0:00

Welcome. This is the

0:02

New England Journal of Medicine. I'm

0:04

Dr. Michael Bierer. This week,

0:06

September 7, 2023, we

0:09

feature articles on the GLP-1 receptor

0:11

agonist or 4-glupron for obesity,

0:15

PCI in older patients with

0:17

myocardial infarction, DNA

0:20

editing in T-cell acute lymphoblastic

0:22

leukemia, and atezolizumab

0:25

in alveolar soft part sarcoma,

0:28

a review article on Wilson's disease, a

0:30

clinical problem solving on how

0:33

it's all in the timing, and perspective

0:35

articles on NIH policy

0:37

changes regarding international research

0:40

collaborations,

0:41

on alleviating medical debt

0:44

in the United States, and

0:46

on mass masking without

0:48

mandates. Daily

0:52

Oral GLP-1 Receptor Agonist

0:54

or 4-glupron for Adults with

0:57

Obesity by Sean Wharton from

0:59

McMaster University, Toronto, Canada.

1:02

Obesity is a major risk factor for

1:05

many leading causes of illness and death worldwide.

1:08

This phase 2 trial evaluated

1:10

the efficacy and safety of the non-peptide

1:13

glucagon-like peptide 1, GLP-1

1:16

receptor agonist, or 4-glupron

1:19

as a once-daily oral therapy for weight

1:21

reduction in adults with obesity. 272

1:24

adults with obesity

1:26

or with overweight, plus at least

1:29

one weight-related coexisting condition,

1:31

and all without diabetes, were

1:34

randomly assigned to receive or 4-glupron

1:36

at one of four doses or placebo

1:39

once daily for 36 weeks.

1:41

At baseline, the mean body weight

1:43

of the participants was 108.7 kilograms,

1:47

and the mean body mass index was 37.9. At

1:49

week 26,

1:51

the

1:53

mean change from baseline in body

1:56

weight ranged from minus 8.6 percent to

1:58

minus 12.5 percent.

1:59

12.6% across the

2:02

Orforg-Lapron dose cohorts and

2:04

was minus 2% in the

2:06

placebo group.

2:08

At week 36, the mean

2:10

change ranged from minus 9.4% to minus 14.7%

2:12

with Orforg-Lapron and was

2:18

minus 2.3% with placebo.

2:21

A weight reduction of at least 10% by week 36 occurred

2:23

in 46 to 75% of the participant groups

2:29

who received Orforg-Lapron as

2:31

compared with 9% that received placebo. The

2:35

use of Orforg-Lapron led to improvement

2:38

in all pre-specified weight-related

2:40

and cardiometabolic measures. The

2:42

most common adverse events reported with Orforg-Lapron

2:45

were gastrointestinal events, which

2:47

were mild to moderate and occurred primarily

2:50

during dose escalation. Such

2:52

events led to discontinuation

2:55

of Orforg-Lapron in 10 to 17%

2:58

of participants across dose cohorts.

3:01

Adverse events reported with Orforg-Lapron

3:04

were similar to those with injectable GLP-1

3:07

receptor agonists. Daily, oral

3:09

Orforg-Lapron was associated

3:11

with weight reduction.

3:14

E. Dale Abel from the University

3:16

of California, Los Angeles notes

3:19

in an editorial that in the Phase II

3:21

trial of Orforg-Lapron by Wharton

3:24

and colleagues,

3:25

the main adverse effects were gastrointestinal

3:28

disturbances, which were reported by

3:30

up to 58% of participants who received

3:33

Orforg-Lapron, the major limitation

3:35

of this oral GLP-1 receptor

3:37

agonist approach.

3:39

Yet, these effects could

3:41

probably be managed with slower

3:44

dose escalation, which is an important

3:46

consideration for Phase III

3:49

trials.

3:50

No clinical pancreatitis events were

3:52

noted. Nevertheless, close

3:54

examination for pancreatitis will

3:56

be important in Phase III trials,

3:59

as well as in post-pancreotid.

3:59

marketing surveillance if FDA approval

4:02

is granted. Patients with type 2 diabetes

4:04

were excluded from the trial by Wharton

4:07

and colleagues. However, it

4:09

is notable

4:10

that a reduction in the glycated hemoglobin

4:12

level of 0.4% from a mean baseline level

4:15

of 5.6% was observed among

4:19

participants who received or forglopron.

