine, the microbe was a resource for explaining the pathogenesis of the disease; in public health, it was used to make visible and to target the routes of influenza transmission. Pfeiffer’s bacillus thus played an important role in aligning epidemiological, clinical and bacteriological knowledge around a new definition of influenza.Between 1890 and 1910 influenza’s medical identity had been transformed. The disease was incorporated into the disciplinary contexts of modern public health, clinical medicine and bacteriology, where new understandings were constructed of its epidemiology, symptomatology, aetiology and pathogenesis. Together, these understandings established influenza as an important modern disease. Yet, as the challenges encountered in each of these contexts demonstrate, influenza resisted classification or control by any one approach. As Clifford Albutt put it in 1907, the outpouring of epidemiological, clinical and laboratory work from 1890 underscored an essential fact: influenza was ‘of protean diseases the most protean’.


Recent pandemic planning has highlighted the importance of understanding the effect that widespread antiviral use will have on the emergence and spread of resistance. A number of recent studies have determined that if resistance to antiviral medication can evolve, then deploying treatment at a less than maximum rate often minimizes the outbreak size. This finding, however, involves the assumption that treatment levels remain constant during the entire outbreak. Using optimal control theory, we address the question of optimal antiviral use by considering a large class of time-varying treatment strategies. We prove that, contrary to previous results, it is always optimal to treat at the maximum rate provided that this treatment occurs at the right time. In general the optimal strategy is to wait some fixed amount of time and then to deploy treatment at the maximum rate for the remainder of the outbreak. We derive analytical conditions that characterize this optimal amount of delay. Our results show that it is optimal to start treatment immediately when one of the following conditions holds: (i) immediate treatment can prevent an outbreak, (ii) the initial pool of susceptibles is small, or (iii) when the maximum possible rate of treatment is low, such that there is little de novo emergence of resistant strains. Finally, we use numerical simulations to verify that the results also hold under more general conditions. Recent studies have considered the consequences of drug resistance on the effectiveness of several intervention strategies, including drug prophylaxis and treatment, vaccination, non-drug interventions, as well as combinations of interventions and multi-drug therapy –17. ManyThis result is somewhat counterintuitive, and arises from a trade-off between the costs and benefits of treating infected individuals. In fact, treatment has three effects on the total outbreak size: (i) treatment is beneficial because it suppresses the spread of the sensitive strain, (ii) treatment is costly because it leads to the de novo appearance of resistant infections, and (iii) treatment is costly because suppression of the sensitive strain frees up susceptible hosts that can then be infected by the resistant strain . The treet al.  > 0.When the maximum treatment level is very large (i.e. situation 1), the marginal change in the attack ratio that comes from increasing the amount of delay before treatment is :τ, and the resistant attack ratio includes all new infections that occur after the treatment start time τ (see equation (S(τ) = SR, at which point there are no longer enough susceptible individuals to sustain a resistant outbreak. The second term represents the cost of delay that comes from an increase in the number of de novo resistant infections once treatment begins. From the perspective of this cost term only, it is best to treat immediately because waiting longer results in a larger pool of infected individuals, which then have the potential to develop de novo resistance once treatment begins. The optimal amount of delay precisely balances these two effects, and this can be readily interpreted graphically. Figure 2a shows the final number of susceptibles as a function of treatment start time for different values of κ. As κ increases, the importance of the second term in equation (b), while the number of susceptibles at the optimal treatment start time increases (c).Equation  emphasizequation ). The twequation  represenequation  increaseequation b, while ncreases c.