How many times have we accelerated something by using our connections? Instead of days, a scan was approved in a matter of hours. A call that puts a loved one on the waiting list. A coworker who discreetly "looks" before a meeting is scheduled. Although these incidents are rarely dramatic, they highlight a basic truth about medicine: those who understand the system can work within it, while those who don't have to endure it.

The majority of physicians do not consider it to be a misuse of privilege. We believe it shields the people we love from a system we no longer completely trust. Too many patients have fallen through the cracks, too many delays have occurred, and too many mistakes have been prevented. Neutrality feels like neglect when it comes to our own family. We therefore take action because we are unable to bear the risks we are too familiar with, not because we wish to gain an advantage.

That ability to "move the system" comes with a hidden price. Each favor granted only deepens the divide - separating those who have access from those who don’t. It might not be corruption in the usual sense, but it still undermines fairness. The more we depend on personal connections to make care feel human, the more we reinforce the idea that true humanity isn't woven into the system itself.

There's no ill intent behind it. Most of us operate on instinct rather than arrogance. We've all witnessed how minor delays can spiral into major crises. We've seen good people struggle because a system is too slow, too congested, or too oblivious. So when it hits close to home, we take action. And perhaps that's what complicates things - it stems from love, not entitlement. Yet, every time we step in, we’re reminded that so much of medicine hinges on connections, not just on what you actually need. It's not documented anywhere, but it's very real - an unseen web of favors and understanding that keeps everything flowing. It works like a charm when you're part of it, and painfully when you're left out.

Dr. Linda Eckert - Most of the research does not bear out that there's a causal relationship. Causal relationships are quite hard to prove, actually. And the research on Tylenol has been quite reassuring overall. And there was actually many studies, several great studies that have looked at this. And the most recent one that is a very powerful study was done in Sweden, where they looked at over 250,000 individuals. And they also were able to look at siblings, where people had environmental and sibling relationships, genetics in common.

The American College of Obstetrics and Gynecology, the Royal College of Obstetrics and Gynecology, the Society for Maternal Fetal Medicine all have looked very extensively at the data. All have come out quite strongly reaffirming their recommendations that Tylenol really is the best choice for controlling pain and fever in pregnancy.

Breast cancer screening remains a critical and widely debated aspect of preventive care, with differing guidelines across countries reflecting varying approaches to balancing benefits and harms. The United States, the United Kingdom, and Canada each offer distinct recommendations for when to start mammography and how frequently to screen. These differences are not trivial; they are rooted in divergent interpretations of epidemiological data, healthcare system priorities, and varying levels of risk tolerance.

In the United States, leading authorities like the American Cancer Society (ACS) and the U.S. Preventive Services Task Force (USPSTF) offer slightly different but generally aggressive screening guidelines. The ACS recommends that women with an average risk of breast cancer begin annual mammograms between ages 45-54 and switch to biennial screening from age 55 onward, with the option to start as early as age 40. In contrast, the USPSTF updated its guidelines in 2024 to recommend biennial mammography starting at age 40 through 74. This shift from previous guidance starting at age 50 was driven by new data suggesting that starting earlier could prevent more breast cancer deaths. However, both organizations acknowledge that earlier and more frequent screening increases false positives and the risk of overdiagnosis-where non-threatening tumors are detected and potentially overtreated.

The United Kingdom takes a more conservative stance, emphasizing population-level risk management. The NHS Breast Screening Programme offers mammography every three years for women aged 50 to 70 (extended to 71 in some regions). According to NHS data, approximately 1,300 deaths are prevented annually in England due to this approach. Large-scale studies like the NIHR AgeX trial suggest that offering screening to women in their 40s can reduce breast cancer mortality by about 25% within the first ten years, but NHS policy still favors starting later to minimize potential harms such as overdiagnosis and unnecessary biopsies. The UK model prioritizes reducing anxiety and the financial and psychological burden of false positives, which are more common when screening starts earlier.