4:22

Because obesity increases

4:24

the risk of type 2 diabetes, this

4:27

intriguing observation suggests

4:29

the possibility that or forglopron

4:32

could ultimately be used to reduce

4:34

the risk of progression to diabetes

4:37

in persons at high risk, including

4:39

those with prediabetes.

4:41

Given the burden of obesity, strategies

4:44

that are durable and safe and

4:46

can be safely prescribed by non-specialists

4:49

would represent an important advance.

4:52

Moreover, affordability of treatment

4:54

and equitable access among vulnerable

4:56

populations who are at high risk for

4:59

obesity and related conditions, including

5:01

those from historically marginalized

5:03

communities,

5:04

are essential to the widespread adoption

5:07

of any new and effective therapeutic

5:10

strategy.

5:11

The trial by Wharton and colleagues

5:13

is an important milestone in

5:15

the development of effective oral therapeutics

5:18

for obesity management that are based on

5:20

a validated mechanism of action and

5:22

target a pathway for which there

5:25

is a long track record

5:26

of clinical experience. Results

5:29

of phase three trials will

5:31

be key. Complete

5:35

or culprit lesion-only

5:38

PCI in older patients

5:40

with myocardial infarction by

5:42

Simone Bescalia from

5:44

the Accienda Ospitaliero Universitaria

5:47

di Ferrara, Italy. The

5:50

benefit of complete revascularization

5:53

in older patients, that is those 75 years

5:56

of age or older, with myocardial

5:58

infarction and multi-year-old patients,

5:59

multivescelled disease remains unclear.

6:03

In this trial, 1,445 older

6:07

patients with myocardial infarction

6:09

and multivescelled disease who were

6:11

undergoing percutaneous coronary

6:14

intervention, PCI, of

6:16

the culprit lesion were randomly

6:18

assigned to receive either physiology-guided

6:22

complete revascularization of non-culpret

6:25

lesions or to receive no

6:27

further revascularization. Functionally

6:30

significant non-culpret lesions

6:32

were identified

6:33

either by pressure wire or angiography.

6:38

36.5% of the patients were women and 35.2% of

6:42

the patients were admitted for ST

6:44

segment elevation myocardial

6:46

infarction. A

6:47

primary outcome event of death,

6:50

myocardial infarction, stroke or

6:52

any revascularization at one

6:54

year occurred in 15.7% of

6:56

patients in the complete revascularization

7:01

group and in 21% of

7:04

patients in the culprit only group.

7:06

Cardiovascular death or myocardial

7:09

infarction occurred in 8.9% of

7:12

patients in the complete revascularization

7:14

group and in 13.5% of

7:17

patients in the culprit only

7:19

group.

7:20

The safety outcome of a composite

7:23

of contrast-associated acute kidney

7:25

injury, stroke or bleeding did

7:27

not appear to differ between the two groups,

7:30

22.5% versus 20.4%.

7:34

Among patients who were 75 years

7:37

of age or older with myocardial

7:39

infarction and multi-vessel disease,

7:42

those who underwent physiology-guided

7:45

complete revascularization

7:47

had a lower risk of a composite of death,

7:50

myocardial infarction, stroke or

7:52

ischemia-driven revascularization

7:54

at one year than those who received culprit

7:56

lesion only, PCI.

8:00

In an editorial, Shamir Mehta

8:02

from McMaster University and Hamilton

8:05

Health Sciences, Hamilton, Ontario,

8:07

Canada writes that first and

8:10

foremost, the trial by Biscalia

8:12

and colleagues confirms the

8:14

benefit of complete revascularization

8:17

that has been observed in previous trials

8:20

and provides additional evidence for this

8:22

approach in older patients.

8:25

Second, in contrast to previous

8:27

trials that enrolled mainly patients with

8:29

ST segment

8:30

elevation myocardial infarction, STEMI,

8:33

most of the patients in this trial

8:35

presented with non-STEMI.

8:37

Although there are important differences in

8:40

the initial triage and treatment of patients

8:42

who present with STEMI, as compared with

8:44

non-STEMI, the data from this trial

8:47

suggests that older patients

8:49

benefited to a similar extent from complete

8:52

revascularization regardless of

8:54

the presence or absence of ST

8:56

segment elevation.