(d)et al. [Figure 1b depicts the treatment model used in Lipsitch et al. [Although the analytic expressions presented above are derived using a simple model, numerical simulations suggest that these results hold more generally. To illustrate this, we use numerical simulations to compare the relationship between treatment start time and attack ratio for our simple model and for the more detailed model in Lipsitch et al. . Figure h et al.  and the et al. [et al. [et al. [To begin, numerical results show that both models exhibit two key features: (i) if the treatment level is constrained to be constant throughout the entire epidemic , then there is an intermediate optimal level of treatment, and (ii) if treatment is delayed by the appropriate amount, then maximum treatment is always optimal . The fact that delaying treatment can be better than constant treatment in both models explains why Lipsitch et al. , Moghada [et al. , Handel  [et al.  and Qiu  [et al.  observeda shows that for the simple model, if an outbreak occurs, then S(τ*) approaches Smin as the treatment level increases . In other words, the optimal solution for the case when umax is very large provides a bound for the case when umax is finite. A similar statement is true for the more detailed model. In the more detailed model, fT denotes the fraction of infections that are treated, and so fT = 1 is the analogous case to umax being unbounded . Using Smin,c to denote the number of susceptibles at the optimal treatment start time when fT = 1, figure 3c shows that, for the detailed model, S(τ*) decreases as the treatment level increases, with Smin,c providing a bound for all other values of fT.A comparison of the panels of figure 3umax is unbounded. Namely, if S(t0) < Smin, then τ* = t0. Similarly, for the more detailed model, electronic supplementary material, figure 4b, suggests that if S(t0) < Smin,c then again it is optimal to start treatment immediately.Both models also demonstrate that it is possible to avoid an outbreak by starting treatment immediately at sufficiently high treatment levels . Furthermore, if the initial pool of susceptibles is small enough, then it is always best to start treatment immediately . For the simple model, ‘small enough’ is measured relative to the number of susceptibles at the optimal treatment start time when RIR > RR, then it is optimal to start treatment immediately. Using the biological interpretation of RIR, namely that RIR is the expected total number of infections caused by an individual initially infected with the treatment-sensitive strain, we can define an analogous quantity for the detailed model . Electronic supplementary material, figures 5 and 6 show that the relationship between RR, RIR and the optimal treatment start time is similar for both the simple and detailed models. This result is particularly interesting because it emphasizes that (i) using a simple model can highlight relationships in more detailed models that may otherwise be undetected, and (ii) the quantity RIR is of general importance and not just an artefact of our simple model.Finally, recall that for the simple model if 4.et al. [et al. [Smin.Perhaps the most salient feature of previous analyses is that the best treatment somehow balances the effects of the sensitive and resistant epidemics. This trade-off, which is very clearly explained in the discussion found in Lipsitch et al. , is also [et al. , this trWe have examined two types of model, a simple model that does not explicitly include the dynamics of the treatment class and a more detailed model that does include treatment dynamics. For the simple model, we showed, using analytic calculations, that the optimal treatment strategy is ‘off–on’ . It is important to emphasize that for model (2.1) this off–on strategy is indeed optimal in the sense that any other, more complicated, strategy that involves intermediate levels of treatment will not result in a lower attack ratio. Conversely, for the more detailed model, we have only shown  that an off–on strategy can outperform a ‘constant’ strategy. Thus, although it seems likely that the off–on strategy is optimal for the more detailed model as well it remains an open problem to explicitly prove that this is indeed the case. Furthermore, although an off–on strategy can be better than a constant strategy, policy makers still face the ethical dilemma of choosing between the rights of individuals to receive treatment and the benefit to the population of delaying treatment.S(t0) < Smin for the simple model and S(t0) < Smin,c for the detailed model), or (iii) the rate of de novo resistance is small (i.e. RIR > RR). Each of these three situations have relevance to public health policy.Given the ethical problems associated with implementing the optimal treatment strategy when it involves a delay, it is useful to clearly delineate the conditions under which implementing treatment immediately is actually optimal. It is always optimal to start treatment immediately if one of three conditions holds: (i) immediate treatment can prevent an outbreak, (ii) the initial pool of susceptibles is small (i.e. S(tf) > SR > SI. As a result, the population will be susceptible to future sensitive and resistant outbreaks. Alternatively, if a treatment strategy is chosen to ensure that a resistant epidemic occurs, then the final number of susceptibles will be small enough to prevent future resistant outbreaks (and the severity of a possible future sensitive outbreak will be significantly decreased). Antia et al. [umax will increase the optimal amount of delay. However, if umax can be increased sufficiently, then treating immediately will effectively prevent the outbreak, and this then becomes the optimal strategy. If this can occur, then policy makers will