Canada's guidelines vary across provinces, reflecting the country's decentralized healthcare system. Generally, most provinces recommend biennial screening for women aged 50-74. However, there is growing flexibility. For example, Ontario updated its guidelines in 2024 to offer screening from age 40, but emphasizes informed, shared decision-making for women under 50. Nationally, the Canadian Task Force continues to advise biennial screening starting at age 50, but allows screening for women aged 40-49 if they choose, after understanding the potential risks. Newer analyses from Dense Breasts Canada (2024) show that starting annual mammography from age 40 for women with dense breast tissue could reduce mortality by up to 37% compared to biennial screening from age 50, further fueling the conversation on personalized screening strategies.

While guidelines differ, the core issue across all regions is balancing the benefit of early cancer detection with the potential harms of overdiagnosis, false positives, and overtreatment. In women aged 50-69, mammography can reduce breast cancer mortality by approximately 14-33%, but among women aged 40-49, the absolute benefit is smaller and false-positive rates are higher. Data suggest that screening 1,000 women in their 50s for ten years prevents one breast cancer death, but about 500 will experience a false positive and several may undergo unnecessary treatment. Additionally, mammograms are less sensitive in women with dense breast tissue, which is more common at younger ages, leading to evolving recommendations for supplemental screening with ultrasound or MRI in high-risk groups.

The study of ancient diseases has rapidly evolved from educated guesswork into a rigorous scientific field, thanks to advances in paleopathology, ancient DNA (aDNA) analysis, and biomolecular archaeology. Through these methods, scientists have uncovered concrete evidence of infectious diseases that afflicted prehistoric hominids and early humans long before recorded history. Far from being a modern phenomenon, disease has been a constant companion throughout human evolution.

One of the earliest confirmed cases of infectious disease in the hominid fossil record comes from a 500,000-year-old Homo erectus specimen found in Turkey, which shows skeletal lesions consistent with brucellosis-a bacterial zoonotic disease that today is transmitted through unpasteurized dairy or contact with infected animals. This is one of the oldest direct pieces of evidence suggesting that early hominids contracted zoonotic infections, likely from their close interactions with wild animals and scavenged carcasses. The discovery fundamentally supports the idea that cross-species disease transmission predates agriculture by hundreds of thousands of years.

Tuberculosis (TB) also has ancient roots. In a particularly well-studied case from a 9,000-year-old Neolithic site in the Eastern Mediterranean, researchers found human skeletal remains with characteristic spinal deformities linked to Pott's disease, a form of TB. Molecular testing confirmed the presence of Mycobacterium tuberculosis complex DNA, making this one of the earliest validated cases of TB in humans. The discovery challenges previous assumptions that TB emerged after animal domestication and instead suggests a much older, possibly pre-agricultural, human-pathogen relationship.

Even more striking is the genetic evidence showing that the tuberculosis pathogen predates Homo sapiens. Molecular clock analyses estimate that Mycobacterium tuberculosis could have co-evolved with human ancestors in Africa over 70,000 years ago. This finding indicates that TB was likely circulating in small, mobile populations of prehistoric humans and their hominid relatives long before the advent of settled farming communities, contradicting the earlier model that population density was necessary for its survival.

In recent years, scientists have also uncovered direct evidence of Yersinia pestis, the bacterium responsible for plague, in ancient human remains from the Late Neolithic and Bronze Age periods, dating back over 5,000 years. Genome sequencing from these remains, found across Europe and Siberia, revealed early strains of plague that lacked the flea-borne transmission gene (ymt), indicating that these early epidemics likely spread through respiratory droplets rather than flea bites. These discoveries not only push the timeline of plague emergence back several millennia but also suggest that its method of transmission and virulence have significantly evolved over time.

Further supporting the widespread impact of plague in prehistory, a large study in Scandinavia analyzed DNA from 108 individuals and found that nearly 17% were infected with Y. pestis at the time of their death. This aligns with archaeological evidence of sudden, large-scale population declines during this period. The correlation strongly suggests that epidemic disease played a key role in shaping prehistoric population dynamics and could have contributed to the Neolithic population collapse in northern Europe.