8:58

Third, uncertainty remains

9:00

as to whether to perform complete revascularization

9:03

with a physiology guided strategy

9:06

in which only functionally significant

9:09

lesions are revascularized or

9:11

with an angiography guided strategy

9:14

in which revascularization is based on

9:16

stenosis severity.

9:18

Finally,

9:19

it merits consideration that treatment

9:22

decisions in older patients with acute

9:24

myocardial infarction should not be based

9:26

solely on chronologic age.

9:29

Such patients differ widely with

9:31

respect to cognitive status, physical

9:33

ability, and severity of underlying

9:36

coexisting illnesses.

9:37

Goals of therapy such as quality

9:39

of life and the ability to live independently

9:42

may have greater value to some patients

9:45

than extending life or preventing

9:47

future ischemic events.

9:48

A combination of shared decision

9:51

making that is informed by evidence

9:53

from randomized trials and individualized

9:56

goals of therapy is therefore critical

9:58

when managing acute myocardial infarction.

9:59

cardiolinfarction and multivessel coronary

10:02

artery disease in this vulnerable

10:04

patient population.

10:08

BACE edited CAR7

10:10

T-cells for relapsed T-cell

10:13

acute lymphoblastic leukemia

10:16

by Robert Kieza from Great

10:18

Ormond Street Hospital for Children NHS

10:21

Trust, London. Cytidine

10:25

deamination that is guided by

10:27

CRISPR Cas9 technology

10:29

can mediate a highly precise

10:32

conversion of one nucleotide

10:35

into another, specifically cytosine

10:37

to thymine, without generating

10:40

breaks in DNA.

10:42

Thus, genes can be base

10:45

edited and rendered inactive without

10:47

inducing translocations and other

10:50

chromosomal aberrations.

10:52

The use of this technique in patients with

10:54

relapsed childhood T-cell leukemia

10:56

is being investigated.

10:58

In this phase 1 trial, the

11:01

investigators evaluated the safety

11:03

of base edited T-cells in 3

11:06

children with relapsed leukemia.

11:09

The first patient, a 13-year-old

11:11

girl who had relapsed T-cell ALL

11:14

after allogeneic stem cell transplantation,

11:17

had molecular remission

11:19

within 28 days after infusion

11:22

of a single dose of base

11:25

edited CAR7, which is

11:27

a chimeric antigen receptor,

11:29

CAR T-cell, with specificity

11:32

for CD7,

11:33

a protein that is expressed in

11:36

T-cell acute lymphoblastic

11:38

leukemia. She then received

11:40

a reduced intensity non-myeloblative

11:43

allogeneic stem cell transplant from

11:46

her original donor with successful

11:48

immunologic reconstitution and

11:51

ongoing leukemic remission.

11:53

Base edited CAR7 cells

11:56

from the same bank showed potent

11:58

activity in two other patients.

11:59

patients, and although fatal

12:02

fungal complications developed in

12:04

one patient, the other patient underwent

12:06

allogeneic stem cell transplantation

12:09

while in remission. Serious

12:11

adverse events included cytokine release

12:13

syndrome, multilinear cytopenia,

12:16

and opportunistic infections.

12:18

The interim results of this Phase

12:21

I study support further investigation

12:24

of base-edited T-cells for

12:26

patients with relapsed leukemia

12:28

and indicate the anticipated risks

12:31

of immunotherapy-related complications.

12:35

In a science behind the study

12:37

editorial,

12:38

Dan Longo, deputy editor

12:41

for the journal, writes that, "...Chiesa

12:43

and colleagues report a proof-of-principle

12:46

clinical experience, the eradication

12:49

of measurable residual disease

12:51

in a girl with T-cell lymphoblastic

12:53

leukemia with tumoricidal

12:55

CAR T-cells generated

12:57

from allogeneic base-edited

12:59

cells."

13:00

The patient had disease relapses

13:03

and had residual tumor cells after

13:06

the last round of salvage treatment.

13:08

The goal was to eliminate the

13:11

residual disease to allow

13:13

her to undergo bone marrow transplantation

13:15

while she was in complete remission,

13:18

a situation that maximizes

13:20

the efficacy of transplantation. Chiesa

13:24

et al. used a particular

13:26

type of editing called C-T

13:29

base editing.