have to balance the benefits of treating immediately (and therefore preventing the current outbreak) with the benefits of delaying treatment (and perhaps minimizing the effects of a second outbreak).Condition (i) underscores that our focus has been to minimize the total outbreak size, and so in this context preventing an outbreak is the best possible outcome. This outcome, however, may not be desirable if there is a high probability of a second epidemic occurring at a later time. For example, although treating immediately at a very high level may minimize the total attack ratio, this will result in a et al.  discusseCondition (ii) highlights that the optimal treatment strategy depends on the size of the target community. Essentially, if a community is small enough, then treatment should start immediately. This observation leads to an interesting hypothesis for combined vaccination–treatment policies. Namely, since vaccination decreases the susceptible population, low vaccination levels make it more likely that treatment should be delayed. This proposed relationship is surprising since, naively, it seems reasonable to expect that if fewer individuals are vaccinated, then it would be better to start treatment early in order to reduce spread. Nevertheless, our results suggest that this intuition is, in fact, incorrect.RIR as a linear combination of the two reproduction numbers RI and RR, we can rewrite RIR > RR asRI/RR > (1 − κχ)/(1 − χ), it is optimal to start treatment immediately and if RI/RR ≤ (1 − κχ)/(1 − χ), then it may be best to delay treatment. For any specific values of RI, RR and κ, we see that as the probability of treating an infected individual, χ, decreases, it becomes more likely that starting treatment immediately is best. Intuitively, this guideline makes sense since if treatment is unlikely to reach many infected individuals, then it makes sense to start administering treatment as soon as possible in order to reach more individuals.Condition (iii) emphasizes that if the probability of receiving treatment is low, then it is more likely that treatment should start immediately. More concretely, by expressing et al. [et al. [Since multiple intervention measures are often used to control a disease, an important next step is to consider a model that includes other intervention measures, in addition to treatment ,5,7,10. et al.  and Qiu et al. , and the [et al. . Interes


Something doesn’t come out of nothing,” Edward Hopper once said. This private and introspective man, known for his dry wit and “monumental silences” and for expressing himself “tersely but with weighted exactness in a slow reluctant monotone,” was offering a glimpse into the creative process as it applied to him. Much was made of the sense of isolation and despair in his work and their connection with modern life. But “The loneliness thing is overdone,” he noted. “My aim in painting is always, using nature as the medium, to try to project upon canvas my most intimate reaction to the subject as it appears when I like it most; when the facts are given unity by my interest and prejudices.”“Hudson River Dutch” is how Hopper described his ancestry in Nyack, New York. The son of a dry goods merchant, he was not discouraged in his artistic ambitions, though his family did steer him toward commercial illustration for its earning potential. The skill stood him in good stead during the lean years. He attended the New York School of Art and studied under Robert Henri, one of the fathers of American Realism, “the most influential teacher I had.” He visited Europe several times. “Paris had no great or immediate impact on me.” But when he returned to the United States, his work reflected what he had seen abroad. “It took me ten years to get over Europe.”Hopper settled in New York, where he would make his primary residence. He moved into a 74-step, cold-water walk-up with a sky-lit studio in Greenwich Village. He had to haul coal for the furnace up four flights of stairs, but the space suited his self-sufficient and frugal nature. He painted many major works there and, despite a reasonable measure of success during his lifetime, never pursued more plush quarters.During a career that spanned 60 years and saw the heyday of abstract expressionism, as well as a resurgence of realism in the United States, he made a unique contribution. In a 1932 exhibition at the Museum of Modern Art, his work was described as “part of a new international progressive trend emerging within modernism, represented by a balance between ‘form’ and ‘content’ in its work.” Hopper’s approach, which appealed to his colleagues from all factions, explored natural and artificial light on surfaces, particularly on the vernacular architecture of American cities: motels, gas stations, storefronts, diners, apartments. “What I wanted to do was to paint sunlight on the side of a house.” His work employed classical elements and formal discipline in the dispassionate presentation of everyday scenes..Hopper captured what he called “our native architecture with its hideous beauty, its fantastic rooms, pseudo-gothic, French Mansard, Colonial, mongrel or what not, with eye searing