Beyond bacterial infections, paleogenetic studies have also shed light on ancient treponemal diseases-caused by the bacterium Treponema pallidum, which includes modern syphilis, yaws, and bejel. Ancient DNA from skeletal remains in the Americas, some dating back 9,000 years, confirmed the presence of treponemal infection, supporting the idea that these diseases were circulating in pre-contact populations. The genetic diversity of these strains indicates that treponemal disease was already well-established in human populations long before the age of transatlantic exploration.

The parasite story is also embedded in our evolutionary past. Genetic analysis of lice suggests that pubic lice jumped to our human ancestors from gorillas roughly 3.3 million years ago. This transfer likely occurred when early hominids began using gorilla nesting areas or interacting with carcasses, providing the ecological bridge for this parasite shift. These lice, which are genetically distinct from head lice, serve as a surprising but reliable evolutionary marker of early human-parasite interaction.

Additional findings from ancient coprolites (fossilized feces) have identified intestinal parasites, including whipworms and roundworms, in prehistoric humans and hominids. Some of these samples date back over 7,000 years and confirm that parasitic infections were endemic in early populations. The discovery of these parasites across geographically diverse prehistoric sites suggests that ancient humans were chronically exposed to these infections regardless of location.

Further evidence of chronic disease in prehistory comes from the widespread presence of skeletal markers such as periostitis and osteomyelitis in early human remains. These conditions, indicative of long-standing infections, show that early humans suffered from bacterial invasions that sometimes spread systemically. In many cases, these individuals survived for extended periods with clear signs of healing, indicating that prehistoric humans had sufficient immune resilience to withstand severe infections even in the absence of modern medical care.

Recent molecular studies of ancient oral microbiomes extracted from dental calculus have also identified DNA from periodontal pathogens, respiratory bacteria, and even antibiotic-resistance genes in prehistoric remains. These findings suggest that pathogenic oral flora, and even microbial resistance traits, have been circulating in human populations for far longer than previously believed.

What all of this data makes abundantly clear is that infectious diseases are not a modern construct born of agriculture or urbanization. Pathogens were already part of the prehistoric human story, shaping genetic susceptibilities, immune system adaptations, and possibly even social behaviors. These discoveries fundamentally challenge the notion that disease was a consequence of sedentary living alone-disease has always been with us.References

• Dudar JC, et al. "Evidence of Brucellosis in a Middle Pleistocene Hominid from Turkey." American Journal of Physical Anthropology.
• Hershkovitz I, et al. "Detection and Molecular Characterization of 9,000-Year-Old Mycobacterium tuberculosis." PLoS One.
• Bos KI, et al. "Prehistoric Pathogen Genomes Reveal the Evolution of Yersinia pestis." Cell.
• Rasmussen S, et al. "Early Divergent Strains of Yersinia pestis in Eurasia 5,000 Years Ago." Cell.
• Spyrou MA, et al. "Yersinia pestis LNBA Genomes Suggest Prehistoric Plague in Scandinavia." Nature Communications.
• Harper KN, et al. "The Origin and Antiquity of Syphilis Revisited." American Journal of Physical Anthropology.
• Reed DL, et al. "Genetic Analysis of Lice Supports Direct Contact Between Modern and Archaic Humans." PLoS Biology.
• Reinhard KJ, et al. "Parasite Remains in Prehistoric Coprolites from North America." American Antiquity.
• Warinner C, et al. "Pathogens and Host Immunity in the Ancient Human Oral Microbiome." Nature Genetics.

Medicine, at its heart, is an enterprise of managing uncertainty. As Atul Gawande put it, "Medicine's ground state is uncertainty. And wisdom - for both patients and doctors - is defined by how one copes with it." 

We often seek diagnoses, treatments, prognoses that offer definitive answers-but more often, we are given probabilities: risk percentages, likelihoods, sensitivity/specificity, confidence intervals. Recognizing this is not a sign of failure, but a crucial part of clinical humility and competence.

William Osler's classic maxim states, "Medicine is a science of uncertainty and an art of probability."  It reminds us that while our tools (labs, imaging, statistical models, RCTs) offer data, they rarely deliver absolute truth. What we do with this probabilistic information-how we integrate patient values, context, comorbidities, and preferences-is the art in medicine. Our decisions rest on balancing the known, the unknown, and what we estimate.