13:30

To achieve this exquisitely precise

13:33

level of editing at the level of

13:35

a single base, they used a modified

13:38

version of the Cas9 protein

13:40

with new properties, one of which

13:43

is the ability to de-aminate cytodines.

13:46

In this study, the CAR T-cells

13:48

recognize CD7, a

13:50

cell surface protein on the neoplastic

13:53

T-cell leukemia cells of the patient.

13:56

The recognition unit, the CAR,

13:58

was introduced to the the allogeneic

14:00

base-edited T-cell by a lentivirus

14:03

vector. But the CD7 target

14:06

introduces another layer of complexity

14:09

because the effector CAR T-cells

14:11

themselves express CD7.

14:14

One does not want the effector cells

14:17

killing each other rather than the

14:19

tumor. And so, Chiesa et al. silenced

14:22

CD7 in the allogeneic

14:25

T-cells using C-to-T

14:27

base editing.

14:28

Chiesa et al. therefore simultaneously

14:31

silenced three genes encoding

14:34

the T-cell receptor beta chain CD7

14:37

and CD52 in the allogeneic

14:40

T-cells before the cells were

14:42

transduced with DNA encoding

14:45

a CAR to facilitate the recognition

14:47

of CD7 on host leukemia

14:50

cells.

14:51

The study by Chiesa et al. is

14:53

continuing. In addition to the patient

14:56

described above, another patient

14:58

has had morphologic and molecular

15:00

remission and one has died.

15:03

The long-term outcomes of

15:05

the two surviving patients and

15:07

those of the others in this study,

15:09

which has a projected enrollment of 10 patients,

15:12

will be of interest.

15:15

A tesalizumab for advanced

15:17

alveolar soft part sarcoma

15:20

by Alice Chen from the National Cancer

15:23

Institute, Bethesda, Maryland.

15:26

Alveolar soft part sarcoma

15:28

is a rare soft tissue sarcoma

15:30

with a poor prognosis and no established

15:33

therapy.

15:34

Recently, encouraging responses

15:37

to immune checkpoint inhibitors have

15:39

been reported. This phase two

15:41

study evaluated the anti-programmed

15:44

death ligand 1, PD-L1,

15:47

agent a tesalizumab in 52

15:50

adult and pediatric patients with

15:52

advanced alveolar soft part sarcoma.

15:55

A tesalizumab was administered

15:57

intravenously once every 21 days. An

16:00

objective response was observed in 37% of

16:03

patients with one complete response

16:06

and 18 partial responses. The

16:08

median time to response was 3.6 months,

16:11

the median duration of response was 24.7

16:14

months, and

16:16

the median progression-free survival

16:18

was 20.8 months.

16:20

Seven patients took a treatment break

16:23

after two years of treatment, and their

16:25

responses were maintained through

16:27

the data cutoff date.

16:29

No treatment-related grade IV or

16:31

V adverse events were recorded. Responses

16:34

were noted despite variable

16:36

baseline expression of Program

16:38

Death I and PD-L1.

16:41

A tesalizumab was effective

16:43

at inducing sustained responses

16:46

in approximately one-third of patients

16:49

with advanced alveolar soft part

16:51

sarcoma.

16:54

Current and Emerging Issues in

16:56

Wilson's Disease A review

16:58

article by Eve Roberts from the University

17:01

of Toronto, Canada. The

17:03

history of Wilson's disease reflects

17:06

modern biomedical progress. Samuel

17:09

Kinnear Wilson's 1912 description of progressive

17:13

lenticular degeneration, a

17:16

lethal neurodegenerative disorder

17:18

associated with inapparent hepatic

17:20

cirrhosis, was based on clinical

17:23

and pathological observations. The

17:25

disorder was subsequently renamed

17:27

hepatolenticular degeneration,

17:30

reflecting the importance of the hepatic

17:32

component.

17:33

At mid-century, advances in biochemistry

17:36

had established the etiologic role

17:38

of copper and the diagnostic

17:40

relevance of ceruloplasmin.

17:42

Life-saving medical treatment was

17:44

introduced in the mid-1950s.

17:47

Liver transplantation became an option

17:49

in the 1970s.