color or delicate harmonies of faded paint, shouldering one another along interminable streets that taper off into swamps or dump heaps,” and by capturing it, he defined it. His images, often described as theatrical or cinematic, went on to inspire the cinema and its greats, among them John Huston, Elia Kazan, John Cassavetes. Alfred Hitchcock credited Hopper for influencing his films Rear Window and Psycho“The whole answer is there on the canvas,” Hopper said in lieu of explaining his paintings. “I hope it will not tell any obvious anecdotes since none are intended.” Just like the content of his paintings, the form was stripped of extraneous details. He sought perfection in perspective, geometric structures, and two-dimensional space, as well as in the use of color and light. “As a child I felt that the light on the upper part of a home was different from that on the lower part. There is a sort of elation about sunlight on the upper part of a house.” He described his style as “an amalgam of many races” and refused to belong to any school.“Hopper is always on the verge of telling a story,” observed novelist and art critic John Updike, referring to scenes whose very stillness suggests that something is about to happen. A room seems either recently vacated or soon to be occupied. If inhabited, it is always sparsely, and that also goes for public places―theaters, restaurants, offices. Any occupant has either just arrived or is ready to leave, psychologically absent, or lost in thought. Human presence is not required, although the viewer is always allowed in, either through an open window or some other vista. And the night is just as paintable as the day, or even more so because of its mysterious, even ominous, contrasts and shadows.Drug Store, on this month’s cover, is one of Hopper’s nocturnal works. During one of his visits to Europe, he saw Rembrandt’s Night Watch, “The most wonderful thing…. It almost amounts to deception.” In his own work, he came to view the night as an opportunity to scrub a scene from the hustle and bustle. In the darkness, it seems, he could focus on the unexceptional and familiar elements of the uninhabited streets and capture the essence of places.In Drug Store, drama resides strictly on the weight of darkness in back of the setting against the brightly lit establishment forward. The lamp above the entrance lights the window, which with the awning pulled up all the way, is unabashedly exposed. Emotion is rendered in place and time, not human terms. In painting this street icon, Hopper as always, sought the “most exact transcription possible.” But what might have been a most sterile, even disturbing, presentation is rendered here with softness and calm. The storefront glows against the surroundings, its curtains and colorful vessels inviting and homelike but for the commercial signage. The wedgelike positioning foreshadows another one of Hopper’s famous corner establishments, Nighthawks.Silbers Pharmacy was typical of the profession in the early part of the 20th century. The move away from artisan plasters, powders, and carbonated waters saw increasingly flamboyant advertising of medications based on better understanding of disease etiology and the mechanisms of drug action.Clostridium difficile. In addition to increased C. difficile–associated disease, severity is also increasing from a new strain. And while clinical illness used to occur almost exclusively among the elderly in healthcare facilities, it is now seen in the community, among the young, and apart from antimicrobial drug treatment. Some retail meats contain the pathogen, though its role there is unknown. Changes in disease setting alter who is at risk and what the risk factors are. The clean, well-lighted healthcare setting where antimicrobial drug use leads to pseudomembranous colitis does not describe the risk for or characteristics of community-acquired infections with C. difficile.These new drugs were a mixed bag of cure and trouble, just like today’s offerings. In this journal issue alone, countless examples underline unintended consequences in the use of otherwise effective medications, among them antimicrobial drugs. Commonly used to treat infections, these drugs also may change intestinal microflora and make patients vulnerable to other infections, as with “I was never able to paint what I set out to paint,” Hopper said. During the unpredictable course of the creative process, inspiration injects itself unawares, the miscellaneous and extraneous intercede, color dictates, or thought transforms the initial intention to an unrecognizable final result. The artist’s discerning eye must complete the process by honing in on the essential. Public health scientists at work to stay ahead of pathogens also come up against unpredictability in the creative process. Much like Hopper, they must have an eye for the setting. One is not like another, and light makes all the difference. And while the whole answer may indeed be there on the canvas, for Hopper the essence was found in the light, whereas for the scientist trying to capture and define risk factors for infection, the essence may still be lurking in the shadows.