Empirical research supports how pervasive uncertainty is in medical decision-making. A scoping review by Helou et al. (2020) examined how uncertainty arises across specialties and found that nearly every clinician interviewed described encountering biomedical, ethical, and prognostic uncertainty in day-to-day work. 

Another recent qualitative study identified three types of uncertainty faced by families and physicians: biomedical (e.g. about cause or prognosis), interpersonal (communication, trust, expectations), and psychosocial (impact on life, suffering)  These uncertainties are not peripheral-they shape outcomes, satisfaction, and even clinician well-being.

One striking area is diagnostic uncertainty. Studies estimate that in the U.S., diagnostic error contributes to about 800,000 patient harms annually. Diagnostic uncertainty can lead to overtesting, overtreatment, and also underdiagnosis. For example, a 2018 review found that when clinicians are uncertain, there is greater tendency toward ordering unnecessary imaging, hospital admissions, surgeries-all with costs, risks, and emotional burdens.  This underscores the cost of failing to properly manage and communicate uncertainties, both for patients and for health systems.

Moreover, intolerance of uncertainty has measurable consequences for practitioners themselves. A narrative review by Scott et al. (2023) showed that clinicians with lower tolerance for uncertainty are more likely to misinterpret clinical goals, delay necessary care, or make overly conservative or aggressive decisions based on what they wish to avoid rather than what data support.  Burnout, stress, anxiety are more common in such settings. Acknowledging uncertainty and developing strategies to tolerate and even leverage it is thus not just philosophically sound-it's pragmatic for the clinician's resilience.

At the end of the day, every physician knows the unease of walking into a room without all the answers. That moment-when the labs are inconclusive, the scan is unclear, or the prognosis remains uncertain-is not a sign of weakness but of what it means to practice real medicine. Patients don't come to us for guarantees; they come for guidance, honesty, and partnership in navigating the unknown. Embracing probability over certainty is not about lowering the standard of care-it's about raising the standard of trust. Perhaps the most human act we can offer is not to promise certainty, but to stand with our patients in the spaces where certainty cannot exist.

The sequencing of the Neanderthal genome has revealed that between 1-4% of the DNA in present-day non-African populations is derived from interbreeding with Neanderthals approximately 50,000-60,000 years ago. Subsequent analyses demonstrated that a significant proportion of these introgressed alleles localize to genes involved in immune regulation and pathogen defense, suggesting that archaic admixture exerted selective pressure on host-pathogen interactions.

During the Covid-19 pandemic, the relevance of this legacy became clinically apparent. Zeberg and Pääbo (2020) identified a Neanderthal-derived haplotype on chromosome 3 that confers a substantially increased risk of severe outcomes. Carriers of this haplotype demonstrated an odds ratio of ~2.0 for ICU admission and mechanical ventilation, with the highest allele frequency observed in South Asian populations (up to 50%). Conversely, subsequent work by the same group (Zeberg & Pääbo, 2021) identified a protective Neanderthal haplotype on chromosome 12, associated with a 22% reduced risk of progression to severe disease.

These findings illustrate the dual nature of archaic introgression. Certain variants provided adaptive advantages to ancient humans encountering novel Eurasian pathogens, enhancing antiviral defenses via toll-like receptor pathways and interferon responses. However, in contemporary settings, the same alleles predispose carriers to maladaptive hyper-inflammatory states, increasing susceptibility to acute respiratory distress in viral infections such as Covid-19.

The clinical implications extend beyond SARS-CoV-2. Genome-wide association studies (GWAS) have linked Neanderthal-derived alleles to a spectrum of immune-mediated disorders, including systemic lupus erythematosus, Crohn's disease, and type 2 diabetes (Dannemann & Kelso, 2017). This highlights an evolutionary trade-off: alleles advantageous in pathogen-rich Pleistocene environments may contribute to autoimmune dysregulation in modern, relatively sanitized conditions.