17:51

Subsequent advances in genetics

17:53

led to the identification of ATP7B, ATPase

17:59

Copper-2B,

17:59

transporting beta, the gene associated

18:02

with Wilson's disease.

18:04

Recently devised scoring systems

18:06

quantitatively describe the disorder,

18:09

facilitate its diagnosis, or

18:11

prognosticate the clinical outcome.

18:14

Innovative diagnostic methods, treatments,

18:16

and monitoring approaches are in development,

18:19

serving as bellwethers for future

18:21

biomedical advances.

18:23

Wilson's disease may present

18:26

as liver disease, a neurologic

18:28

disorder, a psychiatric illness,

18:30

or a combination of these disorders. Clinically

18:33

evident Wilson's disease is relentlessly

18:36

progressive and ultimately fatal,

18:39

if untreated.

18:40

With consistent, effective medical

18:42

treatment, however, the longevity of patients

18:45

with Wilson's disease is close to that

18:47

of the general population.

18:49

The advent of oral chelators

18:51

revolutionized treatment for Wilson's

18:54

disease. Both penicillamine provided

18:56

as D-penicillamine and triantine

18:59

dihydrochloride remain the principal

19:01

treatments. Once the diagnosis

19:04

of Wilson's disease is established, lifelong

19:07

medical therapy should begin. Wilson's

19:09

disease is best managed collaboratively

19:12

by specialists in hepatology, neurology,

19:15

psychiatry, and clinical genetics.

19:20

It's all in the timing. A clinical

19:22

problem solving by Alexander Beagle

19:25

from the University of California, San Francisco.

19:28

A 55-year-old man with acute myeloid

19:31

leukemia began to have shortness

19:33

of breath, cough with blood tinged

19:36

sputum, and hypoxemia 17 days

19:39

after receiving a myeloblative

19:42

allogeneic stem cell transplant from

19:44

a haploidentical donor.

19:47

His preparative regimen included

19:49

fludarabine and total body

19:51

irradiation, and he received cyclophosphamide

19:55

after transplantation.

19:57

He had been hospitalized since transplantation.

20:00

transplantation. The patient's post-transplantation

20:03

hospital course had been notable for

20:05

fevers, mucositis, and abdominal

20:07

pain without vomiting in the context

20:10

of neutropenia on post-transplantation

20:13

day 14.

20:15

At that time, blood cultures

20:17

were negative and urinalysis was

20:19

unremarkable. On the day before

20:21

hypoxemia developed, the patient's

20:24

neutrophil count was increasing. New

20:27

cough and hypoxemia developed.

20:29

Chest CT revealed diffuse,

20:32

bilateral, peri-hyler, confluent

20:35

consolidations, and ground glass

20:37

opacities. The patient's hypoxemia

20:39

worsened, which prompted transfer

20:41

to the ICU and initiation of 100% oxygen

20:45

supplementation administered through a

20:47

high-flow nasal cannula.

20:49

The patient's trachea was intubated to

20:51

permit diagnostic bronchoscopy with

20:54

serial BAL.

20:55

A thorough evaluation for infection,

20:58

including the bronchoscopy,

21:00

was negative. Volume

21:02

overload was considered, but his condition

21:05

worsened despite the use of effective diuretics.

21:08

Given the negative testing for

21:11

infectious causes, the lack

21:13

of improvement in the patient's condition

21:15

after he underwent diuresis, and

21:17

the timing of respiratory failure coincident

21:20

with neutrophil engraftment,

21:22

a diagnosis of peri-engraftment

21:25

respiratory distress syndrome was made.

21:28

His condition improved rapidly after

21:30

the initiation of glucocorticoid therapy,

21:33

and extubation was performed after

21:35

two days.

21:38

Threatening the future of global

21:40

health, NIH policy

21:42

changes on international research

21:45

collaborations, a perspective by

21:47

Albert Koh from the Yale School of Public

21:50

Health, New Haven, Connecticut. The

21:53

U.S. National Institutes of Health,

21:55

responding to audits conducted

21:57

by the Office of Inspector General of the United

21:59

States.

21:59

Department of Health and Human Services

22:02

and the Government Accountability Office recently

22:05

announced a new policy for foreign

22:07

subrecipients, that is, collaborators

22:10

from foreign countries, of NIH

22:12

funding

22:13

that departs sharply from

22:15

decades of NIH efforts to

22:17

promote research integrity and build

22:20

research capacity globally.