Spillover is a single event during which a pathogen from 1 species moves into another species; such movement can result in an outbreak. In 9 chapters, David Quammen chronicles various spillover events by using personal anecdotes and multiple stories to recount these events for the expert and novice alike. He frames the events within an ecologic sense of the pathogen, the host, and the increasing human population. He focuses recurrently on the NBO (next big one) and how, if HIV or Ebola virus were more easily transmissible, no one would remain to read his book.Quammen’s analogies are superb. Instead of trying to turn the reader into a scientist with dry explanations, he uses analogies that have universal relevance. For viral morphology, Ebola and Hendra virions together would resemble a “capellini in a light sauce of capers.” Mathematical modeling can be appreciated in translation, just as Dostoevsky can be appreciated in translation instead of in the original Russian. Quammen compares combining specific antibodies with their virus to splashing holy water on a witch. Regarding airborne transmission, he says that pathogens can “waft into a nearby village as easily as the pleasant, autumnal smell of smoke from a pile of leaves.” Throughout the book, the subjects of human and animal diseases are “. . . strands of one braided cord.”The last chapter, “It Depends,” is particularly sobering. If, in an ecologic sense, an outbreak is a rapid and explosive increase in the abundance of a particular species, then maybe humans are the current outbreak in the world. We have become a dense forest; tinder is dry; and the NBO is around the corner.Who should read this book? Anyone interested in science can enjoy it—those who make their living at the bench, teach, or study—and anyone just looking for a good read.


Health professionals are required to collect data from standardized tests when assessing older patients’ functional ability. Such data provide quantifiable documentation on health outcomes. Little is known, however, about how physiotherapists and occupational therapists who administer standardized tests use test information in their daily clinical work. This article aims to investigate how test administrators in a geriatric setting justify the everyday use of standardized test information.Qualitative study of physiotherapists and occupational therapists on two geriatric hospital wards in Norway that routinely tested their patients with standardized tests. Data draw on seven months of fieldwork, semi-structured interviews with eight physiotherapists and six occupational therapists , as well as observations of 26 test situations. Data were analyzed using Systematic Text Condensation.We identified two test information components in everyday use among physiotherapist and occupational therapist test administrators. While the primary component drew on the test administrators’ subjective observations during testing, the secondary component encompassed the communication of objective test results and test performance.The results of this study illustrate the overlap between objective and subjective data in everyday practice. In clinical practice, by way of the clinicians’ gaze on how the patient functions, the subjective and objective components of test information are merged, allowing individual characteristics to be noticed and made relevant as test performance justifications and as rationales in the overall communication of patient needs. Standardized testing as a diagnostic activity in clinical settings is commonly thought of as a process involving three steps . The fircan be used but on how it is in fact used in a geriatric setting. The article focuses, therefore, on the latter.By focusing on how test administrators in acute geriatric settings justify the use of test information in their everyday practice, this article investigates the complexities of everyday test information use, complexities that are particularly relevant when test administrators also are OTs and PTs who are responsible for parts of the patients’ health care. This focus is partly driven by the fact that test information can be used to determine level of impairment, disability, or activity since test information offers quantifiable documentation on patients’ functional ability. Test information can also be used to inform of and to monitor outcomes and, in some cases, to predict treatment outcomes . Still, Whereas standardized testing has a long history in most medical specialties, non-standardized tests, informal interviews, and unstructured observation have been favored in OT and PT practice . HoweverThe Birth of the Clinic is only as good as what follows” trying to hide something because the right answer isn’t coming. (Rows 568–575)Notice also how the therapist in this quote reasons about patients’ reluctance, but still justifies pressing for an answer.Other test observations described by the therapists highlighted the patients’ physical behavior in test activities: Were patients fast or slow in their bodily movements? Examples of this were often visible in the physical testing; for example, the patient would finish the TUG quickly, but the therapist noticed that the patient almost fell several times during testing. In colleague communication, therapists often referred to such patients as “reckless”– not fully aware of their own physical limitations. Others were slow in their movements, and made sure they did not fall by walking slowly or checking that the chair was in the right position before sitting down. These patients were often referred to as “careful.” “Reckless” and “careful” indicated a mismatch between the patient’s capacity