For clinicians, these discoveries underscore the heterogeneity of patient responses to infection beyond comorbidities and demographics. Ancestral genomic background may constitute an underappreciated risk modifier for disease severity. Although not yet integrated into clinical practice, the growing field of archaic genomics suggests that precision medicine could eventually stratify infection risk and therapeutic response according to both modern and archaic genetic variants.

References

• Green RE, Krause J, Briggs AW, et al. (2010). A Draft Sequence of the Neandertal Genome. Science, 328(5979):710-722. 
• Zeberg H, Pääbo S. (2020). The major genetic risk factor for severe Covid-19 is inherited from Neanderthals. Nature, 587:610-612. 
• Zeberg H, Pääbo S. (2021). A genomic region associated with protection against severe Covid-19 is inherited from Neanderthals. PNAS, 118(9): e2026309118.
• Dannemann M, Prüfer K, Kelso J. (2016). Functional implications of Neandertal introgression in modern humans. Genome Biology, 17:90.
• Dannemann M, Kelso J. (2017). The contribution of Neanderthals to phenotypic variation in modern humans. Am J Hum Genet, 101(4):578-589.

Medical research drives progress in healthcare, but it is also one of the greatest sources of frustration for clinicians. Every day, new studies claim to revolutionize practice, and yet many of them collapse within a few years-or worse, are quietly abandoned. For doctors, the constant churn breeds skepticism: if "the latest evidence" so often turns out to be wrong, why should we trust it in the first place?

The scale of the problem was laid bare by John Ioannidis in 2005, when he published Why Most Published Research Findings Are False in PLoS Medicine. Using a Bayesian framework, he demonstrated that in fields with small sample sizes, low prior probabilities, and high flexibility in design and reporting, the majority of positive findings are likely false positives. Two decades later, his thesis has only grown more relevant.

Evidence bears this out. A landmark JAMA study of highly cited clinical research found that one-third of trials were later contradicted or had much smaller effects when retested in larger, better studies. A Mayo Clinic Proceedings review identified 146 cases of "medical reversals"-treatments once thought effective but later proven ineffective or harmful-within just ten years. In oncology, replication efforts have been especially sobering: a Nature Cancer perspective reported that only 11% of landmark cancer biology experiments could be reproduced under rigorous testing.

The crisis extends to the supposed "gold standard" of evidence-systematic reviews and meta-analyses. A 2025 JAMA Internal Medicine analysis found that 35% of meta-analyses changed their conclusions by at least 10% once retracted studies were removed. A parallel BMJ study showed how retracted trials contaminated guidelines, leading to flawed clinical recommendations. This isn't just noise in the literature-it directly affects what doctors are told is "best practice."

The research community itself acknowledges the depth of the problem. A 2024 international survey of over 1,600 biomedical scientists reported that 72% believe there is a reproducibility crisis, and 62% blame pressure to publish as a key driver. The Brazilian Reproducibility Initiative, one of the largest of its kind, confirmed the same reality on the ground: fewer than half of regional biomedical experiments reproduced successfully, showing this is not just a Western problem but a global one.

This leaves doctors caught in the middle-bombarded with claims, expected to update practice instantly, and later blamed when those claims unravel. The constant cycle erodes trust not just in individual studies, but in the research enterprise itself. It fosters a culture of cynicism where many clinicians quietly roll their eyes at the next "breakthrough" headline, even as academic medicine insists they should celebrate it.

And perhaps here lies the most ironic twist. This very essay, critiquing the biases and weaknesses of research, is itself built entirely on published studies.

And yet, there is a strange kind of hope in this chaos. The fact that medicine overturns itself so often is not just evidence of failure-it is evidence that science is self-correcting. Every reversal is painful, but it is also progress: a sign that medicine is willing to admit its mistakes and move closer to the truth. The problem is not that doctors are too skeptical; the problem is that skepticism is not celebrated as part of good clinical practice.