22:23

Beginning October 1st, foreign

22:26

subaward recipients will be required

22:29

to provide the U.S. prime grantee

22:32

copies of all lab

22:34

notebooks, all data, and

22:36

all documentation that support the research

22:39

outcomes,

22:40

no less than every six months

22:42

or more frequently based on risks.

22:45

The NIH reserves the right to examine

22:48

these documents as part of its oversight

22:50

responsibilities.

22:52

The new policy responds in particular

22:55

to an audit that criticized the NIH's

22:57

inability to secure laboratory

23:00

notebooks and raw data from the

23:02

Wuhan Institute of Virology in

23:04

China, as well as to congressional

23:07

pressure to enhance oversight.

23:09

But the policy's broad and

23:12

often vague language is subject

23:14

to interpretation, which will complicate

23:17

implementation.

23:18

The mandate represents a shift

23:21

from previous requirements for sharing

23:23

scientific data of sufficient quality

23:26

to validate and replicate research

23:28

findings,

23:29

which specifically excluded

23:32

laboratory notebooks, preliminary

23:34

analyses, completed case

23:36

report forms, drafts of scientific

23:38

papers, and communications between

23:41

colleagues.

23:42

These authors believe that imposing these

23:44

new requirements on all foreign

23:47

subrecipients of NIH funding

23:49

without adequate input from U.S.

23:51

grantees and their international collaborators

23:55

sends the message that the NIH

23:58

doesn't trust scientists in other

24:00

countries to meet the highest standards

24:03

of ethical and responsible research

24:05

practice. Alleviating

24:08

medical debt in the United States, a

24:11

perspective by Nishant Uppal from

24:13

Brigham and Women's Hospital, Boston.

24:17

Health care is impoverishing

24:19

U.S. patients and undermining

24:21

their health.

24:22

Nearly 11 percent of U.S. adults

24:25

and 18 percent of households have

24:27

overdue medical debts with mean

24:29

and median debt amounts respectively of $21,687

24:36

and $2,000 per person.

24:38

Such debts affect household finances,

24:41

access to care, and most likely, social

24:43

determinants of health. And medical

24:46

indebtedness will probably increase

24:48

in the months ahead as millions of Americans

24:51

lose insurance with the lapse

24:53

of pandemic-era federal funding

24:56

for maintaining Medicaid coverage.

24:58

The hopeful news is that health

25:00

financing policies created

25:03

medical indebtedness and different

25:05

policies could ameliorate

25:08

it.

25:08

At a minimum, these authors believe Medicare

25:11

should apply the ACA's regulations

25:14

to all hospitals, require

25:16

hospitals to notify all patients

25:19

in multiple languages that financial

25:21

assistance is available, and streamline

25:24

documentation requirements for

25:26

patients seeking assistance with presumptive

25:29

eligibility for uninsured persons.

25:32

Similarly, existing rules limiting

25:35

charges for some low-income

25:37

patients and those who receive out-of-network

25:38

care should be strengthened.

25:41

Providers should be prohibited

25:43

from denying care to patients with unpaid

25:45

balances.

25:46

Policymakers could also develop

25:49

debt forgiveness programs. Although

25:51

collectively such reforms would put a dent

25:54

in medical indebtedness, medical bills

25:56

will continue to inflict hardship until

25:59

the U.S.

25:59

abandons the notion that sick

26:02

people must pay for their misfortune.

26:04

Universal coverage with minimal cost

26:07

sharing is the norm in several

26:09

countries that have lower health expenditures,

26:12

slower cost growth, and far

26:14

better health outcomes.

26:16

That policy choice is politically

26:18

difficult, but these authors are convinced

26:21

that it's the only fully effective

26:23

remedy for endemic medical debt.

26:28

Mass masking without mandates,

26:31

the role of gender in mask use

26:33

in China, a perspective by Meng

26:35

Zhang from Peking University, Beijing.

26:39

During the COVID-19 pandemic, government

26:42

public health mandates in China and

26:44

many parts of the world made wearing

26:46

a mask a social norm for people

26:48

of all genders.

26:50

But when people have been allowed to decide for

26:52

themselves about masking, gender

26:54

norms have sometimes become an important

26:56

factor.