and behavior. Therapists also noted the cognitive aspect of patient behavior: for example, if the patient was adequate in conversation, or how well the patient comprehended test instructions.Being a patient’s assigned therapist also entailed interaction  with the patient outside the test situation. Therapists maintained that observations from outside the test situation often confirmed observations made in the test situation, but as one therapist pointed out, the opposite could also happen:PT13: [Y]ou turn away for a moment and suddenly they may be trying to grab a magazine lying on the table or another typical activity – and then suddenly their arm is as good as new. But when you are testing – oh, no then it’s not any good. But these things are kind of discovered because we see the patient during the whole day, right? (Rows 733–737)The OTs had an additional arena for observation because they habitually observed patients in morning care routines and kitchen safety training. These observations would typically serve as a backdrop for considering patient performance/behavior in the test situation.Test scores are objective measures, but therapists seemed reluctant to accept that quantification was a particularly important aspect of their assessment. Instead, test scores were described as only providing a black and white statement, unable to capture all aspects needed in assessing geriatric patients and, thus, tests were not considered informative enough from the clinicians’ perspective. However, end scores still played a key role in everyday clinical communication.“an assurance of quality of what we do, really. That it’s not just a discretionary, subjective assessment of things, but, like, doing a standardized test is maybe making it a bit more reliable too” (PT11 Rows 614–616). In this quote, the notion of standardized tests as an objective base in professional statements is highlighted. It appears that, objective-based statements are considered to be better than subjective-based statements. And, although a few therapists argued that there must be a balance between subjective and objective statements, most therapists emphasized the test scores’ ability to support professional statements:Therapists claimed that standardized testing functioned as PT11: I feel that, in many ways, if we’ve done that test I’ve more weight in my argument when I call the district needs assessment office and order further physiotherapy (for the patient). Then I can, sort of, say that it isn’t just that the patient has reduced balance – that you’ve observed it, but you’ve also taken a standardized test which shows … (Rows 594–598)To further underline the ambiguity surrounding objectivity and subjectivity, one therapist started out comparing test scores to results from blood tests and computed tomography (CT) to illustrate that test scores are, in fact, as objective as results from blood tests or CTs, but ended the quote pondering the professional dilemma that follows standardized testing:OT6: (…) they will take a blood test, they will take CTs of the head, [but] you will not see the cognitive impairments there. So, we need, sort of, something that can show that you do have cognitive impairments; that you have a problem conceptualizing time and then, the standardized tests are a good thing. (…) So, it’s somewhat the same thing, that these tests are important to provide the patient with the right treatment. At the same time, you cannot use them at random and you need to exercise professional judgment and be … understand that the patient is tired and sleepy – so, you need to consider that, and if the patient is unmotivated, then that may affect the result. (Rows 516–526)So, despite being aware of the possible limitations, and being somewhat critical towards quantifiable results from testing, therapists maintained that such results carry weight. The weight was in part linked to a medical system in which the quantifiable and objective were considered superior to the qualitative and subjective:OT8: That’s always, sort of, been the good and the bad of medicine – that they’ve demanded numbers to ensure that something is true or not, right? And if you cannot quantify … things concerning quality of life and pain and such, then it’s harder to research it. But, the doctors are fond of everything that can be quantified, and what the doctors like propagates downwards in the system. That’s the way it is. (Rows 712–717)But, weight was also given to the meaning inherent in end scores, as these described a specific level of functional ability. When therapists had experience with a particular test and its scoring system, they could define level of functional ability by score information only. One therapist highlighted this ability and exemplified how end scores, as opposed to a subjective statement on functional ability, left neither room nor need for interpretation:PT11: (…) sometimes you may read an assessment where it says that the patient has reduced balance, but, OK, what is reduced balance? Does that mean that he, sometimes, needs to take an extra step when walking, or is he like really unsteady and walks, sort of, like a drunken sailor? That’s when it’s useful to have that number, saying that … yes, maybe it’s 45 points or it’s 5. (Referring to BBS scores. Rows 640–645)Comparably, the therapists would look up earlier test scores on readmitted patients and compare them to new test scores. Two score sets illustrated the patients’ functional development by indicating progress, or lack thereof, over time.