Perhaps the silver lining is this: doctors, by necessity, are becoming the best skeptics in science. We are the ones forced to weigh weak data against lived patient outcomes, to recognize when a study's "significant" finding is clinically meaningless, and to resist the seduction of novelty. If researchers embraced that same pragmatism-valuing replication as highly as discovery-perhaps the literature would become as trustworthy as the doctors who must rely on it. Until then, maybe the most provocative thought is this: the cynicism of clinicians is not the problem in medicine. It might be the solution.

References

• Ioannidis JPA. Why Most Published Research Findings Are False. PLoS Med. 2005;2(8):e124. 

• Prasad V, et al. A Decade of Reversal: An Analysis of 146 Contradicted Medical Practices. Mayo Clin Proc. 2013;88(8):790-798.

• Grimes DR, et al. Towards replicability and sustainability in cancer research. Nat Cancer. 2024;5:609–616.

• Possamai A, et al. Inclusion of Retracted Studies in Systematic Reviews and Meta-analyses. JAMA Intern Med. 2025.

• Xu S, et al. Investigating the impact of trial retractions on evidence synthesis. BMJ. 2025;389:e082068. 

• Cobey KD, et al. Biomedical researchers' perspectives on reproducibility. J Clin Epidemiol. 2024;163:58-68.

Medicine has always wrestled with its central purpose. Is it defined by the pursuit of cure-eradicating disease, extending life, and restoring function-or is it equally, if not more, about relieving suffering, even when cure is impossible? This question has resurfaced in modern practice, especially as physicians encounter chronic illnesses, aging populations, and end-of-life care. The balance between cure and comfort lies at the very heart of our profession.

The historical roots of medicine suggest that both cure and relief of suffering were always present. Hippocrates emphasized  "to cure sometimes, to relieve often, to comfort always." This aphorism captures an enduring truth: medicine cannot promise cures for every condition, but it can promise compassion and relief. The physician's role is not diminished by the impossibility of cure; it is transformed. A doctor who cannot cure still carries immense responsibility to heal in another sense-through alleviation of pain and the preservation of dignity.

Research reinforces the importance of this dual mission. A 2019 systematic review on patient priorities in healthcare found that quality of life and relief from pain often ranked as highly-or higher-than clinical outcomes like survival. Patients facing cancer, for example, reported valuing the ability to spend meaningful time with family more than aggressive treatments that offered little extension of life. These insights challenge a cure-centric model and remind physicians that suffering is not only physical but also existential, social, and spiritual.

Palliative care illustrates this balance most vividly. Studies have shown that integrating palliative care early in serious illness not only improves quality of life but can also extend survival in some cases. One landmark 2010 trial in the New England Journal of Medicine found that patients with metastatic lung cancer receiving early palliative care lived longer than those receiving standard oncologic treatment alone. This paradox-that focusing on relieving suffering may sometimes extend life-undercuts the false dichotomy between cure and comfort.

Yet modern medicine often leans heavily toward cure, sometimes at the expense of the patient's broader well-being. The proliferation of high-cost technologies, experimental therapies, and aggressive interventions in ICUs may prolong life but can also prolong suffering. Ethical debates arise: are we treating the disease, or the person living with the disease? Physicians must constantly navigate the tension between offering every possible medical option and recognizing when the most humane option is to relieve suffering rather than chase cure.

From the physician's perspective, this dilemma is also deeply personal. Many doctors struggle with the feeling of failure when a patient cannot be cured. But reframing success as alleviating pain, supporting families, and respecting patient values shifts the narrative. The physician's role is not measured solely by survival curves or tumor shrinkage, but by whether the patient feels seen, heard, and relieved of unnecessary suffering. This broader definition of healing offers doctors themselves a more sustainable and humane professional identity.

Ultimately, medicine is not an either/or between cure and comfort-it is both, depending on context. In acute infections, fractures, or reversible conditions, cure may rightly be the priority. In chronic illness, terminal diagnoses, or conditions resistant to therapy, relieving suffering takes precedence. What unites both roles is the doctor's fidelity to the patient's well-being. As Osler reminded us, "The good physician treats the disease; the great physician treats the patient who has the disease." Perhaps the true role of medicine is not to choose between cure and comfort, but to integrate them as inseparable dimensions of healing.