26:58

A historical perspective provides a complex

27:00

picture.

27:01

In China, for instance, there have been moments

27:03

in history when both public health authorities

27:06

and the general public considered masking during

27:08

epidemics to be a personal matter

27:10

rather than the domain of the regulatory state.

27:13

During the great Manchurian plague

27:16

of 1910 and 1911, draconian government measures left little

27:21

room for laypeople to choose whether

27:23

to wear a mask. They faced inspection

27:26

by the armed sanitary police

27:29

who could impose quarantines.

27:31

But after the less regulated experiences

27:34

during the Spanish influenza pandemic

27:36

of 1918, the second

27:38

Manchurian plague of 1920 and 1921, members of the

27:41

Chinese medical elite became aware

27:46

that promoting compulsory masking

27:48

among untrained laypeople would

27:51

be very difficult.

27:52

Even as the central government sought

27:55

to prevent meningitis and emerging

27:57

airborne disease from spreading in

27:59

big

27:59

cities in 1929, the

28:02

central government did not issue any

28:04

strict mandates. Instead, it

28:06

simply announced a national recommendation

28:09

that masks be worn.

28:11

It was against this background that

28:13

gender began to influence

28:15

the popularity of masks, and

28:18

public health authorities and businesses took

28:20

advantage of this.

28:21

Going forward, perhaps

28:23

physicians and public health officials

28:26

should consider the role of gender

28:28

norms and their cultural associations

28:31

in different societies in influencing

28:33

people's behaviors and acceptance

28:36

of public health recommendations.

28:41

In our images in Clinical

28:43

Medicine, a 53-year-old

28:45

man who had been hospitalized with ephemeral

28:48

fracture after a fall was

28:50

noted to have an abnormal indentation

28:53

of the lower eyelids.

28:55

He had previously undergone corneal

28:57

transplantation in both eyes, owing

29:00

to increasing visual impairment over

29:02

a 30-year period.

29:03

In recent years, his vision had worsened,

29:06

and his fall before admission had resulted

29:09

from difficulty seeing a stairway.

29:11

A diagnosis of keratoconus

29:14

was made. Keratoconus is a

29:16

non-inflammatory disorder characterized

29:19

by corneal thinning and bulging

29:22

outward in a cone shape.

29:24

In advanced cases, the eyelid

29:26

deflection that was noted in this patient,

29:29

known as Munson's sign,

29:31

can be seen.

29:32

The patient was placed on a waiting list for

29:35

repeat corneal transplantation. In

29:38

another image, a 44-year-old

29:41

man presented with a four-day history

29:43

of spontaneous bruising and

29:46

bloody urine.

29:47

Three hours before symptom onset,

29:49

he was walking in the woods in Brazil

29:52

and felt a sharp prick on

29:54

the back of his left thigh. On

29:56

physical examination, there was a tender

29:59

hematoma with a

29:59

the central bulla on the posterior

30:02

left thigh. The patient also had

30:04

scattered ecchymosis across the body

30:07

and his urine was pink in color.

30:09

Results of laboratory studies were notable

30:12

for mild anemia and thrombocytopenia,

30:14

elevated prothrombin time and D-dimer

30:17

level, and low fibrinogen and

30:19

haptoglobin levels.

30:21

The urinalysis showed hematuria.

30:24

On the basis of the history and clinical

30:26

findings, a diagnosis of hemorrhagic

30:29

diathesis due to envenomation

30:31

by the caterpillar species Lonomia

30:34

obliqua was made. L.

30:36

obliqua caterpillars are found in

30:39

southern Brazil. When their bristles

30:41

contact human skin, consumptive

30:44

coagulopathy and hemorrhage

30:46

may develop, a syndrome known as

30:48

lonomism.

30:50

Treatment with a single dose of

30:52

immune globulin against L. obliqua

30:54

venom was administered and three

30:56

hours later, the hematuria had

30:59

abated.

30:59

Within 12 hours after treatment was

31:02

administered, the coagulation studies

31:04

had begun normalizing.

31:07

This concludes our summary. Let

31:09

us know what you think about our audio summaries.

31:12

Any comments or suggestions may be sent

31:14

to audio at NEJM.org.

31:18

Thank

31:18

you for listening.