“So, if you were to talk about a benefit then you’ve got shared understanding” (OT8 Rows 731–732). In fact, it was the test scores’ position as objective and as a platform for shared professional understanding that made them function in communication with patients, colleagues, and districts’ needs assessment offices. A functional score may be used to assess patients’ needs for services and to allocate in-home aid equipment, placements in nursing homes, and other public health services in Norway. Thus, although we observed that OTs were somewhat reluctant to use scores in patient communication, in the interviews they stated that reluctance was mainly an issue if patients were frail or had low scores. PTs used test scores to communicate the age-appropriate function of patients or to illustrate fall risk. However, PTs communicated a score to patients with certain reservations well aware that:This ability to understand scores was also emphasized as positive because it was knowledge most clinicians on the ward had in common: PT1: It doesn’t mean anything to them, and I have to explain a little what it means. (…) Then I explain a little what the number means in relation to – in relation to the whole scale. And what the risk is, but then I’ll draw on … if I have seen the patient a lot I might know what the problem is.” (Refers to BBS. Rows 1104–1110).Scores would be related to the patient in the following manner:PT4: We talk a lot about the fact that “this test shows that you have a risk of falling and you have fallen, so this agrees well.” And we usually say something about the use of walking aids, and I say that “I see you’re good at using the walker and that you check that you sit down in the chair properly, because that’s what you need to do now. If you can (continue to) do that I’ll not worry.” (Rows 685–689)As shown in the two quotes above, the quantifiable aspect of testing was not the main message to the patient. The few times therapists presented the end score as a main message seemed to be in communication with the district’s needs assessment office, because they knew that a low score could prompt allocation of public services. Still, therapists expressed reluctance toward this particular use of scores because it might entail testing patients who normally might be deemed unfit for testing:OT8: I’ve had the district’s needs assessment office wanting MMSE to see if they can place the patient in a locked ward – and when you’re that impaired cognitively, then you’ll score down towards 15, 16. And then it’s a little … what’s the purpose of testing patients when we know that they’re pretty demented? (Rows 695–698)“We never just write the end score in the chart. We always state what the problem is, because we are more concerned with the problem than with the actual end score” (OT6 Rows 514–516). Also in verbal communication, for example, with the multidisciplinary team, end scores were likely to be commented upon:Nevertheless, seeing that not all health care providers were familiar with tests’ scoring systems and that no end score could spell out the patient’s specific impairment, therapists habitually commented on the end score in writing: OT12: (…) it is important to me that you don’t say, in multidisciplinary meetings and reports, “27 of 30” and nothing more. You need to say what it is they scored poorly on and assess, that, yes, [the patient] was not oriented to place. (…). To me there is a difference between, like, you say one day wrong on date and day (questions) when you, like, are in a hospital and have been there for many weeks. Really, I’m not on top of dates and stuff every single day. You sort of need to consider this. But, if you say you’re in England when you’re in Norway, well, that’s a bit different. So, I think it is quite important to present what it was they scored poorly on, in order to get a more holistic impression of the patient. (Rows 443–453)– when there was a mismatch between observed behavior and end score.A clarification of test scores, such as the clarification presented above, could help other health professionals localize and assess the clinical significance of a patient’s impairment. Testing benefitted from clarifications when therapists found that the end score did not approximate the real-life person OT14: (…) I had this patient who scored well on the MMSE, but when she was to brew a pot of coffee she didn’t have a clue how to do it. She didn’t understand why the water started to flow through and stuff. She’d turned the knob without noticing it. The same thing happened twice – and, like, according to the test score she should be pretty alert. (Rows 609–614)Mismatches, such as this one, would typically be written down by the PT or OT as a caveat in the test form, communicated to the multidisciplinary team and, most likely, prompt further testing. Mismatches could, also, have an impact on how test results were communicated to the patient. For instance, if a patient scored high, but was considered reckless, the therapist would communicate the necessity of being more careful.The tests delivered in this setting focused on loss of functional ability or on level of impairment, but since their administration is standardized, the results will not capture the individual characteristics of the patient . Yet, th“because we see the patient during the whole day” (PT13). If tests were delivered by a technician, as suggested by DeLuca and Putnam [The primary component of test information is gathered in the test situation, where it is apparent that therapists are not only test administrators; they are also observers. The therapists see the individual they test; they see their patients. During testing, they take in the patient’s physical and cognitive functioning, emotional state, coping strategies, conduct, and ability to take instructions. In fact, these observations are, in the therapists’ accounts, often presented as the therapists’ key concerns and they can be used to support or challenge decisions regarding patients’ forthcoming activity and treatment plan: the patient is sad, the patient needs to use a walker, or the patient is slow/fast and careful/reckless. Such concerns and typologies resonate with Thornquist’s  portrayad Putnam , this ind Putnam .status quo functional ability. Insights on how therapists use quantifiable data can be summed up by Fujiura and Rutkowski-Kmitta’s statement: “Numerical associations facilitate independent verification, standardization, and economy of communication” (p92) [The secondary component of information falls, principally, in the category of quantifiable test data: end scores. Scores and end scores provide the health care professional with quantifiable documentation on patients’ n” (p92) . There wwe know more than we can tell (p4) [“the outcome of individual minds, operating in a social vacuum” (p54) [The two components presented in our study find a parallel in Polanyi’s  distinctell (p4) ), whereaell (p4) , our stuell (p4) ,43. Thusm” (p54) ; rather the economy of communication.” The economy of communication on the wards studied here is seemingly sustained in a multifaceted communication practice that, in fact, goes beyond numerical representation. Thus, we argue that to the therapist familiar with the specific standardized test, the score numbers contain information that goes beyond mere numerical representation. Test scores state level of impairment, often in relation to a normative sample and are, as such, encoded [At the outset, numbers are considered objective, and in the therapists’ accounts, objective data, that is, numerical data, are associated with quality, reliability, and credibility. A similar association between objective data, reliability, and quality is noticeable in the rhetoric surrounding continuous upgrading of health care provision . S encoded . Knowled encoded . Atkinso encoded  describe encoded , it prov encoded ,45.“we are more concerned with the problem than with the actual end score” (OT6). This practice also underlines the therapists’ pragmatic stance towards testing. A similar approach to test interpretation is found in Dingwall et al. [The ambivalence noted among the participants regarding numerical representation was not directed at the scores’ inability to provide insight into level of impairment; it was directed at the scores’ inability to capture patient’s characteristics . Our anal et al. . CaveatsExternal clinical evidence can inform, but can never replace, individual clinical expertise, and it is this expertise that decides whether the external evidence applies to the individual patient at all and, if so, how it should be integrated into a clinical decision. (p71) [n. (p71) The objective contribution of standardized tests proved to be moderated by caveats. Caveats were actively used in seeking agreement between the subjective and objective components of test information. Therefore, therapists challenge the sole use of one of the components.Although the focus of this article has been on professionals’ test information use, important issues possibly affecting their everyday use of such information are left unexplored. First, the health professional’s work experience is likely to influence how results are interpreted and, also, what test observations are deemed relevant in planning rehabilitation and communicating patient performance. Second, two wards and two professional groups were studied, but we did not explore the potential differences between test information use on the wards or between the two groups of professionals. Taken together, these issues could help provide a fuller picture of standardized testing. In addition, we suggest that the use of caveats should be investigated further. Yet, to fully contrast our findings, we recommend research into health care settings where end scores are delivered by a technician.We stand a better chance of understanding the complexities of everyday use of test information in this particular setting if we take into account the twin position of the therapist, as the patient’s OT or PT and as test administrator. Our findings suggests that, in clinical practice, by way of the clinicians’ gaze on how the patient functions, two different components of test information are merged, and that in the overlapping of these components, individual characteristics are made relevant as test performance justifications and as rationales in the overall communication of patient needs. The overlapping of subjective and objective test information should be investigated further to make known the implications the clinical use of test information may have on the provision of health care.The authors declare no conflict of interest with regard to the authorship and/or publication of this article.ÅS and AB conceived of the study and KK developed its methodology. KK conducted fieldwork and interviews. KK, ST, ÅS, and AB contributed to the interpretation of the findings. KK drafted and wrote the manuscript. All authors commented on different versions of the manuscript, and read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/14/72/prepub


The first two authors, Alexander Zoufaly and Jakob P. Cramer, should be noted as having contributed equally to the article.In addition, a funding organization and grant are incorrectly omitted from the Funding statement. The following sentence should be included with the Funding statement: “This research was funded by a grant from the German Ministry of Health (BMG).”